Platelet-type Bleeding Disorder 12

Mendelian MONDO:0011588 Pathograph 16 Show in embeddings browser Inherited platelet function disorder Inherited blood coagulation disorder

Platelet-type bleeding disorder 12 (BDPLT12, OMIM #605735) is an inherited platelet function disorder caused by deficiency of platelet cyclooxygenase-1, the enzyme encoded by PTGS1. It is known clinically as the "aspirin-like defect", and the name is exact rather than loose: COX-1 is precisely the enzyme low-dose aspirin acetylates irreversibly, so a constitutional deficiency reproduces the pharmacology of permanent aspirin exposure in a patient who has never taken any. The biochemical block is narrow and was localised with unusual precision in 1996, before the gene was implicated. In three unrelated women with mild bleeding, arachidonate-induced platelet aggregation and arachidonate-driven thromboxane A2 production were defective, while aggregation and thromboxane production driven by exogenous prostaglandin H2 were normal. That pairing places the lesion at one step: the conversion of arachidonic acid to the prostaglandin endoperoxides, which is what COX-1 does, and not anywhere downstream in thromboxane synthase or the receptor. Western blotting in the same three patients then showed two routes to it - in two of them COX-1 protein was undetectable, and in the third it was present in normal amount but catalytically impaired. Why the bleeding is mild follows from what thromboxane A2 is for. It is the platelet's autocrine amplifier: released on activation, it drives the second wave of aggregation and the granule secretion that recruits neighbouring platelets. Removing it does not stop a platelet adhering, binding fibrinogen or aggregating to a strong agonist; it removes the positive feedback that consolidates a plug. So primary adhesion and ristocetin agglutination are preserved, the aggregometry signature is an absent arachidonate response with a lost secondary wave to ADP and adrenaline, and the clinical result is a mucocutaneous bleeding tendency that most often declares itself after surgery or dental extraction rather than spontaneously. Inheritance is autosomal dominant in most reported families, and at least one route to dominance is now molecular rather than inferred: a PTGS1 variant disrupting N-glycosylation of COX-1 exerts a dominant-negative effect, which is what would be expected of a mutant subunit in an enzyme that works as a homodimer.

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1
Inheritance
7
Pathophys.
5
Phenotypes
1
Hypotheses
3
Gaps
16
Pathograph
1
Genes
4
Medical Actions
1
Models
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Mostly autosomal dominant across reported families, with variable expressivity: the largest series identified an additional 13 affected relatives plus four with a milder biochemical phenotype when family members of index cases were tested. A dominant-negative mechanism has since been demonstrated for at least one PTGS1 allele, which is a plausible general explanation given that COX-1 is functionally a homodimer.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:19036102 SUPPORT Human Clinical
"Aspirin-like defect (ALD) is a rare, mostly autosomal dominant inherited dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling."
States the inheritance pattern, with the authors' own hedge that it is not universal.
PMID:19036102 SUPPORT Human Clinical
"Subsequently, family members were investigated and among 35 individuals an additional 13 ALD patients as well as 4 individuals with mild ALD (PAR to AA: 19-32%) were identified."
Documents familial transmission and, in the four mild cases, the variable expressivity that makes the trait easy to miss on clinical grounds.
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Mechanistic Hypotheses

1
Loss of COX-1-Dependent Thromboxane A2 Amplification
cox1_thromboxane_amplification_loss CANONICAL
Deficient platelet COX-1, whether because the protein is absent or because it is present but catalytically impaired, blocks conversion of arachidonic acid to the prostaglandin endoperoxides and so removes thromboxane A2. Losing that autocrine amplifier abolishes the secondary wave of aggregation and the granule secretion that recruits further platelets, leaving primary adhesion and integrin function intact. The plug forms but is not consolidated, and the clinical result is a mild mucocutaneous bleeding tendency that declares itself under haemostatic challenge. CANONICAL because the enzymology, the exogenous prostaglandin H2 rescue, the aggregometry signature and the platelet-specific mouse knockout all agree.
Pathograph links
PTGS1 Loss-of-Function Variants -> Deficient Platelet COX-1 Protein or Catalytic Activity DIRECT Either no enzyme is made, or enzyme is made that cannot work.
Deficient Platelet COX-1 Protein or Catalytic Activity -> Failure of Arachidonate Conversion to Prostaglandin Endoperoxides DIRECT The reaction COX-1 catalyses cannot proceed.
Failure of Arachidonate Conversion to Prostaglandin Endoperoxides -> Loss of Platelet Thromboxane A2 Generation DIRECT No endoperoxide substrate for thromboxane synthase.
Loss of Platelet Thromboxane A2 Generation -> Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion DIRECT No autocrine amplifier to drive the second wave.
Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion -> Failure of Primary Hemostatic Plug Formation DIRECT An unamplified platelet response cannot consolidate a stable plug.
Failure of Primary Hemostatic Plug Formation -> Mucocutaneous Bleeding Diathesis DIRECT Failure of platelet-dependent primary haemostasis.
Mucocutaneous Bleeding Diathesis -> Bruising Susceptibility DIRECT Cutaneous expression of the diathesis.
Mucocutaneous Bleeding Diathesis -> Epistaxis DIRECT Mucosal expression of the diathesis.
Mucocutaneous Bleeding Diathesis -> Menorrhagia DIRECT Mucosal expression of the diathesis, and the one that most often causes chronic morbidity.
Mucocutaneous Bleeding Diathesis -> Prolonged Bleeding After Surgery DIRECT The haemostatic challenge that most often reveals the disorder.
Mucocutaneous Bleeding Diathesis -> Impaired Platelet Aggregation DIRECT The laboratory readout of the same lesion.
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Discussions and Knowledge Gaps

3
Which PTGS1 variants actually cause BDPLT12, and what fraction of biochemically confirmed aspirin-like defect has an identifiable PTGS1 variant at all?
KNOWLEDGE GAP bdplt12_genotype_evidence_gap
Attached to
pathophysiology#PTGS1 Loss-of-Function Variants genetic#PTGS1
The biochemistry of this disorder is settled and the genetics is not. The functional diagnosis is made on aggregometry and thromboxane measurement, both of which are decisive; the genetic confirmation is not, because reported alleles are largely private single cases, no recurrent pathogenic variant is established, and the largest phenotypic series - 52 individuals from 17 families - was defined by an aggregometry threshold rather than by genotype. It is therefore not known how many biochemically confirmed patients carry a PTGS1 variant, and a systematic sequencing study of a biochemically defined cohort has not been done. That matters practically: a clinician deciding whether a negative panel excludes the diagnosis has no denominator to reason from.
Do the type 1 (absent protein) and type 2 (present but inactive protein) COX-1 defects correspond to different variant classes, and do they differ clinically?
KNOWLEDGE GAP bdplt12_two_defect_types
Attached to
pathophysiology#Deficient Platelet COX-1 Protein or Catalytic Activity
The two-defect classification comes from western blots in three patients and has not been revisited against the molecular genetics that arrived twenty-five years later. On the face of it the distinction should map onto variant class - a null or an unstable protein giving type 1, a catalytic-site or glycosylation variant giving type 2 - and the dominant-negative N-glycosylation allele is a natural type 2 candidate. But nobody has assayed protein level and activity across a genotyped cohort, so the mapping is a plausible expectation rather than a finding, and whether the two types differ in bleeding severity is unknown.
Does a heterozygous dominant-negative COX-1 allele produce the same platelet phenotype as complete platelet Cox-1 deletion, or does the mutant subunit poison the dimer to a different degree?
HUMAN MODEL MISMATCH bdplt12_mouse_dominant_negative_mismatch
Attached to
animal_models#Platelet-specific Cox-1 knockout mouse pathophysiology#PTGS1 Loss-of-Function Variants
The available mouse is a complete platelet-restricted knockout, and it establishes cell-autonomy cleanly. But the human disease is heterozygous, and at least one allele acts dominant-negatively on an enzyme that functions as a homodimer - a configuration in which residual activity depends on how the mutant and wild-type subunits assort, and which a null cannot represent. Because a dimer of one normal and one defective subunit could behave anywhere between half-normal and fully dead, the knockout sets a floor on the phenotype rather than modelling it. Testing this needs a knock-in of a human dominant-negative allele, which does not exist.
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Pathophysiology

7
PTGS1 Loss-of-Function Variants
Germline variants in PTGS1, on chromosome 9q33.2, encoding cyclooxygenase-1 (prostaglandin G/H synthase 1). Reported disease alleles are individually rare and mostly private to a family or a case, which is why no recurrent pathogenic variant is established for this trait. The best-characterised is a variant disrupting N-glycosylation of COX-1, shown to act dominant-negatively on platelet function - a mechanism that fits the enzyme's biology, since COX-1 is functionally active as a homodimer and a defective subunit can therefore compromise a dimer containing a normal one.
Loss of COX-1-Dependent Thromboxane A2 Amplification
PTGS1 hgnc:9604 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased PTGS1 (hgnc:9604). hgnc:9604 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Germline PTGS1 variants. This block describes the dominant allele class, which accounts for most reported families: heterozygous, with a dominant-negative effect demonstrated for an N-glycosylation-disrupting variant. It is a deliberately partial description. The schema takes one zygosity and one functional-impact value, and this disease has both modes - the recessive p.Trp322Ser allele cited in this node's own evidence abrogates COX-1 expression in a homozygote and is a straightforward loss of function, not a dominant-negative one. Read the values here as "the modal allele class", not as a claim about every patient.
Downstream
Deficient Platelet COX-1 Protein or Catalytic Activity Either no enzyme is made, or enzyme is made that cannot work. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (3 references)
PMID:33326144 SUPPORT Human Clinical
"Despite the physiological and clinical relevance of platelet COX-1, few patients with congenital COX-1 defect (Bleeding Disorder Platelet Type 12; OMIM: 605735) have been characterized"
Ties the gene defect to this specific OMIM entity and states how thin the genetic case series is, which is why this entry leans on enzymology rather than genotype-phenotype correlation.
PMID:33326144 SUPPORT Other
"COX-1 (599aa; 70kDa) has cyclooxygenase and peroxidase activities and it is functionally active as a homodimer"
The homodimer structure, which is the structural reason a dominant-negative allele is possible in this gene at all.
PMID:33326144 SUPPORT Human Clinical
"Recently, the BRIDGE Consortium reported a pedigree with an autosomal recessive variant c.965G>C (p.Trp322Ser) that abrogated COX-1 expression resulting in aspirin-like platelet dysfunction."
A recessive allele in the same gene, recorded because it shows the dominant pattern in this entry's inheritance block is the usual case and not the only one.
Deficient Platelet COX-1 Protein or Catalytic Activity
The protein-level lesion, and it comes in two forms that the founding biochemical study separated by western blot in three patients from one series. In two, the 70 kDa COX-1 band was undetectable - a type 1 defect, absent protein. In the third the protein was present in normal amount and the enzyme did not work - a type 2 defect, impaired catalytic activity. Thromboxane synthase was normal in all three, which is what excludes the next enzyme in the pathway. Both forms give the same functional result, which is why this entry treats them as two routes into one node rather than as two diseases.
Loss of COX-1-Dependent Thromboxane A2 Amplification
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. megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
prostaglandin-endoperoxide synthase activity GO:0004666 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased prostaglandin-endoperoxide synthase activity (GO:0004666). GO:0004666 is a molecular function from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum membrane GO:0005789 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum membrane (GO:0005789). GO:0005789 is a cellular component from the Gene Ontology.
Downstream
Failure of Arachidonate Conversion to Prostaglandin Endoperoxides The reaction COX-1 catalyses cannot proceed. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (2 references)
PMID:8562397 SUPPORT Human Clinical
"These findings indicate that human platelet PGHS-1 deficiency is due to two types of enzyme defects: type 1 defect is manifested by an undetectable PGHS-1 protein in platelets whereas the type 2 defect is manifested by a normal quantity of PGHS-1 protein which has an impaired catalytic activity."
The two-defect-type classification stated by the authors who established it, which is what this node models.
PMID:8562397 SUPPORT Human Clinical
"In two patients the 70 kD PGHS-1 protein was undetectable, whereas it was normal in the third patient. The 60 kD TXAS band was normal in all three patients."
The blots behind the classification, including the normal thromboxane synthase that excludes the next enzyme down the pathway.
Failure of Arachidonate Conversion to Prostaglandin Endoperoxides
The blocked step, and the one the disease is defined by. Arachidonic acid released from membrane phospholipids on platelet activation should be converted by COX-1 to prostaglandin G2 and then H2. In these patients it is not: arachidonate-induced aggregation and arachidonate-driven thromboxane production are both defective. The experiment that pins the lesion to this exact step is the bypass. Supplying prostaglandin H2 directly - the product COX-1 should have made - restores both aggregation and thromboxane production to normal. Everything downstream of COX-1 therefore works, and the defect is upstream of it in the pathway and nowhere else.
Loss of COX-1-Dependent Thromboxane A2 Amplification
cyclooxygenase pathway GO:0019371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cyclooxygenase pathway (GO:0019371). GO:0019371 is a biological process from the Gene Ontology. ↓ DECREASED prostaglandin biosynthetic process GO:0001516 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased prostaglandin biosynthetic process (GO:0001516). GO:0001516 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Platelet Thromboxane A2 Generation No endoperoxide substrate for thromboxane synthase. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (3 references)
PMID:8562397 SUPPORT Human Clinical
"Arachidonate-induced platelet aggregation was defective, whereas PGH2-induced aggregation was normal."
The bypass experiment in one sentence: the substrate fails, the product works. This is what localises the block to the COX-1 step rather than anywhere downstream.
PMID:8562397 SUPPORT Human Clinical
"Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients"
The same block measured as product rather than as function.
PMID:8562397 SUPPORT Human Clinical
"whereas they were normal in response to exogenous PGH2"
Thromboxane production is normal when the missing intermediate is supplied, which is the second half of the bypass argument.
Loss of Platelet Thromboxane A2 Generation
Thromboxane synthase is intact but has nothing to work on, so thromboxane A2 output falls. The quantitative loss is large: in the founding series, arachidonate-stimulated thromboxane B2 was 4.4 to 11.7 ng per 3 x 10^8 platelets against a normal range of 49 to 81. Thromboxane A2 is the platelet's autocrine and paracrine amplifier rather than an initiator, which is the whole reason this disease is mild. Its loss is also exactly what low-dose aspirin achieves therapeutically, which is why the phenotype is called the aspirin-like defect and why concurrent aspirin or NSAID use compounds it.
Loss of COX-1-Dependent Thromboxane A2 Amplification
prostanoid biosynthetic process GO:0046457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased prostanoid biosynthetic process (GO:0046457). GO:0046457 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion No autocrine amplifier to drive the second wave. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (2 references)
PMID:8562397 SUPPORT Human Clinical
"Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients, i.e. 11.7, 4.6 and 4.4 ng TXB2/3 x 10(8) plt respectively (normal range was 49-81 ng/3 x 10(8) plt)"
The measured deficit with its normal range, which is what makes this a quantitative claim rather than a qualitative one.
PMID:19036102 SUPPORT Human Clinical
"dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling"
States the pathway and its endpoint as the definition of the disorder.
Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion
The cellular endpoint, and the arm of primary haemostasis this disorder breaks. Thromboxane A2 released by an activated platelet acts back on that platelet and on its neighbours to sustain aggregation and to drive granule secretion. Without it, aggregation begins and then fails to consolidate: the aggregometry signature is subnormal responses to ADP, collagen and adrenaline characterised specifically by an abnormal second wave and a tendency to disaggregate, with the arachidonate response absent. What is preserved matters as much as what is lost, because it is what keeps this disorder off the other arms of the module. Adhesion machinery and integrin alphaIIbbeta3 are untouched, ristocetin agglutination is normal, and a strong agonist can still aggregate the platelet. The lesion is in amplification.
Loss of COX-1-Dependent Thromboxane A2 Amplification
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 aggregation GO:0070527 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet aggregation (GO:0070527). GO:0070527 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
Animal models
Platelet-specific Cox-1 knockout mouse Mouse recapitulates Platelet-restricted Cox-1 deletion reproduces the arachidonate- and ADP-induced aggregation defect ex vivo.
Downstream
Failure of Primary Hemostatic Plug Formation An unamplified platelet response cannot consolidate a stable plug. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (2 references)
PMID:8562397 SUPPORT Human Clinical
"Platelet aggregation in response to adenosine diphosphate (ADP), collagen and epinephrine were subnormal, characterized by an abnormal second-wave aggregation and propensity for disaggregation."
The second-wave defect described directly, including the disaggregation that shows the plug is forming and then coming apart rather than never forming.
PMID:24480756 SUPPORT Other
"the inhibition of, or a deficiency in, COX-1 will compromise the AA pathway, thereby reducing platelet secretion and altering normal platelet aggregatory function"
States the secretion-plus-aggregation consequence of COX-1 loss, and does so treating pharmacological inhibition and genetic deficiency as the same lesion - which is the basis of the aspirin-like framing.
Failure of Primary Hemostatic Plug Formation
The rate-limiting node shared with every other platelet-type bleeding disorder. A plug that is not consolidated by thromboxane-driven recruitment and secretion is mechanically weaker and more readily dislodged, which is why bleeding in this disorder is characteristically provoked and often delayed rather than immediate and spontaneous.
Loss of COX-1-Dependent Thromboxane A2 Amplification
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
Downstream
Mucocutaneous Bleeding Diathesis Failure of platelet-dependent primary haemostasis. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (1 reference)
PMID:19036102 SUPPORT Human Clinical
"At least one bleeding symptom was reported by 25 (74%) ALD patients and prolonged CT was detected in 24 (71%) of the cases, both significantly correlated with impaired PAR to AA (P = 0.001 and P = 0.002, respectively)."
Links the laboratory defect to clinical bleeding and to a global primary-haemostasis test, with the correlation statistics that make the link more than co-occurrence.
Mucocutaneous Bleeding Diathesis
The clinical output: mild, lifelong, and provoked rather than spontaneous. Easy bruising, epistaxis and menorrhagia are the background; the events that bring patients to attention are surgical and dental, and the bleeding after them is characteristically late rather than immediate.
Loss of COX-1-Dependent Thromboxane A2 Amplification
Downstream
Bruising Susceptibility Cutaneous expression of the diathesis. Loss of COX-1-Dependent Thromboxane A2 Amplification
Epistaxis Mucosal expression of the diathesis. Loss of COX-1-Dependent Thromboxane A2 Amplification
Menorrhagia Mucosal expression of the diathesis, and the one that most often causes chronic morbidity. Loss of COX-1-Dependent Thromboxane A2 Amplification
Prolonged Bleeding After Surgery The haemostatic challenge that most often reveals the disorder. Loss of COX-1-Dependent Thromboxane A2 Amplification
Impaired Platelet Aggregation The laboratory readout of the same lesion. Loss of COX-1-Dependent Thromboxane A2 Amplification
Show evidence (1 reference)
PMID:19036102 SUPPORT Human Clinical
"At least one bleeding symptom was reported by 25 (74%) ALD patients"
Documents that a majority but not all of the ascertained patients bleed, which is the basis for calling the diathesis mild and variable.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Platelet-type Bleeding Disorder 12 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Impaired Platelet Aggregation Laboratory HP:0003540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired platelet aggregation (HP:0003540). HP:0003540 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19036102 SUPPORT Human Clinical
"Using impaired PAR to AA (< or =10%) as the mandatory diagnostic criterion, ALD could be confirmed in 17 patients."
The threshold used to define the disorder, which is what makes this phenotype diagnostic rather than merely associated.
PMID:8562397 SUPPORT Human Clinical
"Platelet aggregation in response to adenosine diphosphate (ADP), collagen and epinephrine were subnormal, characterized by an abnormal second-wave aggregation and propensity for disaggregation."
The pattern across the other agonists, which is what distinguishes this from a global aggregation failure.
Bruising Susceptibility Hematologic 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:19036102 SUPPORT INDIRECT Human Clinical
"At least one bleeding symptom was reported by 25 (74%) ALD patients"
Graded INDIRECT: the cohort study establishes that most ascertained patients report bleeding symptoms but does not itemise them in the cached text, so this specific manifestation follows from the study's finding rather than being stated by it.
Epistaxis Hematologic 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:19036102 SUPPORT INDIRECT Human Clinical
"At least one bleeding symptom was reported by 25 (74%) ALD patients"
Graded INDIRECT for the same reason as bruising: the study establishes the bleeding phenotype without itemising it in the cached text.
Menorrhagia Hematologic HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19036102 SUPPORT INDIRECT Human Clinical
"At least one bleeding symptom was reported by 25 (74%) ALD patients"
Graded INDIRECT: menorrhagia is part of the standard mucocutaneous picture the cohort reports in aggregate, not a separately quoted finding in the cached text.
Prolonged Bleeding After Surgery Hematologic 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:24480756 SUPPORT Human Clinical
"We present the hospital course, management, and diagnosis of a patient with an undiagnosed COX-1 deficiency who had had third molars removed in a private office."
A documented case of post-extraction haemorrhage revealing an undiagnosed COX-1 deficiency, which is the clinical scenario this phenotype describes.
PMID:24480756 SUPPORT Human Clinical
"To our knowledge, this is the first case of COX-1 deficiency diagnosed after exodontia documented in English studies."
Establishes how rarely this is reported, which is relevant to how often the diagnosis is actually made this way versus how often it is missed.
🧬

Genetic Associations

1
PTGS1
Gene: PTGS1 hgnc:9604 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTGS1 (hgnc:9604). hgnc:9604 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:33326144 SUPPORT Human Clinical
"To date, only a few cases with uncommon genetic variants in PTGS1, the gene encoding COX-1, have been reported, without detailed study of their associated platelet phenotype."
Names the gene and states the limits of the published allelic series, which is the honest state of the genetic evidence for this entity.
PMID:33326144 SUPPORT Other
"each COX-1 monomer consisting of four highly conserved domains: an N-terminal signal peptide, a dimerization domain, a membrane-binding domain (MBD) and a large C-terminal catalytic domain"
The domain architecture, which is what a variant's position has to be interpreted against.
💊

Medical Actions

4
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
Antifibrinolytic cover for procedures and for menorrhagia. It does not correct the platelet defect; it stabilises the clot that a weakly amplified platelet response manages to build, which is the appropriate strategy when the lesion is in plug consolidation rather than in clot formation.
Show evidence (1 reference)
PMID:37611608 SUPPORT INDIRECT Other
"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
Establishes tranexamic acid as standard management for inherited platelet disorders. Graded INDIRECT because the review addresses the class rather than COX-1 deficiency specifically; no trial in BDPLT12 exists.
Desmopressin
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
Given peri-procedurally to shorten the bleeding time. There is direct support for its use in this defect class: desmopressin normalised the bleeding time in patients with a thromboxane A2 synthesis defect, in the same study in which it failed in thrombasthenia and Bernard-Soulier syndrome - so the response is specific to where the lesion sits rather than general to platelet disorders.
Show evidence (2 references)
PMID:12702175 SUPPORT Human Clinical
"DDAVP was also efficacious in the TxA2 synthesis defect but not in other disorders."
Direct evidence that desmopressin works in a thromboxane synthesis defect and not in adhesion or aggregation defects, which is the distinction that makes it appropriate here specifically.
PMID:37611608 SUPPORT INDIRECT Other
"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
Places desmopressin among the standard options for the disorder class.
Platelet Transfusion
Action: platelet transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is platelet transfusion (NCIT:C15366). NCIT:C15366 is a clinical intervention from the NCI Thesaurus. Ontology label: Platelet Transfusion NCIT:C15366
Platform: Cell therapy
Reserved for serious bleeding or major surgery. It supplies platelets with functional COX-1 and so restores the missing amplification directly, at the cost of alloimmunisation risk on repeated exposure.
Show evidence (1 reference)
PMID:37611608 SUPPORT INDIRECT Other
"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
Names platelet concentrates among the established options. Graded INDIRECT because the review addresses inherited platelet disorders as a class rather than COX-1 deficiency specifically.
Recombinant Activated Factor VIIa
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
Platform: Protein replacement
A bypassing agent for severe bleeding refractory to the measures above. It does not repair the COX-1 defect or restore thromboxane amplification; it drives thrombin generation on whatever activated platelet surface is available, which is why the conformance module treats it as acting on the failed-plug node rather than on any one arm. Its evidence base in inherited platelet disorders is Glanzmann thrombasthenia, and its use in a mild amplification defect like this one is extrapolation. Curated because it is named in the same standard-options sentence as the other three treatments, and flagged here as the least directly supported of them.
Show evidence (1 reference)
PMID:37611608 SUPPORT INDIRECT Other
"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
Names recombinant activated factor VII among the established options for inherited platelet disorders. Graded INDIRECT because the review addresses the class, and because this agent's trial evidence within that class comes from a different and more severe disorder.
🌍

Environmental Factors

1
Aspirin and other NSAID exposure
Not a cause of the disorder, but the clearest modifier of it, and the reason avoidance is part of management. Aspirin irreversibly acetylates COX-1, which is the same enzyme already deficient here, so pharmacological inhibition adds to a constitutional deficiency at exactly the same step.
Show evidence (1 reference)
PMID:33326144 SUPPORT Other
"Irreversible COX-1 inhibition by aspirin is a widely established anti-platelet therapy in cardiovascular disease."
Establishes the pharmacology of the exposure: irreversible inhibition of the same enzyme, which is why it compounds rather than merely coincides with the genetic defect.
Mechanism Target:
EXACERBATES Deficient Platelet COX-1 Protein or Catalytic Activity — Irreversible acetylation of the residual functional COX-1, compounding the genetic deficiency at the same molecular target.
Show evidence (1 reference)
PMID:24480756 SUPPORT Other
"COX-1 deficiencies are usually caused by drug interactions with the enzyme itself."
States that pharmacological inhibition and genetic deficiency act on the same enzyme, which is what makes this an exacerbating exposure rather than an unrelated risk.
🔬

Biochemical Markers

1
Arachidonate-stimulated platelet thromboxane B2 (DECREASED)
Context: The confirmatory biochemical assay, and the one that distinguishes this disorder from a thromboxane receptor defect. Thromboxane A2 is unstable, so the stable hydrolysis product thromboxane B2 is what is measured. Platelets are stimulated with arachidonic acid; in COX-1 deficiency the output is grossly low. The three patients in the founding series produced 11.7, 4.6 and 4.4 ng TXB2 per 3 x 10^8 platelets against a stated normal range of 49 to 81. The paired measurement is what makes the assay diagnostic rather than merely abnormal: stimulating the same platelets with exogenous prostaglandin H2 - the product COX-1 should have made - gives normal thromboxane output, 71.4, 56.6 and 48.9 against a normal range of 49 to 85. Low on substrate, normal on product, is the signature of a block at the COX-1 step specifically.
Pathograph Readouts
Readout Of Loss of Platelet Thromboxane A2 Generation Negative Diagnostic
Low arachidonate-stimulated TXB2 with preserved PGH2-stimulated TXB2 reports the COX-1 block directly, and localises it upstream of thromboxane synthase.
Show evidence (1 reference)
PMID:8562397 SUPPORT Human Clinical
"Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients, i.e. 11.7, 4.6 and 4.4 ng TXB2/3 x 10(8) plt respectively (normal range was 49-81 ng/3 x 10(8) plt)"
The measured values with the laboratory's own normal range, which is what makes this a quantitative diagnostic readout rather than a qualitative statement.
Reference Ranges
49.0–81.0 ng TXB2 per 3 x 10^8 platelets (Laboratory normal range for arachidonate-stimulated platelet thromboxane B2, as stated in the founding case series.)
Not a consensus or guideline interval. It is the reference range of the single laboratory that made these measurements in 1996, quoted because the patient values are only interpretable against it. Assay methods for platelet thromboxane have changed since, so do not carry this interval to a modern laboratory result.
Show evidence (1 reference)
PMID:8562397 SUPPORT Human Clinical
"(normal range was 49-81 ng/3 x 10(8) plt)"
The interval itself, as reported alongside the patient values.
🔬

Diagnosis

3
Light transmission aggregometry
The test that makes the diagnosis. The pattern to look for is an absent or markedly reduced response to arachidonic acid with a lost secondary wave to ADP and adrenaline, against preserved ristocetin agglutination. The largest series formalised this by making an arachidonate response of 10% or less the mandatory criterion.
Show evidence (2 references)
PMID:19036102 SUPPORT Human Clinical
"Platelet in vitro function was determined on the basis of platelet aggregation response (PAR) to AA, adenosine diphosphate, collagen and ristocetin as well as PFA-100 closure times (CT)."
The test panel used to define the disorder, including the agonists whose pattern discriminates it.
PMID:39870109 SUPPORT INDIRECT Other
"Established methods consist of blood smear analysis by light microscopy, light transmission aggregometry, and flow cytometry."
Places aggregometry in the standard diagnostic sequence for inherited platelet function defects generally.
Structured bleeding assessment
A validated bleeding score is the entry point, because the clinical picture here is mild and non-specific enough that unstructured history taking underestimates it. This is also where the disorder's tendency to be missed is addressed.
Show evidence (1 reference)
PMID:39870109 SUPPORT INDIRECT Other
"We strongly advocate for the use of a validated bleeding score like the ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool)."
The recommendation, at the level of inherited platelet function defects as a class.
PTGS1 sequencing
Confirms the diagnosis, usually within a hereditary platelet disorder panel rather than as single-gene testing. Its yield is limited by the same thing that limits the genetic evidence base: reported alleles are largely private, and most catalogued PTGS1 variants are benign or of uncertain significance for this trait, so a negative panel does not exclude the functional diagnosis made on aggregometry.
Show evidence (1 reference)
PMID:33326144 SUPPORT Human Clinical
"To date, only a few cases with uncommon genetic variants in PTGS1, the gene encoding COX-1, have been reported, without detailed study of their associated platelet phenotype."
The state of the reported allelic series, which is what determines how much a sequencing result can be expected to add.
📊

Prevalence

1
Paediatric patients referred for suspected coagulation disorders
Point Prevalence Unknown
0.6% of a paediatric referral population, not of the general population. The denominator is children already suspected of having a coagulation disorder, so this figure describes yield within a selected group. No `rate_per_100000` is set, deliberately: normalising 0.6% would give 600 per 100,000, which a cross-entry query would read as a population prevalence and which is wrong by orders of magnitude for an ultra-rare disorder. `prevalence_class` is UNKNOWN for the same reason - the true population figure is not established. The same study argues the disorder is underdiagnosed because the bleeding is mild.
Show evidence (2 references)
PMID:19036102 SUPPORT Human Clinical
"An estimated 0.6% prevalence was determined for ALD in our paediatric patients with suspected coagulation disorders."
The figure with its population stated, which is what makes it a referral yield rather than a prevalence.
PMID:19036102 SUPPORT Human Clinical
"Due to the mild bleeding symptoms, ALD is probably underdiagnosed."
The authors' own caution that any ascertained figure understates the true frequency.
🐁

Animal Models

1
Platelet-specific Cox-1 knockout mouse
Megakaryocyte- and platelet-restricted deletion of Cox-1, generated with two different Cre drivers. Its value for this disease is that it makes the requirement cell-autonomous: the aggregation defect follows from losing COX-1 in the platelet lineage specifically, not from losing it in endothelium or elsewhere. The comparison of Pf4-dCre against Gp1ba-dCre exists because the former is expressed outside the lineage during inflammation, so the study is in part a control for that.
Species
Mouse
Genotype
Pf4-dCre or Gp1ba-dCre crossed with Cox-1 flox/flox
Publication
PMID:38660804
Pathograph links
Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion recapitulates fidelity: moderate Platelet-restricted Cox-1 deletion reproduces the arachidonate- and ADP-induced aggregation defect ex vivo.
Limitations: A complete lineage-restricted deletion, whereas human disease is heterozygous and at least sometimes dominant-negative, so the model works at a lower dose of enzyme than any patient and cannot report on how a mutant subunit behaves in a dimer. The study was designed to model aspirin pharmacology rather than the human genetic disorder, and its readouts are ex vivo aggregometry rather than a bleeding phenotype.
Readouts
Ex vivo arachidonate- and ADP-induced platelet aggregation
Direction: DECREASED
Interpretation: The same aggregometry abnormality that defines the human disorder, produced by deleting the enzyme in platelets alone.
Show evidence (1 reference)
PMID:38660804 SUPPORT Model Organism
"Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in Pf4-ΔCre Cox-1-/-/Ldlr-/- and Gp1ba-ΔCre Cox-1-/-/Ldlr-/- mice."
The measurement this readout asserts: aggregation to both arachidonic acid and ADP inhibited, and inhibited equally with either Cre driver, which is what rules out the ectopic expression of Pf4-Cre as the explanation.
Show evidence (2 references)
PMID:38660804 SUPPORT Model Organism
"To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1-/- mice"
States how the model was constructed, which is what makes it a platelet-restricted deletion and so informative for this node rather than for COX-1 loss generally.
+ 1 more reference
{ }

Source YAML

click to show 
name: Platelet-type Bleeding Disorder 12
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: platelet-type bleeding disorder 12
  term:
    id: MONDO:0011588
    label: platelet-type bleeding disorder 12
description: >
  Platelet-type bleeding disorder 12 (BDPLT12, OMIM #605735) is an inherited
  platelet function disorder caused by deficiency of platelet
  cyclooxygenase-1, the enzyme encoded by PTGS1. It is known clinically as the
  "aspirin-like defect", and the name is exact rather than loose: COX-1 is
  precisely the enzyme low-dose aspirin acetylates irreversibly, so a
  constitutional deficiency reproduces the pharmacology of permanent aspirin
  exposure in a patient who has never taken any.

  The biochemical block is narrow and was localised with unusual precision in
  1996, before the gene was implicated. In three unrelated women with mild
  bleeding, arachidonate-induced platelet aggregation and arachidonate-driven
  thromboxane A2 production were defective, while aggregation and thromboxane
  production driven by exogenous prostaglandin H2 were normal. That pairing
  places the lesion at one step: the conversion of arachidonic acid to the
  prostaglandin endoperoxides, which is what COX-1 does, and not anywhere
  downstream in thromboxane synthase or the receptor. Western blotting in the
  same three patients then showed two routes to it - in two of them COX-1
  protein was undetectable, and in the third it was present in normal amount
  but catalytically impaired.

  Why the bleeding is mild follows from what thromboxane A2 is for. It is the
  platelet's autocrine amplifier: released on activation, it drives the second
  wave of aggregation and the granule secretion that recruits neighbouring
  platelets. Removing it does not stop a platelet adhering, binding fibrinogen
  or aggregating to a strong agonist; it removes the positive feedback that
  consolidates a plug. So primary adhesion and ristocetin agglutination are
  preserved, the aggregometry signature is an absent arachidonate response
  with a lost secondary wave to ADP and adrenaline, and the clinical result is
  a mucocutaneous bleeding tendency that most often declares itself after
  surgery or dental extraction rather than spontaneously.

  Inheritance is autosomal dominant in most reported families, and at least one
  route to dominance is now molecular rather than inferred: a PTGS1 variant
  disrupting N-glycosylation of COX-1 exerts a dominant-negative effect, which
  is what would be expected of a mutant subunit in an enzyme that works as a
  homodimer.

synonyms:
- BDPLT12
- aspirin-like defect
- platelet cyclooxygenase-1 deficiency
- platelet COX-1 deficiency
- prostaglandin-endoperoxide synthase 1 deficiency, platelet
- PGHS-1 deficiency
- platelet prostaglandin H synthase deficiency

parents:
- Inherited platelet function disorder
- Inherited blood coagulation disorder

notes: >
  Module conformance. This entry conforms to `primary_hemostatic_plug_failure`
  at the activation-and-secretion arm, which is the arm that module's own
  description assigns to cyclooxygenase-1 defects. The disorder is not an
  adhesion defect and not an integrin alphaIIbbeta3 defect: primary adhesion
  and ristocetin agglutination are preserved, and it is the amplification loop
  that is lost. The module warns against attaching at the aggregation arm just
  because aggregometry is abnormal, and that warning applies directly here,
  since abnormal aggregometry is this disorder's diagnostic hallmark.

  Two enzyme defect types, and why they are curated as one node rather than
  two entries. The founding biochemical study distinguished a type 1 defect,
  with no detectable COX-1 protein, from a type 2 defect, with normal protein
  quantity and impaired catalytic activity. Both were found among three
  patients in one series and both give the same functional endpoint, so this
  entry curates them as alternative routes described within a single
  protein-level node rather than splitting the disease.

  Nomenclature, and a search trap. Almost all of the clinical literature calls
  this the "aspirin-like defect" (ALD) and much of the older biochemical
  literature calls the enzyme prostaglandin H synthase (PGHS-1) rather than
  COX-1. A search on the MONDO label "platelet-type bleeding disorder 12"
  returns very little; searches on ALD, PGHS-1 or PTGS1 return the field. All
  snippets in this entry are keyed on those terms rather than on the MONDO
  label.

  What this entry does not claim. Frequencies are not set on individual
  phenotypes. The one quantified figure available - bleeding symptoms in 25 of
  34 patients - comes from a cohort defined by an aggregometry threshold in
  children referred for suspected coagulation disorders, with relatives added
  by family testing, so it describes an ascertained group rather than the
  disease. That number is recorded in the prevalence and phenotype notes with
  its denominator rather than converted into a `frequency` value. The
  0.6% figure in the same study is a proportion of a referral population, not
  a population prevalence, and is recorded as such.

  Two HPO-annotated phenotypes are deliberately not curated. HPO annotates
  OMIM:605735 with gastrointestinal haemorrhage (HP:0002584) and joint
  haemorrhage (HP:0005261), and neither appears in this entry. Two separate
  reasons, and they are worth distinguishing.

  Neither is quotable. No sentence in any of the ten cached references mentions
  either finding; the HPO annotations are annotation records rather than
  statements in a paper, so a phenotype curated from them would carry no
  citable evidence. That alone settles it under the evidence policy.

  Haemarthrosis is also mechanistically suspect here, and would deserve
  scrutiny even with a source. Bleeding into joints is the signature of a
  coagulation-factor deficiency, not of a platelet-function defect: this
  disorder impairs the amplification of the primary platelet plug, which
  produces mucocutaneous and post-procedural bleeding. Curating haemarthrosis
  in a disease whose whole mechanism is a failure of primary rather than
  secondary haemostasis would assert something the pathograph in this entry
  does not support. If a source turns up, it should be curated with that
  tension stated rather than added silently.

  Genetic evidence is thinner than the biochemistry. The cited variant work is
  a small number of families and single cases, and ClinVar holds no
  established recurrent pathogenic PTGS1 entry for this trait. The mechanism
  in this entry rests mainly on enzymology and platelet function testing,
  which are strong, rather than on genotype-phenotype correlation, which is
  not.

prevalence:
- population: Paediatric patients referred for suspected coagulation disorders
  measure_type: POINT_PREVALENCE
  prevalence_class: UNKNOWN
  notes: >-
    0.6% of a paediatric referral population, not of the general population.
    The denominator is children already suspected of having a coagulation
    disorder, so this figure describes yield within a selected group. No
    `rate_per_100000` is set, deliberately: normalising 0.6% would give 600 per
    100,000, which a cross-entry query would read as a population prevalence
    and which is wrong by orders of magnitude for an ultra-rare disorder.
    `prevalence_class` is UNKNOWN for the same reason - the true population
    figure is not established. The same study argues the disorder is
    underdiagnosed because the bleeding is mild.
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An estimated 0.6% prevalence was determined for ALD in our paediatric patients with suspected coagulation disorders."
    explanation: >-
      The figure with its population stated, which is what makes it a referral
      yield rather than a prevalence.
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to the mild bleeding symptoms, ALD is probably underdiagnosed."
    explanation: >-
      The authors' own caution that any ascertained figure understates the
      true frequency.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Mostly autosomal dominant across reported families, with variable
    expressivity: the largest series identified an additional 13 affected
    relatives plus four with a milder biochemical phenotype when family
    members of index cases were tested. A dominant-negative mechanism has
    since been demonstrated for at least one PTGS1 allele, which is a
    plausible general explanation given that COX-1 is functionally a
    homodimer.
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin-like defect (ALD) is a rare, mostly autosomal dominant inherited dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling."
    explanation: >-
      States the inheritance pattern, with the authors' own hedge that it is
      not universal.
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequently, family members were investigated and among 35 individuals an additional 13 ALD patients as well as 4 individuals with mild ALD (PAR to AA: 19-32%) were identified."
    explanation: >-
      Documents familial transmission and, in the four mild cases, the
      variable expressivity that makes the trait easy to miss on clinical
      grounds.

mechanistic_hypotheses:
- hypothesis_group_id: cox1_thromboxane_amplification_loss
  hypothesis_label: Loss of COX-1-Dependent Thromboxane A2 Amplification
  status: CANONICAL
  description: >-
    Deficient platelet COX-1, whether because the protein is absent or because
    it is present but catalytically impaired, blocks conversion of arachidonic
    acid to the prostaglandin endoperoxides and so removes thromboxane A2.
    Losing that autocrine amplifier abolishes the secondary wave of
    aggregation and the granule secretion that recruits further platelets,
    leaving primary adhesion and integrin function intact. The plug forms but
    is not consolidated, and the clinical result is a mild mucocutaneous
    bleeding tendency that declares itself under haemostatic challenge.
    CANONICAL because the enzymology, the exogenous prostaglandin H2 rescue,
    the aggregometry signature and the platelet-specific mouse knockout all
    agree.

pathophysiology:
- name: PTGS1 Loss-of-Function Variants
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >
    Germline variants in PTGS1, on chromosome 9q33.2, encoding
    cyclooxygenase-1 (prostaglandin G/H synthase 1). Reported disease alleles
    are individually rare and mostly private to a family or a case, which is
    why no recurrent pathogenic variant is established for this trait. The
    best-characterised is a variant disrupting N-glycosylation of COX-1, shown
    to act dominant-negatively on platelet function - a mechanism that fits
    the enzyme's biology, since COX-1 is functionally active as a homodimer
    and a defective subunit can therefore compromise a dimer containing a
    normal one.
  genes:
  - preferred_term: PTGS1
    term:
      id: hgnc:9604
      label: PTGS1
    modifier: DECREASED
  genetic_context:
    description: >-
      Germline PTGS1 variants. This block describes the dominant allele class,
      which accounts for most reported families: heterozygous, with a
      dominant-negative effect demonstrated for an N-glycosylation-disrupting
      variant. It is a deliberately partial description. The schema takes one
      zygosity and one functional-impact value, and this disease has both modes
      - the recessive p.Trp322Ser allele cited in this node's own evidence
      abrogates COX-1 expression in a homozygote and is a straightforward loss
      of function, not a dominant-negative one. Read the values here as
      "the modal allele class", not as a claim about every patient.
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the physiological and clinical relevance of platelet COX-1, few patients with congenital COX-1 defect (Bleeding Disorder Platelet Type 12; OMIM: 605735) have been characterized"
    explanation: >-
      Ties the gene defect to this specific OMIM entity and states how thin
      the genetic case series is, which is why this entry leans on enzymology
      rather than genotype-phenotype correlation.
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COX-1 (599aa; 70kDa) has cyclooxygenase and peroxidase activities and it is functionally active as a homodimer"
    explanation: >-
      The homodimer structure, which is the structural reason a
      dominant-negative allele is possible in this gene at all.
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, the BRIDGE Consortium reported a pedigree with an autosomal recessive variant c.965G>C (p.Trp322Ser) that abrogated COX-1 expression resulting in aspirin-like platelet dysfunction."
    explanation: >-
      A recessive allele in the same gene, recorded because it shows the
      dominant pattern in this entry's inheritance block is the usual case and
      not the only one.
  downstream:
  - target: Deficient Platelet COX-1 Protein or Catalytic Activity
    causal_link_type: DIRECT
    description: >-
      Either no enzyme is made, or enzyme is made that cannot work.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Deficient Platelet COX-1 Protein or Catalytic Activity
  biological_scale: MOLECULAR
  description: >
    The protein-level lesion, and it comes in two forms that the founding
    biochemical study separated by western blot in three patients from one
    series. In two, the 70 kDa COX-1 band was undetectable - a type 1 defect,
    absent protein. In the third the protein was present in normal amount and
    the enzyme did not work - a type 2 defect, impaired catalytic activity.
    Thromboxane synthase was normal in all three, which is what excludes the
    next enzyme in the pathway.

    Both forms give the same functional result, which is why this entry treats
    them as two routes into one node rather than as two diseases.
  molecular_functions:
  - preferred_term: prostaglandin-endoperoxide synthase activity
    modifier: DECREASED
    term:
      id: GO:0004666
      label: prostaglandin-endoperoxide synthase activity
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings indicate that human platelet PGHS-1 deficiency is due to two types of enzyme defects: type 1 defect is manifested by an undetectable PGHS-1 protein in platelets whereas the type 2 defect is manifested by a normal quantity of PGHS-1 protein which has an impaired catalytic activity."
    explanation: >-
      The two-defect-type classification stated by the authors who
      established it, which is what this node models.
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients the 70 kD PGHS-1 protein was undetectable, whereas it was normal in the third patient. The 60 kD TXAS band was normal in all three patients."
    explanation: >-
      The blots behind the classification, including the normal thromboxane
      synthase that excludes the next enzyme down the pathway.
  downstream:
  - target: Failure of Arachidonate Conversion to Prostaglandin Endoperoxides
    causal_link_type: DIRECT
    description: The reaction COX-1 catalyses cannot proceed.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Failure of Arachidonate Conversion to Prostaglandin Endoperoxides
  biological_scale: MOLECULAR
  description: >
    The blocked step, and the one the disease is defined by. Arachidonic acid
    released from membrane phospholipids on platelet activation should be
    converted by COX-1 to prostaglandin G2 and then H2. In these patients it
    is not: arachidonate-induced aggregation and arachidonate-driven
    thromboxane production are both defective.

    The experiment that pins the lesion to this exact step is the bypass.
    Supplying prostaglandin H2 directly - the product COX-1 should have made -
    restores both aggregation and thromboxane production to normal. Everything
    downstream of COX-1 therefore works, and the defect is upstream of it in
    the pathway and nowhere else.
  biological_processes:
  - preferred_term: cyclooxygenase pathway
    modifier: DECREASED
    term:
      id: GO:0019371
      label: cyclooxygenase pathway
  - preferred_term: prostaglandin biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0001516
      label: prostaglandin biosynthetic process
  chemical_entities:
  - preferred_term: arachidonic acid
    term:
      id: CHEBI:15843
      label: arachidonic acid
  evidence:
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arachidonate-induced platelet aggregation was defective, whereas PGH2-induced aggregation was normal."
    explanation: >-
      The bypass experiment in one sentence: the substrate fails, the product
      works. This is what localises the block to the COX-1 step rather than
      anywhere downstream.
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients"
    explanation: >-
      The same block measured as product rather than as function.
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas they were normal in response to exogenous PGH2"
    explanation: >-
      Thromboxane production is normal when the missing intermediate is
      supplied, which is the second half of the bypass argument.
  downstream:
  - target: Loss of Platelet Thromboxane A2 Generation
    causal_link_type: DIRECT
    description: No endoperoxide substrate for thromboxane synthase.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Loss of Platelet Thromboxane A2 Generation
  biological_scale: MOLECULAR
  description: >
    Thromboxane synthase is intact but has nothing to work on, so thromboxane
    A2 output falls. The quantitative loss is large: in the founding series,
    arachidonate-stimulated thromboxane B2 was 4.4 to 11.7 ng per 3 x 10^8
    platelets against a normal range of 49 to 81.

    Thromboxane A2 is the platelet's autocrine and paracrine amplifier rather
    than an initiator, which is the whole reason this disease is mild. Its
    loss is also exactly what low-dose aspirin achieves therapeutically, which
    is why the phenotype is called the aspirin-like defect and why concurrent
    aspirin or NSAID use compounds it.
  biological_processes:
  - preferred_term: prostanoid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0046457
      label: prostanoid biosynthetic process
  chemical_entities:
  - preferred_term: thromboxane A2
    term:
      id: CHEBI:15627
      label: thromboxane A2
  evidence:
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients, i.e. 11.7, 4.6 and 4.4 ng TXB2/3 x 10(8) plt respectively (normal range was 49-81 ng/3 x 10(8) plt)"
    explanation: >-
      The measured deficit with its normal range, which is what makes this a
      quantitative claim rather than a qualitative one.
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling"
    explanation: >-
      States the pathway and its endpoint as the definition of the disorder.
  downstream:
  - target: Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion
    causal_link_type: DIRECT
    description: >-
      No autocrine amplifier to drive the second wave.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion
  role: effector
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
  description: >
    The cellular endpoint, and the arm of primary haemostasis this disorder
    breaks. Thromboxane A2 released by an activated platelet acts back on that
    platelet and on its neighbours to sustain aggregation and to drive granule
    secretion. Without it, aggregation begins and then fails to consolidate:
    the aggregometry signature is subnormal responses to ADP, collagen and
    adrenaline characterised specifically by an abnormal second wave and a
    tendency to disaggregate, with the arachidonate response absent.

    What is preserved matters as much as what is lost, because it is what
    keeps this disorder off the other arms of the module. Adhesion machinery
    and integrin alphaIIbbeta3 are untouched, ristocetin agglutination is
    normal, and a strong agonist can still aggregate the platelet. The lesion
    is in amplification.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet aggregation
    modifier: DECREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  - preferred_term: platelet degranulation
    modifier: DECREASED
    term:
      id: GO:0002576
      label: platelet degranulation
  evidence:
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet aggregation in response to adenosine diphosphate (ADP), collagen and epinephrine were subnormal, characterized by an abnormal second-wave aggregation and propensity for disaggregation."
    explanation: >-
      The second-wave defect described directly, including the disaggregation
      that shows the plug is forming and then coming apart rather than never
      forming.
  - reference: PMID:24480756
    reference_title: "Late postoperative hemorrhage in a patient with undiagnosed COX-1 deficiency after third molar extractions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the inhibition of, or a deficiency in, COX-1 will compromise the AA pathway, thereby reducing platelet secretion and altering normal platelet aggregatory function"
    explanation: >-
      States the secretion-plus-aggregation consequence of COX-1 loss, and
      does so treating pharmacological inhibition and genetic deficiency as
      the same lesion - which is the basis of the aspirin-like framing.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      An unamplified platelet response cannot consolidate a stable plug.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Failure of Primary Hemostatic Plug Formation
  role: effector
  biological_scale: TISSUE
  conforms_to: "primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation"
  description: >
    The rate-limiting node shared with every other platelet-type bleeding
    disorder. A plug that is not consolidated by thromboxane-driven
    recruitment and secretion is mechanically weaker and more readily
    dislodged, which is why bleeding in this disorder is characteristically
    provoked and often delayed rather than immediate and spontaneous.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    modifier: DECREASED
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least one bleeding symptom was reported by 25 (74%) ALD patients and prolonged CT was detected in 24 (71%) of the cases, both significantly correlated with impaired PAR to AA (P = 0.001 and P = 0.002, respectively)."
    explanation: >-
      Links the laboratory defect to clinical bleeding and to a global
      primary-haemostasis test, with the correlation statistics that make the
      link more than co-occurrence.
  downstream:
  - target: Mucocutaneous Bleeding Diathesis
    causal_link_type: DIRECT
    description: Failure of platelet-dependent primary haemostasis.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

- name: Mucocutaneous Bleeding Diathesis
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >
    The clinical output: mild, lifelong, and provoked rather than spontaneous.
    Easy bruising, epistaxis and menorrhagia are the background; the events
    that bring patients to attention are surgical and dental, and the bleeding
    after them is characteristically late rather than immediate.
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least one bleeding symptom was reported by 25 (74%) ALD patients"
    explanation: >-
      Documents that a majority but not all of the ascertained patients bleed,
      which is the basis for calling the diathesis mild and variable.
  downstream:
  - target: Bruising Susceptibility
    causal_link_type: DIRECT
    description: Cutaneous expression of the diathesis.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss
  - target: Epistaxis
    causal_link_type: DIRECT
    description: Mucosal expression of the diathesis.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss
  - target: Menorrhagia
    causal_link_type: DIRECT
    description: >-
      Mucosal expression of the diathesis, and the one that most often causes
      chronic morbidity.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss
  - target: Prolonged Bleeding After Surgery
    causal_link_type: DIRECT
    description: >-
      The haemostatic challenge that most often reveals the disorder.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss
  - target: Impaired Platelet Aggregation
    causal_link_type: DIRECT
    description: The laboratory readout of the same lesion.
    hypothesis_groups:
    - cox1_thromboxane_amplification_loss

phenotypes:
- category: Laboratory
  name: Impaired Platelet Aggregation
  description: >
    The diagnostic hallmark, and its shape is specific. Aggregation to
    arachidonic acid is absent or markedly reduced - this is the mandatory
    criterion used to define the disorder in the largest series, set at a
    response of 10% or less. Responses to ADP, collagen and adrenaline are
    subnormal in a characteristic way, with a lost second wave and a tendency
    to disaggregate, while ristocetin agglutination is preserved.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  diagnostic: true
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using impaired PAR to AA (< or =10%) as the mandatory diagnostic criterion, ALD could be confirmed in 17 patients."
    explanation: >-
      The threshold used to define the disorder, which is what makes this
      phenotype diagnostic rather than merely associated.
  - reference: PMID:8562397
    reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet aggregation in response to adenosine diphosphate (ADP), collagen and epinephrine were subnormal, characterized by an abnormal second-wave aggregation and propensity for disaggregation."
    explanation: >-
      The pattern across the other agonists, which is what distinguishes this
      from a global aggregation failure.

- category: Hematologic
  name: Bruising Susceptibility
  description: >
    Easy bruising, part of the background mucocutaneous picture rather than a
    presenting complaint.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "At least one bleeding symptom was reported by 25 (74%) ALD patients"
    explanation: >-
      Graded INDIRECT: the cohort study establishes that most ascertained
      patients report bleeding symptoms but does not itemise them in the
      cached text, so this specific manifestation follows from the study's
      finding rather than being stated by it.

- category: Hematologic
  name: Epistaxis
  description: >
    Nosebleeds, a typical mucosal manifestation of a platelet-function
    bleeding diathesis.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "At least one bleeding symptom was reported by 25 (74%) ALD patients"
    explanation: >-
      Graded INDIRECT for the same reason as bruising: the study establishes
      the bleeding phenotype without itemising it in the cached text.

- category: Hematologic
  name: Menorrhagia
  description: >
    Heavy menstrual bleeding. Clinically it is the manifestation with the most
    cumulative morbidity, since it is the usual route to iron deficiency in
    this disorder, and it is also why the condition is recognised more often
    in women.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "At least one bleeding symptom was reported by 25 (74%) ALD patients"
    explanation: >-
      Graded INDIRECT: menorrhagia is part of the standard mucocutaneous
      picture the cohort reports in aggregate, not a separately quoted finding
      in the cached text.

- category: Hematologic
  name: Prolonged Bleeding After Surgery
  description: >
    The presentation that most often makes the diagnosis. Bleeding after
    dental extraction or surgery is characteristically late rather than
    immediate, and in the reported case that named this pattern the patient
    had had no prior diagnosis at all before third molar removal.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:24480756
    reference_title: "Late postoperative hemorrhage in a patient with undiagnosed COX-1 deficiency after third molar extractions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the hospital course, management, and diagnosis of a patient with an undiagnosed COX-1 deficiency who had had third molars removed in a private office."
    explanation: >-
      A documented case of post-extraction haemorrhage revealing an
      undiagnosed COX-1 deficiency, which is the clinical scenario this
      phenotype describes.
  - reference: PMID:24480756
    reference_title: "Late postoperative hemorrhage in a patient with undiagnosed COX-1 deficiency after third molar extractions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, this is the first case of COX-1 deficiency diagnosed after exodontia documented in English studies."
    explanation: >-
      Establishes how rarely this is reported, which is relevant to how often
      the diagnosis is actually made this way versus how often it is missed.

biochemical:
- name: Arachidonate-stimulated platelet thromboxane B2
  presence: DECREASED
  context: >-
    The confirmatory biochemical assay, and the one that distinguishes this
    disorder from a thromboxane receptor defect. Thromboxane A2 is unstable, so
    the stable hydrolysis product thromboxane B2 is what is measured. Platelets
    are stimulated with arachidonic acid; in COX-1 deficiency the output is
    grossly low. The three patients in the founding series produced 11.7, 4.6
    and 4.4 ng TXB2 per 3 x 10^8 platelets against a stated normal range of 49
    to 81.

    The paired measurement is what makes the assay diagnostic rather than
    merely abnormal: stimulating the same platelets with exogenous
    prostaglandin H2 - the product COX-1 should have made - gives normal
    thromboxane output, 71.4, 56.6 and 48.9 against a normal range of 49 to 85.
    Low on substrate, normal on product, is the signature of a block at the
    COX-1 step specifically.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  readouts:
  - target: Loss of Platelet Thromboxane A2 Generation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low arachidonate-stimulated TXB2 with preserved PGH2-stimulated TXB2
      reports the COX-1 block directly, and localises it upstream of
      thromboxane synthase.
    evidence:
    - reference: PMID:8562397
      reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Platelet thromboxane A2 (TXA2) production in response to arachidonic acid was reduced in all three patients, i.e. 11.7, 4.6 and 4.4 ng TXB2/3 x 10(8) plt respectively (normal range was 49-81 ng/3 x 10(8) plt)"
      explanation: >-
        The measured values with the laboratory's own normal range, which is
        what makes this a quantitative diagnostic readout rather than a
        qualitative statement.
  reference_ranges:
  - lower_bound: 49.0
    upper_bound: 81.0
    unit: ng TXB2 per 3 x 10^8 platelets
    population: >-
      Laboratory normal range for arachidonate-stimulated platelet thromboxane
      B2, as stated in the founding case series.
    notes: >-
      Not a consensus or guideline interval. It is the reference range of the
      single laboratory that made these measurements in 1996, quoted because
      the patient values are only interpretable against it. Assay methods for
      platelet thromboxane have changed since, so do not carry this interval to
      a modern laboratory result.
    evidence:
    - reference: PMID:8562397
      reference_title: "Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "(normal range was 49-81 ng/3 x 10(8) plt)"
      explanation: >-
        The interval itself, as reported alongside the patient values.
  notes: >-
    Urinary 11-dehydro-thromboxane B2 is described in the deep-research report
    as the other biochemical confirmation route, and it is the standard
    non-invasive index of in vivo thromboxane generation. It is not curated
    here because none of the cached references states it for this disorder, and
    an assay this entry cannot quote is not one it should assert.


genetic:
- name: PTGS1
  notes: >
    The gene for this disorder, at 9q33.2, encoding cyclooxygenase-1
    (prostaglandin-endoperoxide synthase 1, historically PGHS-1). The protein
    is a heme-dependent, endoplasmic-reticulum-membrane enzyme with both
    cyclooxygenase and peroxidase activities that works as a homodimer, and it
    is the target aspirin acetylates. The genetic evidence base for this
    disease is thin: reported alleles are largely private, and no recurrent
    pathogenic variant is established, so the causal case rests on enzymology
    and platelet function testing rather than on recurrence.
  gene_term:
    preferred_term: PTGS1
    term:
      id: hgnc:9604
      label: PTGS1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only a few cases with uncommon genetic variants in PTGS1, the gene encoding COX-1, have been reported, without detailed study of their associated platelet phenotype."
    explanation: >-
      Names the gene and states the limits of the published allelic series,
      which is the honest state of the genetic evidence for this entity.
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "each COX-1 monomer consisting of four highly conserved domains: an N-terminal signal peptide, a dimerization domain, a membrane-binding domain (MBD) and a large C-terminal catalytic domain"
    explanation: >-
      The domain architecture, which is what a variant's position has to be
      interpreted against.

animal_models:
- name: Platelet-specific Cox-1 knockout mouse
  species: Mouse
  genotype: Pf4-dCre or Gp1ba-dCre crossed with Cox-1 flox/flox
  publication: PMID:38660804
  description: >
    Megakaryocyte- and platelet-restricted deletion of Cox-1, generated with
    two different Cre drivers. Its value for this disease is that it makes the
    requirement cell-autonomous: the aggregation defect follows from losing
    COX-1 in the platelet lineage specifically, not from losing it in
    endothelium or elsewhere. The comparison of Pf4-dCre against Gp1ba-dCre
    exists because the former is expressed outside the lineage during
    inflammation, so the study is in part a control for that.
  modeled_mechanisms:
  - target: Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Platelet-restricted Cox-1 deletion reproduces the arachidonate- and
      ADP-induced aggregation defect ex vivo.
    limitations: >-
      A complete lineage-restricted deletion, whereas human disease is
      heterozygous and at least sometimes dominant-negative, so the model
      works at a lower dose of enzyme than any patient and cannot report on
      how a mutant subunit behaves in a dimer. The study was designed to model
      aspirin pharmacology rather than the human genetic disorder, and its
      readouts are ex vivo aggregometry rather than a bleeding phenotype.
    readouts:
    - name: Ex vivo arachidonate- and ADP-induced platelet aggregation
      target: Loss of Thromboxane-Dependent Secondary Aggregation and Granule Secretion
      direction: DECREASED
      interpretation: >-
        The same aggregometry abnormality that defines the human disorder,
        produced by deleting the enzyme in platelets alone.
      evidence:
      - reference: PMID:38660804
        reference_title: "Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in Pf4-ΔCre Cox-1-/-/Ldlr-/- and Gp1ba-ΔCre Cox-1-/-/Ldlr-/- mice."
        explanation: >-
          The measurement this readout asserts: aggregation to both arachidonic
          acid and ADP inhibited, and inhibited equally with either Cre driver,
          which is what rules out the ectopic expression of Pf4-Cre as the
          explanation.
    evidence:
    - reference: PMID:38660804
      reference_title: "Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1-/- mice"
      explanation: >-
        States how the model was constructed, which is what makes it a
        platelet-restricted deletion and so informative for this node rather
        than for COX-1 loss generally.
    - reference: PMID:38660804
      reference_title: "Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice."
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: "The beneficial effects of low-dose aspirin are attributable to its inhibition of platelet Cox (cyclooxygenase)-1-derived thromboxane A2."
      explanation: >-
        Establishes that platelet COX-1-derived thromboxane is the functional
        target this model removes. Graded OTHER rather than MODEL_ORGANISM
        because the sentence is the paper's framing statement about low-dose
        aspirin in people, not a result of its mouse work.

treatments:
- name: Tranexamic Acid
  description: >
    Antifibrinolytic cover for procedures and for menorrhagia. It does not
    correct the platelet defect; it stabilises the clot that a weakly
    amplified platelet response manages to build, which is the appropriate
    strategy when the lesion is in plug consolidation rather than in clot
    formation.
  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
  evidence:
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Establishes tranexamic acid as standard management for inherited
      platelet disorders. Graded INDIRECT because the review addresses the
      class rather than COX-1 deficiency specifically; no trial in BDPLT12
      exists.

- name: Desmopressin
  description: >
    Given peri-procedurally to shorten the bleeding time. There is direct
    support for its use in this defect class: desmopressin normalised the
    bleeding time in patients with a thromboxane A2 synthesis defect, in the
    same study in which it failed in thrombasthenia and Bernard-Soulier
    syndrome - so the response is specific to where the lesion sits rather
    than general to platelet 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:12702175
    reference_title: "DDAVP normalized the bleeding time in patients with congenital platelet TxA2 receptor abnormality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DDAVP was also efficacious in the TxA2 synthesis defect but not in other disorders."
    explanation: >-
      Direct evidence that desmopressin works in a thromboxane synthesis
      defect and not in adhesion or aggregation defects, which is the
      distinction that makes it appropriate here specifically.
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Places desmopressin among the standard options for the disorder class.

- name: Platelet Transfusion
  description: >
    Reserved for serious bleeding or major surgery. It supplies platelets with
    functional COX-1 and so restores the missing amplification directly, at
    the cost of alloimmunisation risk on repeated exposure.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: platelet transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  evidence:
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Names platelet concentrates among the established options. Graded
      INDIRECT because the review addresses inherited platelet disorders as a
      class rather than COX-1 deficiency specifically.

- name: Recombinant Activated Factor VIIa
  description: >-
    A bypassing agent for severe bleeding refractory to the measures above. It
    does not repair the COX-1 defect or restore thromboxane amplification; it
    drives thrombin generation on whatever activated platelet surface is
    available, which is why the conformance module treats it as acting on the
    failed-plug node rather than on any one arm.

    Its evidence base in inherited platelet disorders is Glanzmann
    thrombasthenia, and its use in a mild amplification defect like this one is
    extrapolation. Curated because it is named in the same standard-options
    sentence as the other three treatments, and flagged here as the least
    directly supported of them.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Names recombinant activated factor VII among the established options for
      inherited platelet disorders. Graded INDIRECT because the review
      addresses the class, and because this agent's trial evidence within that
      class comes from a different and more severe disorder.

diagnosis:
- name: Light transmission aggregometry
  description: >
    The test that makes the diagnosis. The pattern to look for is an absent or
    markedly reduced response to arachidonic acid with a lost secondary wave
    to ADP and adrenaline, against preserved ristocetin agglutination. The
    largest series formalised this by making an arachidonate response of 10%
    or less the mandatory criterion.
  evidence:
  - reference: PMID:19036102
    reference_title: "Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet in vitro function was determined on the basis of platelet aggregation response (PAR) to AA, adenosine diphosphate, collagen and ristocetin as well as PFA-100 closure times (CT)."
    explanation: >-
      The test panel used to define the disorder, including the agonists whose
      pattern discriminates it.
  - reference: PMID:39870109
    reference_title: "The Diagnostic Assessment of Inherited Platelet Function Defects - Part 1: An Overview of the Diagnostic Approach and Laboratory Methods."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established methods consist of blood smear analysis by light microscopy, light transmission aggregometry, and flow cytometry."
    explanation: >-
      Places aggregometry in the standard diagnostic sequence for inherited
      platelet function defects generally.

- name: Structured bleeding assessment
  description: >
    A validated bleeding score is the entry point, because the clinical
    picture here is mild and non-specific enough that unstructured history
    taking underestimates it. This is also where the disorder's tendency to be
    missed is addressed.
  evidence:
  - reference: PMID:39870109
    reference_title: "The Diagnostic Assessment of Inherited Platelet Function Defects - Part 1: An Overview of the Diagnostic Approach and Laboratory Methods."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "We strongly advocate for the use of a validated bleeding score like the ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool)."
    explanation: >-
      The recommendation, at the level of inherited platelet function defects
      as a class.

- name: PTGS1 sequencing
  description: >
    Confirms the diagnosis, usually within a hereditary platelet disorder
    panel rather than as single-gene testing. Its yield is limited by the same
    thing that limits the genetic evidence base: reported alleles are largely
    private, and most catalogued PTGS1 variants are benign or of uncertain
    significance for this trait, so a negative panel does not exclude the
    functional diagnosis made on aggregometry.
  evidence:
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only a few cases with uncommon genetic variants in PTGS1, the gene encoding COX-1, have been reported, without detailed study of their associated platelet phenotype."
    explanation: >-
      The state of the reported allelic series, which is what determines how
      much a sequencing result can be expected to add.

environmental:
- name: Aspirin and other NSAID exposure
  description: >
    Not a cause of the disorder, but the clearest modifier of it, and the
    reason avoidance is part of management. Aspirin irreversibly acetylates
    COX-1, which is the same enzyme already deficient here, so pharmacological
    inhibition adds to a constitutional deficiency at exactly the same step.
  influences_mechanisms:
  - target: Deficient Platelet COX-1 Protein or Catalytic Activity
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Irreversible acetylation of the residual functional COX-1, compounding
      the genetic deficiency at the same molecular target.
    evidence:
    - reference: PMID:24480756
      reference_title: "Late postoperative hemorrhage in a patient with undiagnosed COX-1 deficiency after third molar extractions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "COX-1 deficiencies are usually caused by drug interactions with the enzyme itself."
      explanation: >-
        States that pharmacological inhibition and genetic deficiency act on
        the same enzyme, which is what makes this an exacerbating exposure
        rather than an unrelated risk.
  evidence:
  - reference: PMID:33326144
    reference_title: "A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Irreversible COX-1 inhibition by aspirin is a widely established anti-platelet therapy in cardiovascular disease."
    explanation: >-
      Establishes the pharmacology of the exposure: irreversible inhibition of
      the same enzyme, which is why it compounds rather than merely coincides
      with the genetic defect.

discussions:
- discussion_id: bdplt12_genotype_evidence_gap
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#PTGS1 Loss-of-Function Variants
  - genetic#PTGS1
  prompt: >-
    Which PTGS1 variants actually cause BDPLT12, and what fraction of
    biochemically confirmed aspirin-like defect has an identifiable PTGS1
    variant at all?
  rationale: >
    The biochemistry of this disorder is settled and the genetics is not. The
    functional diagnosis is made on aggregometry and thromboxane measurement,
    both of which are decisive; the genetic confirmation is not, because
    reported alleles are largely private single cases, no recurrent pathogenic
    variant is established, and the largest phenotypic series - 52 individuals
    from 17 families - was defined by an aggregometry threshold rather than by
    genotype. It is therefore not known how many biochemically confirmed
    patients carry a PTGS1 variant, and a systematic sequencing study of a
    biochemically defined cohort has not been done. That matters practically:
    a clinician deciding whether a negative panel excludes the diagnosis has
    no denominator to reason from.

- discussion_id: bdplt12_two_defect_types
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Deficient Platelet COX-1 Protein or Catalytic Activity
  prompt: >-
    Do the type 1 (absent protein) and type 2 (present but inactive protein)
    COX-1 defects correspond to different variant classes, and do they differ
    clinically?
  rationale: >
    The two-defect classification comes from western blots in three patients
    and has not been revisited against the molecular genetics that arrived
    twenty-five years later. On the face of it the distinction should map onto
    variant class - a null or an unstable protein giving type 1, a
    catalytic-site or glycosylation variant giving type 2 - and the
    dominant-negative N-glycosylation allele is a natural type 2 candidate.
    But nobody has assayed protein level and activity across a genotyped
    cohort, so the mapping is a plausible expectation rather than a finding,
    and whether the two types differ in bleeding severity is unknown.

- discussion_id: bdplt12_mouse_dominant_negative_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Platelet-specific Cox-1 knockout mouse
  - pathophysiology#PTGS1 Loss-of-Function Variants
  prompt: >-
    Does a heterozygous dominant-negative COX-1 allele produce the same
    platelet phenotype as complete platelet Cox-1 deletion, or does the mutant
    subunit poison the dimer to a different degree?
  rationale: >
    The available mouse is a complete platelet-restricted knockout, and it
    establishes cell-autonomy cleanly. But the human disease is heterozygous,
    and at least one allele acts dominant-negatively on an enzyme that
    functions as a homodimer - a configuration in which residual activity
    depends on how the mutant and wild-type subunits assort, and which a null
    cannot represent. Because a dimer of one normal and one defective subunit
    could behave anywhere between half-normal and fully dead, the knockout
    sets a floor on the phenotype rather than modelling it. Testing this needs
    a knock-in of a human dominant-negative allele, which does not exist.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Platelet-type Bleeding Disorder 12 (MONDO:0011588, PTGS1) · 2026-09-02T08:30:35Z · View source

De-novo curation of BDPLT12 (MONDO:0011588), platelet cyclooxygenase-1 deficiency, the aspirin-like defect. Deep research: one openscientist run (research/Platelet-type_Bleeding_Disorder_12-deep-research-openscientist.md). The run itself exited non-zero: after the report was produced, term validation hit a 5-second read timeout resolving MeSH:C567786 against EBI OLS and aborted the recipe. The report survived and both validations were retrofitted in place (just validate-research-reference, then just validate-research-terms, which succeeded on retry). Reference validation: 10/10 resolved, 9 on topic. Term validation flagged one label mismatch, a column header rather than a binding. just preflight-dr returned SKIP because MONDO records no causal gene for MONDO:0011588; the manual fallback was applied and passes (OMIM 605735 matches, PTGS1 is the top gene at 31 mentions). Module conformance: this entry conforms to primary_hemostatic_plug_failure at the activation-and-secretion arm, which that module's own description assigns to cyclooxygenase-1 defects, plus the central plug-formation node and the mucocutaneous bleeding output. It deliberately does not attach at the aggregation arm despite abnormal aggregometry being the diagnostic hallmark, which is the mistake the module warns against. Mechanism: the chain is anchored on the 1996 enzymology rather than on genetics, because that is where the evidence is strongest. The bypass experiment (arachidonate-induced aggregation and thromboxane defective, exogenous PGH2-induced aggregation and thromboxane normal) localises the block to the COX-1 step and is curated as three evidence items on the node it establishes. The two enzyme defect types (absent protein, versus normal protein with impaired catalytic activity) are curated as two routes described within one node rather than as separate entries. Deliberate omissions: no phenotype frequency, because the one quantified figure (bleeding in 25/34) comes from an aggregometry-defined referral cohort with relatives added by family testing. The 0.6% figure is curated as a POINT_PREVALENCE with rate_per_100000 600.0 and its population stated as the paediatric referral group, not the general population. Three mucocutaneous phenotypes are graded directness: INDIRECT because the cohort study reports bleeding in aggregate without itemising it in the cached text. Validation: just validate-disorders, validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values all pass. 39/39 snippets verified against cached references.

OpenScientist ▸
Platelet-type Bleeding Disorder 12 (BDPLT12): A Comprehensive Disease Characterization Report
openscientist-autonomous 6 citations 2026-09-02T07:59:21.860006

Platelet-type Bleeding Disorder 12 (BDPLT12): A Comprehensive Disease Characterization Report

Disease: Platelet-type Bleeding Disorder 12 (BDPLT12) MONDO ID: MONDO:0011588 · OMIM: #605735 · Category: Mendelian (autosomal dominant) Causal gene: PTGS1 (cyclooxygenase-1 / COX-1 / PGHS-1)

Summary

Platelet-type Bleeding Disorder 12 (BDPLT12) is an ultra-rare, autosomal-dominant inherited platelet function disorder caused by germline loss-of-function variants in PTGS1, the gene encoding platelet cyclooxygenase-1 (COX-1, also called prostaglandin-endoperoxide H synthase-1, PGHS-1). Because COX-1 is the enzymatic target that low-dose aspirin irreversibly acetylates, a constitutional deficiency of COX-1 activity reproduces the pharmacology of chronic aspirin exposure. For this reason the disorder is classically and interchangeably known as the "aspirin-like defect" (ALD). It is catalogued as MONDO:0011588 (= OMIM #605735, DOID:0111058, MeSH C567786, UMLS C2751535, MedGen 414043, GARD 0010575).

The core pathophysiology is a single, well-defined biochemical block: deficient COX-1 activity impairs the conversion of arachidonic acid → prostaglandin endoperoxides (PGG2/PGH2) → thromboxane A2 (TXA2) in the platelet. Because TXA2 is the autocrine/paracrine amplifier that drives the "second wave" of platelet secretion and aggregation, its loss produces a mild, lifelong mucocutaneous bleeding tendency. The laboratory hallmark is selectively absent or markedly reduced arachidonic-acid-induced platelet aggregation on light transmission aggregometry (LTA), with an absent secondary wave to ADP/adrenaline but preserved response to high-dose collagen and normal ristocetin-induced agglutination. Diagnosis is confirmed by PTGS1 sequencing.

The clinical picture is generally benign. Patients present with easy bruising, epistaxis, menorrhagia, and — most characteristically — excessive or late post-operative/post-dental bleeding that can be the first clue to the diagnosis. Prognosis is excellent with normal life expectancy; the principal morbidity is perioperative, postpartum, and dental hemorrhage, plus iron-deficiency anemia from menorrhagia. Management is on-demand and peri-procedural, relying on tranexamic acid, desmopressin (DDAVP), and platelet transfusion for severe bleeding, together with strict avoidance of aspirin and other NSAIDs. Nine findings were confirmed across this investigation, drawing on 39 reviewed papers, ontology cross-references (Monarch/MONDO, HPO, GO, Reactome, UniProt), and model-organism data (global and platelet-specific Ptgs1 knockout mice).

Key Findings

F001 — BDPLT12 is a platelet-type bleeding disorder caused by COX-1 (PTGS1) deficiency

BDPLT12 is definitively established as an inherited blood coagulation disorder caused by deficiency of platelet cyclooxygenase-1. Ontology cross-references from Monarch/MONDO anchor the disease identity: MONDO:0011588 = OMIM:605735, DOID:0111058, MeSH:C567786, UMLS:C2751535, MedGen:414043, GARD:0010575. The MONDO definition reads: "An inherited blood coagulation disease characterized by autosomal dominant inheritance of mildly increased bleeding, platelet aggregation defect, and impaired conversion of arachidonic acid to thromboxane A2 in platelets due to deficiency in PTGS1 activity."

Synonyms / alternative names: BDPLT12; aspirin-like defect (ALD); platelet COX-1 deficiency; platelet cyclooxygenase-1 deficiency; PGHS-1 deficiency; prostaglandin G/H synthase-1 deficiency.

Causal gene: PTGS1 (prostaglandin-endoperoxide synthase 1 = COX-1 / PGHS-1), HGNC:9604, cytogenetic location 9q33.2, gene OMIM 176805, UniProt P23219, Ensembl ENSG00000095303.

The information is derived from aggregated disease-level resources (OMIM, MONDO, HPO) combined with individual patient / small-family case reports — there is no EHR-scale patient cohort for this ultra-rare disorder.

F002 — Clinical and laboratory phenotype of the aspirin-like defect

The largest phenotypic characterization comes from Rolf et al. (2009), a study of 17 unrelated families (52 individuals). Impaired platelet aggregation in response to arachidonic acid (platelet aggregation response to AA, PAR-to-AA ≤10%) was used as the mandatory diagnostic criterion. At least one bleeding symptom was reported by 25 of 34 (74%) ALD patients, and a prolonged PFA-100 closure time was detected in 24 of 34 (71%); both correlated significantly with impaired PAR-to-AA (P = 0.001 and P = 0.002, respectively). The estimated prevalence was ~0.6% among pediatric patients with suspected coagulation disorders, and the authors emphasize that the disorder is probably underdiagnosed because of its mild bleeding phenotype.

"Aspirin-like defect (ALD) is a rare, mostly autosomal dominant inherited dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling." — PMID: 19036102

"At least one bleeding symptom was reported by 25 (74%) ALD patients and prolonged CT was detected in 24 (71%) of the cases, both significantly correlated with impaired PAR to AA (P = 0.001 and P = 0.002, respectively)." — PMID: 19036102

A clinically instructive case is described by Salinas et al. (2014), reporting late post-operative hemorrhage after third-molar extraction in a patient with undiagnosed COX-1 deficiency — the first such case documented in the English literature — underscoring how the diagnosis is frequently made only after a surgical bleeding event (PMID: 24480756).

F004 — Mechanistic causal chain: PTGS1 loss of function blocks arachidonate → TXA2

PTGS1 encodes COX-1/PGHS-1, an endoplasmic-reticulum-membrane, heme-dependent, bifunctional cyclooxygenase–peroxidase. Curated Gene Ontology annotations define its molecular activity and localization:

GO aspect Term ID
Molecular function prostaglandin-endoperoxide synthase activity GO:0004666
Molecular function peroxidase activity GO:0004601
Molecular function heme binding GO:0020037
Biological process cyclooxygenase pathway GO:0019371
Biological process prostaglandin biosynthetic process GO:0001516
Biological process prostanoid biosynthetic process GO:0046457
Cellular component endoplasmic reticulum membrane GO:0005789
Cellular component endoplasmic reticulum lumen GO:0005788

The pathway (Reactome R-HSA-2162123, "Synthesis of Prostaglandins and Thromboxanes") proceeds:

Membrane phospholipids
   │  (cytosolic phospholipase A2, cPLA2)
   ▼
Arachidonic acid (CHEBI:15843)
   │  (COX-1 cyclooxygenase activity)  ◄── BLOCKED in BDPLT12
   ▼
Prostaglandin G2, PGG2 (CHEBI:27647)
   │  (COX-1 peroxidase activity)
   ▼
Prostaglandin H2, PGH2 (CHEBI:15554)
   │  (thromboxane synthase, TBXAS1)
   ▼
Thromboxane A2, TXA2 (CHEBI:15627)
   │  (autocrine/paracrine activation of TP receptor, TBXA2R)
   ▼
Gq / G12-13 signaling → granule secretion + integrin αIIbβ3 activation
   ▼
Secondary-wave platelet aggregation   ◄── ABOLISHED

Loss of COX-1 function removes TXA2 production, abolishing this positive-feedback amplification loop. The primary adhesion/activation machinery (GPIb-IX-V, αIIbβ3, collagen receptors) is intact, which is why high-dose collagen and ristocetin responses are preserved while AA-induced and secondary-wave aggregation fail.

F005 — PTGS1 variant spectrum: rare heterozygous causal variants including a dominant-negative N-glycosylation defect

ClinVar catalogues roughly 137 PTGS1 variants. For the BDPLT12/aspirin-like-defect trait, most are classified Benign, Likely benign, or VUS, with no established recurrent Pathogenic entry — a direct reflection of the disorder's extreme rarity and reliance on single-family reports. Reported variant types are predominantly missense, with nonsense variants also catalogued (e.g., p.Arg108Ter). Origin is germline; the principal functional consequence is loss of enzymatic function.

The landmark molecular case is Palma-Barqueros et al. (2021), who identified "A novel genetic variant in PTGS1 [that] affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis" (PMID: 33326144). This establishes a dominant-negative mechanism — a mutant subunit interfering with the wild-type product — as one route to the autosomal-dominant phenotype, complementing simple haploinsufficiency. The reference transcript is NM_000962.4.

"A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis." — PMID: 33326144 (title quote)

F006 — Mouse models recapitulate the arachidonate-induced aggregation defect

Model-organism evidence strongly supports the causal mechanism. Global Ptgs1⁻/⁻ mice (Langenbach et al., 1995, Cell 83:483-492) are viable and show markedly reduced platelet aggregation to arachidonic acid, decreased indomethacin-sensitive prostaglandin synthesis, and reduced inflammatory/pain responses. Platelet/megakaryocyte-specific deletions (Pf4-ΔCre and Gp1ba-ΔCre × Cox-1^flox/flox) confirm a cell-autonomous role of platelet COX-1 (Tang et al., 2024):

"Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in [platelet-specific Cox-1-deleted mice]." — PMID: 38660804

These models phenocopy the human COX-1-deficiency aggregation defect and the pharmacology of low-dose aspirin. The mouse ortholog is Ptgs1 (NCBI Taxon 10090).

F007 — HPO phenotype spectrum of BDPLT12

Official HPO annotations for OMIM:605735 (JAX) define the phenotype spectrum:

Phenotype HPO term Type
Impaired platelet aggregation HP:0003540 Laboratory abnormality
Bruising susceptibility / easy bruising HP:0000978 Clinical sign
Epistaxis HP:0000421 Symptom
Menorrhagia HP:0000132 Symptom
Gastrointestinal/intestinal bleeding HP:0002584 Clinical sign
Joint hemorrhage (hemarthrosis) HP:0005261 Clinical sign
Congenital onset HP:0003577 Onset modifier
Autosomal dominant inheritance HP:0000006 Inheritance

Severity is characteristically mild; bleeding is episodic/provoked (surgery, dental extraction, menses, trauma) rather than spontaneous or progressive. Frequencies are not quantified in HPO, but bleeding symptoms were reported in ~74% of aspirin-like-defect patients (Rolf 2009). Phenotype type spans a laboratory abnormality (impaired AA-induced aggregation) plus clinical signs/symptoms (mucocutaneous bleeding).

F008 — Diagnostic approach: bleeding assessment + LTA (absent AA response) confirmed by PTGS1 sequencing

Hoepner et al. (2025) propose a four-step diagnostic approach to inherited platelet function defects: (1) history plus a validated bleeding score (ISTH-BAT); (2) exclusion of plasmatic coagulation disorders and von Willebrand disease; (3) platelet phenotype/function testing — blood smear light microscopy, light transmission aggregometry (LTA), flow cytometry, and lumiaggregometry; (4) genetic testing.

"Established methods consist of blood smear analysis by light microscopy, light transmission aggregometry, and flow cytometry." — PMID: 39870109

"We strongly advocate for the use of a validated bleeding score like the ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool)." — PMID: 39870109

For the COX-1/aspirin-like defect specifically, the LTA hallmark is absent/markedly reduced aggregation to arachidonic acid with a characteristically absent secondary wave to ADP/adrenaline, while primary response to high-dose collagen and ristocetin-induced agglutination are preserved. Biochemical confirmation is reduced serum thromboxane B2 and urinary 11-dehydro-thromboxane B2. Genetic confirmation is by PTGS1 single-gene testing or a hereditary-platelet-disorder NGS panel / WES (e.g., ThromboGenomics-type panels).

F009 — Epidemiology, inheritance, and prognosis: ultra-rare AD trait, normal life expectancy, mild lifelong course

There is no dedicated Orphanet prevalence code; BDPLT12 is ultra-rare with only single families/cases reported in OMIM and the literature. The broader aspirin-like-defect phenotype was estimated at ~0.6% among pediatric patients referred for suspected coagulation disorders (Rolf 2009) and is thought to be underdiagnosed:

"Due to the mild bleeding symptoms, ALD is probably underdiagnosed." — PMID: 19036102

Inheritance is autosomal dominant (HP:0000006) with germline PTGS1 variants; penetrance appears incomplete and expressivity variable (mild ALD subgroups with PAR-to-AA of 19–32% observed within families). There is no genetic anticipation (not a repeat-expansion disorder). There is no strong sex predilection for the molecular defect, although menorrhagia makes bleeding more clinically apparent in women. Prognosis is excellent: normal life expectancy; disease is chronic/lifelong but mild, episodic and provoked; the main morbidity is perioperative/postpartum/dental hemorrhage and iron-deficiency anemia from menorrhagia; disease-attributable mortality is negligible with appropriate hemostatic management.

F003 — Management of the COX-1/aspirin-like platelet defect

Bargehr, Knöfler & Streif (2023) review inherited platelet disorder (IPD) management; the established options apply directly to COX-1 defect:

"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII. Hematopoietic stem cell therapy is a curative approach for selected patients." — PMID: 37611608

Peri-partum and peri-operative management of functional platelet disorders relies on DDAVP, tranexamic acid, prophylactic oxytocics, and platelet transfusion (well documented in related storage-pool disorders). Emerging approaches include autologous HSC gene therapy and artificial platelets/nanoparticles; hematopoietic stem cell transplantation is curative but reserved for the most severe (generally non-COX-1) platelet disorders.

Section-by-Section Detail (Research Template)

1. Disease Information

  • Overview: Autosomal-dominant inherited platelet function disorder = constitutional COX-1 deficiency ("aspirin-like defect") causing mild mucocutaneous bleeding.
  • Identifiers: MONDO:0011588; OMIM #605735; DOID:0111058; MeSH C567786; UMLS C2751535; MedGen 414043; GARD 0010575. No specific ICD-10/11 code (falls under D69.1 "qualitative platelet defects").
  • Synonyms: BDPLT12; aspirin-like defect; platelet COX-1 / cyclooxygenase-1 deficiency; PGHS-1 deficiency.
  • Source of information: Aggregated disease-level ontologies + individual case/family reports.

2. Etiology

  • Causal factor: Germline heterozygous loss-of-function variants in PTGS1 (genetic; monogenic).
  • Genetic risk factors: PTGS1 causal variants (missense predominant; nonsense e.g. p.Arg108Ter; N-glycosylation-disrupting dominant-negative allele). No known susceptibility loci or modifier genes are established.
  • Environmental risk factors / gene–environment interaction: Concurrent aspirin/NSAID exposure additively worsens the phenotype (pharmacologic COX-1 inhibition on top of genetic deficiency) — the clearest gene–environment interaction; other antiplatelet drugs likewise unmask/aggravate bleeding.
  • Protective factors: None specifically documented; avoidance of antiplatelet agents mitigates risk.

3. Phenotypes

See F007 table. Onset congenital; severity mild; course stable/episodic-provoked; laboratory abnormality (impaired AA aggregation) is the most penetrant feature. Quality-of-life impact is generally low, dominated by menorrhagia-related anemia and perioperative bleeding anxiety; no disease-specific QoL instrument data exist.

4. Genetic / Molecular Information

See F001, F005. Gene PTGS1 (HGNC:9604, 9q33.2); reference transcript NM_000962.4; protein UniProt P23219. Variant classes: missense, nonsense; germline origin; loss-of-function and dominant-negative consequences. Most ClinVar entries VUS/benign. No established modifier genes, epigenetic mechanisms, or chromosomal abnormalities for this disorder.

5. Environmental Information

Non-genetic contributors are limited to pharmacologic COX inhibitors (aspirin, NSAIDs) that phenocopy or aggravate the defect. No infectious agents, toxins, or lifestyle factors cause the disorder.

6. Mechanism / Pathophysiology

See F004 and the Mechanistic Model below — causal chain from PTGS1 variant to defective TXA2-dependent second-wave aggregation.

7. Anatomical Structures Affected

  • Organ/system: Hematopoietic and hemostatic system; primary "organ" is the circulating platelet.
  • Cell types: Platelet (CL:0000233); megakaryocyte (CL:0000556, site of COX-1 synthesis).
  • Subcellular: ER membrane (GO:0005789) where COX-1 resides.
  • Localization of bleeding: Mucocutaneous surfaces — skin (UBERON:0002097), nasal mucosa (UBERON:0001825), endometrium/uterus (UBERON:0000995); occasionally GI tract and joints. Bleeding is systemic/bilateral, not lateralized.

8. Temporal Development

Congenital onset (HP:0003577); insidious/chronic; lifelong and stable (non-progressive); manifestations episodic and provoked by hemostatic challenge. No disease stages, no remission/relapse cycles; critical periods are surgical, dental, obstetric, and menstrual events.

9. Inheritance and Population

See F009. Autosomal dominant, incomplete penetrance, variable expressivity, no anticipation; ultra-rare with no reliable prevalence estimate; no founder effect or consanguinity role documented (AD, not AR).

10. Diagnostics

See F008. Core: ISTH-BAT bleeding score → exclude VWD/coagulation factor defects → LTA (absent AA response, absent second wave) → serum TXB2 / urinary 11-dehydro-TXB2 → PTGS1 sequencing (single-gene or NGS platelet-disorder panel/WES). Platelet count and morphology are normal.

11. Outcome / Prognosis

Excellent; normal life expectancy; negligible disease-specific mortality. Morbidity = perioperative/postpartum/dental hemorrhage and iron-deficiency anemia from menorrhagia. Prognostic factor: residual COX-1 activity (PAR-to-AA level) correlates with bleeding tendency.

12. Treatment

See F003. Pharmacotherapy/procedural: tranexamic acid (NCIT antifibrinolytic), desmopressin/DDAVP, platelet concentrates, recombinant activated factor VIIa for refractory bleeding; local hemostatic measures. Pharmacogenomic caution: strict avoidance of aspirin/NSAIDs. Advanced/experimental: autologous HSC gene therapy and engineered/artificial platelets are emerging but not standard for this mild disorder.

13. Prevention

No primary prevention (genetic). Secondary/tertiary prevention = pre-procedure hemostatic planning, avoidance of antiplatelet drugs, treatment of iron deficiency, and genetic counseling for AD inheritance with variable penetrance. Cascade testing of at-risk relatives is appropriate once a family variant is identified.

14. Other Species / Natural Disease

Mouse ortholog Ptgs1 (NCBI Taxon 10090). No naturally occurring companion-animal BDPLT12 equivalent is catalogued in OMIA; the disease is understood chiefly through engineered mouse models (see F006). COX-1/prostanoid biology is evolutionarily conserved across mammals.

15. Model Organisms

Global Ptgs1⁻/⁻ mice (Langenbach 1995) and platelet/megakaryocyte-specific conditional knockouts (Pf4-ΔCre, Gp1ba-ΔCre × Cox-1^flox/flox; PMID 38660804, 31248980) recapitulate the AA-induced aggregation defect and reduced platelet prostanoid biosynthesis — strong phenotype recapitulation of the human loss-of-function state. Limitation: these model complete loss/haploinsufficiency, not the specific human dominant-negative N-glycosylation allele; a knock-in model is lacking.

Mechanistic Model / Interpretation

BDPLT12 is a textbook example of a single-enzyme, single-pathway platelet function disorder in which the clinical phenotype maps cleanly onto a defined biochemical lesion. The causal chain, from mutation to bleeding, is:

1. Germline heterozygous PTGS1 variant (missense, nonsense, or N-glycosylation-disrupting)
│  leads to
2. Reduced or dysfunctional COX-1 protein in megakaryocytes/platelets
│  (haploinsufficiency OR dominant-negative interference with wild-type subunit)
│  results in
3. Impaired cyclooxygenase conversion: arachidonic acid ─╳→ PGG2/PGH2
│  results in
4. Deficient thromboxane A2 (TXA2) synthesis (↓ serum TXB2, ↓ urinary 11-dehydro-TXB2)
│  results in
5. Loss of TXA2/TP-receptor autocrine amplification of platelet activation
│  results in
6. Absent secondary wave of secretion & aggregation; selectively absent AA-induced aggregation on LTA
│  results in
7. Impaired primary hemostasis (defective platelet plug formation at sites of injury)
│  manifests as
8. Mild, provoked mucocutaneous bleeding: bruising, epistaxis, menorrhagia,
   and late post-surgical/post-dental hemorrhage

Upstream vs downstream. The initiating lesion (steps 1–2) is the PTGS1 variant and reduced COX-1 protein. The proximate biochemical defect (steps 3–4) is the arachidonate→TXA2 block. The downstream physiological consequence (steps 5–7) is loss of the amplification loop and defective platelet plug formation, and the clinical manifestation (step 8) is the mild bleeding tendency.

Two molecular routes to autosomal dominance. A heterozygous variant can cause disease either by (a) haploinsufficiency — 50% enzyme is insufficient for full second-wave amplification under stress — or (b) dominant-negative interference, as demonstrated for the N-glycosylation-disrupting variant (Palma-Barqueros 2021), where the mutant subunit impairs function beyond simple dose reduction. Variable penetrance/expressivity (PAR-to-AA ranging 19–32% in mild subgroups) is consistent with residual COX-1 activity determining phenotype severity.

Cell types and biological processes. The affected cell is the platelet (CL:0000233) and its precursor the megakaryocyte (CL:0000556); COX-1 protein synthesis occurs primarily in megakaryocytes and is loaded into circulating platelets. The relevant biological processes are the cyclooxygenase pathway (GO:0019371) and prostanoid/thromboxane biosynthesis (GO:0046457, GO:0001516), localized to the ER membrane (GO:0005789).

Distinguishing feature vs other platelet disorders. Unlike Glanzmann thrombasthenia (αIIbβ3 defect, absent aggregation to all agonists), Bernard-Soulier syndrome (GPIb-IX-V, macrothrombocytopenia), and platelet-type von Willebrand disease (GP1BA gain-of-function, platelet hyperresponsiveness), BDPLT12 shows a selective aggregation defect confined to the AA/TXA2 pathway with normal platelet count and morphology. The single most discriminating test is the isolated absence of AA-induced aggregation with preserved high-dose collagen and ristocetin responses.

Disorder Gene Defect type Platelet count Aggregation pattern
BDPLT12 (COX-1 def.) PTGS1 LoF / dominant-negative Normal Selective loss of AA response; absent 2nd wave
Glanzmann thrombasthenia ITGA2B/ITGB3 LoF Normal Absent to all agonists (except ristocetin)
Bernard-Soulier syndrome GP1BA/GP1BB/GP9 LoF Low (large platelets) Absent ristocetin agglutination
Platelet-type VWD GP1BA Gain-of-function Low Enhanced low-dose ristocetin

Evidence Base

PMID Title (abbrev.) Evidence type Supports
19036102 Clinical and laboratory phenotypes associated with the aspirin-like defect (17 families) Human clinical cohort F002, F009 — bleeding frequency (74%), PFA-100 (71%), prevalence ~0.6%, AD inheritance, underdiagnosis
33326144 Novel PTGS1 variant affects N-glycosylation of COX-1, dominant-negative effect Human genetics + functional F005 — dominant-negative molecular mechanism
24480756 Late postoperative hemorrhage in undiagnosed COX-1 deficiency after third molar extraction Human case report F002 — surgical/dental bleeding presentation
38660804 Pf4-ΔCre vs Gp1ba-ΔCre depletion of COX-1 in platelets Model organism (mouse) F006 — cell-autonomous AA-induced aggregation defect
39870109 Diagnostic assessment of inherited platelet function defects, Part 1 Clinical methodology review F008 — LTA, flow cytometry, ISTH-BAT diagnostic pathway
37611608 Treatment of Inherited Platelet Disorders: Current Status and Future Options Treatment review F003 — tranexamic acid, DDAVP, platelet concentrates, HSCT
16684008 Congenital platelet disorders: mechanisms, diagnosis, treatment Review Background — second-wave aggregation defects, management
16102044 Qualitative disorders of platelets and megakaryocytes Review Background — differential diagnosis landscape
31248980 Platelet-specific deletion of COX-1 ameliorates DSS colitis Model organism F006 — platelet COX-1 conditional KO recapitulates low-dose-aspirin pharmacology
26272103 Abnormal megakaryopoiesis and platelet function in COX-2-deficient mice Model organism Contrast — COX-2 vs COX-1 roles in platelets

How the evidence fits together. The human cohort (PMID 19036102) establishes the clinical/laboratory phenotype and epidemiology; the molecular case report (PMID 33326144) provides the mechanistic proof that a PTGS1 variant is causal and defines a dominant-negative route; the mouse conditional-knockout studies (PMIDs 38660804, 31248980) supply cell-autonomous causal evidence that platelet COX-1 loss reproduces the exact aggregation defect; the diagnostic and treatment reviews (PMIDs 39870109, 37611608) translate the mechanism into clinical practice. No reviewed paper challenges the core model; the main tension in the literature is between COX-1 and COX-2 contributions in vascular (not platelet) prostanoid balance (PMIDs 31510878, 27020548), which is peripheral to the platelet-intrinsic BDPLT12 phenotype.

Limitations and Knowledge Gaps

  1. Genotype–phenotype ambiguity. No recurrent pathogenic PTGS1 variant is established for BDPLT12; most ClinVar entries are VUS/benign. ACMG-grade classification of causal variants is limited by absence of segregation and functional data for most alleles.
  2. Nomenclature and cohort mixing. The literature conflates the clinically defined "aspirin-like defect" (a functional label that can arise from several upstream signaling or thromboxane-pathway defects) with genetically confirmed PTGS1 deficiency (BDPLT12 proper). Some ALD cohort statistics (e.g., the 74% bleeding frequency) derive from functionally defined patients not all genotyped for PTGS1.
  3. No epidemiological denominator. There is no Orphanet prevalence code or registry; true prevalence, carrier frequency, and population/geographic distribution are unknown. The ~0.6% figure is restricted to a pediatric referral population and is not a general-population estimate.
  4. Incomplete penetrance/expressivity not mechanistically resolved. Modifier genes, environmental factors (concurrent NSAID use), and residual-activity thresholds that determine bleeding risk are undefined.
  5. No disease-specific outcome data. Quality-of-life instruments (EQ-5D, SF-36, PROMIS), long-term natural-history cohorts, and treatment-response rates specific to BDPLT12 are unpublished; management is extrapolated from the broader inherited-platelet-disorder literature.
  6. No animal model of a human dominant-negative allele. Mouse data derive from complete/conditional Cox-1 knockouts, which model loss-of-function/haploinsufficiency but not the N-glycosylation dominant-negative human variant.

Proposed Follow-up Experiments / Actions

  1. Curate a PTGS1–BDPLT12 variant registry linking each reported variant to LTA phenotype (PAR-to-AA), serum TXB2, and bleeding score (ISTH-BAT), enabling ACMG reclassification and genotype–phenotype correlation.
  2. Functional validation of VUS in a heterologous COX-1 expression system (PGH2/TXA2 output assay) and in patient- or iPSC-derived megakaryocytes, to distinguish loss-of-function, dominant-negative, and benign alleles.
  3. Prospective phenotyping study genotyping all functionally defined ALD patients for PTGS1, to separate true BDPLT12 from phenocopies and derive genotype-specific bleeding frequencies and prevalence.
  4. Standardize a confirmatory biochemical panel: pair LTA (AA agonist) with serum TXB2 and urinary 11-dehydro-TXB2 cutoffs to build a reproducible diagnostic algorithm distinguishing COX-1 deficiency from thromboxane-synthase and TP-receptor defects.
  5. Knock-in mouse of a human dominant-negative Ptgs1 allele (e.g., an N-glycosylation-disrupting variant) to test whether it reproduces the AD phenotype beyond haploinsufficiency and to serve as a therapeutic testing platform.
  6. Treatment-outcome case series in genetically confirmed BDPLT12, documenting response to tranexamic acid, DDAVP, and platelet transfusion, including perioperative and obstetric outcomes.
  7. Genetic counseling framework for AD inheritance with incomplete penetrance: cascade testing and pre-procedure risk assessment for affected families.

Ontology Term Index

  • Disease: MONDO:0011588; OMIM #605735; DOID:0111058; MeSH C567786; UMLS C2751535
  • Gene/Protein: PTGS1 HGNC:9604; UniProt P23219; Ensembl ENSG00000095303; gene OMIM 176805; mouse Ptgs1, NCBI Taxon 10090
  • GO (BP): GO:0019371 (cyclooxygenase pathway); GO:0001516 (prostaglandin biosynthesis); GO:0046457 (prostanoid biosynthesis)
  • GO (MF): GO:0004666 (prostaglandin-endoperoxide synthase activity); GO:0004601 (peroxidase); GO:0020037 (heme binding)
  • GO (CC): GO:0005789 (ER membrane); GO:0005788 (ER lumen)
  • CL: CL:0000233 (platelet); CL:0000556 (megakaryocyte)
  • UBERON: UBERON:0002097 (skin); UBERON:0001825 (nasal mucosa); UBERON:0000995 (uterus)
  • CHEBI: 15843 (arachidonic acid); 27647 (PGG2); 15554 (PGH2); 15627 (thromboxane A2)
  • HPO: HP:0003540, HP:0000978, HP:0000421, HP:0000132, HP:0002584, HP:0005261, HP:0003577, HP:0000006
  • Reactome: R-HSA-2162123 (Synthesis of Prostaglandins and Thromboxanes)
  • NCIT (treatment): tranexamic acid, desmopressin, platelet transfusion, recombinant factor VIIa

Report compiled from 9 confirmed findings and 39 reviewed papers across a 5-iteration autonomous investigation. Evidence types are labeled human clinical, model organism, in vitro, or computational/ontology throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 33
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 21
Terms named correctly 9
Terms named as a different term 1
Terms whose name is worth a second look 11

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • UBERON:0002097 (2 mentions) - the report calls it "Localization of bleeding: Mucocutaneous surfaces — skin", "skin"; UBERON calls it skin of body**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0004601 (2 mentions) - the report calls it "peroxidase activity", "peroxidase"; GO calls it peroxidase activity, and lists "heme peroxidase" among its other names
  • GO:0001516 (3 mentions) - the report calls it "prostaglandin biosynthetic process", "prostaglandin biosynthesis"; GO calls it prostaglandin biosynthetic process, and lists "prostaglandin biosynthesis" among its other names
  • GO:0046457 (3 mentions) - the report calls it "prostanoid biosynthetic process", "prostanoid biosynthesis"; GO calls it prostanoid biosynthetic process, and lists "prostanoid biosynthesis" among its other names
  • GO:0005789 (4 mentions) - the report calls it "endoplasmic reticulum membrane", "Subcellular: ER membrane", "ER membrane"; GO calls it endoplasmic reticulum membrane**, and lists "ER membrane" among its other names
  • GO:0005788 (2 mentions) - the report calls it "endoplasmic reticulum lumen", "ER lumen"; GO calls it endoplasmic reticulum lumen, and lists "ER lumen" among its other names
  • HP:0000978 (2 mentions) - the report calls it "Bruising susceptibility / easy bruising"; HP calls it Bruising susceptibility
  • HP:0002584 (2 mentions) - the report calls it "Gastrointestinal/intestinal bleeding"; HP calls it Intestinal bleeding
  • HP:0005261 (2 mentions) - the report calls it "Joint hemorrhage (hemarthrosis)"; HP calls it Joint hemorrhage
  • HP:0000006 (3 mentions) - the report calls it "Autosomal dominant inheritance", "autosomal dominant"; HP calls it Autosomal dominant inheritance, and lists "Autosomal dominant" among its other names
  • CL:0000233 (3 mentions) - the report calls it "Cell types: Platelet", "platelet"; CL calls it platelet**, and lists "blood platelet" among its other names
  • UBERON:0001825 (2 mentions) - the report calls it "nasal mucosa"; UBERON calls it paranasal sinus, and lists "nasal sinus" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0004601 - called "peroxidase activity", "peroxidase"
  • GO:0001516 - called "prostaglandin biosynthetic process", "prostaglandin biosynthesis"
  • GO:0046457 - called "prostanoid biosynthetic process", "prostanoid biosynthesis"
  • GO:0005789 - called "endoplasmic reticulum membrane", "Subcellular:** ER membrane", "ER membrane"
  • GO:0005788 - called "endoplasmic reticulum lumen", "ER lumen"
  • HP:0000006 - called "Autosomal dominant inheritance", "autosomal dominant"
  • CL:0000233 - called "Cell types:** Platelet", "platelet"
  • UBERON:0002097 - called "Localization of bleeding:** Mucocutaneous surfaces — skin", "skin"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, UMLS, GARD.