Bleeding Disorder of Unknown Cause

Hematologic Disease MONDO:0002243 Pathograph 21 Show in embeddings browser Hemorrhagic disease Mild-to-moderate bleeding disorder

Bleeding disorder of unknown cause (BDUC) is the diagnosis assigned to a patient with an objectively increased mucocutaneous bleeding tendency in whom a rigorous hemostatic work-up returns entirely normal results. It is defined by exclusion rather than by a positive finding: von Willebrand disease, platelet function defects, coagulation factor deficiencies, and non-hemostatic causes of bleeding must all have been ruled out. It is not a rare curiosity — it is the single most frequent outcome of referral for a mild-to-moderate bleeding tendency, accounting for roughly half to three-quarters of such referrals, and the bleeding phenotype is as severe as in patients who do receive a named diagnosis. Up to 80% of cohorts are women, in whom heavy menstrual bleeding, iron deficiency, and postpartum hemorrhage dominate the clinical picture. This entry is curated deliberately as a mechanism-gap entry. There is no canonical pathophysiological chain for BDUC. What exists instead is a set of competing, individually under-powered candidate mechanisms — subclinical platelet dysfunction below the detection threshold of light transmission aggregometry, impaired thrombin generation, excess of natural anticoagulants such as free TFPI-alpha and activated protein C, altered fibrinolytic balance, and altered fibrin clot architecture — each supported by case-control cohort data, none established as causal, and several mutually inconsistent in the direction of their reported effect. The pathograph below models these as parallel arms converging on a shared final common node rather than forcing one to be primary, and the disagreements are recorded explicitly as `mechanistic_hypotheses` and `discussions` rather than silently averaged away.

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Mappings
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Pathophys.
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Phenotypes
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Hypotheses
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Gaps
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Pathograph
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Medical Actions
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Differentials
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Mappings

MONDO
MONDO:0002243 hemorrhagic disease
skos:broadMatch MONDO
MONDO has no term for bleeding disorder of unknown cause. Searches of the MONDO label and synonym space for "bleeding disorder", "bleeding diathesis", "hemorrhagic diathesis", "unclassified bleeding", and "unknown cause" return only mechanism-specific or gene-specific entities (the platelet-type bleeding disorder series, factor V and thrombomodulin variants, vascular-type bleeding disorder) and no residual/unexplained category. MONDO:0002243 hemorrhagic disease, whose exact synonyms include "bleeding disorder" and "bleeding tendency", is therefore used as the closest available anchor and is a strict superclass, not an exact match: it also covers every entity that BDUC is defined by excluding. A MONDO new term request is warranted.
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Mechanistic Hypotheses

7
Occult platelet function or secretion defect below assay resolution
occult_platelet_defect EMERGING
Evidence balance 1 support
Bleeding is caused by a platelet activation, secretion, or receptor-signaling defect that light transmission aggregometry cannot resolve. Supported indirectly by the acknowledged reproducibility limits of aggregometry and directly by immature-platelet receptor profiling and platelet lipidomics — both of which, importantly, were performed in patients with abnormal aggregometry rather than in formally defined BDUC, so their transfer to BDUC is assumed rather than shown.
Pathograph links
Hemostatic Defect Below the Detection Threshold of Routine Testing -> Occult Platelet Function and Secretion Defect INDIRECT UNKNOWN INTERMEDIATES Candidate arm in which the unresolved defect lies in platelet activation, granule secretion, or receptor signaling below the sensitivity of light transmission aggregometry.
Occult Platelet Function and Secretion Defect -> Impaired Hemostatic Plug Formation and Clot Stability DIRECT Reduced platelet activation and secretion would weaken primary hemostatic plug formation at the site of vascular injury.
Show evidence (1 reference)
PMID:41348021 SUPPORT Other
"The etiology of bleeding is postulated to be due to defects in platelet function, fibrinolysis, collagen integrity, and/or other coagulation defects not well measured in standard laboratory assays."
Expert review naming platelet function as one of the postulated etiologies, and framing all of them as postulated rather than demonstrated.
Reduced thrombin-generating capacity on global assays
impaired_thrombin_generation EMERGING
Evidence balance 2 support
Bleeding is caused by a globally reduced thrombin burst despite normal individual factor activities. This is the most replicated of the candidate mechanisms — demonstrated in 382 patients in Vienna and independently reproduced on an automated platform — which is why it is the strongest arm in this entry. It is nonetheless EMERGING rather than CANONICAL for two reasons: an independent Rotterdam cohort found no meaningful thrombin generation difference, and in every cohort including the replication study, thrombin generation parameters fail to correlate with bleeding score.
Pathograph links
Hemostatic Defect Below the Detection Threshold of Routine Testing -> Impaired Thrombin Generation INDIRECT UNKNOWN INTERMEDIATES Candidate arm in which the unresolved defect manifests as reduced thrombin-generating capacity on global assays despite normal individual factor levels.
Impaired Thrombin Generation -> Impaired Hemostatic Plug Formation and Clot Stability DIRECT Lower thrombin burst yields slower and less robust fibrin formation and less thrombin-dependent platelet and factor XIII activation.
Show evidence (2 references)
PMID:42027303 SUPPORT Human Clinical
"Given that BDUC pathophysiology remains largely unknown, these findings suggest impaired TG may represent a common underlying feature of BDUC"
The strongest available statement for this hypothesis, phrased by its own authors as a suggestion within an acknowledged unknown pathophysiology.
PMID:31177606 SUPPORT Human Clinical
"Bleeding severity did not correlate with parameters of thrombin generation, clot formation, or clot lysis."
The dose-response failure in the largest cohort supporting this hypothesis: the abnormality is present but its magnitude does not track the phenotype, which is the principal reason this hypothesis is not promoted to CANONICAL.
Excess of natural anticoagulants (free TFPI-alpha, activated protein C)
natural_anticoagulant_excess EMERGING
Evidence balance 1 support
Bleeding is caused by an excess of physiological anticoagulants rather than by any procoagulant deficiency. Free TFPI-alpha above the 95th percentile is over-represented specifically in the unexplained-bleeding subgroup, TFPI activity is raised in a subset of an independent unclassified-bleeding cohort, and activated protein C antigen is highest in BDUC. Attractive because it reconciles a normal factor panel with a damped thrombin burst, and because it is the only candidate arm whose authors have proposed a concrete therapeutic target.
Pathograph links
Hemostatic Defect Below the Detection Threshold of Routine Testing -> Natural Anticoagulant Excess INDIRECT UNKNOWN INTERMEDIATES Candidate arm in which physiological inhibitors of coagulation are present in excess, damping thrombin generation without any factor deficiency.
Natural Anticoagulant Excess -> Impaired Thrombin Generation DIRECT Excess free TFPI-alpha inhibits the tissue factor/factor VIIa initiation complex and factor Xa, delaying and damping the thrombin burst; raised activated protein C degrades factors Va and VIIIa with the same net effect.
Show evidence (1 reference)
PMID:38454298 SUPPORT Other
"For patients with BDUC, further evaluation may include non-routine testing to look for rare bleeding disorders not detected by routine hemostasis tests, such as thrombomodulin-associated coagulopathy, tissue factor pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding disorders..."
Places TFPI-related bleeding among the recognized non-routine entities to test for in BDUC.
Altered fibrinolytic balance with premature clot lysis
altered_fibrinolysis EMERGING
Bleeding is caused by dysregulated plasminogen activation, classically premature clot lysis. This is the arm with the most direct therapeutic corollary, since tranexamic acid is the mainstay of BDUC management, and a tPA-modified thromboelastometry assay identifies a hyperfibrinolytic profile in about 21% of patients. It is kept EMERGING and deliberately named for "balance" rather than "hyperfibrinolysis" because the direction of effect is not consistent: direct plasmin generation measurement found reduced peak plasmin, and whole-blood viscoelastometry in 464 patients found reduced lysis potential. See the `bduc_fibrinolysis_direction_conflict` discussion.
Pathograph links
Hemostatic Defect Below the Detection Threshold of Routine Testing -> Altered Fibrinolytic Balance INDIRECT UNKNOWN INTERMEDIATES Candidate arm in which a formed clot is lysed prematurely, or in which the fibrinolytic system is dysregulated in a direction that is not consistent across cohorts.
Altered Fibrinolytic Balance -> Impaired Hemostatic Plug Formation and Clot Stability DIRECT Premature plasmin-mediated dissolution of a formed fibrin clot, or a dysregulated lysis profile, would shorten the durability of hemostasis and produce delayed rather than immediate bleeding.
Altered fibrin clot architecture determining mechanical stability
altered_clot_structure EMERGING
Bleeding is caused by the structure of the fibrin network rather than by the quantity of any component: thicker fibers, a slower rate of protofibril formation, and increased permeability yield a clot that is mechanically inadequate. Proposed by the plasmin generation study as the explanation for its own counterintuitive result, and partially supported by turbidimetric and permeability data. Bounded by the largest dedicated clot-properties study, which found only the reduced formation rate and no other difference.
Pathograph links
Hemostatic Defect Below the Detection Threshold of Routine Testing -> Altered Fibrin Clot Architecture INDIRECT UNKNOWN INTERMEDIATES Candidate arm in which fibrin network structure, rather than the amount of any component, determines clot mechanical stability.
Altered Fibrin Clot Architecture -> Impaired Hemostatic Plug Formation and Clot Stability DIRECT A clot that forms more slowly and with altered fiber architecture is mechanically less stable at the injury site.
Undetected monogenic hemostatic defect
undetected_monogenic_cause ALTERNATIVE
Evidence balance 3 support 1 refute
BDUC is a temporary label that sequencing will progressively dissolve into named monogenic disorders. Retained as a genuine ALTERNATIVE because it is the implicit expectation behind most genetic work in this field, but the yield data argue strongly against it as a general explanation: a targeted high-throughput panel across 2396 patients achieved 49.2% diagnostic yield overall and only 3.2% in patients with unexplained bleeding and normal hemostasis testing, and an independent unclassified-bleeding cohort had entirely normal panel results in all 45 patients tested.
Show evidence (4 references)
PMID:31064749 SUPPORT Human Clinical
"The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results."
The decisive yield comparison: a monogenic cause is found in a small minority, so this hypothesis can explain only a fraction of BDUC, which is why it is not promoted beyond ALTERNATIVE.
PMID:31747136 REFUTE Human Clinical
"ThromboGenomics was normal in 45 tested patients."
A completely negative panel result in an independent unclassified-bleeding cohort, refuting a general monogenic explanation.
PMID:33094877 SUPPORT Other
"Thus far, detailed genetic analysis of these patients has not been fruitful in unravelling the cause of bleeding."
Review-level summary of the low genetic yield, while leaving the hypothesis open for a subset.
+ 1 more reference
Soluble thrombomodulin excess as a cause of unexplained bleeding
soluble_thrombomodulin_excess ⚠ DEPRECATED
⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 2 refute
A specific and testable proposal, derived from families with THBD variants causing massively raised soluble thrombomodulin, that the same mechanism underlies unexplained mild bleeding more broadly. It is curated here precisely because it was tested and failed: in 507 patients with mild bleeding disorders including BUC, soluble thrombomodulin levels, their distribution, their relationship to bleeding severity, and THBD sequencing were all unremarkable. Retained as DEPRECATED rather than deleted so that the negative result is visible and the hypothesis is not silently re-proposed.
Show evidence (2 references)
PMID:34628704 REFUTE Human Clinical
"No difference in sTM levels between patients and controls was found overall"
The primary negative finding in 507 patients versus 90 controls.
PMID:34628704 REFUTE Human Clinical
"TM-associated coagulopathy appears to be rare, as it was not identified in our large cohort of patients with MBD. Soluble TM did not arise as a risk factor for bleeding or altered haemostasis in these patients."
The authors' explicit conclusion that this mechanism does not explain the cohort, which is the basis for the DEPRECATED status.
?

Discussions and Knowledge Gaps

6
Is the fibrinolytic abnormality in BDUC accelerated clot lysis or reduced lysis potential? Published cohorts report both directions, so the two cannot both be the mechanism.
CONTROVERSY OPEN bduc_fibrinolysis_direction_conflict
Attached to
pathophysiology#Altered Fibrinolytic Balance pathophysiology#Altered Fibrin Clot Architecture
The Vienna cohort reported a shorter clot lysis time, consistent with accelerated lysis, and a tPA-modified thromboelastometry study classified 21% of BDUC patients as hyperfibrinolytic. In the opposite direction, an independent Rotterdam cohort found a significantly prolonged clot lysis time, direct plasmin generation measurement found reduced rather than increased peak plasmin, and whole-blood viscoelastometry in 464 patients found reduced maximal lysis and a larger area under the curve. This is not a difference of magnitude but of sign, and it is why this entry names the arm "altered fibrinolytic balance" rather than "hyperfibrinolysis" and refuses to give it CANONICAL status. A plausible reconciliation is that the cohorts differ in the assay's dependence on clot structure rather than on plasmin activity, but this has not been tested directly.
Proposed experiments
Head-to-head fibrinolytic assay panel in a single BDUC cohort
exp_bduc_head_to_head_fibrinolysis_assays
Apply plasmin generation, turbidimetric clot formation and lysis, tPA-modified ROTEM, and non-activated whole-blood viscoelastometry to the same BDUC patients in a single study, to establish whether the reported direction of effect is a property of the patients or of the assays.
tPA-ROTEM-stratified tranexamic acid response study
exp_bduc_hyperfibrinolytic_stratified_txa
Stratify BDUC patients by tPA-ROTEM hyperfibrinolytic status and test prospectively whether that subgroup, and only that subgroup, derives benefit from tranexamic acid.
Show evidence (3 references)
PMID:32337845 SUPPORT Human Clinical
"BUC patients did have a significantly prolonged clot lysis time. The underlying mechanism for this finding is unknown."
One pole of the conflict, with the authors themselves recording that the mechanism is unknown.
PMID:42004172 SUPPORT Human Clinical
"Overall, we observed a delayed clot formation process with reduced lysis potential resulting in a larger ROTEM-AUC in patients with BDUC."
Largest cohort, reporting reduced rather than enhanced lysis potential.
PMID:40680469 SUPPORT Human Clinical
"tPA-ROTEM identified a hyperfibrinolytic profile in 19/92 (21 %) of BDUC patients."
The opposing pole: a substantial hyperfibrinolytic subgroup by a different assay.
Why does no laboratory abnormality identified in BDUC correlate with bleeding severity, and can any candidate mechanism be causal if it shows no dose-response relationship with the phenotype?
KNOWLEDGE GAP OPEN bduc_assay_severity_dissociation
Attached to
pathophysiology#Impaired Thrombin Generation pathophysiology#Altered Fibrinolytic Balance pathophysiology#Altered Fibrin Clot Architecture pathophysiology#Impaired Hemostatic Plug Formation and Clot Stability
This is the central unresolved problem of the field and the reason no hypothesis in this entry is CANONICAL. Every major study reports the same dissociation: thrombin generation, clot formation and clot lysis parameters do not correlate with bleeding severity; plasma clot properties show no clear association with clinical severity; thromboelastometry parameters do not correlate with bleeding scores; and peak plasmin does not correlate with bleeding severity. A group-level difference from controls without any within-group dose-response is compatible with the abnormality being a correlate or an epiphenomenon rather than the cause, and the possibility that the true determinant has not yet been measured cannot be excluded.
Proposed experiments
Composite multi-assay model versus prospective bleeding events
exp_bduc_composite_assay_dose_response
Test whether composite models combining thrombin generation, clot structure, and fibrinolytic parameters, rather than single parameters, recover a dose-response relationship with prospectively collected bleeding events rather than with retrospective bleeding scores.
Standardized hemostatic challenge as the bleeding outcome
exp_bduc_standardized_challenge_outcome
Use prospectively adjudicated bleeding after a standardized hemostatic challenge such as dental extraction as the outcome measure, to reduce the recall and scoring noise that a retrospective bleeding assessment tool introduces into any dose-response analysis.
Show evidence (3 references)
PMID:31177606 SUPPORT Human Clinical
"Bleeding severity did not correlate with parameters of thrombin generation, clot formation, or clot lysis."
The dissociation in the largest thrombin generation study.
PMID:42004172 SUPPORT Human Clinical
"However, ROTEM parameters did not correlate with bleeding scores."
The same dissociation for whole-blood viscoelastometry.
PMID:25971840 SUPPORT Human Clinical
"There was no clear association of plasma clot properties with the clinical severity of bleeding in patients with MBDs."
The same dissociation for plasma clot properties.
Is BDUC a disease entity with a shared pathophysiology, or a residual administrative category that will dissolve into several distinct mechanisms and a group of patients without a bleeding disorder at all?
OPEN QUESTION OPEN bduc_entity_versus_residual_category
Attached to
pathophysiology#Hemostatic Defect Below the Detection Threshold of Routine Testing
dismech models BDUC as a single entry with parallel candidate arms, which is a modeling decision and not a settled fact. The case for an entity is that the phenotype is reproducible, severe, persistent over years, and indistinguishable in severity from named bleeding disorders. The case against is that reviews describe it explicitly as a heterogeneous group that mixes undiagnosed monogenic disease, polygenic contributions, and patients with a past bleeding event but no disorder — and that bleeding assessment tools cannot discriminate BDUC from named disorders, which is equally consistent with the label capturing several different things. If the heterogeneous view prevails, the correct dismech representation would eventually be a Grouping over several mechanism-defined entries rather than this single entry, and the hypothesis arms curated here are the natural seeds for those entries.
Show evidence (2 references)
PMID:33094877 SUPPORT Other
"BUC/UBD encompasses a heterogenous group of disorders which may include undiagnosed rare monogenic diseases, polygenic reasons for bleeding; and patients without a clear bleeding disorder but with a previous bleeding event."
The explicit statement of the heterogeneity that makes the entity question live.
PMID:32317240 SUPPORT Human Clinical
"The bleeding scores were similar in patients with an established diagnosis of a bleeding disorder compared to patients with BUC."
Phenotypic indistinguishability, which cuts both ways in this argument.
BDUC has a formal ISTH SSC definition but no MONDO term. Should a MONDO new term request be filed, and what should this entry's `disease_term` be until then?
CURATION TODO OPEN bduc_no_mondo_term
Attached to
pathophysiology#Hemostatic Defect Below the Detection Threshold of Routine Testing
Searches of MONDO for "bleeding disorder", "bleeding diathesis", "hemorrhagic diathesis", "unclassified bleeding" and "unknown cause" return only mechanism-specific and gene-specific entities plus broad umbrella terms; there is no residual or unexplained category. HPO and NCIT likewise have no equivalent. This entry therefore anchors `disease_term` to MONDO:0002243 hemorrhagic disease, which is a strict superclass that also subsumes every entity BDUC is defined by excluding, and records the inexactness as a `skos:broadMatch` mapping. Since BDUC now has a published consensus definition and a preferred term endorsed by the ISTH SSC, it meets the usual bar for a MONDO new term request. This is the same class of upstream ontology gap recorded for postpartum haemorrhage and preterm birth in issue #7837 and should be folded into a single consolidated request rather than filed separately.
Show evidence (1 reference)
PMID:38518896 SUPPORT Other
"We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology."
The consensus definition and preferred term that make this a well-formed new term request rather than a curator coinage.
Every hemostatic agent used in BDUC is prescribed on the basis of extrapolation from other bleeding disorders. Do tranexamic acid, desmopressin and platelet transfusion actually work in BDUC?
KNOWLEDGE GAP OPEN bduc_treatment_evidence_extrapolated
Attached to
pathophysiology#Mucocutaneous and Post-Challenge Bleeding
No randomized trial has been performed in a BDUC-defined population. The treatment recommendations are explicitly derived from phenotypically similar disorders, and the observational data are ambiguous: two cohorts show lower bleeding rates with periprocedural prophylaxis, while a third reports frequent bleeding complications irrespective of treatment, and postpartum hemorrhage occurs in a quarter to a third of deliveries despite prophylaxis. This is the most clinically consequential gap in the entry, because the affected population is largely young women facing surgery and childbirth.
Proposed experiments
Randomized trial of tranexamic acid for periprocedural prophylaxis in BDUC
exp_bduc_txa_randomized_periprocedural_trial
A randomized trial of tranexamic acid versus placebo for periprocedural hemostatic prophylaxis, restricted to patients meeting the ISTH SSC BDUC definition and powered on adjudicated bleeding after a standardized procedure.
Mechanism-stratified antifibrinolytic trial in BDUC
exp_bduc_mechanism_stratified_antifibrinolytic_trial
A trial stratified by fibrinolytic phenotype, testing whether the hyperfibrinolytic subgroup derives greater benefit from antifibrinolytic therapy than the rest of the BDUC population.
Show evidence (2 references)
PMID:41348021 SUPPORT Other
"Primary research in BDUC remains limited; future multisite observational and therapeutic clinical trials in BDUC may help us better understand multifactorial bleeding risk and further define the role of hemostatic therapies."
Expert statement of the evidence gap and the trials needed to close it.
PMID:36053176 SUPPORT Human Clinical
"Further prospective studies of BDUC patients are required to determine optimal management in pregnancy as well as determine the pathophysiological basis of bleeding."
The same gap stated for the pregnancy setting, which carries the highest consequence.
The strongest mechanistic data for an occult platelet defect come from patients selected for ABNORMAL light transmission aggregometry. Do those findings transfer to BDUC, which by definition requires aggregometry to be normal?
KNOWLEDGE GAP OPEN bduc_platelet_evidence_cohort_mismatch
Attached to
pathophysiology#Occult Platelet Function and Secretion Defect
The immature-platelet receptor profiling and platelet lipidomics studies both recruited patients with aggregometry alterations, that is, suspected platelet function defects. These patients sit immediately adjacent to BDUC and are plausibly the same biology sampled at a more detectable point on a continuum, but that is an assumption, not a result. Both evidence items are therefore graded INDIRECT on the platelet node. Until the same assays are applied to a formally BDUC-defined cohort, the platelet arm rests on transfer rather than on direct observation.
Proposed experiments
Immature-platelet profiling and lipidomics in a normal-aggregometry BDUC cohort
exp_bduc_platelet_profiling_in_normal_lta_cohort
Repeat immature-platelet surface receptor profiling and platelet lipidomics in patients meeting the ISTH SSC BDUC definition with normal light transmission aggregometry, retaining the abnormal-aggregometry group as a positive comparator, to test whether the reported platelet abnormalities transfer to BDUC proper.
Show evidence (1 reference)
PMID:40702900 SUPPORT Human Clinical
"In patients with a mild to moderate bleeding disorder (MBD) and abnormal light transmission aggregometry (LTA), a platelet function defect (PFD) is suspected. However, in many patients with PFD, the underlying mechanism remains elusive."
Documents the cohort definition used in these studies, which is what creates the transfer problem for the BDUC platelet arm.
⚙

Pathophysiology

10
Hemostatic Defect Below the Detection Threshold of Routine Testing
The definitional starting point of BDUC. The patient bleeds, but every assay in the recommended panel is normal. This node asserts only what the evidence supports: that a hemostatic abnormality exists which the available assays do not resolve, without committing to which limb of hemostasis is at fault. It is deliberately modeled as a trigger with several parallel, non-exclusive downstream arms rather than as a placeholder for one hidden defect, because the cohort data are most consistent with a multifactorial and heterogeneous origin.
Altered fibrin clot architecture determining mechanical stability Altered fibrinolytic balance with premature clot lysis Excess of natural anticoagulants (free TFPI-alpha, activated protein C) Occult platelet function or secretion defect below assay resolution Reduced thrombin-generating capacity on global assays
hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Occult Platelet Function and Secretion Defect Candidate arm in which the unresolved defect lies in platelet activation, granule secretion, or receptor signaling below the sensitivity of light transmission aggregometry. Occult platelet function or secretion defect below assay resolution
Impaired Thrombin Generation Candidate arm in which the unresolved defect manifests as reduced thrombin-generating capacity on global assays despite normal individual factor levels. Reduced thrombin-generating capacity on global assays
Natural Anticoagulant Excess Candidate arm in which physiological inhibitors of coagulation are present in excess, damping thrombin generation without any factor deficiency. Excess of natural anticoagulants (free TFPI-alpha, activated protein C)
Altered Fibrinolytic Balance Candidate arm in which a formed clot is lysed prematurely, or in which the fibrinolytic system is dysregulated in a direction that is not consistent across cohorts. Altered fibrinolytic balance with premature clot lysis
Altered Fibrin Clot Architecture Candidate arm in which fibrin network structure, rather than the amount of any component, determines clot mechanical stability. Altered fibrin clot architecture determining mechanical stability
Show evidence (3 references)
PMID:38518896 SUPPORT Other
"To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission..."
ISTH SSC consensus specifying the exact panel that must be normal, which is what makes this node a statement about assay resolution rather than about a known molecular lesion. Evidence source is OTHER because this is a standardization communication rather than primary data.
PMID:29388750 SUPPORT Human Clinical
"The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests."
The Vienna Bleeding Biobank authors' own conclusion that the residual category reflects assay incompleteness, which is the claim this node makes.
PMID:33496735 SUPPORT Human Clinical
"An imbalance of natural coagulation inhibitors such as TFPIα could be an underlying cause or contributor for unexplained bleeding, which is most probably multifactorial in a majority of patients."
Supports modeling the trigger as multifactorial with parallel arms rather than as a single occult lesion.
Occult Platelet Function and Secretion Defect
Mechanism confidence: Hypothetical
A platelet-intrinsic defect that routine light transmission aggregometry fails to resolve, or that it resolves only as an unspecific and poorly reproducible alteration. Two orthogonal lines of evidence point here: surface-receptor profiling shows that the immature (RNA-rich) platelet subpopulation carries a distinct and abnormal receptor phenotype while mature platelets appear normal, and platelet lipidomics shows intrinsic lipid shifts that track with impaired aggregation. Both are curated as leads rather than as established BDUC mechanisms: each was measured in patients selected for abnormal aggregometry, which is adjacent to, but formally outside, the BDUC definition.
Occult platelet function or secretion defect below assay resolution
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↓ DECREASED platelet degranulation GO:0002576 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet degranulation (GO:0002576). GO:0002576 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Hemostatic Plug Formation and Clot Stability Reduced platelet activation and secretion would weaken primary hemostatic plug formation at the site of vascular injury. Occult platelet function or secretion defect below assay resolution
Show evidence (4 references)
PMID:38412996 SUPPORT Human Clinical
"PFDs are identified through repeated abnormalities in light transmission aggregometry (LTA), flow cytometric mepacrine fluorescence, and glycoprotein expression analysis. Nevertheless, we experience diagnostic challenges with regard to reproducibility and unspecific alterations of LTA."
Establishes that aggregometry has limited reproducibility and resolution, which is the premise of an occult platelet defect arm.
PMID:40403972 SUPPORT INDIRECT Human Clinical
"In patients, immature platelets expressed lower levels of CD62P, CD36, CD31, TLR2, and TLR4 but increased TLR9 expression, while mature platelets showed no differences."
Identifies an abnormality confined to immature platelets that whole-platelet assays would average away. Graded INDIRECT because the cohort was selected for abnormal aggregometry (suspected platelet function defect), not for BDUC, so reaching this node takes a transfer step: it is a mechanistic lead for this arm rather than a direct BDUC finding.
PMID:40702900 SUPPORT INDIRECT Human Clinical
"Baseline and stimulated platelet analyses in a female subgroup showed intrinsic lipidomic changes, including upregulated polyunsaturated triacylglycerols (PUFA-TG), acylcarnitines (CAR), and reduced lysophosphatidylethanolamines (LPE)."
Lipid-mediated platelet signaling as a candidate substrate for an occult defect. INDIRECT for the same cohort-selection reason as above.
+ 1 more reference
Impaired Thrombin Generation
Mechanism confidence: Hypothetical
Reduced thrombin-generating capacity on calibrated global assays despite normal individual coagulation factor activities. This is the most frequently replicated laboratory abnormality in BDUC: the Vienna Bleeding Biobank reported prolonged lag time and time to peak with reduced peak and velocity in 382 patients, and an independent automated assay reproduced the same pattern. It is nonetheless curated as HYPOTHETICAL rather than established, because an independent Rotterdam cohort found no meaningful thrombin generation difference, and because in every cohort the degree of impairment fails to track bleeding severity.
Reduced thrombin-generating capacity on global assays
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Hemostatic Plug Formation and Clot Stability Lower thrombin burst yields slower and less robust fibrin formation and less thrombin-dependent platelet and factor XIII activation. Reduced thrombin-generating capacity on global assays
Show evidence (4 references)
PMID:31177606 SUPPORT Human Clinical
"Thrombin generation was significantly impaired in BUC patients compared to healthy controls, exhibiting a prolonged lag time and time to peak and decreased maximum thrombin generation, velocity index, and area under the curve (AUC)."
Primary case-control evidence in 382 BUC patients versus 100 controls.
PMID:42027303 SUPPORT Human Clinical
"This study highlights the reproducibility of impaired TG in patients with BDUC."
Independent replication with a fully automated assay at two tissue factor concentrations, which is what raises this arm above the others in support.
PMID:32337845 SUPPORT Human Clinical
"BUC patients demonstrated a significantly prolonged lag time in TG (median 7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5 minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM variables were found."
An independent Rotterdam cohort that reproduces only the prolonged lag time and finds no thromboelastometry difference. It supports the arm only weakly, contradicts its magnitude, and its clot lysis result runs in the opposite direction to the Vienna finding.
+ 1 more reference
Natural Anticoagulant Excess
Mechanism confidence: Hypothetical
An excess of physiological anticoagulants rather than a deficiency of procoagulants. Free tissue factor pathway inhibitor alpha is elevated above the 95th percentile disproportionately in the subgroup with no identifiable bleeding disorder, and activated protein C antigen is likewise raised, most markedly in BDUC. This arm is mechanistically attractive because it explains a normal factor panel together with a damped thrombin burst, and it supplies the only currently named druggable target in BDUC. Note that the related soluble thrombomodulin hypothesis was explicitly tested in the same cohort programme and refuted.
Excess of natural anticoagulants (free TFPI-alpha, activated protein C)
negative regulation of blood coagulation GO:0030195 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of blood coagulation (GO:0030195). GO:0030195 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Thrombin Generation Excess free TFPI-alpha inhibits the tissue factor/factor VIIa initiation complex and factor Xa, delaying and damping the thrombin burst; raised activated protein C degrades factors Va and VIIIa with the same net effect. Excess of natural anticoagulants (free TFPI-alpha, activated protein C)
Show evidence (5 references)
PMID:33496735 SUPPORT Human Clinical
"This was pronounced in the subgroup of patients in whom no bleeding disorder could be identified (bleeding of unknown cause [BUC; n = 420]"
Locates the free TFPI-alpha excess specifically in the BUC subgroup rather than in mild bleeding disorders generally.
PMID:33496735 SUPPORT Human Clinical
"An increase in free TFPIα was associated with a mild delay in thrombin generation (prolonged lag time and time to peak), but not with alterations in routinely used global clotting tests."
Supplies the mechanistic link from this node to the impaired thrombin generation node, and explains why routine clotting tests stay normal.
PMID:32003946 SUPPORT Human Clinical
"TFPI activity may be increased in a subset of UBD patients."
Independent cohort confirming raised TFPI activity in a subset, supporting the subset framing used here.
+ 2 more references
Altered Fibrinolytic Balance
Mechanism confidence: Hypothetical
Dysregulation of the plasminogen activation system, classically framed as accelerated clot breakdown. Support is real but internally inconsistent: tissue plasminogen activator activity is detectable far more often in patients than controls, a tPA-modified thromboelastometry assay classifies roughly a fifth of BDUC patients as hyperfibrinolytic, and adding fibrinolytic assays to the work-up raises diagnostic yield. Against that, direct plasmin generation measurement found reduced, not increased, peak plasmin, and whole-blood viscoelastometry in the largest cohort found reduced rather than enhanced lysis potential. The entry keeps this arm deliberately named for the balance rather than for hyperfibrinolysis, and the direction conflict is recorded as an explicit controversy.
Altered fibrinolytic balance with premature clot lysis
fibrinolysis GO:0042730 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology.
Downstream
Impaired Hemostatic Plug Formation and Clot Stability Premature plasmin-mediated dissolution of a formed fibrin clot, or a dysregulated lysis profile, would shorten the durability of hemostasis and produce delayed rather than immediate bleeding. Altered fibrinolytic balance with premature clot lysis
Show evidence (6 references)
PMID:28018998 SUPPORT Human Clinical
"We conclude that the fibrinolytic system can play an etiological role for bleeding in patients with BUC."
Primary case-control study of 270 BUC patients concluding an etiological role for the fibrinolytic system.
PMID:28018998 SUPPORT Human Clinical
"tPA activity levels were more often above the detection limit in patients than in controls"
The specific quantitative finding underlying this arm. Note that the same study found alpha2-antiplasmin and TAFI higher, not lower, in patients, so a simple antiplasmin-deficiency model is not supported.
PMID:40680469 SUPPORT Human Clinical
"tPA-ROTEM identified a hyperfibrinolytic profile in 19/92 (21 %) of BDUC patients. Multivariable regression analysis showed that lower PAI-1 antigen levels were independently associated with hyperfibrinolysis."
Quantifies the fraction of BDUC patients with a hyperfibrinolytic profile and identifies low PAI-1 as its correlate. This is the strongest direct support for the accelerated-lysis direction.
+ 3 more references
Altered Fibrin Clot Architecture
Mechanism confidence: Hypothetical
A structural rather than quantitative model: the fibrin network in BDUC forms at a lower rate and with altered fiber morphology, and it is that architecture, not the concentration of any single component, that determines mechanical stability and susceptibility to lysis. Confocal microscopy shows a tendency to thicker fibers that correlates inversely with peak plasmin, and turbidimetric studies show a reduced rate of fibrin formation. The evidence here is mixed: the largest dedicated clot-properties study found the reduced formation rate but no difference in the remaining clot parameters.
Altered fibrin clot architecture determining mechanical stability
blood coagulation, fibrin clot formation GO:0072378 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Hemostatic Plug Formation and Clot Stability A clot that forms more slowly and with altered fiber architecture is mechanically less stable at the injury site. Altered fibrin clot architecture determining mechanical stability
Show evidence (3 references)
PMID:39231312 SUPPORT Human Clinical
"Confocal microscopy analysis revealed a tendency towards thicker fibers in clots of patients with BDUC"
Direct structural imaging evidence for altered fibrin architecture in BDUC.
PMID:25971840 SUPPORT Human Clinical
"In the fibrinolysis assay, Vmax was lower in patients than in healthy controls. No differences in the other parameters of clot formation and lysis were detected between the groups."
Supports a reduced rate of fibrin formation while finding no broader clot property derangement, which bounds how widely this arm may be asserted.
PMID:25909989 SUPPORT INDIRECT Human Clinical
"Increased clot permeability and susceptibility to fibrinolysis are associated with HMB, suggesting that altered plasma fibrin clot properties might contribute to bleeding disorders of unknown origin."
Links looser, more permeable clot structure to bleeding in the heavy menstrual bleeding subgroup. INDIRECT because the cohort is defined by unexplained heavy menstrual bleeding rather than by a formal BDUC diagnosis. Note its direction of lysis susceptibility is opposite to the plasmin generation and viscoelastometry findings above, which is the direction conflict this arm is named to preserve.
Impaired Hemostatic Plug Formation and Clot Stability
Mechanism confidence: Provisional
The shared convergence node. Whichever upstream arm is operative in a given patient, the common consequence is a hemostatic plug that forms too slowly, holds too weakly, or dissolves too early at sites of vascular injury, particularly at mucosal surfaces and surgical wounds where the hemostatic challenge is sustained. Whole-blood viscoelastometry in the largest BDUC cohort captures this as a globally altered clot formation and lysis profile that discriminates patients from controls.
hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Mucocutaneous and Post-Challenge Bleeding Failure of durable hemostasis at sites of minor and surgical vascular injury produces the clinical bleeding phenotype.
Show evidence (2 references)
PMID:42004172 SUPPORT Human Clinical
"nonactivated ROTEM revealed altered clot formation and fibrinolytic profiles in BDUC and could distinguish patients with BDUC from healthy individuals."
Whole-blood evidence that the composite hemostatic process is measurably abnormal in BDUC even though its individual components test normal, which is exactly what this convergence node claims.
PMID:31177606 SUPPORT Human Clinical
"Patients with BUC have an impaired hemostatic capacity reflected by a lower thrombin-generation potential, a lower clot formation rate, increased clot turbidity, and shorter clot lysis time, which might contribute to their increased bleeding tendency."
States the composite impaired hemostatic capacity that this node represents, drawing together the thrombin generation, clot formation, and lysis arms.
Mucocutaneous and Post-Challenge Bleeding
Mechanism confidence: Established
The clinical phenotype: spontaneous mucocutaneous bleeding (epistaxis, easy bruising, gingival and oral bleeding, heavy menstrual bleeding) together with excessive bleeding after hemostatic challenges such as surgery, dental extraction, and childbirth. Its severity, as quantified by bleeding assessment tools, is indistinguishable from that of patients who do carry a named diagnosis such as von Willebrand disease or a platelet function defect — which is the central clinical argument that BDUC is a real bleeding phenotype rather than a labeling artifact of over-referral.
Downstream
Chronic Blood Loss and Iron Depletion Recurrent bleeding, dominated in this predominantly female population by heavy menstrual bleeding, causes cumulative iron loss.
Impaired Health-Related Quality of Life The bleeding phenotype, the associated uncertainty, and the long diagnostic delay together impair physical and mental health.
Show evidence (3 references)
PMID:39687924 SUPPORT Other
"The mucocutaneous bleeding phenotype of individuals with BDUC is generally comparable to that of individuals with inherited bleeding disorders such as von Willebrand disease or platelet function disorders."
Establishes the character and severity of the phenotype at this node. Evidence source OTHER because this is a narrative review.
PMID:34398949 SUPPORT Other
"Importantly, BAT scores suggest that patients with BDUC display bleeding phenotypes comparable to those seen in patients with VWD or PFD."
Quantified phenotype equivalence to named bleeding disorders, from an expert How-I-Treat review.
PMID:42417170 SUPPORT Other
"Their clinical bleeding phenotype is characterized by mucocutaneous bleeding, as well as bleeding following surgical challenges or childbirth, and is associated with impaired health-related quality of life."
Enumerates the two components of this node, spontaneous mucocutaneous bleeding and post-challenge bleeding, and links it downstream to quality of life.
Chronic Blood Loss and Iron Depletion
Mechanism confidence: Provisional
Cumulative iron loss from recurrent mucosal and menstrual bleeding, leading to iron deficiency with or without anemia. Curated with an explicit caveat: although iron deficiency is common in BDUC (39%), the rate was not significantly higher than in matched healthy controls in the one study that included a control arm, and female sex, younger age, and body mass index rather than the bleeding diagnosis were the associated factors. The node is therefore retained as a clinically important consequence to screen for, not as a BDUC-specific finding.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:42417170 SUPPORT Other
"Iron deficiency, with or without anemia, is common, particularly among women, who comprise up to 80% of BDUC cohorts and frequently report heavy menstrual bleeding."
Establishes iron deficiency as a common consequence and ties it to the female predominance and heavy menstrual bleeding.
PMID:40994886 SUPPORT Human Clinical
"bleeding disorder of unknown cause: 39%; platelet function disorders: 33%; and coagulation factor deficiencies: 28%"
Quantifies iron deficiency in BDUC at 39%. Read with the caveat the same controlled analysis reports: this was not significantly different from the 31% seen in matched healthy controls.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Bleeding Disorder of Unknown Cause Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Increased Mucocutaneous Bleeding Tendency OBLIGATE Clinical HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased bleeding tendency, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39687924 SUPPORT Other
"BDUC is a diagnosis of exclusion, characterized by normal hemostatic investigations despite a clinically significant bleeding tendency."
The ISTH SSC definition as restated in review, establishing this phenotype as obligate and diagnostic.
Heavy Menstrual Bleeding Clinical HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heavy menstrual bleeding, annotated with Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42417170 SUPPORT Other
"Iron deficiency, with or without anemia, is common, particularly among women, who comprise up to 80% of BDUC cohorts and frequently report heavy menstrual bleeding."
Supports the disease-phenotype association and the female predominance of BDUC cohorts. The 80% figure is the proportion of the cohort that is female, not the proportion with heavy menstrual bleeding, so it carries no frequency band.
PMID:41347990 SUPPORT Other
"Currently available data suggest that a substantial portion of BDUC patients continue to experience spontaneous bleeding symptoms, such as easy bruising, epistaxis, and heavy menstrual bleeding."
Confirms persistence of heavy menstrual bleeding, easy bruising and epistaxis as the leading spontaneous symptoms during follow-up.
Epistaxis Clinical HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36924834 SUPPORT Human Clinical
"Most persistent bleeding manifestations were hematomas (n = 146/245, 59.6%) and bleeding from small wounds (n = 69/141, 48.9%), followed by epistaxis (n = 42/132, 31.8%), oral mucosal bleeding (n = 26/87, 29.9%), and joint bleeding (n = 7/14, 50.0%)."
Establishes epistaxis as a recorded bleeding manifestation in a cohort that was 62.8% BDUC. The 31.8% is 42/132 — persistence at follow-up among patients who already had epistaxis at baseline — so it is not a cohort prevalence and supports no frequency band.
Easy Bruising and Spontaneous Hematoma Clinical HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36924834 SUPPORT Human Clinical
"Most persistent bleeding manifestations were hematomas (n = 146/245, 59.6%) and bleeding from small wounds (n = 69/141, 48.9%)"
Hematomas were the most frequently persisting manifestation on prospective follow-up (146/245 of those affected at baseline). This is a persistence rate, not a cohort prevalence, so it supports the disease-phenotype association only and no frequency band.
Oral and Gingival Bleeding Clinical HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36924834 SUPPORT Human Clinical
"oral mucosal bleeding (n = 26/87, 29.9%)"
Records oral mucosal bleeding as a persisting manifestation in 26/87 of the patients who had it at baseline. This is a persistence rate, not a cohort prevalence, so it supports the disease-phenotype association only and no frequency band.
Prolonged Bleeding After Surgery FREQUENT Clinical HP:0004846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after surgery (HP:0004846). HP:0004846 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41348021 SUPPORT Other
"In previously described cohorts of patients with BDUC, a history of postoperative bleeding is common, reported in 44% to 75% of patients."
Direct frequency evidence (44-75%) for post-surgical bleeding in BDUC cohorts, supporting the FREQUENT band.
PMID:33853179 SUPPORT Human Clinical
"In 14/72 (19%) surgical procedures major bleeding occurred and 14/41 (34%) deliveries were complicated by major postpartum hemorrhage (PPH)."
Prospectively collected per-procedure major bleeding rate following a BUC diagnosis.
Prolonged Bleeding After Dental Extraction FREQUENT Clinical HP:0006298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after dental extraction (HP:0006298). HP:0006298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41006857 SUPPORT Other
"The incidence of bleeding in patients with BDUC following dental surgery can range from 36–84%."
Reported incidence range of 36-84% after dental surgery. The range straddles the FREQUENT/VERY_FREQUENT boundary (80%), so the conservative lower band FREQUENT (30-79%) is used.
Postpartum Hemorrhage FREQUENT Clinical HP:0011891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Post-partum hemorrhage (HP:0011891). HP:0011891 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39498237 SUPPORT Human Clinical
"Postpartum hemorrhage occurred in 26% (5/19) of deliveries."
Per-delivery postpartum hemorrhage rate in a two-center BDUC cohort. The denominator is deliveries, not patients, and 26% sits just below the FREQUENT band; the band is carried by the larger 41-delivery cohort below (34%), with this figure recorded as the concordant lower estimate.
PMID:33853179 SUPPORT Human Clinical
"14/41 (34%) deliveries were complicated by major postpartum hemorrhage (PPH)"
Independent cohort giving a 34% major postpartum hemorrhage rate (14/41 deliveries), which falls in the FREQUENT band (30-79%) and is the quantitative basis for the band on this phenotype.
Iron Deficiency Anemia OCCASIONAL Clinical HP:0001891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iron deficiency anemia (HP:0001891). HP:0001891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40994886 SUPPORT Human Clinical
"250 patients with MBD (39%) had ID and 40 (6%) had IDA"
Iron deficiency anemia in 6% of the mild bleeding disorder cohort, which is the basis for the OCCASIONAL band; iron deficiency without anemia is far more common at 39%.
Joint Bleeding Clinical HP:0005261 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hemorrhage (HP:0005261). HP:0005261 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37720482 SUPPORT Human Clinical
"Of all analyzed bleeding symptoms, only joint bleeding was associated with impaired physical health and gastrointestinal bleeding with mental health in BDUC."
Documents joint bleeding as an analyzed symptom in the BDUC cohort and its specific association with impaired physical health.
💊

Medical Actions

5
Tranexamic Acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The first-line hemostatic agent in BDUC, used both for heavy menstrual bleeding and as periprocedural prophylaxis, where antifibrinolytic monotherapy is the most commonly advised strategy. Its use in BDUC is largely extrapolated from phenotypically similar bleeding disorders, but it is also the treatment with the clearest mechanistic rationale, since about a fifth of BDUC patients show a hyperfibrinolytic profile.
Mechanism Target:
INHIBITS Altered Fibrinolytic Balance — Tranexamic acid blocks the lysine binding sites of plasminogen, preventing its assembly on fibrin and inhibiting plasmin-mediated clot breakdown.
Show evidence (5 references)
PMID:38518896 SUPPORT Other
"Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions."
ISTH SSC statement of the treatment options in BDUC.
PMID:39498237 SUPPORT Human Clinical
"Antifibrinolytic monotherapy was advised for 57% of major procedures, 59% of minor procedures, and 67% of childbirths."
Documents antifibrinolytic monotherapy as the dominant periprocedural strategy in real-world BDUC practice.
PMID:40680469 SUPPORT Human Clinical
"These findings suggest that antifibrinolytic medications may be useful to control bleeding or prevent bleeding in surgical interventions in a group of patients with BDUC."
Supplies the mechanistic rationale linking the fibrinolytic arm to this treatment.
+ 2 more references
Desmopressin (DDAVP)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: desmopressin CHEBI:4450 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses desmopressin (CHEBI:4450). CHEBI:4450 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Second hemostatic agent, used alone or with tranexamic acid, particularly before procedures. As with tranexamic acid, the BDUC evidence is observational and extrapolated from phenotypically similar disorders.
Show evidence (2 references)
PMID:31747136 SUPPORT Human Clinical
"TxA and desmopressin were effective at preventing bleeding in 69 procedures and 13 deliveries."
Observational effectiveness of tranexamic acid and desmopressin as procedural prophylaxis in an unclassified bleeding disorder cohort.
PMID:31747136 SUPPORT INDIRECT Human Clinical
"Tranexamic acid and desmopressin are effective as haemostatic prophylaxis but there is an urgent need for clinical trials."
The same authors' explicit statement that the evidence base is inadequate. Graded INDIRECT because it is an observational judgement carrying its own call for trials, which is what the treatment description records.
Levonorgestrel 52-mg Intrauterine System
Action: Hormone TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone Therapy (NCIT:C15445). NCIT:C15445 is a clinical intervention from the NCI Thesaurus. NCIT:C15445
Agent: levonorgestrel CHEBI:6443 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levonorgestrel (CHEBI:6443). CHEBI:6443 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Device
Hormonal control of heavy menstrual bleeding, addressing the dominant symptom and the principal route of iron loss in this predominantly female population. Evidence is from women with inherited bleeding disorders rather than BDUC specifically.
Target Phenotypes: Heavy menstrual bleeding HP:0000132 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Heavy menstrual bleeding, annotated with Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32470465 SUPPORT INDIRECT Human Clinical
"LNG 52-mg IUS placement can effectively control abnormal uterine bleeding in women with inherited bleeding disorders and consequently improve their quality of life."
Prospective efficacy in women with inherited bleeding disorders. INDIRECT because the cohort is inherited bleeding disorders, not BDUC.
PMID:32470465 SUPPORT INDIRECT Human Clinical
"The amenorrhea rate was 70% after 12 months."
Quantifies the magnitude of menstrual suppression achieved. INDIRECT for the same reason as the item above: the cohort is inherited bleeding disorders, not BDUC.
Platelet Transfusion and Recombinant Factor VIIa for Major Bleeding
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Escalation options reserved for major bleeding or invasive surgery when antifibrinolytics and desmopressin are judged insufficient.
Show evidence (2 references)
PMID:41006857 SUPPORT Other
"For more invasive surgeries, fresh frozen plasma, platelet transfusions, or recombinant factor VIIa may be necessary."
Names the escalation options for invasive procedures in BDUC.
PMID:41348021 SUPPORT Other
"Extrapolating from the management of phenotypically similar bleeding disorders, a therapeutic approach may include antifibrinolytic agents (tranexamic acid), desmopressin, and/or platelet transfusion."
States both the therapeutic approach and, explicitly, that it is extrapolated rather than BDUC-derived.
Periprocedural and Peripartum Hemostatic Prophylaxis
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
A management strategy rather than a single agent: administering hemostatic cover before surgery, dental extraction, and delivery. Two independent cohorts support a low threshold for prophylaxis, since untreated procedures and deliveries carry markedly higher bleeding rates — though a third cohort found bleeding complications frequent irrespective of prophylaxis, so the strategy reduces but does not abolish risk.
Target Phenotypes: Post-partum hemorrhage HP:0011891 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Post-partum hemorrhage (HP:0011891). HP:0011891 is a phenotype from the Human Phenotype Ontology. Prolonged bleeding after surgery HP:0004846 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Prolonged bleeding after surgery (HP:0004846). HP:0004846 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:36053176 SUPPORT Human Clinical
"the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary hemostatic prophylaxis versus prophylaxis"
Quantifies the protective association of peripartum prophylaxis in a BDUC cohort.
PMID:39498237 SUPPORT Human Clinical
"Major or clinically relevant nonmajor bleeding occurred in 4.1% (4/98) of procedures with prophylaxis and 10% (2/20) of procedures without prophylaxis."
Independent cohort showing lower bleeding rates with periprocedural prophylaxis.
PMID:33853179 SUPPORT Human Clinical
"Bleeding complications are frequent in BUC patients, irrespective of pre- or perioperative hemostatic treatment."
Bounds the claim: prophylaxis does not abolish the risk. The same paper nonetheless recommends a low threshold for treatment, so this is a limit on efficacy rather than an argument against treating.
+ 1 more reference
🔬

Biochemical Markers

5
Thrombin Generation (Endogenous Thrombin Potential) (Impaired: prolonged lag time and time to peak with reduced peak, velocity index and area under the curve, on a normal routine coagulation panel)
Context: The most frequently replicated laboratory abnormality in BDUC, and the marker on which the leading mechanistic arm rests. Reproducibility is genuinely contested rather than merely unreplicated: two Vienna-linked cohorts find the full pattern, an independent Rotterdam cohort reproduces only the prolonged lag time, and a third cohort finds abnormalities in a minority with no diagnostic pattern.
Pathograph Readouts
Readout Of Impaired Thrombin Generation Negative Diagnostic
Calibrated thrombin generation is the direct assay readout of this mechanism node; lower thrombin-generating capacity corresponds to the hypothesized defect.
Show evidence (3 references)
PMID:31177606 SUPPORT Human Clinical
"Thrombin generation was significantly impaired in BUC patients compared to healthy controls, exhibiting a prolonged lag time and time to peak and decreased maximum thrombin generation, velocity index, and area under the curve (AUC)."
Primary case-control evidence in 382 BUC patients versus 100 controls, naming the specific parameters that are deranged.
PMID:42027303 SUPPORT Human Clinical
"This study highlights the reproducibility of impaired TG in patients with BDUC."
Independent replication with a fully automated assay.
PMID:31747136 SUPPORT Human Clinical
"TG revealed 26% patients with a long lag time and 19% with a decreased endogenous thrombin potential but no diagnostic pattern was seen."
Quantifies how often the marker is abnormal in an unselected cohort and is the basis for the specificity caveat recorded above.
Free Tissue Factor Pathway Inhibitor Alpha (Elevated above the 95th percentile, disproportionately in the subgroup with no identifiable bleeding disorder)
Context: The best-localized biomarker in BDUC, because the excess is reported specifically in the unexplained-bleeding subgroup rather than across mild bleeding disorders generally, and because it is mechanistically tied to the thrombin generation defect in the same study.
Pathograph Readouts
Readout Of Natural Anticoagulant Excess Positive Diagnostic
Free TFPI-alpha is the primary measured quantity behind the natural anticoagulant excess arm.
Correlates With Impaired Thrombin Generation Negative Diagnostic
Higher free TFPI-alpha is associated with a delayed thrombin burst while routine global clotting tests stay normal, which is the observational link between the two mechanism nodes.
Show evidence (1 reference)
PMID:33496735 SUPPORT Human Clinical
"An increase in free TFPIα was associated with a mild delay in thrombin generation (prolonged lag time and time to peak), but not with alterations in routinely used global clotting tests."
States the association between the marker and the thrombin generation readout directly.
Show evidence (2 references)
PMID:33496735 SUPPORT Human Clinical
"This was pronounced in the subgroup of patients in whom no bleeding disorder could be identified (bleeding of unknown cause [BUC; n = 420]"
Locates the elevation specifically in the BUC subgroup.
PMID:32003946 SUPPORT Human Clinical
"TFPI activity may be increased in a subset of UBD patients."
Independent cohort confirming the finding and supporting the subset framing used in the specificity field.
Activated Protein C Antigen (Increased antigen levels in BDUC)
Context: Extends the natural-anticoagulant arm beyond TFPI, and is the finding its authors nominate as a future therapeutic target in BDUC.
Pathograph Readouts
Readout Of Natural Anticoagulant Excess Positive Diagnostic
Raised activated protein C degrades factors Va and VIIIa, giving the same net anticoagulant excess as the TFPI limb.
Show evidence (2 references)
PMID:38324941 SUPPORT Human Clinical
"Our data demonstrate increased antigen levels of APC in BDUC, which might contribute to the bleeding tendency in some patients and could be a future therapeutic target in BDUC."
Primary evidence for the elevation and for the therapeutic-target framing.
PMID:38324941 SUPPORT Human Clinical
"No differences in PS antigen levels between patients and HC were seen overall, or according to specific diagnoses."
The negative protein S result that bounds the claim, recorded here so the marker is not read as a whole-pathway abnormality.
Plasma Clot Lysis Time (Prolonged relative to controls in the Rotterdam cohort, which is the opposite direction to the accelerated-lysis model)
Context: The clearest example in BDUC of a biomarker whose measured direction contradicts the mechanism it is usually invoked for. Curated so the conflict is visible rather than resolved by selective citation.
Pathograph Readouts
Readout Of Altered Fibrinolytic Balance Diagnostic
Reports on the fibrinolytic arm, but in the direction opposite to the accelerated-lysis reading of that node. Direction is deliberately left unset because the cohorts disagree on sign.
Show evidence (1 reference)
PMID:32337845 SUPPORT Human Clinical
"BUC patients demonstrated a significantly prolonged lag time in TG (median 7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5 minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM variables were found."
Source for both the prolonged clot lysis time and its median/IQR.
Plasmin Generation (Peak Plasmin) (Reduced peak plasmin, counter to the hyperfibrinolysis model)
Context: Direct measurement of plasmin generation, as opposed to inference from lysis assays. Its authors redirect the explanation towards clot architecture rather than accelerated lysis, which is why the entry carries a separate Altered Fibrin Clot Architecture node.
Pathograph Readouts
Readout Of Altered Fibrinolytic Balance Negative Diagnostic
Directly measures the plasminogen activation output of this node and finds it reduced, which is the principal evidence against naming the node hyperfibrinolysis.
Correlates With Altered Fibrin Clot Architecture Diagnostic
The authors attribute the reduced peak plasmin to altered clot structure, linking this marker to the clot architecture arm.
Show evidence (1 reference)
PMID:39231312 SUPPORT Human Clinical
"Overall, patients with BDUC counterintuitively exhibited reduced peak plasmin levels, potentially related to altered clot structure."
Source for both the direction of the finding and the clot-architecture attribution.
🔬

Diagnosis

4
Objective Bleeding Phenotype Quantification (ISTH-BAT)
A standardized bleeding assessment tool score is the mandated first step, because in a diagnosis of exclusion the phenotype is the only positive finding. Its limitation must be stated alongside it: bleeding assessment tools quantify severity well but discriminate poorly between BDUC and named bleeding disorders, so a high score establishes that bleeding is real, not what is causing it.
Show evidence (2 references)
PMID:38518896 SUPPORT Other
"We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool."
ISTH SSC recommendation establishing the ISTH-BAT as the required first step.
PMID:32317240 SUPPORT Human Clinical
"The Vicenza- and the ISTH BAT have a low ability to distinguish patients with an established bleeding disorder from those with BUC."
Bounds the tool's role: it is required, but it does not discriminate BDUC from an established bleeding disorder.
Minimum Exclusion Panel of Hemostatic Laboratory Tests
The ISTH SSC minimum panel that must all be normal before BDUC may be assigned: complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen and function, factors VIII, IX and XI, and platelet light transmission aggregometry. Non-hemostatic and acquired causes must also be excluded, although exactly which and by what testing is not specified.
Show evidence (2 references)
PMID:38518896 SUPPORT Other
"We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology."
Establishes both the diagnostic rule and the preferred terminology.
PMID:39687924 SUPPORT Other
"Importantly, other nonhemostatic and acquired causes of bleeding should be excluded, but details on exclusion criteria and associated diagnostic testing remain undefined."
Records that the non-hemostatic half of the exclusion is not operationalized, which is a live gap in the diagnostic definition.
Non-Routine and Global Hemostatic Testing
Optional second-tier testing for rare mechanisms — thrombomodulin-associated coagulopathy, TFPI-related bleeding, hyperfibrinolytic disorders, impaired tissue factor production — plus global assays (thrombin generation, thromboelastometry, clot lysis). These are research or specialist tools, not diagnostic criteria: the ISTH SSC states explicitly that their abnormalities are variable and of uncertain clinical significance.
Show evidence (3 references)
PMID:38454298 SUPPORT Other
"For patients with BDUC, further evaluation may include non-routine testing to look for rare bleeding disorders not detected by routine hemostasis tests, such as thrombomodulin-associated coagulopathy, tissue factor pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding disorders..."
Enumerates the second-tier tests and the entities they target.
PMID:38518896 SUPPORT Other
"Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain."
The consensus caveat that prevents global assays from being curated as diagnostic criteria.
PMID:35316940 SUPPORT Human Clinical
"Analysis of fibrinolytic disorders in selected patients has a high diagnostic yield."
Counterweight showing that in selected patients the fibrinolytic arm of second-tier testing does reclassify a substantial minority.
Targeted Genomic Sequencing of Hemostatic Genes
Panel or exome sequencing of hemostasis genes. Included for completeness and because it is frequently requested, but with an explicitly low expected yield of about 3% in patients with normal hemostasis testing.
Show evidence (2 references)
PMID:38518896 SUPPORT Other
"Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield."
Consensus statement of the low expected yield.
PMID:42320587 SUPPORT Other
"Genetic testing should therefore be regarded as a complementary tool rather than a replacing conventional diagnostics."
Positions sequencing as complementary, matching how it is curated here.
📈

Progression

1
Long-term follow-up after diagnosis
Duration: median 4.3 years (IQR 2.6-6.7)
BDUC is persistent rather than self-limiting. In prospective follow-up of a cohort that was 62.8% BDUC, 72% of patients experienced at least one further bleeding event, and prior post-interventional bleeding predicted recurrence after surgery and tooth extraction.
Show evidence (3 references)
PMID:36924834 SUPPORT Human Clinical
"During the follow-up time of median (IQR) 4.3 years (2.6-6.7), 72% of patients had at least 1 bleeding event."
Prospective recurrence rate over the stated follow-up period.
PMID:41347990 SUPPORT Other
"Although BDUC remains a diagnosis of exclusion, accumulating data underscore the need to recognize it as a potentially persistent clinically relevant condition."
Supports the persistence framing of this progression phase.
PMID:41347990 SUPPORT Other
"Patients with prior bleeding complications after such events, patients with blood group O, and patients who did not receive hemostatic prophylaxis demonstrate an increased risk for postinterventional bleeding during follow-up."
Identifies the risk factors for recurrence during follow-up.
📊

Prevalence

3
Patients referred to a tertiary hemostasis service for a mild-to-moderate bleeding tendency (Vienna Bleeding Biobank, Austria)
Unknown Unknown
72.5% of 418 consecutively investigated patients (303/418). This is a diagnostic-yield fraction within a referral population, NOT a general-population prevalence, which is unknown. It is recorded here because the referral fraction is the only occurrence measure the literature reports for BDUC. measure_type and prevalence_class are deliberately UNKNOWN and rate_per_100000 is deliberately omitted: emitting 72500 per 100,000 as a structured rate would be read as a population prevalence in any cross-disease comparison or export.
Show evidence (1 reference)
PMID:29388750 SUPPORT Human Clinical
"Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC)."
Source for the referral-cohort fraction.
Patients referred to hemostasis experts for a clinically relevant bleeding tendency (international)
Unknown Unknown
"More than half" of referrals, as summarized across cohorts; individual cohorts range from about half to three-quarters. A referral diagnostic-yield fraction, not a population prevalence, so no structured rate or prevalence class is asserted.
Show evidence (1 reference)
PMID:39687924 SUPPORT Other
"In more than half of the individuals with a clinically relevant bleeding tendency who are referred to hemostasis experts, no biological etiology can be found after extensive laboratory testing."
Cross-cohort summary of the referral fraction.
Patients referred for assessment of a possible bleeding tendency (complement of the mild-bleeding-disorder diagnostic yield)
Unknown Unknown
Derived as the complement of the 30% of referrals who receive a named mild bleeding disorder diagnosis. Recorded separately from the Vienna figure because it is an independent estimate. A referral diagnostic-yield fraction, not a population prevalence, so no structured rate or prevalence class is asserted.
Show evidence (1 reference)
PMID:34398949 SUPPORT Other
"Recent studies have demonstrated that only 30% of patients referred for assessment of a possible bleeding tendency will eventually be diagnosed with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or platelet function defect (PFD). Rather, most of these patients will be..."
Source for the complementary 30% named-diagnosis yield.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Bleeding Disorder of Unknown Cause:

von Willebrand disease Not Yet Curated MONDO:0024574
Overlapping Features The first entity that must be excluded. Diagnosis rests on von Willebrand factor antigen and activity, with repeat testing when levels are below 80 IU/dL because levels fluctuate diagnostically in a high proportion of patients with a mild bleeding tendency.
Show evidence (1 reference)
PMID:38412996 SUPPORT Human Clinical
"Patients with an unexplained mild to moderate bleeding tendency are diagnosed with bleeding disorder of unknown cause (BDUC), a classification reached after ruling out other mild to moderate bleeding disorders (MBD) including von Willebrand disease (VWD), platelet function defects (PFDs),..."
Names the full exclusion set that defines the differential for this entry.
Low von Willebrand factor
Overlapping Features The nearest neighbour and the hardest boundary. Patients with von Willebrand factor in the 30-50 IU/dL range often lack a pathogenic VWF variant and show poor correlation between level and bleeding phenotype, so the entity is argued to sit between type 1 von Willebrand disease and BDUC rather than cleanly on either side.
Distinguishing Features
  • Von Willebrand factor antigen or activity of 30-50 IU/dL places a patient in the low VWF category rather than BDUC, which requires normal levels.
  • The ISTH SSC panel uses repeat VWF testing below 80 IU/dL to avoid misassigning a patient with fluctuating levels to BDUC.
Show evidence (2 references)
PMID:36807819 SUPPORT Other
"low VWF represents an entity that appears to fall between type 1 VWD on the one hand and bleeding disorders of unknown cause on the other."
States the intermediate position of low VWF relative to this entry, which is why the boundary is curated explicitly.
PMID:38412996 SUPPORT Human Clinical
"we diagnose VWD based on VWF antigen and/or activity levels ≤50 IU/dL, with repeated VWF testing if VWF levels are <80 IU/dL"
Gives the operational cutoffs that separate this differential from BDUC.
Inherited platelet function disorder
Overlapping Features Excluded by repeated light transmission aggregometry, supplemented by flow cytometric mepacrine fluorescence and glycoprotein expression analysis. The exclusion is imperfect: aggregometry alterations are frequently unspecific and poorly reproducible, which is exactly the gap the occult platelet defect hypothesis occupies.
Distinguishing Features
  • Reproducible abnormalities on light transmission aggregometry define a platelet function defect; BDUC requires that aggregometry be normal.
Show evidence (1 reference)
PMID:38412996 SUPPORT Human Clinical
"PFDs are identified through repeated abnormalities in light transmission aggregometry (LTA), flow cytometric mepacrine fluorescence, and glycoprotein expression analysis."
Specifies the tests by which this differential is excluded.
Mild coagulation factor deficiency
Overlapping Features Mild reductions in factors VIII, IX and XI may cause bleeding despite normal prothrombin time, activated partial thromboplastin time and thrombin time, and factor XIII deficiency is invisible to all global screening assays. These are the deficiencies most likely to be missed and mislabeled as BDUC.
Distinguishing Features
  • Specific factor assays, not global screening tests, are required; a 50% cutoff is applied for factors VIII and IX.
  • Factor XIII must be assayed separately because global screening tests do not detect its deficiency.
Show evidence (1 reference)
PMID:42417170 SUPPORT Other
"CFD evaluation should extend beyond routine assays (prothrombin time, activated thromboplastin time, thrombin time), as clinically relevant mild reductions in factors VIII, IX, and XI may occur despite normal screening tests; and factor XIII deficiency is not detected by global assays."
States precisely why global screening tests are insufficient to exclude this differential.
Non-hemostatic and acquired causes of bleeding
Overlapping Features Structural, vascular, gynecological, drug-related and acquired causes must also be excluded before BDUC is assigned. This is the least operationalized part of the definition: the requirement is stated but the criteria and testing are not specified, so practice varies.
Show evidence (1 reference)
PMID:39687924 SUPPORT Other
"Importantly, other nonhemostatic and acquired causes of bleeding should be excluded, but details on exclusion criteria and associated diagnostic testing remain undefined."
Establishes both the requirement and its lack of operational definition.
{ }

Source YAML

click to show 
name: Bleeding Disorder of Unknown Cause
creation_date: "2026-08-05T00:00:00Z"
category: Hematologic Disease
disease_term:
  preferred_term: bleeding disorder of unknown cause
  term:
    id: MONDO:0002243
    label: hemorrhagic disease
description: >
  Bleeding disorder of unknown cause (BDUC) is the diagnosis assigned to a
  patient with an objectively increased mucocutaneous bleeding tendency in whom
  a rigorous hemostatic work-up returns entirely normal results. It is defined
  by exclusion rather than by a positive finding: von Willebrand disease,
  platelet function defects, coagulation factor deficiencies, and non-hemostatic
  causes of bleeding must all have been ruled out. It is not a rare curiosity —
  it is the single most frequent outcome of referral for a mild-to-moderate
  bleeding tendency, accounting for roughly half to three-quarters of such
  referrals, and the bleeding phenotype is as severe as in patients who do
  receive a named diagnosis. Up to 80% of cohorts are women, in whom heavy
  menstrual bleeding, iron deficiency, and postpartum hemorrhage dominate the
  clinical picture.

  This entry is curated deliberately as a mechanism-gap entry. There is no
  canonical pathophysiological chain for BDUC. What exists instead is a set of
  competing, individually under-powered candidate mechanisms — subclinical
  platelet dysfunction below the detection threshold of light transmission
  aggregometry, impaired thrombin generation, excess of natural anticoagulants
  such as free TFPI-alpha and activated protein C, altered fibrinolytic balance,
  and altered fibrin clot architecture — each supported by case-control cohort
  data, none established as causal, and several mutually inconsistent in the
  direction of their reported effect. The pathograph below models these as
  parallel arms converging on a shared final common node rather than forcing one
  to be primary, and the disagreements are recorded explicitly as
  `mechanistic_hypotheses` and `discussions` rather than silently averaged away.
synonyms:
- bleeding of unknown cause
- BUC
- BDUC
- unclassified bleeding disorder
- UBD
- unexplained bleeding tendency
- mild bleeding disorder of unknown cause
parents:
- Hemorrhagic disease
- Mild-to-moderate bleeding disorder

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0002243
      label: hemorrhagic disease
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO has no term for bleeding disorder of unknown cause. Searches of the
      MONDO label and synonym space for "bleeding disorder", "bleeding
      diathesis", "hemorrhagic diathesis", "unclassified bleeding", and "unknown
      cause" return only mechanism-specific or gene-specific entities (the
      platelet-type bleeding disorder series, factor V and thrombomodulin
      variants, vascular-type bleeding disorder) and no residual/unexplained
      category. MONDO:0002243 hemorrhagic disease, whose exact synonyms include
      "bleeding disorder" and "bleeding tendency", is therefore used as the
      closest available anchor and is a strict superclass, not an exact match:
      it also covers every entity that BDUC is defined by excluding. A MONDO new
      term request is warranted.

pathophysiology:
- name: Hemostatic Defect Below the Detection Threshold of Routine Testing
  biological_scale: MOLECULAR
  role: trigger
  description: >
    The definitional starting point of BDUC. The patient bleeds, but every assay
    in the recommended panel is normal. This node asserts only what the evidence
    supports: that a hemostatic abnormality exists which the available assays do
    not resolve, without committing to which limb of hemostasis is at fault. It
    is deliberately modeled as a trigger with several parallel, non-exclusive
    downstream arms rather than as a placeholder for one hidden defect, because
    the cohort data are most consistent with a multifactorial and heterogeneous
    origin.
  biological_processes:
  - preferred_term: hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To diagnose bleeding disorder of unknown cause (BDUC), normal complete
      blood count, prothrombin time, activated partial thromboplastin time,
      thrombin time, von Willebrand factor antigen, von Willebrand factor
      function, coagulation factors VIII, IX, and XI, and platelet light
      transmission aggregometry should be the minimum laboratory assessment.
    explanation: >-
      ISTH SSC consensus specifying the exact panel that must be normal, which is
      what makes this node a statement about assay resolution rather than about a
      known molecular lesion. Evidence source is OTHER because this is a
      standardization communication rather than primary data.
  - reference: PMID:29388750
    reference_title: "High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The high rate of patients with BUC despite in-depth haemostatic assessment
      underlines the incompleteness of available routine laboratory tests.
    explanation: >-
      The Vienna Bleeding Biobank authors' own conclusion that the residual
      category reflects assay incompleteness, which is the claim this node makes.
  - reference: PMID:33496735
    reference_title: "Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An imbalance of natural coagulation inhibitors such as TFPIα could be an
      underlying cause or contributor for unexplained bleeding, which is most
      probably multifactorial in a majority of patients.
    explanation: >-
      Supports modeling the trigger as multifactorial with parallel arms rather
      than as a single occult lesion.
  downstream:
  - target: Occult Platelet Function and Secretion Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - occult_platelet_defect
    description: >-
      Candidate arm in which the unresolved defect lies in platelet activation,
      granule secretion, or receptor signaling below the sensitivity of light
      transmission aggregometry.
  - target: Impaired Thrombin Generation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - impaired_thrombin_generation
    description: >-
      Candidate arm in which the unresolved defect manifests as reduced
      thrombin-generating capacity on global assays despite normal individual
      factor levels.
  - target: Natural Anticoagulant Excess
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - natural_anticoagulant_excess
    description: >-
      Candidate arm in which physiological inhibitors of coagulation are present
      in excess, damping thrombin generation without any factor deficiency.
  - target: Altered Fibrinolytic Balance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - altered_fibrinolysis
    description: >-
      Candidate arm in which a formed clot is lysed prematurely, or in which the
      fibrinolytic system is dysregulated in a direction that is not consistent
      across cohorts.
  - target: Altered Fibrin Clot Architecture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - altered_clot_structure
    description: >-
      Candidate arm in which fibrin network structure, rather than the amount of
      any component, determines clot mechanical stability.

- name: Occult Platelet Function and Secretion Defect
  biological_scale: CELLULAR
  description: >
    A platelet-intrinsic defect that routine light transmission aggregometry
    fails to resolve, or that it resolves only as an unspecific and
    poorly reproducible alteration. Two orthogonal lines of evidence point here:
    surface-receptor profiling shows that the immature (RNA-rich) platelet
    subpopulation carries a distinct and abnormal receptor phenotype while mature
    platelets appear normal, and platelet lipidomics shows intrinsic lipid shifts
    that track with impaired aggregation. Both are curated as leads rather than
    as established BDUC mechanisms: each was measured in patients selected for
    abnormal aggregometry, which is adjacent to, but formally outside, the BDUC
    definition.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: DECREASED
  - preferred_term: platelet degranulation
    term:
      id: GO:0002576
      label: platelet degranulation
    modifier: DECREASED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:38412996
    reference_title: "Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PFDs are identified through repeated abnormalities in light transmission
      aggregometry (LTA), flow cytometric mepacrine fluorescence, and
      glycoprotein expression analysis. Nevertheless, we experience diagnostic
      challenges with regard to reproducibility and unspecific alterations of
      LTA.
    explanation: >-
      Establishes that aggregometry has limited reproducibility and resolution,
      which is the premise of an occult platelet defect arm.
  - reference: PMID:40403972
    reference_title: "Impaired surface receptor expression on immature platelets in bleeding patients with abnormal light transmission aggregometry."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients, immature platelets expressed lower levels of CD62P, CD36,
      CD31, TLR2, and TLR4 but increased TLR9 expression, while mature platelets
      showed no differences.
    explanation: >-
      Identifies an abnormality confined to immature platelets that whole-platelet
      assays would average away. Graded INDIRECT because the cohort was selected
      for abnormal aggregometry (suspected platelet function defect), not for
      BDUC, so reaching this node takes a transfer step: it is a mechanistic lead
      for this arm rather than a direct BDUC finding.
  - reference: PMID:40702900
    reference_title: "Altered platelet lipidome in bleeding patients with unexplained platelet function defects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Baseline and stimulated platelet analyses in a female subgroup showed
      intrinsic lipidomic changes, including upregulated polyunsaturated
      triacylglycerols (PUFA-TG), acylcarnitines (CAR), and reduced
      lysophosphatidylethanolamines (LPE).
    explanation: >-
      Lipid-mediated platelet signaling as a candidate substrate for an occult
      defect. INDIRECT for the same cohort-selection reason as above.
  - reference: PMID:41348021
    reference_title: "Buckle up! Managing surgery in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The etiology of bleeding is postulated to be due to defects in platelet
      function, fibrinolysis, collagen integrity, and/or other coagulation
      defects not well measured in standard laboratory assays.
    explanation: >-
      Expert-review enumeration of the candidate arms modeled in this pathograph,
      naming platelet function first. Evidence source OTHER (educational review,
      not primary data).
  downstream:
  - target: Impaired Hemostatic Plug Formation and Clot Stability
    causal_link_type: DIRECT
    hypothesis_groups:
    - occult_platelet_defect
    description: >-
      Reduced platelet activation and secretion would weaken primary hemostatic
      plug formation at the site of vascular injury.

- name: Impaired Thrombin Generation
  biological_scale: MOLECULAR
  description: >
    Reduced thrombin-generating capacity on calibrated global assays despite
    normal individual coagulation factor activities. This is the most frequently
    replicated laboratory abnormality in BDUC: the Vienna Bleeding Biobank
    reported prolonged lag time and time to peak with reduced peak and velocity
    in 382 patients, and an independent automated assay reproduced the same
    pattern. It is nonetheless curated as HYPOTHETICAL rather than established,
    because an independent Rotterdam cohort found no meaningful thrombin
    generation difference, and because in every cohort the degree of impairment
    fails to track bleeding severity.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: DECREASED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:31177606
    reference_title: "Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombin generation was significantly impaired in BUC patients compared to
      healthy controls, exhibiting a prolonged lag time and time to peak and
      decreased maximum thrombin generation, velocity index, and area under the
      curve (AUC).
    explanation: >-
      Primary case-control evidence in 382 BUC patients versus 100 controls.
  - reference: PMID:42027303
    reference_title: "Impaired thrombin generation as a reproducible feature of bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study highlights the reproducibility of impaired TG in patients with
      BDUC.
    explanation: >-
      Independent replication with a fully automated assay at two tissue factor
      concentrations, which is what raises this arm above the others in support.
  - reference: PMID:32337845
    reference_title: "Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: A prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BUC patients demonstrated a significantly prolonged lag time in TG (median
      7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5
      minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM
      variables were found.
    explanation: >-
      An independent Rotterdam cohort that reproduces only the prolonged lag time
      and finds no thromboelastometry difference. It supports the arm only
      weakly, contradicts its magnitude, and its clot lysis result runs in the
      opposite direction to the Vienna finding.
  - reference: PMID:31747136
    reference_title: "Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TG revealed 26% patients with a long lag time and 19% with a decreased
      endogenous thrombin potential but no diagnostic pattern was seen.
    explanation: >-
      A third cohort in which thrombin generation abnormalities are present in a
      minority and do not form a diagnostic pattern, constraining how strongly
      this arm may be asserted.
  downstream:
  - target: Impaired Hemostatic Plug Formation and Clot Stability
    causal_link_type: DIRECT
    hypothesis_groups:
    - impaired_thrombin_generation
    description: >-
      Lower thrombin burst yields slower and less robust fibrin formation and
      less thrombin-dependent platelet and factor XIII activation.

- name: Natural Anticoagulant Excess
  biological_scale: MOLECULAR
  description: >
    An excess of physiological anticoagulants rather than a deficiency of
    procoagulants. Free tissue factor pathway inhibitor alpha is elevated above
    the 95th percentile disproportionately in the subgroup with no identifiable
    bleeding disorder, and activated protein C antigen is likewise raised, most
    markedly in BDUC. This arm is mechanistically attractive because it explains
    a normal factor panel together with a damped thrombin burst, and it supplies
    the only currently named druggable target in BDUC. Note that the related
    soluble thrombomodulin hypothesis was explicitly tested in the same cohort
    programme and refuted.
  biological_processes:
  - preferred_term: negative regulation of blood coagulation
    term:
      id: GO:0030195
      label: negative regulation of blood coagulation
    modifier: INCREASED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:33496735
    reference_title: "Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was pronounced in the subgroup of patients in whom no bleeding
      disorder could be identified (bleeding of unknown cause [BUC; n = 420]
    explanation: >-
      Locates the free TFPI-alpha excess specifically in the BUC subgroup rather
      than in mild bleeding disorders generally.
  - reference: PMID:33496735
    reference_title: "Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An increase in free TFPIα was associated with a mild delay in thrombin
      generation (prolonged lag time and time to peak), but not with alterations
      in routinely used global clotting tests.
    explanation: >-
      Supplies the mechanistic link from this node to the impaired thrombin
      generation node, and explains why routine clotting tests stay normal.
  - reference: PMID:32003946
    reference_title: "Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TFPI activity may be increased in a subset of UBD patients.
    explanation: >-
      Independent cohort confirming raised TFPI activity in a subset, supporting
      the subset framing used here.
  - reference: PMID:38324941
    reference_title: "Activated protein C and free protein S in patients with mild to moderate bleeding disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate increased antigen levels of APC in BDUC, which might
      contribute to the bleeding tendency in some patients and could be a future
      therapeutic target in BDUC.
    explanation: >-
      Extends the arm from TFPI to activated protein C and states the therapeutic
      implication.
  - reference: PMID:38324941
    reference_title: "Activated protein C and free protein S in patients with mild to moderate bleeding disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No differences in PS antigen levels between patients and HC were seen
      overall, or according to specific diagnoses.
    explanation: >-
      Bounds the arm: the protein S limb of the same pathway is not implicated,
      so this is not a general anticoagulant-pathway derangement.
  downstream:
  - target: Impaired Thrombin Generation
    causal_link_type: DIRECT
    hypothesis_groups:
    - natural_anticoagulant_excess
    description: >-
      Excess free TFPI-alpha inhibits the tissue factor/factor VIIa initiation
      complex and factor Xa, delaying and damping the thrombin burst; raised
      activated protein C degrades factors Va and VIIIa with the same net effect.

- name: Altered Fibrinolytic Balance
  biological_scale: MOLECULAR
  description: >
    Dysregulation of the plasminogen activation system, classically framed as
    accelerated clot breakdown. Support is real but internally inconsistent:
    tissue plasminogen activator activity is detectable far more often in
    patients than controls, a tPA-modified thromboelastometry assay classifies
    roughly a fifth of BDUC patients as hyperfibrinolytic, and adding
    fibrinolytic assays to the work-up raises diagnostic yield. Against that,
    direct plasmin generation measurement found reduced, not increased, peak
    plasmin, and whole-blood viscoelastometry in the largest cohort found reduced
    rather than enhanced lysis potential. The entry keeps this arm deliberately
    named for the balance rather than for hyperfibrinolysis, and the direction
    conflict is recorded as an explicit controversy.
  biological_processes:
  - preferred_term: fibrinolysis
    term:
      id: GO:0042730
      label: fibrinolysis
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:28018998
    reference_title: "Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that the fibrinolytic system can play an etiological role for
      bleeding in patients with BUC.
    explanation: >-
      Primary case-control study of 270 BUC patients concluding an etiological
      role for the fibrinolytic system.
  - reference: PMID:28018998
    reference_title: "Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tPA activity levels were more often above the detection limit in patients
      than in controls
    explanation: >-
      The specific quantitative finding underlying this arm. Note that the same
      study found alpha2-antiplasmin and TAFI higher, not lower, in patients, so
      a simple antiplasmin-deficiency model is not supported.
  - reference: PMID:40680469
    reference_title: "tPA-ROTEM identifies hyperfibrinolytic profile in a significant proportion of patients with bleeding disorder of unknown cause (BDUC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tPA-ROTEM identified a hyperfibrinolytic profile in 19/92 (21 %) of BDUC
      patients. Multivariable regression analysis showed that lower PAI-1 antigen
      levels were independently associated with hyperfibrinolysis.
    explanation: >-
      Quantifies the fraction of BDUC patients with a hyperfibrinolytic profile
      and identifies low PAI-1 as its correlate. This is the strongest direct
      support for the accelerated-lysis direction.
  - reference: PMID:39231312
    reference_title: "Plasmin generation analysis in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, patients with BDUC counterintuitively exhibited reduced peak
      plasmin levels, potentially related to altered clot structure.
    explanation: >-
      Direct measurement of plasmin generation finds the fibrinolytic system
      measurably abnormal in BDUC, which is what this node claims: the node is
      named for altered fibrinolytic balance rather than for hyperfibrinolysis.
      Paired with the REFUTE item below quoting the same sentence, because that
      sentence carries both directions.
  - reference: PMID:39231312
    reference_title: "Plasmin generation analysis in patients with bleeding disorder of unknown cause."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, patients with BDUC counterintuitively exhibited reduced peak
      plasmin levels, potentially related to altered clot structure.
    explanation: >-
      The same measurement runs opposite to the accelerated-lysis direction the
      arm is classically framed around: peak plasmin is reduced, not increased,
      and the authors redirect the explanation towards clot architecture. Split
      from the SUPPORT item above rather than collapsed, so the direction
      conflict this entry exists to preserve stays visible.
  - reference: PMID:35316940
    reference_title: "Fibrinolytic assays in bleeding of unknown cause: Improvement in diagnostic yield."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      General incorporation of fibrinolytic analysis in the diagnostic workup of
      patients with bleeding of unknown cause can improve diagnosis and
      management of their bleeding episodes.
    explanation: >-
      Supports the clinical relevance of the fibrinolytic arm by showing that
      testing for it reclassifies patients.
  downstream:
  - target: Impaired Hemostatic Plug Formation and Clot Stability
    causal_link_type: DIRECT
    hypothesis_groups:
    - altered_fibrinolysis
    description: >-
      Premature plasmin-mediated dissolution of a formed fibrin clot, or a
      dysregulated lysis profile, would shorten the durability of hemostasis and
      produce delayed rather than immediate bleeding.

- name: Altered Fibrin Clot Architecture
  biological_scale: MOLECULAR
  description: >
    A structural rather than quantitative model: the fibrin network in BDUC forms
    at a lower rate and with altered fiber morphology, and it is that
    architecture, not the concentration of any single component, that determines
    mechanical stability and susceptibility to lysis. Confocal microscopy shows a
    tendency to thicker fibers that correlates inversely with peak plasmin, and
    turbidimetric studies show a reduced rate of fibrin formation. The evidence
    here is mixed: the largest dedicated clot-properties study found the reduced
    formation rate but no difference in the remaining clot parameters.
  biological_processes:
  - preferred_term: blood coagulation, fibrin clot formation
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
    modifier: ABNORMAL
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:39231312
    reference_title: "Plasmin generation analysis in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Confocal microscopy analysis revealed a tendency towards thicker fibers in
      clots of patients with BDUC
    explanation: >-
      Direct structural imaging evidence for altered fibrin architecture in BDUC.
  - reference: PMID:25971840
    reference_title: "Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the fibrinolysis assay, Vmax was lower in patients than in healthy
      controls. No differences in the other parameters of clot formation and
      lysis were detected between the groups.
    explanation: >-
      Supports a reduced rate of fibrin formation while finding no broader clot
      property derangement, which bounds how widely this arm may be asserted.
  - reference: PMID:25909989
    reference_title: "Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased clot permeability and susceptibility to fibrinolysis are
      associated with HMB, suggesting that altered plasma fibrin clot properties
      might contribute to bleeding disorders of unknown origin.
    explanation: >-
      Links looser, more permeable clot structure to bleeding in the heavy
      menstrual bleeding subgroup. INDIRECT because the cohort is defined by
      unexplained heavy menstrual bleeding rather than by a formal BDUC
      diagnosis. Note its direction of lysis susceptibility is opposite to the
      plasmin generation and viscoelastometry findings above, which is the
      direction conflict this arm is named to preserve.
  downstream:
  - target: Impaired Hemostatic Plug Formation and Clot Stability
    causal_link_type: DIRECT
    hypothesis_groups:
    - altered_clot_structure
    description: >-
      A clot that forms more slowly and with altered fiber architecture is
      mechanically less stable at the injury site.

- name: Impaired Hemostatic Plug Formation and Clot Stability
  biological_scale: TISSUE
  description: >
    The shared convergence node. Whichever upstream arm is operative in a given
    patient, the common consequence is a hemostatic plug that forms too slowly,
    holds too weakly, or dissolves too early at sites of vascular injury,
    particularly at mucosal surfaces and surgical wounds where the hemostatic
    challenge is sustained. Whole-blood viscoelastometry in the largest BDUC
    cohort captures this as a globally altered clot formation and lysis profile
    that discriminates patients from controls.
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  biological_processes:
  - preferred_term: hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42004172
    reference_title: "Abnormal whole-blood viscoelastic test results in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nonactivated ROTEM revealed altered clot formation and fibrinolytic
      profiles in BDUC and could distinguish patients with BDUC from healthy
      individuals.
    explanation: >-
      Whole-blood evidence that the composite hemostatic process is measurably
      abnormal in BDUC even though its individual components test normal, which
      is exactly what this convergence node claims.
  - reference: PMID:31177606
    reference_title: "Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with BUC have an impaired hemostatic capacity reflected by a lower
      thrombin-generation potential, a lower clot formation rate, increased clot
      turbidity, and shorter clot lysis time, which might contribute to their
      increased bleeding tendency.
    explanation: >-
      States the composite impaired hemostatic capacity that this node
      represents, drawing together the thrombin generation, clot formation, and
      lysis arms.
  downstream:
  - target: Mucocutaneous and Post-Challenge Bleeding
    causal_link_type: DIRECT
    description: >-
      Failure of durable hemostasis at sites of minor and surgical vascular
      injury produces the clinical bleeding phenotype.

- name: Mucocutaneous and Post-Challenge Bleeding
  biological_scale: ORGANISM
  description: >
    The clinical phenotype: spontaneous mucocutaneous bleeding (epistaxis, easy
    bruising, gingival and oral bleeding, heavy menstrual bleeding) together with
    excessive bleeding after hemostatic challenges such as surgery, dental
    extraction, and childbirth. Its severity, as quantified by bleeding
    assessment tools, is indistinguishable from that of patients who do carry a
    named diagnosis such as von Willebrand disease or a platelet function defect
    — which is the central clinical argument that BDUC is a real bleeding
    phenotype rather than a labeling artifact of over-referral.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39687924
    reference_title: "Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mucocutaneous bleeding phenotype of individuals with BDUC is generally
      comparable to that of individuals with inherited bleeding disorders such as
      von Willebrand disease or platelet function disorders.
    explanation: >-
      Establishes the character and severity of the phenotype at this node.
      Evidence source OTHER because this is a narrative review.
  - reference: PMID:34398949
    reference_title: "How I treat bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Importantly, BAT scores suggest that patients with BDUC display bleeding
      phenotypes comparable to those seen in patients with VWD or PFD.
    explanation: >-
      Quantified phenotype equivalence to named bleeding disorders, from an
      expert How-I-Treat review.
  - reference: PMID:42417170
    reference_title: "How I Investigate Bleeding Disorders of Unknown Cause: Current Diagnostic Pathways and Gaps in Laboratory Investigation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Their clinical bleeding phenotype is characterized by mucocutaneous
      bleeding, as well as bleeding following surgical challenges or childbirth,
      and is associated with impaired health-related quality of life.
    explanation: >-
      Enumerates the two components of this node, spontaneous mucocutaneous
      bleeding and post-challenge bleeding, and links it downstream to quality of
      life.
  downstream:
  - target: Chronic Blood Loss and Iron Depletion
    causal_link_type: DIRECT
    description: >-
      Recurrent bleeding, dominated in this predominantly female population by
      heavy menstrual bleeding, causes cumulative iron loss.
  - target: Impaired Health-Related Quality of Life
    causal_link_type: DIRECT
    description: >-
      The bleeding phenotype, the associated uncertainty, and the long diagnostic
      delay together impair physical and mental health.

- name: Chronic Blood Loss and Iron Depletion
  biological_scale: ORGANISM
  description: >
    Cumulative iron loss from recurrent mucosal and menstrual bleeding, leading
    to iron deficiency with or without anemia. Curated with an explicit caveat:
    although iron deficiency is common in BDUC (39%), the rate was not
    significantly higher than in matched healthy controls in the one study that
    included a control arm, and female sex, younger age, and body mass index
    rather than the bleeding diagnosis were the associated factors. The node is
    therefore retained as a clinically important consequence to screen for, not
    as a BDUC-specific finding.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42417170
    reference_title: "How I Investigate Bleeding Disorders of Unknown Cause: Current Diagnostic Pathways and Gaps in Laboratory Investigation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Iron deficiency, with or without anemia, is common, particularly among
      women, who comprise up to 80% of BDUC cohorts and frequently report heavy
      menstrual bleeding.
    explanation: >-
      Establishes iron deficiency as a common consequence and ties it to the
      female predominance and heavy menstrual bleeding.
  - reference: PMID:40994886
    reference_title: "Prevalence of iron deficiency in patients with mild to moderate bleeding disorders and bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bleeding disorder of unknown cause: 39%; platelet function disorders: 33%;
      and coagulation factor deficiencies: 28%
    explanation: >-
      Quantifies iron deficiency in BDUC at 39%. Read with the caveat the same
      controlled analysis reports: this was not significantly different from the
      31% seen in matched healthy controls.

- name: Impaired Health-Related Quality of Life
  biological_scale: ORGANISM
  description: >
    Measured impairment of both physical and mental health-related quality of
    life relative to the general population, persisting after adjustment for age
    and sex. Notably, the impairment is not explained by bleeding severity, and
    is comparable to that of patients with named bleeding disorders — consistent
    with diagnostic uncertainty itself, and the long delay preceding it, being
    part of the burden.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:37720482
    reference_title: "Health-related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with BDUC (n = 207, 62%) had significantly impaired HrQoL both in
      physical (47.8 vs 49.2) and mental health parameters (42.9 vs 51.0)
      compared to the general population
    explanation: >-
      Quantified SF-36 impairment versus a general population comparator.
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Underlying BDUC should be considered in patients with heavy menstrual
      bleeding since delays in diagnosis often extend to many years and
      negatively impact quality of life.
    explanation: >-
      Attributes part of the quality-of-life burden to diagnostic delay rather
      than to bleeding alone.

mechanistic_hypotheses:
- hypothesis_group_id: occult_platelet_defect
  hypothesis_label: Occult platelet function or secretion defect below assay resolution
  status: EMERGING
  description: >
    Bleeding is caused by a platelet activation, secretion, or receptor-signaling
    defect that light transmission aggregometry cannot resolve. Supported
    indirectly by the acknowledged reproducibility limits of aggregometry and
    directly by immature-platelet receptor profiling and platelet lipidomics —
    both of which, importantly, were performed in patients with abnormal
    aggregometry rather than in formally defined BDUC, so their transfer to BDUC
    is assumed rather than shown.
  evidence:
  - reference: PMID:41348021
    reference_title: "Buckle up! Managing surgery in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The etiology of bleeding is postulated to be due to defects in platelet
      function, fibrinolysis, collagen integrity, and/or other coagulation
      defects not well measured in standard laboratory assays.
    explanation: >-
      Expert review naming platelet function as one of the postulated etiologies,
      and framing all of them as postulated rather than demonstrated.

- hypothesis_group_id: impaired_thrombin_generation
  hypothesis_label: Reduced thrombin-generating capacity on global assays
  status: EMERGING
  description: >
    Bleeding is caused by a globally reduced thrombin burst despite normal
    individual factor activities. This is the most replicated of the candidate
    mechanisms — demonstrated in 382 patients in Vienna and independently
    reproduced on an automated platform — which is why it is the strongest arm in
    this entry. It is nonetheless EMERGING rather than CANONICAL for two
    reasons: an independent Rotterdam cohort found no meaningful thrombin
    generation difference, and in every cohort including the replication study,
    thrombin generation parameters fail to correlate with bleeding score.
  evidence:
  - reference: PMID:42027303
    reference_title: "Impaired thrombin generation as a reproducible feature of bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given that BDUC pathophysiology remains largely unknown, these findings
      suggest impaired TG may represent a common underlying feature of BDUC
    explanation: >-
      The strongest available statement for this hypothesis, phrased by its own
      authors as a suggestion within an acknowledged unknown pathophysiology.
  - reference: PMID:31177606
    reference_title: "Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bleeding severity did not correlate with parameters of thrombin generation,
      clot formation, or clot lysis.
    explanation: >-
      The dose-response failure in the largest cohort supporting this hypothesis:
      the abnormality is present but its magnitude does not track the phenotype,
      which is the principal reason this hypothesis is not promoted to CANONICAL.

- hypothesis_group_id: natural_anticoagulant_excess
  hypothesis_label: Excess of natural anticoagulants (free TFPI-alpha, activated protein C)
  status: EMERGING
  description: >
    Bleeding is caused by an excess of physiological anticoagulants rather than
    by any procoagulant deficiency. Free TFPI-alpha above the 95th percentile is
    over-represented specifically in the unexplained-bleeding subgroup, TFPI
    activity is raised in a subset of an independent unclassified-bleeding
    cohort, and activated protein C antigen is highest in BDUC. Attractive
    because it reconciles a normal factor panel with a damped thrombin burst, and
    because it is the only candidate arm whose authors have proposed a concrete
    therapeutic target.
  evidence:
  - reference: PMID:38454298
    reference_title: "How to investigate mild to moderate bleeding disorders and bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with BDUC, further evaluation may include non-routine testing
      to look for rare bleeding disorders not detected by routine hemostasis
      tests, such as thrombomodulin-associated coagulopathy, tissue factor
      pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding
      disorders or impaired tissue factor production.
    explanation: >-
      Places TFPI-related bleeding among the recognized non-routine entities to
      test for in BDUC.

- hypothesis_group_id: altered_fibrinolysis
  hypothesis_label: Altered fibrinolytic balance with premature clot lysis
  status: EMERGING
  description: >
    Bleeding is caused by dysregulated plasminogen activation, classically
    premature clot lysis. This is the arm with the most direct therapeutic
    corollary, since tranexamic acid is the mainstay of BDUC management, and a
    tPA-modified thromboelastometry assay identifies a hyperfibrinolytic profile
    in about 21% of patients. It is kept EMERGING and deliberately named for
    "balance" rather than "hyperfibrinolysis" because the direction of effect is
    not consistent: direct plasmin generation measurement found reduced peak
    plasmin, and whole-blood viscoelastometry in 464 patients found reduced
    lysis potential. See the `bduc_fibrinolysis_direction_conflict` discussion.

- hypothesis_group_id: altered_clot_structure
  hypothesis_label: Altered fibrin clot architecture determining mechanical stability
  status: EMERGING
  description: >
    Bleeding is caused by the structure of the fibrin network rather than by the
    quantity of any component: thicker fibers, a slower rate of protofibril
    formation, and increased permeability yield a clot that is mechanically
    inadequate. Proposed by the plasmin generation study as the explanation for
    its own counterintuitive result, and partially supported by turbidimetric and
    permeability data. Bounded by the largest dedicated clot-properties study,
    which found only the reduced formation rate and no other difference.

- hypothesis_group_id: undetected_monogenic_cause
  hypothesis_label: Undetected monogenic hemostatic defect
  status: ALTERNATIVE
  description: >
    BDUC is a temporary label that sequencing will progressively dissolve into
    named monogenic disorders. Retained as a genuine ALTERNATIVE because it is
    the implicit expectation behind most genetic work in this field, but the
    yield data argue strongly against it as a general explanation: a targeted
    high-throughput panel across 2396 patients achieved 49.2% diagnostic yield
    overall and only 3.2% in patients with unexplained bleeding and normal
    hemostasis testing, and an independent unclassified-bleeding cohort had
    entirely normal panel results in all 45 patients tested.
  evidence:
  - reference: PMID:31064749
    reference_title: "Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The molecular diagnostic rate was determined by the clinical phenotype,
      with an overall rate of 49.2% for all thrombotic, coagulation, platelet
      count, and function disorder patients and a rate of 3.2% for patients with
      unexplained bleeding disorders characterized by normal hemostasis test
      results.
    explanation: >-
      The decisive yield comparison: a monogenic cause is found in a small
      minority, so this hypothesis can explain only a fraction of BDUC, which is
      why it is not promoted beyond ALTERNATIVE.
  - reference: PMID:31747136
    reference_title: "Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ThromboGenomics was normal in 45 tested patients.
    explanation: >-
      A completely negative panel result in an independent unclassified-bleeding
      cohort, refuting a general monogenic explanation.
  - reference: PMID:33094877
    reference_title: "Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thus far, detailed genetic analysis of these patients has not been fruitful
      in unravelling the cause of bleeding.
    explanation: >-
      Review-level summary of the low genetic yield, while leaving the hypothesis
      open for a subset.
  - reference: PMID:42320587
    reference_title: "Beyond Conventional Hemostasis Testing: The Diagnostic Impact of Genetic Analysis in inherited Mild Bleeding Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In BDUC, genetic testing has revealed monogenic causes in some patients and
      multifactorial contributions in others.
    explanation: >-
      Contemporary review position: monogenic in some, multifactorial in others,
      which is exactly the ALTERNATIVE-status framing used here.

- hypothesis_group_id: soluble_thrombomodulin_excess
  hypothesis_label: Soluble thrombomodulin excess as a cause of unexplained bleeding
  status: DEPRECATED
  description: >
    A specific and testable proposal, derived from families with THBD variants
    causing massively raised soluble thrombomodulin, that the same mechanism
    underlies unexplained mild bleeding more broadly. It is curated here
    precisely because it was tested and failed: in 507 patients with mild
    bleeding disorders including BUC, soluble thrombomodulin levels, their
    distribution, their relationship to bleeding severity, and THBD sequencing
    were all unremarkable. Retained as DEPRECATED rather than deleted so that
    the negative result is visible and the hypothesis is not silently re-proposed.
  evidence:
  - reference: PMID:34628704
    reference_title: "Thrombomodulin in patients with mild to moderate bleeding tendency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No difference in sTM levels between patients and controls was found overall
    explanation: >-
      The primary negative finding in 507 patients versus 90 controls.
  - reference: PMID:34628704
    reference_title: "Thrombomodulin in patients with mild to moderate bleeding tendency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TM-associated coagulopathy appears to be rare, as it was not identified in
      our large cohort of patients with MBD. Soluble TM did not arise as a risk
      factor for bleeding or altered haemostasis in these patients.
    explanation: >-
      The authors' explicit conclusion that this mechanism does not explain the
      cohort, which is the basis for the DEPRECATED status.

phenotypes:
- category: Clinical
  name: Increased Mucocutaneous Bleeding Tendency
  description: >
    The defining phenotype: an objectively increased bleeding tendency, assessed
    with a standardized bleeding assessment tool, in the presence of entirely
    normal hemostatic investigations.
  phenotype_term:
    preferred_term: Increased bleeding tendency
    term:
      id: HP:0001892
      label: Abnormal bleeding
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:39687924
    reference_title: "Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      BDUC is a diagnosis of exclusion, characterized by normal hemostatic
      investigations despite a clinically significant bleeding tendency.
    explanation: >-
      The ISTH SSC definition as restated in review, establishing this phenotype
      as obligate and diagnostic.

- category: Clinical
  name: Heavy Menstrual Bleeding
  description: >
    A leading presenting symptom in the predominantly female BDUC population,
    and the presentation most often responsible for years of diagnostic delay
    before referral to a hemostasis service. No published cohort reports the
    proportion of BDUC patients affected, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  # frequency intentionally omitted: no source reports the proportion of BDUC
  # patients with heavy menstrual bleeding. "Up to 80% of BDUC cohorts" is the
  # female fraction of the cohort, not the fraction with menorrhagia, and
  # "frequently report" is unquantified. See docs/frequency-evidence-guidelines.md.
  evidence:
  - reference: PMID:42417170
    reference_title: "How I Investigate Bleeding Disorders of Unknown Cause: Current Diagnostic Pathways and Gaps in Laboratory Investigation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Iron deficiency, with or without anemia, is common, particularly among
      women, who comprise up to 80% of BDUC cohorts and frequently report heavy
      menstrual bleeding.
    explanation: >-
      Supports the disease-phenotype association and the female predominance of
      BDUC cohorts. The 80% figure is the proportion of the cohort that is
      female, not the proportion with heavy menstrual bleeding, so it carries no
      frequency band.
  - reference: PMID:41347990
    reference_title: "Predictors for future bleeding in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently available data suggest that a substantial portion of BDUC
      patients continue to experience spontaneous bleeding symptoms, such as easy
      bruising, epistaxis, and heavy menstrual bleeding.
    explanation: >-
      Confirms persistence of heavy menstrual bleeding, easy bruising and
      epistaxis as the leading spontaneous symptoms during follow-up.

- category: Clinical
  name: Epistaxis
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  # frequency intentionally omitted: the only quantitative source (PMID:36924834)
  # reports persistence among patients who already had the symptom (denominator
  # 132), not the proportion of the 392-patient cohort affected.
  evidence:
  - reference: PMID:36924834
    reference_title: "Risk factors for future bleeding in patients with mild bleeding disorders: longitudinal data from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most persistent bleeding manifestations were hematomas (n = 146/245, 59.6%)
      and bleeding from small wounds (n = 69/141, 48.9%), followed by epistaxis
      (n = 42/132, 31.8%), oral mucosal bleeding (n = 26/87, 29.9%), and joint
      bleeding (n = 7/14, 50.0%).
    explanation: >-
      Establishes epistaxis as a recorded bleeding manifestation in a cohort that
      was 62.8% BDUC. The 31.8% is 42/132 — persistence at follow-up among
      patients who already had epistaxis at baseline — so it is not a cohort
      prevalence and supports no frequency band.

- category: Clinical
  name: Easy Bruising and Spontaneous Hematoma
  description: >
    Hematomas were the most frequently persisting bleeding manifestation on
    prospective follow-up of the Vienna cohort.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  # frequency intentionally omitted: 59.6% is 146/245 persistence among patients
  # who already had hematomas, not the fraction of the 392-patient cohort. It
  # would in any case fall in FREQUENT (30-79%), not VERY_FREQUENT.
  evidence:
  - reference: PMID:36924834
    reference_title: "Risk factors for future bleeding in patients with mild bleeding disorders: longitudinal data from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most persistent bleeding manifestations were hematomas (n = 146/245, 59.6%)
      and bleeding from small wounds (n = 69/141, 48.9%)
    explanation: >-
      Hematomas were the most frequently persisting manifestation on prospective
      follow-up (146/245 of those affected at baseline). This is a persistence
      rate, not a cohort prevalence, so it supports the disease-phenotype
      association only and no frequency band.

- category: Clinical
  name: Oral and Gingival Bleeding
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  # frequency intentionally omitted: 29.9% is 26/87 persistence among patients
  # who already had oral mucosal bleeding, not the fraction of the 392-patient
  # cohort. It would in any case fall in OCCASIONAL (5-29%), not FREQUENT.
  evidence:
  - reference: PMID:36924834
    reference_title: "Risk factors for future bleeding in patients with mild bleeding disorders: longitudinal data from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oral mucosal bleeding (n = 26/87, 29.9%)
    explanation: >-
      Records oral mucosal bleeding as a persisting manifestation in 26/87 of the
      patients who had it at baseline. This is a persistence rate, not a cohort
      prevalence, so it supports the disease-phenotype association only and no
      frequency band.

- category: Clinical
  name: Prolonged Bleeding After Surgery
  description: >
    Post-procedural bleeding is one of the two hemostatic-challenge phenotypes
    that dominate management, and prior post-interventional bleeding is itself
    the strongest predictor of future post-interventional bleeding.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  frequency: FREQUENT
  evidence:
  - reference: PMID:41348021
    reference_title: "Buckle up! Managing surgery in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In previously described cohorts of patients with BDUC, a history of
      postoperative bleeding is common, reported in 44% to 75% of patients.
    explanation: >-
      Direct frequency evidence (44-75%) for post-surgical bleeding in BDUC
      cohorts, supporting the FREQUENT band.
  - reference: PMID:33853179
    reference_title: "Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 14/72 (19%) surgical procedures major bleeding occurred and 14/41 (34%)
      deliveries were complicated by major postpartum hemorrhage (PPH).
    explanation: >-
      Prospectively collected per-procedure major bleeding rate following a BUC
      diagnosis.

- category: Clinical
  name: Prolonged Bleeding After Dental Extraction
  phenotype_term:
    preferred_term: Prolonged bleeding after dental extraction
    term:
      id: HP:0006298
      label: Prolonged bleeding after dental extraction
  frequency: FREQUENT
  evidence:
  - reference: PMID:41006857
    reference_title: "Dental surgery for patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The incidence of bleeding in patients with BDUC following dental surgery
      can range from 36–84%.
    explanation: >-
      Reported incidence range of 36-84% after dental surgery. The range straddles
      the FREQUENT/VERY_FREQUENT boundary (80%), so the conservative lower band
      FREQUENT (30-79%) is used.

- category: Clinical
  name: Postpartum Hemorrhage
  description: >
    The highest-consequence phenotype in BDUC. Postpartum hemorrhage complicates
    roughly a quarter to a third of deliveries, occurs despite prophylaxis, and
    is the management problem most consistently identified as unmet.
  phenotype_term:
    preferred_term: Post-partum hemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  frequency: FREQUENT
  evidence:
  - reference: PMID:39498237
    reference_title: "Periprocedural hemostatic prophylaxis and outcomes in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postpartum hemorrhage occurred in 26% (5/19) of deliveries.
    explanation: >-
      Per-delivery postpartum hemorrhage rate in a two-center BDUC cohort. The
      denominator is deliveries, not patients, and 26% sits just below the
      FREQUENT band; the band is carried by the larger 41-delivery cohort below
      (34%), with this figure recorded as the concordant lower estimate.
  - reference: PMID:33853179
    reference_title: "Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      14/41 (34%) deliveries were complicated by major postpartum hemorrhage
      (PPH)
    explanation: >-
      Independent cohort giving a 34% major postpartum hemorrhage rate
      (14/41 deliveries), which falls in the FREQUENT band (30-79%) and is the
      quantitative basis for the band on this phenotype.

- category: Clinical
  name: Iron Deficiency Anemia
  description: >
    Iron deficiency is present in about 39% of BDUC patients, but was not
    significantly more frequent than in matched healthy controls, so it is
    curated as a clinically important comorbidity to screen for rather than as a
    BDUC-discriminating feature.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40994886
    reference_title: "Prevalence of iron deficiency in patients with mild to moderate bleeding disorders and bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      250 patients with MBD (39%) had ID and 40 (6%) had IDA
    explanation: >-
      Iron deficiency anemia in 6% of the mild bleeding disorder cohort, which is
      the basis for the OCCASIONAL band; iron deficiency without anemia is far
      more common at 39%.

- category: Clinical
  name: Joint Bleeding
  description: >
    Recorded in only a small minority of the Vienna cohort at baseline (14
    patients), but notable because joint bleeding was the only bleeding symptom
    associated with impaired physical quality of life in BDUC.
  phenotype_term:
    preferred_term: Joint hemorrhage
    term:
      id: HP:0005261
      label: Joint hemorrhage
  # frequency intentionally omitted: the cited evidence is a quality-of-life
  # association and gives no frequency figure. PMID:36924834 records joint
  # bleeding in only 14 patients at baseline, again as a persistence denominator
  # rather than a cohort prevalence.
  evidence:
  - reference: PMID:37720482
    reference_title: "Health-related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of all analyzed bleeding symptoms, only joint bleeding was associated with
      impaired physical health and gastrointestinal bleeding with mental health
      in BDUC.
    explanation: >-
      Documents joint bleeding as an analyzed symptom in the BDUC cohort and its
      specific association with impaired physical health.

prevalence:
- population: >-
    Patients referred to a tertiary hemostasis service for a mild-to-moderate
    bleeding tendency (Vienna Bleeding Biobank, Austria)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    72.5% of 418 consecutively investigated patients (303/418). This is a
    diagnostic-yield fraction within a referral population, NOT a
    general-population prevalence, which is unknown. It is recorded here because
    the referral fraction is the only occurrence measure the literature reports
    for BDUC. measure_type and prevalence_class are deliberately UNKNOWN and
    rate_per_100000 is deliberately omitted: emitting 72500 per 100,000 as a
    structured rate would be read as a population prevalence in any cross-disease
    comparison or export.
  evidence:
  - reference: PMID:29388750
    reference_title: "High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three hundred three patients (72.5%) had normal results in the coagulation
      assays and were categorized as patients with bleeding of unknown cause
      (BUC).
    explanation: >-
      Source for the referral-cohort fraction.

- population: Patients referred to hemostasis experts for a clinically relevant bleeding tendency (international)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    "More than half" of referrals, as summarized across cohorts; individual
    cohorts range from about half to three-quarters. A referral diagnostic-yield
    fraction, not a population prevalence, so no structured rate or prevalence
    class is asserted.
  evidence:
  - reference: PMID:39687924
    reference_title: "Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In more than half of the individuals with a clinically relevant bleeding
      tendency who are referred to hemostasis experts, no biological etiology can
      be found after extensive laboratory testing.
    explanation: >-
      Cross-cohort summary of the referral fraction.

- population: >-
    Patients referred for assessment of a possible bleeding tendency
    (complement of the mild-bleeding-disorder diagnostic yield)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Derived as the complement of the 30% of referrals who receive a named mild
    bleeding disorder diagnosis. Recorded separately from the Vienna figure
    because it is an independent estimate. A referral diagnostic-yield fraction,
    not a population prevalence, so no structured rate or prevalence class is
    asserted.
  evidence:
  - reference: PMID:34398949
    reference_title: "How I treat bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent studies have demonstrated that only 30% of patients referred for
      assessment of a possible bleeding tendency will eventually be diagnosed
      with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or
      platelet function defect (PFD). Rather, most of these patients will be
      diagnosed with bleeding disorder of unknown cause (BDUC).
    explanation: >-
      Source for the complementary 30% named-diagnosis yield.

progression:
- phase: Long-term follow-up after diagnosis
  duration: median 4.3 years (IQR 2.6-6.7)
  notes: >-
    BDUC is persistent rather than self-limiting. In prospective follow-up of a
    cohort that was 62.8% BDUC, 72% of patients experienced at least one further
    bleeding event, and prior post-interventional bleeding predicted recurrence
    after surgery and tooth extraction.
  evidence:
  - reference: PMID:36924834
    reference_title: "Risk factors for future bleeding in patients with mild bleeding disorders: longitudinal data from the Vienna Bleeding Biobank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the follow-up time of median (IQR) 4.3 years (2.6-6.7), 72% of
      patients had at least 1 bleeding event.
    explanation: >-
      Prospective recurrence rate over the stated follow-up period.
  - reference: PMID:41347990
    reference_title: "Predictors for future bleeding in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although BDUC remains a diagnosis of exclusion, accumulating data
      underscore the need to recognize it as a potentially persistent clinically
      relevant condition.
    explanation: >-
      Supports the persistence framing of this progression phase.
  - reference: PMID:41347990
    reference_title: "Predictors for future bleeding in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with prior bleeding complications after such events, patients with
      blood group O, and patients who did not receive hemostatic prophylaxis
      demonstrate an increased risk for postinterventional bleeding during
      follow-up.
    explanation: >-
      Identifies the risk factors for recurrence during follow-up.

biochemical:
- name: Thrombin Generation (Endogenous Thrombin Potential)
  presence: >-
    Impaired: prolonged lag time and time to peak with reduced peak, velocity
    index and area under the curve, on a normal routine coagulation panel
  context: >-
    The most frequently replicated laboratory abnormality in BDUC, and the
    marker on which the leading mechanistic arm rests. Reproducibility is
    genuinely contested rather than merely unreplicated: two Vienna-linked
    cohorts find the full pattern, an independent Rotterdam cohort reproduces
    only the prolonged lag time, and a third cohort finds abnormalities in a
    minority with no diagnostic pattern.
  specificity: >-
    Not diagnostic. Group-level separation from controls does not translate into
    a per-patient discriminator, and the degree of impairment does not track
    bleeding severity in any cohort.
  biomarker_term:
    preferred_term: Thrombin generation (endogenous thrombin potential)
    term:
      id: NCIT:C102266
      label: Endogenous Thrombin Potential Measurement
  readouts:
  - target: Impaired Thrombin Generation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Calibrated thrombin generation is the direct assay readout of this
      mechanism node; lower thrombin-generating capacity corresponds to the
      hypothesized defect.
  notes: >-
    Global assay, not part of the ISTH minimum exclusion panel; see the
    Non-Routine and Global Hemostatic Testing diagnosis entry.
  evidence:
  - reference: PMID:31177606
    reference_title: "Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombin generation was significantly impaired in BUC patients compared to
      healthy controls, exhibiting a prolonged lag time and time to peak and
      decreased maximum thrombin generation, velocity index, and area under the
      curve (AUC).
    explanation: >-
      Primary case-control evidence in 382 BUC patients versus 100 controls,
      naming the specific parameters that are deranged.
  - reference: PMID:42027303
    reference_title: "Impaired thrombin generation as a reproducible feature of bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study highlights the reproducibility of impaired TG in patients with
      BDUC.
    explanation: >-
      Independent replication with a fully automated assay.
  - reference: PMID:31747136
    reference_title: "Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TG revealed 26% patients with a long lag time and 19% with a decreased
      endogenous thrombin potential but no diagnostic pattern was seen.
    explanation: >-
      Quantifies how often the marker is abnormal in an unselected cohort and is
      the basis for the specificity caveat recorded above.

- name: Free Tissue Factor Pathway Inhibitor Alpha
  presence: >-
    Elevated above the 95th percentile, disproportionately in the subgroup with
    no identifiable bleeding disorder
  context: >-
    The best-localized biomarker in BDUC, because the excess is reported
    specifically in the unexplained-bleeding subgroup rather than across mild
    bleeding disorders generally, and because it is mechanistically tied to the
    thrombin generation defect in the same study.
  specificity: >-
    Subset marker. Raised TFPI activity is reported in a subset of patients, not
    the whole population, so it partitions BDUC rather than defining it.
  biomarker_term:
    preferred_term: Free tissue factor pathway inhibitor alpha antigen
    term:
      id: NCIT:C202391
      label: Free Tissue Factor Pathway Inhibitor Antigen Measurement
  readouts:
  - target: Natural Anticoagulant Excess
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Free TFPI-alpha is the primary measured quantity behind the natural
      anticoagulant excess arm.
  - target: Impaired Thrombin Generation
    relationship: CORRELATES_WITH
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Higher free TFPI-alpha is associated with a delayed thrombin burst while
      routine global clotting tests stay normal, which is the observational link
      between the two mechanism nodes.
    evidence:
    - reference: PMID:33496735
      reference_title: "Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An increase in free TFPIα was associated with a mild delay in thrombin
        generation (prolonged lag time and time to peak), but not with alterations
        in routinely used global clotting tests.
      explanation: >-
        States the association between the marker and the thrombin generation
        readout directly.
  evidence:
  - reference: PMID:33496735
    reference_title: "Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was pronounced in the subgroup of patients in whom no bleeding
      disorder could be identified (bleeding of unknown cause [BUC; n = 420]
    explanation: >-
      Locates the elevation specifically in the BUC subgroup.
  - reference: PMID:32003946
    reference_title: "Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TFPI activity may be increased in a subset of UBD patients.
    explanation: >-
      Independent cohort confirming the finding and supporting the subset
      framing used in the specificity field.

- name: Activated Protein C Antigen
  presence: Increased antigen levels in BDUC
  context: >-
    Extends the natural-anticoagulant arm beyond TFPI, and is the finding its
    authors nominate as a future therapeutic target in BDUC.
  specificity: >-
    Bounded to the activated protein C limb. In the same study protein S antigen
    showed no difference between patients and healthy controls overall or by
    diagnosis, so this is not a general derangement of the protein C/S pathway.
  biomarker_term:
    preferred_term: Activated protein C antigen
    term:
      id: NCIT:C102272
      label: Factor XIV Measurement
  readouts:
  - target: Natural Anticoagulant Excess
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Raised activated protein C degrades factors Va and VIIIa, giving the same
      net anticoagulant excess as the TFPI limb.
  notes: >-
    Bound to the NCIT protein C measurement term (Factor XIV is the protein C
    synonym used by NCIT); NCIT has no separate activated-protein-C antigen
    measurement term, so preferred_term carries the added specificity.
  evidence:
  - reference: PMID:38324941
    reference_title: "Activated protein C and free protein S in patients with mild to moderate bleeding disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate increased antigen levels of APC in BDUC, which might
      contribute to the bleeding tendency in some patients and could be a future
      therapeutic target in BDUC.
    explanation: >-
      Primary evidence for the elevation and for the therapeutic-target framing.
  - reference: PMID:38324941
    reference_title: "Activated protein C and free protein S in patients with mild to moderate bleeding disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No differences in PS antigen levels between patients and HC were seen
      overall, or according to specific diagnoses.
    explanation: >-
      The negative protein S result that bounds the claim, recorded here so the
      marker is not read as a whole-pathway abnormality.

- name: Plasma Clot Lysis Time
  presence: >-
    Prolonged relative to controls in the Rotterdam cohort, which is the
    opposite direction to the accelerated-lysis model
  context: >-
    The clearest example in BDUC of a biomarker whose measured direction
    contradicts the mechanism it is usually invoked for. Curated so the conflict
    is visible rather than resolved by selective citation.
  specificity: >-
    Direction-conflicted. A prolonged lysis time indicates slower, not faster,
    clot breakdown, so this result argues against hyperfibrinolysis as the
    general BDUC mechanism even though fibrinolytic testing improves diagnostic
    yield in other cohorts.
  readouts:
  - target: Altered Fibrinolytic Balance
    relationship: READOUT_OF
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reports on the fibrinolytic arm, but in the direction opposite to the
      accelerated-lysis reading of that node. Direction is deliberately left
      unset because the cohorts disagree on sign.
  notes: >-
    biomarker_term deliberately omitted: the cited study uses a turbidimetric
    plasma clot lysis assay, and the only NCIT clot-lysis-time term
    (NCIT:C187805) is specific to the euglobulin method, which is a different
    assay.
  evidence:
  - reference: PMID:32337845
    reference_title: "Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: A prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BUC patients demonstrated a significantly prolonged lag time in TG (median
      7.7 minutes, IQR 6.7-8.7) and a significantly prolonged CLT (median 60.5
      minutes, IQR 54.7-66.1) compared to controls. No differences in ROTEM
      variables were found.
    explanation: >-
      Source for both the prolonged clot lysis time and its median/IQR.

- name: Plasmin Generation (Peak Plasmin)
  presence: Reduced peak plasmin, counter to the hyperfibrinolysis model
  context: >-
    Direct measurement of plasmin generation, as opposed to inference from lysis
    assays. Its authors redirect the explanation towards clot architecture
    rather than accelerated lysis, which is why the entry carries a separate
    Altered Fibrin Clot Architecture node.
  specificity: >-
    Mechanistically informative rather than diagnostic; no threshold or
    per-patient discrimination has been reported.
  readouts:
  - target: Altered Fibrinolytic Balance
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Directly measures the plasminogen activation output of this node and finds
      it reduced, which is the principal evidence against naming the node
      hyperfibrinolysis.
  - target: Altered Fibrin Clot Architecture
    relationship: CORRELATES_WITH
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The authors attribute the reduced peak plasmin to altered clot structure,
      linking this marker to the clot architecture arm.
  notes: >-
    biomarker_term deliberately omitted: NCIT has plasminogen and
    plasmin/alpha-2-antiplasmin complex measurement terms but none for peak
    plasmin from a plasmin generation assay.
  evidence:
  - reference: PMID:39231312
    reference_title: "Plasmin generation analysis in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, patients with BDUC counterintuitively exhibited reduced peak
      plasmin levels, potentially related to altered clot structure.
    explanation: >-
      Source for both the direction of the finding and the clot-architecture
      attribution.

diagnosis:
- name: Objective Bleeding Phenotype Quantification (ISTH-BAT)
  description: >
    A standardized bleeding assessment tool score is the mandated first step,
    because in a diagnosis of exclusion the phenotype is the only positive
    finding. Its limitation must be stated alongside it: bleeding assessment
    tools quantify severity well but discriminate poorly between BDUC and named
    bleeding disorders, so a high score establishes that bleeding is real, not
    what is causing it.
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We recommend that bleeding history in these patients should be objectively
      assessed using the International Society on Thrombosis and Haemostasis
      (ISTH) bleeding assessment tool.
    explanation: >-
      ISTH SSC recommendation establishing the ISTH-BAT as the required first
      step.
  - reference: PMID:32317240
    reference_title: "The discriminatory power of bleeding assessment tools in adult patients with a mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Vicenza- and the ISTH BAT have a low ability to distinguish patients
      with an established bleeding disorder from those with BUC.
    explanation: >-
      Bounds the tool's role: it is required, but it does not discriminate BDUC
      from an established bleeding disorder.

- name: Minimum Exclusion Panel of Hemostatic Laboratory Tests
  description: >
    The ISTH SSC minimum panel that must all be normal before BDUC may be
    assigned: complete blood count, prothrombin time, activated partial
    thromboplastin time, thrombin time, von Willebrand factor antigen and
    function, factors VIII, IX and XI, and platelet light transmission
    aggregometry. Non-hemostatic and acquired causes must also be excluded,
    although exactly which and by what testing is not specified.
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We recommend that patients with a significant bleeding phenotype but normal
      laboratory investigations should be registered with a diagnosis of BDUC in
      preference to other terminology.
    explanation: >-
      Establishes both the diagnostic rule and the preferred terminology.
  - reference: PMID:39687924
    reference_title: "Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Importantly, other nonhemostatic and acquired causes of bleeding should be
      excluded, but details on exclusion criteria and associated diagnostic
      testing remain undefined.
    explanation: >-
      Records that the non-hemostatic half of the exclusion is not operationalized,
      which is a live gap in the diagnostic definition.

- name: Non-Routine and Global Hemostatic Testing
  description: >
    Optional second-tier testing for rare mechanisms — thrombomodulin-associated
    coagulopathy, TFPI-related bleeding, hyperfibrinolytic disorders, impaired
    tissue factor production — plus global assays (thrombin generation,
    thromboelastometry, clot lysis). These are research or specialist tools, not
    diagnostic criteria: the ISTH SSC states explicitly that their abnormalities
    are variable and of uncertain clinical significance.
  evidence:
  - reference: PMID:38454298
    reference_title: "How to investigate mild to moderate bleeding disorders and bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with BDUC, further evaluation may include non-routine testing
      to look for rare bleeding disorders not detected by routine hemostasis
      tests, such as thrombomodulin-associated coagulopathy, tissue factor
      pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding
      disorders or impaired tissue factor production.
    explanation: >-
      Enumerates the second-tier tests and the entities they target.
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Global hemostatic tests and markers of fibrinolysis demonstrate variable
      abnormalities, and their clinical significance remains uncertain.
    explanation: >-
      The consensus caveat that prevents global assays from being curated as
      diagnostic criteria.
  - reference: PMID:35316940
    reference_title: "Fibrinolytic assays in bleeding of unknown cause: Improvement in diagnostic yield."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of fibrinolytic disorders in selected patients has a high
      diagnostic yield.
    explanation: >-
      Counterweight showing that in selected patients the fibrinolytic arm of
      second-tier testing does reclassify a substantial minority.

- name: Targeted Genomic Sequencing of Hemostatic Genes
  description: >
    Panel or exome sequencing of hemostasis genes. Included for completeness and
    because it is frequently requested, but with an explicitly low expected
    yield of about 3% in patients with normal hemostasis testing.
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Targeted genomic sequencing examining candidate hemostatic genes has a low
      diagnostic yield.
    explanation: >-
      Consensus statement of the low expected yield.
  - reference: PMID:42320587
    reference_title: "Beyond Conventional Hemostasis Testing: The Diagnostic Impact of Genetic Analysis in inherited Mild Bleeding Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic testing should therefore be regarded as a complementary tool rather
      than a replacing conventional diagnostics.
    explanation: >-
      Positions sequencing as complementary, matching how it is curated here.

treatments:
- name: Tranexamic Acid
  description: >
    The first-line hemostatic agent in BDUC, used both for heavy menstrual
    bleeding and as periprocedural prophylaxis, where antifibrinolytic
    monotherapy is the most commonly advised strategy. Its use in BDUC is
    largely extrapolated from phenotypically similar bleeding disorders, but it
    is also the treatment with the clearest mechanistic rationale, since about a
    fifth of BDUC patients show a hyperfibrinolytic profile.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Altered Fibrinolytic Balance
    treatment_effect: INHIBITS
    description: >-
      Tranexamic acid blocks the lysine binding sites of plasminogen, preventing
      its assembly on fibrin and inhibiting plasmin-mediated clot breakdown.
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment options for BDUC patients include tranexamic acid, desmopressin,
      and platelet transfusions.
    explanation: >-
      ISTH SSC statement of the treatment options in BDUC.
  - reference: PMID:39498237
    reference_title: "Periprocedural hemostatic prophylaxis and outcomes in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antifibrinolytic monotherapy was advised for 57% of major procedures, 59%
      of minor procedures, and 67% of childbirths.
    explanation: >-
      Documents antifibrinolytic monotherapy as the dominant periprocedural
      strategy in real-world BDUC practice.
  - reference: PMID:40680469
    reference_title: "tPA-ROTEM identifies hyperfibrinolytic profile in a significant proportion of patients with bleeding disorder of unknown cause (BDUC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that antifibrinolytic medications may be useful to
      control bleeding or prevent bleeding in surgical interventions in a group
      of patients with BDUC.
    explanation: >-
      Supplies the mechanistic rationale linking the fibrinolytic arm to this
      treatment.
  - reference: PMID:20859150
    reference_title: "Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a new oral tranexamic acid treatment was well tolerated and significantly
      improved both menstrual blood loss and health-related quality of life in
      women with heavy menstrual bleeding.
    explanation: >-
      Randomized efficacy evidence for the heavy menstrual bleeding indication.
      INDIRECT because the trial enrolled women with heavy menstrual bleeding
      generally, not a BDUC-defined population, so applying it here takes a
      population-scope inference step.
  - reference: PMID:29656433
    reference_title: "Antifibrinolytics for heavy menstrual bleeding."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that if 11% of women improve without treatment, 43% to 63% of
      women taking antifibrinolytics will do so.
    explanation: >-
      Cochrane meta-analytic effect size for the heavy menstrual bleeding
      indication. INDIRECT for the same population-scope reason.
  notes: >-
    No randomized trial of tranexamic acid has been conducted in a
    BDUC-defined population; the BDUC evidence is observational and
    extrapolated.

- name: Desmopressin (DDAVP)
  description: >
    Second hemostatic agent, used alone or with tranexamic acid, particularly
    before procedures. As with tranexamic acid, the BDUC evidence is
    observational and extrapolated from phenotypically similar disorders.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  evidence:
  - reference: PMID:31747136
    reference_title: "Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TxA and desmopressin were effective at preventing bleeding in 69 procedures
      and 13 deliveries.
    explanation: >-
      Observational effectiveness of tranexamic acid and desmopressin as
      procedural prophylaxis in an unclassified bleeding disorder cohort.
  - reference: PMID:31747136
    reference_title: "Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tranexamic acid and desmopressin are effective as haemostatic prophylaxis
      but there is an urgent need for clinical trials.
    explanation: >-
      The same authors' explicit statement that the evidence base is inadequate.
      Graded INDIRECT because it is an observational judgement carrying its own
      call for trials, which is what the treatment description records.

- name: Levonorgestrel 52-mg Intrauterine System
  description: >
    Hormonal control of heavy menstrual bleeding, addressing the dominant symptom
    and the principal route of iron loss in this predominantly female population.
    Evidence is from women with inherited bleeding disorders rather than BDUC
    specifically.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Hormone Therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
    therapeutic_agent:
    - preferred_term: levonorgestrel
      term:
        id: CHEBI:6443
        label: levonorgestrel
  target_phenotypes:
  - preferred_term: Heavy menstrual bleeding
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:32470465
    reference_title: "Use of a levonorgestrel 52-mg intrauterine system in the control of abnormal uterine bleeding in women with inherited bleeding disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LNG 52-mg IUS placement can effectively control abnormal uterine bleeding
      in women with inherited bleeding disorders and consequently improve their
      quality of life.
    explanation: >-
      Prospective efficacy in women with inherited bleeding disorders. INDIRECT
      because the cohort is inherited bleeding disorders, not BDUC.
  - reference: PMID:32470465
    reference_title: "Use of a levonorgestrel 52-mg intrauterine system in the control of abnormal uterine bleeding in women with inherited bleeding disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amenorrhea rate was 70% after 12 months.
    explanation: >-
      Quantifies the magnitude of menstrual suppression achieved. INDIRECT for
      the same reason as the item above: the cohort is inherited bleeding
      disorders, not BDUC.

- name: Platelet Transfusion and Recombinant Factor VIIa for Major Bleeding
  description: >
    Escalation options reserved for major bleeding or invasive surgery when
    antifibrinolytics and desmopressin are judged insufficient.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41006857
    reference_title: "Dental surgery for patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For more invasive surgeries, fresh frozen plasma, platelet transfusions, or
      recombinant factor VIIa may be necessary.
    explanation: >-
      Names the escalation options for invasive procedures in BDUC.
  - reference: PMID:41348021
    reference_title: "Buckle up! Managing surgery in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Extrapolating from the management of phenotypically similar bleeding
      disorders, a therapeutic approach may include antifibrinolytic agents
      (tranexamic acid), desmopressin, and/or platelet transfusion.
    explanation: >-
      States both the therapeutic approach and, explicitly, that it is
      extrapolated rather than BDUC-derived.

- name: Periprocedural and Peripartum Hemostatic Prophylaxis
  description: >
    A management strategy rather than a single agent: administering hemostatic
    cover before surgery, dental extraction, and delivery. Two independent
    cohorts support a low threshold for prophylaxis, since untreated procedures
    and deliveries carry markedly higher bleeding rates — though a third cohort
    found bleeding complications frequent irrespective of prophylaxis, so the
    strategy reduces but does not abolish risk.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Post-partum hemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  - preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:36053176
    reference_title: "Outcomes and management of pregnancy in women with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the odds ratio for post partum hemorrhage (PPH) was 6.3 for no primary
      hemostatic prophylaxis versus prophylaxis
    explanation: >-
      Quantifies the protective association of peripartum prophylaxis in a BDUC
      cohort.
  - reference: PMID:39498237
    reference_title: "Periprocedural hemostatic prophylaxis and outcomes in bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Major or clinically relevant nonmajor bleeding occurred in 4.1% (4/98) of
      procedures with prophylaxis and 10% (2/20) of procedures without
      prophylaxis.
    explanation: >-
      Independent cohort showing lower bleeding rates with periprocedural
      prophylaxis.
  - reference: PMID:33853179
    reference_title: "Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bleeding complications are frequent in BUC patients, irrespective of pre-
      or perioperative hemostatic treatment.
    explanation: >-
      Bounds the claim: prophylaxis does not abolish the risk. The same paper
      nonetheless recommends a low threshold for treatment, so this is a limit on
      efficacy rather than an argument against treating.
  - reference: PMID:36053176
    reference_title: "Outcomes and management of pregnancy in women with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite hemostatic prophylaxis PPH was commonly seen.
    explanation: >-
      Second source for the residual risk despite prophylaxis.

differential_diagnoses:
- name: von Willebrand disease
  description: >
    The first entity that must be excluded. Diagnosis rests on von Willebrand
    factor antigen and activity, with repeat testing when levels are below 80
    IU/dL because levels fluctuate diagnostically in a high proportion of
    patients with a mild bleeding tendency.
  disease_term:
    preferred_term: von Willebrand disease
    term:
      id: MONDO:0024574
      label: von Willebrand disease (hereditary or acquired)
  evidence:
  - reference: PMID:38412996
    reference_title: "Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with an unexplained mild to moderate bleeding tendency are
      diagnosed with bleeding disorder of unknown cause (BDUC), a classification
      reached after ruling out other mild to moderate bleeding disorders (MBD)
      including von Willebrand disease (VWD), platelet function defects (PFDs),
      coagulation factor deficiencies (CFDs), and non-hemostatic causes for
      bleeding.
    explanation: >-
      Names the full exclusion set that defines the differential for this entry.

- name: Low von Willebrand factor
  description: >
    The nearest neighbour and the hardest boundary. Patients with von Willebrand
    factor in the 30-50 IU/dL range often lack a pathogenic VWF variant and show
    poor correlation between level and bleeding phenotype, so the entity is
    argued to sit between type 1 von Willebrand disease and BDUC rather than
    cleanly on either side.
  distinguishing_features:
  - >-
    Von Willebrand factor antigen or activity of 30-50 IU/dL places a patient in
    the low VWF category rather than BDUC, which requires normal levels.
  - >-
    The ISTH SSC panel uses repeat VWF testing below 80 IU/dL to avoid
    misassigning a patient with fluctuating levels to BDUC.
  evidence:
  - reference: PMID:36807819
    reference_title: "Low von Willebrand Disease: A Bleeding Disorder of Unknown Cause?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      low VWF represents an entity that appears to fall between type 1 VWD on the
      one hand and bleeding disorders of unknown cause on the other.
    explanation: >-
      States the intermediate position of low VWF relative to this entry, which
      is why the boundary is curated explicitly.
  - reference: PMID:38412996
    reference_title: "Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we diagnose VWD based on VWF antigen and/or activity levels ≤50 IU/dL, with
      repeated VWF testing if VWF levels are <80 IU/dL
    explanation: >-
      Gives the operational cutoffs that separate this differential from BDUC.

- name: Inherited platelet function disorder
  description: >
    Excluded by repeated light transmission aggregometry, supplemented by flow
    cytometric mepacrine fluorescence and glycoprotein expression analysis. The
    exclusion is imperfect: aggregometry alterations are frequently unspecific
    and poorly reproducible, which is exactly the gap the occult platelet defect
    hypothesis occupies.
  distinguishing_features:
  - >-
    Reproducible abnormalities on light transmission aggregometry define a
    platelet function defect; BDUC requires that aggregometry be normal.
  evidence:
  - reference: PMID:38412996
    reference_title: "Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PFDs are identified through repeated abnormalities in light transmission
      aggregometry (LTA), flow cytometric mepacrine fluorescence, and
      glycoprotein expression analysis.
    explanation: >-
      Specifies the tests by which this differential is excluded.

- name: Mild coagulation factor deficiency
  description: >
    Mild reductions in factors VIII, IX and XI may cause bleeding despite normal
    prothrombin time, activated partial thromboplastin time and thrombin time,
    and factor XIII deficiency is invisible to all global screening assays.
    These are the deficiencies most likely to be missed and mislabeled as BDUC.
  distinguishing_features:
  - >-
    Specific factor assays, not global screening tests, are required; a 50%
    cutoff is applied for factors VIII and IX.
  - >-
    Factor XIII must be assayed separately because global screening tests do not
    detect its deficiency.
  evidence:
  - reference: PMID:42417170
    reference_title: "How I Investigate Bleeding Disorders of Unknown Cause: Current Diagnostic Pathways and Gaps in Laboratory Investigation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CFD evaluation should extend beyond routine assays (prothrombin time,
      activated thromboplastin time, thrombin time), as clinically relevant mild
      reductions in factors VIII, IX, and XI may occur despite normal screening
      tests; and factor XIII deficiency is not detected by global assays.
    explanation: >-
      States precisely why global screening tests are insufficient to exclude
      this differential.

- name: Non-hemostatic and acquired causes of bleeding
  description: >
    Structural, vascular, gynecological, drug-related and acquired causes must
    also be excluded before BDUC is assigned. This is the least operationalized
    part of the definition: the requirement is stated but the criteria and
    testing are not specified, so practice varies.
  evidence:
  - reference: PMID:39687924
    reference_title: "Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Importantly, other nonhemostatic and acquired causes of bleeding should be
      excluded, but details on exclusion criteria and associated diagnostic
      testing remain undefined.
    explanation: >-
      Establishes both the requirement and its lack of operational definition.

discussions:
- discussion_id: bduc_fibrinolysis_direction_conflict
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is the fibrinolytic abnormality in BDUC accelerated clot lysis or reduced
    lysis potential? Published cohorts report both directions, so the two cannot
    both be the mechanism.
  attaches_to:
  - pathophysiology#Altered Fibrinolytic Balance
  - pathophysiology#Altered Fibrin Clot Architecture
  rationale: >-
    The Vienna cohort reported a shorter clot lysis time, consistent with
    accelerated lysis, and a tPA-modified thromboelastometry study classified 21%
    of BDUC patients as hyperfibrinolytic. In the opposite direction, an
    independent Rotterdam cohort found a significantly prolonged clot lysis time,
    direct plasmin generation measurement found reduced rather than increased
    peak plasmin, and whole-blood viscoelastometry in 464 patients found reduced
    maximal lysis and a larger area under the curve. This is not a difference of
    magnitude but of sign, and it is why this entry names the arm "altered
    fibrinolytic balance" rather than "hyperfibrinolysis" and refuses to give it
    CANONICAL status. A plausible reconciliation is that the cohorts differ in
    the assay's dependence on clot structure rather than on plasmin activity, but
    this has not been tested directly.
  proposed_experiments:
  - experiment_id: exp_bduc_head_to_head_fibrinolysis_assays
    name: Head-to-head fibrinolytic assay panel in a single BDUC cohort
    description: >-
      Apply plasmin generation, turbidimetric clot formation and lysis,
      tPA-modified ROTEM, and non-activated whole-blood viscoelastometry to the
      same BDUC patients in a single study, to establish whether the reported
      direction of effect is a property of the patients or of the assays.
  - experiment_id: exp_bduc_hyperfibrinolytic_stratified_txa
    name: tPA-ROTEM-stratified tranexamic acid response study
    description: >-
      Stratify BDUC patients by tPA-ROTEM hyperfibrinolytic status and test
      prospectively whether that subgroup, and only that subgroup, derives
      benefit from tranexamic acid.
  evidence:
  - reference: PMID:32337845
    reference_title: "Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: A prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BUC patients did have a significantly prolonged clot lysis time. The
      underlying mechanism for this finding is unknown.
    explanation: >-
      One pole of the conflict, with the authors themselves recording that the
      mechanism is unknown.
  - reference: PMID:42004172
    reference_title: "Abnormal whole-blood viscoelastic test results in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, we observed a delayed clot formation process with reduced lysis
      potential resulting in a larger ROTEM-AUC in patients with BDUC.
    explanation: >-
      Largest cohort, reporting reduced rather than enhanced lysis potential.
  - reference: PMID:40680469
    reference_title: "tPA-ROTEM identifies hyperfibrinolytic profile in a significant proportion of patients with bleeding disorder of unknown cause (BDUC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tPA-ROTEM identified a hyperfibrinolytic profile in 19/92 (21 %) of BDUC
      patients.
    explanation: >-
      The opposing pole: a substantial hyperfibrinolytic subgroup by a different
      assay.

- discussion_id: bduc_assay_severity_dissociation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does no laboratory abnormality identified in BDUC correlate with bleeding
    severity, and can any candidate mechanism be causal if it shows no
    dose-response relationship with the phenotype?
  attaches_to:
  - pathophysiology#Impaired Thrombin Generation
  - pathophysiology#Altered Fibrinolytic Balance
  - pathophysiology#Altered Fibrin Clot Architecture
  - pathophysiology#Impaired Hemostatic Plug Formation and Clot Stability
  rationale: >-
    This is the central unresolved problem of the field and the reason no
    hypothesis in this entry is CANONICAL. Every major study reports the same
    dissociation: thrombin generation, clot formation and clot lysis parameters
    do not correlate with bleeding severity; plasma clot properties show no clear
    association with clinical severity; thromboelastometry parameters do not
    correlate with bleeding scores; and peak plasmin does not correlate with
    bleeding severity. A group-level difference from controls without any
    within-group dose-response is compatible with the abnormality being a
    correlate or an epiphenomenon rather than the cause, and the possibility that
    the true determinant has not yet been measured cannot be excluded.
  proposed_experiments:
  - experiment_id: exp_bduc_composite_assay_dose_response
    name: Composite multi-assay model versus prospective bleeding events
    description: >-
      Test whether composite models combining thrombin generation, clot
      structure, and fibrinolytic parameters, rather than single parameters,
      recover a dose-response relationship with prospectively collected bleeding
      events rather than with retrospective bleeding scores.
  - experiment_id: exp_bduc_standardized_challenge_outcome
    name: Standardized hemostatic challenge as the bleeding outcome
    description: >-
      Use prospectively adjudicated bleeding after a standardized hemostatic
      challenge such as dental extraction as the outcome measure, to reduce the
      recall and scoring noise that a retrospective bleeding assessment tool
      introduces into any dose-response analysis.
  evidence:
  - reference: PMID:31177606
    reference_title: "Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bleeding severity did not correlate with parameters of thrombin generation,
      clot formation, or clot lysis.
    explanation: >-
      The dissociation in the largest thrombin generation study.
  - reference: PMID:42004172
    reference_title: "Abnormal whole-blood viscoelastic test results in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, ROTEM parameters did not correlate with bleeding scores.
    explanation: >-
      The same dissociation for whole-blood viscoelastometry.
  - reference: PMID:25971840
    reference_title: "Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was no clear association of plasma clot properties with the clinical
      severity of bleeding in patients with MBDs.
    explanation: >-
      The same dissociation for plasma clot properties.

- discussion_id: bduc_entity_versus_residual_category
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is BDUC a disease entity with a shared pathophysiology, or a residual
    administrative category that will dissolve into several distinct mechanisms
    and a group of patients without a bleeding disorder at all?
  attaches_to:
  - pathophysiology#Hemostatic Defect Below the Detection Threshold of Routine Testing
  rationale: >-
    dismech models BDUC as a single entry with parallel candidate arms, which is
    a modeling decision and not a settled fact. The case for an entity is that
    the phenotype is reproducible, severe, persistent over years, and
    indistinguishable in severity from named bleeding disorders. The case against
    is that reviews describe it explicitly as a heterogeneous group that mixes
    undiagnosed monogenic disease, polygenic contributions, and patients with a
    past bleeding event but no disorder — and that bleeding assessment tools
    cannot discriminate BDUC from named disorders, which is equally consistent
    with the label capturing several different things. If the heterogeneous view
    prevails, the correct dismech representation would eventually be a Grouping
    over several mechanism-defined entries rather than this single entry, and the
    hypothesis arms curated here are the natural seeds for those entries.
  evidence:
  - reference: PMID:33094877
    reference_title: "Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      BUC/UBD encompasses a heterogenous group of disorders which may include
      undiagnosed rare monogenic diseases, polygenic reasons for bleeding; and
      patients without a clear bleeding disorder but with a previous bleeding
      event.
    explanation: >-
      The explicit statement of the heterogeneity that makes the entity question
      live.
  - reference: PMID:32317240
    reference_title: "The discriminatory power of bleeding assessment tools in adult patients with a mild to moderate bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The bleeding scores were similar in patients with an established diagnosis
      of a bleeding disorder compared to patients with BUC.
    explanation: >-
      Phenotypic indistinguishability, which cuts both ways in this argument.

- discussion_id: bduc_no_mondo_term
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    BDUC has a formal ISTH SSC definition but no MONDO term. Should a MONDO new
    term request be filed, and what should this entry's `disease_term` be until
    then?
  attaches_to:
  - pathophysiology#Hemostatic Defect Below the Detection Threshold of Routine Testing
  rationale: >-
    Searches of MONDO for "bleeding disorder", "bleeding diathesis", "hemorrhagic
    diathesis", "unclassified bleeding" and "unknown cause" return only
    mechanism-specific and gene-specific entities plus broad umbrella terms;
    there is no residual or unexplained category. HPO and NCIT likewise have no
    equivalent. This entry therefore anchors `disease_term` to MONDO:0002243
    hemorrhagic disease, which is a strict superclass that also subsumes every
    entity BDUC is defined by excluding, and records the inexactness as a
    `skos:broadMatch` mapping. Since BDUC now has a published consensus
    definition and a preferred term endorsed by the ISTH SSC, it meets the usual
    bar for a MONDO new term request. This is the same class of upstream ontology
    gap recorded for postpartum haemorrhage and preterm birth in issue #7837 and
    should be folded into a single consolidated request rather than filed
    separately.
  evidence:
  - reference: PMID:38518896
    reference_title: "Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We recommend that patients with a significant bleeding phenotype but normal
      laboratory investigations should be registered with a diagnosis of BDUC in
      preference to other terminology.
    explanation: >-
      The consensus definition and preferred term that make this a well-formed
      new term request rather than a curator coinage.

- discussion_id: bduc_treatment_evidence_extrapolated
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Every hemostatic agent used in BDUC is prescribed on the basis of
    extrapolation from other bleeding disorders. Do tranexamic acid, desmopressin
    and platelet transfusion actually work in BDUC?
  attaches_to:
  - pathophysiology#Mucocutaneous and Post-Challenge Bleeding
  rationale: >-
    No randomized trial has been performed in a BDUC-defined population. The
    treatment recommendations are explicitly derived from phenotypically similar
    disorders, and the observational data are ambiguous: two cohorts show lower
    bleeding rates with periprocedural prophylaxis, while a third reports frequent
    bleeding complications irrespective of treatment, and postpartum hemorrhage
    occurs in a quarter to a third of deliveries despite prophylaxis. This is the
    most clinically consequential gap in the entry, because the affected
    population is largely young women facing surgery and childbirth.
  proposed_experiments:
  - experiment_id: exp_bduc_txa_randomized_periprocedural_trial
    name: Randomized trial of tranexamic acid for periprocedural prophylaxis in BDUC
    description: >-
      A randomized trial of tranexamic acid versus placebo for periprocedural
      hemostatic prophylaxis, restricted to patients meeting the ISTH SSC BDUC
      definition and powered on adjudicated bleeding after a standardized
      procedure.
  - experiment_id: exp_bduc_mechanism_stratified_antifibrinolytic_trial
    name: Mechanism-stratified antifibrinolytic trial in BDUC
    description: >-
      A trial stratified by fibrinolytic phenotype, testing whether the
      hyperfibrinolytic subgroup derives greater benefit from antifibrinolytic
      therapy than the rest of the BDUC population.
  evidence:
  - reference: PMID:41348021
    reference_title: "Buckle up! Managing surgery in patients with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary research in BDUC remains limited; future multisite observational
      and therapeutic clinical trials in BDUC may help us better understand
      multifactorial bleeding risk and further define the role of hemostatic
      therapies.
    explanation: >-
      Expert statement of the evidence gap and the trials needed to close it.
  - reference: PMID:36053176
    reference_title: "Outcomes and management of pregnancy in women with bleeding disorder of unknown cause."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further prospective studies of BDUC patients are required to determine
      optimal management in pregnancy as well as determine the pathophysiological
      basis of bleeding.
    explanation: >-
      The same gap stated for the pregnancy setting, which carries the highest
      consequence.

- discussion_id: bduc_platelet_evidence_cohort_mismatch
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    The strongest mechanistic data for an occult platelet defect come from
    patients selected for ABNORMAL light transmission aggregometry. Do those
    findings transfer to BDUC, which by definition requires aggregometry to be
    normal?
  attaches_to:
  - pathophysiology#Occult Platelet Function and Secretion Defect
  rationale: >-
    The immature-platelet receptor profiling and platelet lipidomics studies both
    recruited patients with aggregometry alterations, that is, suspected platelet
    function defects. These patients sit immediately adjacent to BDUC and are
    plausibly the same biology sampled at a more detectable point on a continuum,
    but that is an assumption, not a result. Both evidence items are therefore
    graded INDIRECT on the platelet node. Until the same assays are applied to
    a formally BDUC-defined cohort, the platelet arm rests on transfer rather
    than on direct observation.
  proposed_experiments:
  - experiment_id: exp_bduc_platelet_profiling_in_normal_lta_cohort
    name: Immature-platelet profiling and lipidomics in a normal-aggregometry BDUC cohort
    description: >-
      Repeat immature-platelet surface receptor profiling and platelet
      lipidomics in patients meeting the ISTH SSC BDUC definition with normal
      light transmission aggregometry, retaining the abnormal-aggregometry group
      as a positive comparator, to test whether the reported platelet
      abnormalities transfer to BDUC proper.
  evidence:
  - reference: PMID:40702900
    reference_title: "Altered platelet lipidome in bleeding patients with unexplained platelet function defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with a mild to moderate bleeding disorder (MBD) and abnormal
      light transmission aggregometry (LTA), a platelet function defect (PFD) is
      suspected. However, in many patients with PFD, the underlying mechanism
      remains elusive.
    explanation: >-
      Documents the cohort definition used in these studies, which is what
      creates the transfer problem for the BDUC platelet arm.

notes: >-
  Curated for issue #5970, which posed the scope question of whether BDUC should
  be a disease entry or a research synthesis document. It is curated as a disease
  entry: it has a formal ISTH SSC consensus definition, a reproducible and
  persistent phenotype, dedicated cohorts, and an active mechanistic literature —
  and the absence of a settled mechanism is precisely the kind of state dismech's
  `mechanistic_hypotheses` and `discussions` machinery exists to represent.

  Three claims that a naive reading of the literature would produce were checked
  and deliberately NOT curated, and should not be added without new evidence:
  (1) an angiogenesis/VEGF/sFlt-1 arm — no such study exists in BDUC; the Vienna
  group's vascular-adjacent work is the thrombomodulin, TFPI and activated
  protein C papers cited here, and the phrase "vascular contributions" in
  PMID:42417170 is forward-looking rather than a finding; (2) low
  alpha2-antiplasmin — PMID:28018998 found alpha2-antiplasmin and TAFI HIGHER in
  patients, so the naive antiplasmin-deficiency model is contradicted by the data
  usually cited for it; (3) elevated von Willebrand factor propeptide or
  increased vascular permeability — no BDUC study found.

  Three further BDUC papers were identified but are not cited because PubMed
  holds no abstract text for them, so no snippet could be verified:
  PMID:37330263, PMID:38292351, PMID:39526290. Their content is covered by
  PMID:36924834, PMID:39498237 and PMID:41348021 respectively.