Congenital Thrombotic Thrombocytopenic Purpura

Mendelian MONDO:0010122 Pathograph 17 Show in embeddings browser Hematologic Disease Thrombotic Microangiopathy Inherited Blood Coagulation Disorder

Congenital thrombotic thrombocytopenic purpura (cTTP, Upshaw-Schulman syndrome) is an autosomal recessive thrombotic microangiopathy caused by biallelic loss-of-function variants in ADAMTS13, the plasma metalloprotease that cleaves von Willebrand factor (VWF) at the Tyr1605-Met1606 bond. Without that cleavage, ultralarge VWF multimers persist in the circulation, unfurl under shear, and recruit platelets into disseminated microvascular platelet-VWF thrombi. The downstream triad is consumptive thrombocytopenia, microangiopathic hemolytic anemia from mechanical fragmentation of erythrocytes, and ischemic end-organ injury. The mechanism is a constitutional enzyme deficiency, not an autoantibody, which is what separates cTTP from immune-mediated TTP and is why definitive therapy is ADAMTS13 replacement rather than immunosuppression. Presentation is strikingly bimodal — neonatal or early childhood in one group, and adulthood, overwhelmingly triggered by pregnancy, in another — and residual ADAMTS13 activity alone does not determine which. Recombinant ADAMTS13 prophylaxis now restores activity to approximately normal levels, and long-term prophylaxis of any kind reduces the ischemic stroke and end-organ damage that otherwise accumulate silently.

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1
Definitions
1
Inheritance
7
Pathophys.
7
Phenotypes
1
Gaps
17
Pathograph
1
Genes
2
Variants
4
Medical Actions
3
Differentials
1
Trials
1
Models
5
References
1
Deep Research
📘

Definitions

1
Congenital TTP case definition
Severe ADAMTS13 deficiency (activity at or below 10% of normal) in the absence of a functional inhibitor, together with ADAMTS13 variants on both alleles. The absence of an inhibitor is the discriminating element: severe deficiency alone does not distinguish cTTP from immune TTP.
CASE_DEFINITION Disease-level distinction between congenital and immune-mediated TTP.
Show evidence (1 reference)
PMID:30792199 SUPPORT Human Clinical
"Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles."
The international registry states the operational case definition used to enrol confirmed cTTP patients.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Disease requires ADAMTS13 variants on both alleles. In the UK cohort 36% of patients were homozygous and 64% compound heterozygous.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30792199 SUPPORT Human Clinical
"Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation."
The registry states the mode of inheritance directly.
PMID:30770395 SUPPORT Human Clinical
"Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations."
The cohort gives the observed split of homozygous and compound heterozygous genotypes.
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Discussions and Knowledge Gaps

1
Why do two patients with the same residual ADAMTS13 activity present decades apart — one in the neonatal period and one in a first pregnancy?
KNOWLEDGE GAP onset_timing_not_explained_by_residual_activity
Attached to
pathophysiology#Severe Plasma ADAMTS13 Activity Deficiency
The bimodal age distribution of cTTP is not explained by the enzyme deficiency alone. The international registry showed directly that residual ADAMTS13 activity is not the only determinant of age at first manifestation, and produced a counterintuitive result: compound heterozygous carriers of the recurrent c.4143_4144dupA allele had a *larger* proportion with onset before three months than homozygotes, despite homozygotes having lower measured activity. Something beyond the ADAMTS13 genotype sets when disease becomes overt. The mouse work says the same thing from the other direction, and narrows it usefully. Adamts13-null mice are viable with normal survival; spontaneous thrombocytopenia requires a permissive genetic background, and a full TTP-like syndrome requires an added toxin challenge. Two constraints follow. The permissive factor is not simply VWF level, because plasma VWF did not correlate with severity, so the modifying genes are distinct from VWF. And the human triggers are identifiable in outline (birth, pregnancy, infection) without those modifiers being known at all. The open question is therefore specific rather than vague: what are the non-VWF susceptibility loci, and do they account for the residual-activity paradox in the registry?
Show evidence (3 references)
PMID:30792199 SUPPORT Human Clinical
"We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers."
This is the specific result that makes residual activity insufficient as an explanation for onset timing.
PMID:30792199 SUPPORT Human Clinical
"an incompletely understood genotype-phenotype correlation"
The registry states the genotype-phenotype relationship is incompletely understood.
PMID:16200209 SUPPORT Model Organism
"no correlation was observed between plasma vWF level and severity of TTP, implying the existence of TTP-modifying genes distinct from vWF"
Rules out plasma VWF level as the modifier and asserts unidentified non-VWF modifying genes, which is what makes this gap specific.
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Pathophysiology

7
Biallelic ADAMTS13 Loss of Function
Variants on both ADAMTS13 alleles abolish or severely reduce production of functional ADAMTS13 protein. ADAMTS13 is synthesised mainly in hepatic stellate cells and also in vascular endothelial cells, so the deficiency is a plasma-protein deficiency rather than a lesion in the target vessel wall. That distinction is what makes the disease correctable from outside: the microvasculature itself is normal.
hepatic stellate cell CL:0000632 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatic stellate cell (CL:0000632). CL:0000632 is a cell type from the Cell Ontology. vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Genetic context ADAMTS13 hgnc:1366 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ADAMTS13 (hgnc:1366). hgnc:1366 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Variants on both alleles abolish or severely reduce VWF-cleaving protease activity. Patients are homozygous or, more often, compound heterozygous.
Downstream
Severe Plasma ADAMTS13 Activity Deficiency Loss of both functional alleles leaves circulating VWF-cleaving protease activity in the severe-deficiency range.
Show evidence (1 reference)
PMID:16388417 SUPPORT Other
"ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells."
Establishes the cellular source of the deficient protease, which is why plasma replacement corrects the defect.
Severe Plasma ADAMTS13 Activity Deficiency
Circulating VWF-cleaving metalloprotease activity is at or below 10% of normal, with no functional inhibitor present. Residual activity varies between genotypes and, importantly, is not by itself sufficient to predict when disease will first manifest.
VWF-cleaving metalloendopeptidase activity GO:0004222 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased VWF-cleaving metalloendopeptidase activity, annotated with metalloendopeptidase activity (GO:0004222). GO:0004222 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Adamts13-knockout mouse Mouse recapitulates The knockout reproduces the enzymatic lesion exactly and shows its direct consequence on VWF-mediated platelet-endothelial interaction.
Downstream
Persistence of Ultralarge VWF Multimers Without ADAMTS13 the Tyr1605-Met1606 bond in the VWF A2 domain is not cleaved, so ultralarge multimers are not processed to smaller, less adhesive forms.
Show evidence (1 reference)
PMID:30792199 SUPPORT Human Clinical
"An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation."
Directly supports the claim that residual activity does not fully determine phenotype, which is the basis for the knowledge gap recorded below.
Persistence of Ultralarge VWF Multimers
Uncleaved ultralarge VWF multimers remain in plasma and anchored to endothelium. Their adhesive function is shear-dependent, and ADAMTS13 proteolysis of VWF is itself modulated by shear force and by binding to platelet glycoprotein Ib-alpha, so the substrate is most dangerous exactly where the enzyme is most needed.
Downstream
Shear-Driven Platelet Adhesion and Microthrombus Formation Ultralarge multimers unfurl under high shear in the microcirculation and recruit platelets, which is the step ADAMTS13 normally prevents.
Show evidence (1 reference)
PMID:16388417 SUPPORT Other
"Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1balpha, heparin, inflammatory cytokine (interleukin-6), and chloride ion."
Supports the shear- and platelet-dependence of the VWF/ADAMTS13 interaction that makes this node microvascular.
Shear-Driven Platelet Adhesion and Microthrombus Formation
Platelets bind the exposed A1 domains of unfurled ultralarge VWF and aggregate, building platelet-VWF thrombi in arterioles and capillaries. The thrombi are platelet- and VWF-rich rather than fibrin-rich, which is why coagulation screens are typically normal in TTP.
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 increased platelet aggregation (GO:0070527). GO:0070527 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Adamts13-knockout mouse Mouse fails to recapitulate Enzyme deficiency by itself does not produce microthrombotic disease in this model. Disseminated microthrombosis appears only when a permissive genetic background is combined with a toxin challenge.
Downstream
Microvascular Occlusion and Ischemic End-Organ Injury Accumulated microthrombi occlude arterioles and capillaries, producing tissue ischaemia in brain, kidney, heart and other organs.
Consumptive Thrombocytopenia Platelets are consumed into disseminated microthrombi faster than they are replaced, producing peripheral thrombocytopenia.
Mechanical Erythrocyte Fragmentation Erythrocytes are sheared as they traverse partially occluded, VWF-platelet-strung microvessels, producing schistocytes and intravascular haemolysis.
Show evidence (1 reference)
PMID:16388417 SUPPORT Other
"Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP)."
Connects the enzyme deficiency, of either aetiology, to the microangiopathic syndrome built on this node.
Consumptive Thrombocytopenia
Peripheral platelet count falls as platelets are incorporated into microthrombi. This is the most frequently recorded manifestation of cTTP and the one that responds most directly to ADAMTS13 replacement.
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.
Show evidence (1 reference)
PMID:38692292 SUPPORT Human Clinical
"Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy)."
The phase 3 trial identifies thrombocytopenia as the most frequent manifestation and quantifies it under both treatments.
Mechanical Erythrocyte Fragmentation
Red cells are physically fragmented in the obstructed microcirculation, producing schistocytes, intravascular haemolysis, raised lactate dehydrogenase and a reticulocyte response.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:27868334 SUPPORT Other
"Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates."
Attaches the microangiopathic haemolysis directly to the capillary and small-vessel platelet aggregates that cause it, which is this node.
PMID:39161536 SUPPORT INDIRECT Other
"Congenital (cTTP) and immune-mediated (iTTP) thrombotic thrombocytopenic purpura are serious and rare clotting disorders resulting from a deficiency in the ADAMTS13 enzyme."
Places cTTP within the ADAMTS13-deficiency microangiopathies whose defining lesion includes this haemolysis.
Microvascular Occlusion and Ischemic End-Organ Injury
Cumulative microvascular occlusion produces ischaemic injury, most consequentially cerebral infarction. In cTTP this damage accrues over years and is substantially preventable: 75% of late-diagnosed patients had end-organ damage, and prophylactic ADAMTS13 replacement cut stroke incidence from 17% to 2%.
Show evidence (2 references)
PMID:30770395 SUPPORT Human Clinical
"Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP."
Quantifies cumulative end-organ damage in the late-diagnosed group.
PMID:30770395 SUPPORT Human Clinical
"Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04)."
Shows the ischaemic injury is modifiable by replacing the missing protease.
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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 Congenital Thrombotic Thrombocytopenic Purpura 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

7
Blood 2
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38692292 SUPPORT Human Clinical
"Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy)."
The phase 3 crossover trial records thrombocytopenia as the dominant manifestation in this population.
Microangiopathic hemolytic anemia HP:0001937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microangiopathic hemolytic anemia (HP:0001937). HP:0001937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27868334 SUPPORT Other
"Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates."
The consensus statement defines the microangiopathic process that produces this haemolytic anaemia and names its microvascular platelet-aggregate substrate.
Cardiovascular 1
Stroke HP:0001297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke (HP:0001297). HP:0001297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04)."
Reports stroke incidence in both prophylaxed and non-prophylaxed cTTP patients, establishing it as a disease phenotype.
Digestive 1
Jaundice FREQUENT HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38536644 SUPPORT Human Clinical
"The greatest risk for hTTP is in their first days after birth, when 35-50% of patients will have severe hemolysis, jaundice, and thrombocytopenia."
Names jaundice as one of the three neonatal presenting features, with its frequency in that window.
Genitourinary 1
Renal insufficiency OCCASIONAL HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30792199 SUPPORT Human Clinical
"Renal insufficiency occurred in 25% of the cohort."
A denominator-backed frequency from the international registry.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy."
Headache is named as a symptom present with normal counts that resolved on ADAMTS13 replacement.
Constitutional 1
Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy."
Abdominal pain is named among the non-overt symptoms responsive to replacement therapy.
🧬

Genetic Associations

1
ADAMTS13
Gene: ADAMTS13 hgnc:1366 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADAMTS13 (hgnc:1366). hgnc:1366 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:30792199 SUPPORT Human Clinical
"Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles."
The registry quantifies the allelic heterogeneity and names the one recurrent variant.
PMID:12393505 SUPPORT Human Clinical
"homozygous or compound heterozygous mutations of ADAMTS13 are responsible for recessively inherited TTP"
Establishes biallelic ADAMTS13 variants as the cause of the inherited form.
PMID:16807643 SUPPORT Human Clinical
"We established ADAMTS13 haplotypes by analyzing 17 polymorphic intragenic markers. The haplotypes linked to 4143insA were identical in all informative families."
The haplotype evidence establishing the recurrent allele as a founder mutation rather than repeated independent events.
+ 2 more references
Variants (2)
ADAMTS13 c.4143_4144dupA (p.Glu1382Argfs*6)
The one recurrent allele in an otherwise largely private mutational spectrum: present on 60 of 246 alleles in the international registry. Its frequency is a founder effect rather than a mutational hotspot - haplotype analysis across 17 intragenic markers found identical haplotypes in every informative family, and carriers cluster in Northern and Central Europe.
ADAMTS13 p.R1060W
A recurrent missense allele associated with low but measurable residual ADAMTS13 activity, reported alongside the founder-mutation haplotype study.
💊

Medical Actions

4
Recombinant ADAMTS13 Prophylaxis
Action: Protein Replacement TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Protein Replacement Therapy (NCIT:C16221). NCIT:C16221 is a clinical intervention from the NCI Thesaurus. NCIT:C16221
Agent: apadamtase alfa NCIT:C169784 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses apadamtase alfa (NCIT:C169784). NCIT:C169784 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Intravenous recombinant ADAMTS13 (40 IU/kg) given as routine prophylaxis replaces the missing protease directly. In the phase 3 crossover trial no acute TTP event occurred during recombinant ADAMTS13 prophylaxis, activity reached approximately 100% of normal, drug-related adverse events occurred in 9% of patients against 48% on standard therapy, no patient discontinued for an adverse event, and no neutralising antibodies developed.
Mechanism Target:
RESTORES Severe Plasma ADAMTS13 Activity Deficiency — Exogenous recombinant enzyme restores circulating VWF-cleaving protease activity, correcting the deficiency node itself rather than a downstream consequence.
Show evidence (1 reference)
PMID:38692292 SUPPORT Human Clinical
"During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels"
Demonstrates that the intervention acts on and corrects the enzyme deficiency node.
Show evidence (3 references)
PMID:38692292 SUPPORT Human Clinical
"No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05)."
The trial's primary outcome supports recombinant ADAMTS13 prophylaxis.
PMID:38692292 SUPPORT Human Clinical
"Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy."
Supports the tolerability advantage over plasma-derived standard therapy.
PMID:38692292 SUPPORT Human Clinical
"No neutralizing antibodies developed during recombinant ADAMTS13 treatment."
Addresses the main theoretical hazard of protein replacement in a constitutionally protein-null patient.
Plasma-Derived ADAMTS13 Replacement
Action: Fresh Frozen Plasma TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fresh Frozen Plasma Transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. NCIT:C116475
Platform: Protein replacement
Fresh-frozen plasma and intermediate-purity factor VIII concentrate supply ADAMTS13 indirectly and were the standard of care before recombinant enzyme. They work, but incompletely: mean maximum activity reaches only 19% of normal, the commonly used three-weekly FFP schedule was insufficient for 70% of UK patients, and drug-related adverse events were far commoner than with recombinant enzyme.
Mechanism Target:
RESTORES Severe Plasma ADAMTS13 Activity Deficiency — Donor plasma contains ADAMTS13 and partially replaces the missing enzyme activity.
Show evidence (1 reference)
PMID:38692292 SUPPORT Human Clinical
"The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy."
Quantifies the partial activity restoration achieved by plasma-derived standard therapy.
Show evidence (2 references)
PMID:30770395 SUPPORT Human Clinical
"Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment."
Documents the plasma-derived products used as replacement therapy in the national cohort.
PMID:30770395 SUPPORT Human Clinical
"The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required."
Documents the inadequacy of the conventional plasma schedule, the practical limitation of this modality.
Prophylactic Replacement to Prevent End-Organ Damage
Action: Protein Replacement TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Protein Replacement Therapy (NCIT:C16221). NCIT:C16221 is a clinical intervention from the NCI Thesaurus. NCIT:C16221
Platform: Protein replacement
Regular prophylaxis, as opposed to on-demand treatment of acute episodes, is what prevents the accumulated ischaemic injury of cTTP. It reduced stroke incidence from 17% to 2% and resolved symptoms in 88% of patients who had normal blood counts but ongoing headache, lethargy or abdominal pain — a group who would previously have been considered to have inactive disease.
Mechanism Target:
RESTORES Microvascular Occlusion and Ischemic End-Organ Injury — Maintaining circulating protease activity prevents the microthrombotic burden from accumulating into ischaemic organ damage.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease."
States the preventive effect of prophylaxis on the end-organ injury node.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy."
Supports prophylaxis for non-overt disease, not only for overt episodes.
Plasma Prophylaxis in Pregnancy
Action: Fresh Frozen Plasma TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fresh Frozen Plasma Transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. NCIT:C116475
Platform: Protein replacement
Pregnancy physiologically raises VWF and is the dominant trigger of adult cTTP, so prophylaxis through pregnancy is a distinct management question rather than a special case of routine prophylaxis. In a cohort of 14 women with hereditary TTP across 71 pregnancies, 24% ended in pregnancy loss and 45% were complicated by severe obstetric morbidity; plasma-treated pregnancies had markedly less severe obstetric morbidity and far fewer preterm TTP exacerbations. Response is not uniform: higher non-pregnant VWF antigen predicted morbidity even among treated women, which is a candidate stratifier rather than an established one.
Mechanism Target:
RESTORES Microvascular Occlusion and Ischemic End-Organ Injury — Replacing ADAMTS13 through pregnancy prevents the microthrombotic exacerbations that drive obstetric morbidity and fetal loss.
Show evidence (1 reference)
PMID:36889591 SUPPORT Human Clinical
"Treated women had decreased SOM (28% vs 72%, p < .001) and preterm thrombotic thrombocytopenic purpura exacerbations (18% vs 82%, p < .001)"
Quantifies the effect of plasma prophylaxis on obstetric morbidity and on preterm exacerbations.
Show evidence (2 references)
PMID:36889591 SUPPORT Human Clinical
"Fourteen women with hTTP had 71 pregnancies; of which 17 (24%) culminated in pregnancy loss and 32 (45%) were complicated by SOM."
Establishes the untreated obstetric burden this treatment addresses.
PMID:36889591 SUPPORT Human Clinical
"Among the treated women, median NPVWF antigen levels were higher in those with SOM than in those without SOM (225% vs 165%, p = .047)."
Records the residual-risk signal among treated women, which is why this is not framed as uniformly effective.
🌍

Environmental Factors

2
Systemic physiological stressors that raise VWF or shear
pregnancy or systemic infection as a physiological stressor Relation: this environmental factor is this exposure This environmental factor is pregnancy or systemic infection as a physiological stressor.
Pregnancy and infection are the two commonest precipitants of an acute cTTP episode, and they are the same triggers as in immune TTP - which is informative, because it says the trigger acts on the shared downstream pathway rather than on the aetiology. In cTTP the enzyme deficiency is constitutional and lifelong, so what varies is not the protease but the load placed on it; the disease is episodic because the trigger is.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Sixty-nine percent of adult presentations were associated with pregnancy."
Quantifies how much of adult-onset disease is unmasked by one of these stressors.
Mechanism Target:
TRIGGERS Shear-Driven Platelet Adhesion and Microthrombus Formation — States of raised von Willebrand factor or altered shear tip a constitutionally protease-deficient circulation into overt microthrombosis.
Show evidence (1 reference)
PMID:39161536 SUPPORT Other
"Triggers of acute episodes were similar for cTTP and iTTP, with pregnancy and infection the most commonly observed."
Identifies the two dominant precipitants and, by their being shared with immune TTP, locates their action downstream of the aetiology.
Neonatal ductal flow transition
turbulent ductal blood flow in the neonatal transition Relation: this environmental factor is this exposure This environmental factor is turbulent ductal blood flow in the neonatal transition.
A physiological rather than exogenous exposure, and the clearest worked example of the trigger mechanism. Fetal flow through the ductus arteriosus is low-shear; at birth the shunt reverses and the duct narrows, producing turbulence that unfolds ultralarge VWF. Prompt ductal closure ends the exposure and the newborn survives; a patent duct sustains it.
Show evidence (1 reference)
PMID:38536644 SUPPORT Human Clinical
"The greatest risk for hTTP is in their first days after birth, when 35-50% of patients will have severe hemolysis, jaundice, and thrombocytopenia."
Quantifies the clinical consequence of this exposure window.
Mechanism Target:
TRIGGERS Shear-Driven Platelet Adhesion and Microthrombus Formation — Turbulent circulation at the closing ductus unfolds ultralarge VWF and permits platelet aggregation, precipitating neonatal microthrombosis.
Show evidence (1 reference)
PMID:38536644 SUPPORT Human Clinical
"This causes turbulent circulation that unfolds UL-VWF, allowing platelet aggregation. If the DA closes promptly, hTTP newborns survive, but if it remains patent, turbulent circulation persists, triggering microvascular thrombosis."
States the shear mechanism and its dependence on ductal closure, which is what makes this a bounded exposure rather than a constant.
🔬

Biochemical Markers

1
Plasma ADAMTS13 activity
Show evidence (2 references)
PMID:38692292 SUPPORT Human Clinical
"The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy."
Quantifies the analyte under both treatment arms.
PMID:30792199 SUPPORT Human Clinical
"ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers"
Documents the distribution of residual activity by genotype class.
🔬

Diagnosis

4
ADAMTS13 activity assay with inhibitor testing
Severe deficiency at or below 10% of normal establishes TTP; the absence of a functional inhibitor is what makes it congenital rather than immune. Both halves are required - activity alone does not separate the two diseases, and getting it wrong sends the patient to immunosuppression that cannot work.
Show evidence (1 reference)
PMID:30792199 SUPPORT Human Clinical
"Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles."
The operational diagnostic definition used by the international registry.
ADAMTS13 sequencing
Demonstration of variants on both alleles is the confirmatory element. Expect a private variant: 98 different variants were found across 123 registry patients, with only one recurrent founder allele.
Show evidence (1 reference)
PMID:30792199 SUPPORT Human Clinical
"Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles."
Sets the expectation for what sequencing returns in an unselected patient.
Coagulation screen to exclude disseminated intravascular coagulation
Normal in TTP, because the microthrombi are platelet-VWF rather than fibrin based. Abnormal coagulation points to DIC, the commonest cause of thrombotic microangiopathy overall.
Show evidence (1 reference)
PMID:27868334 SUPPORT Other
"The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation."
Names the discriminating laboratory feature against the leading alternative.
Recognising neonatal cTTP behind a haemolytic-disease-of-the-newborn label
Not a test but a decision point, and the one most often missed. Newborn cTTP is commonly treated as HDFN with exchange transfusion, which prevents kernicterus and so conceals the error. Severe thrombocytopenia is the feature that should stop that reading, because HDFN does not cause it.
Show evidence (1 reference)
PMID:38536644 SUPPORT Human Clinical
"The diagnosis of newborn-onset hTTP should be considered because HDFN does not cause severe thrombocytopenia, which might be effectively treated with recombinant ADAMTS13."
States the discriminating feature and the reason it matters.
📈

Progression

4
Neonatal onset
Age: First days of life
Between 35% and 50% of patients present in the first days after birth with severe haemolysis, jaundice and thrombocytopenia, and the presentation is often fatal without effective treatment. The proposed trigger is haemodynamic rather than infective: fetal flow through the ductus arteriosus is low-shear, but at birth the shunt reverses and the duct narrows, producing turbulent circulation that unfolds ultralarge VWF and permits platelet aggregation. On this account prompt ductal closure is protective and a patent duct sustains the trigger. Clinically the important consequence is a misdiagnosis trap: newborn cTTP is commonly called haemolytic disease of the fetus and newborn and treated with exchange transfusion, which prevents kernicterus and so masks the error. Severe thrombocytopenia is the feature that should stop that reading, because HDFN does not cause it.
Show evidence (3 references)
PMID:38536644 SUPPORT Human Clinical
"The greatest risk for hTTP is in their first days after birth, when 35-50% of patients will have severe hemolysis, jaundice, and thrombocytopenia."
Quantifies the neonatal presentation and names its features.
PMID:38536644 SUPPORT Human Clinical
"This causes turbulent circulation that unfolds UL-VWF, allowing platelet aggregation. If the DA closes promptly, hTTP newborns survive, but if it remains patent, turbulent circulation persists, triggering microvascular thrombosis."
States the proposed haemodynamic trigger mechanism for neonatal disease and its dependence on ductal closure.
PMID:38536644 SUPPORT Human Clinical
"The diagnosis of newborn-onset hTTP should be considered because HDFN does not cause severe thrombocytopenia, which might be effectively treated with recombinant ADAMTS13."
Names the discriminating feature against the usual misdiagnosis.
Childhood-onset disease
Age: From around birth through early childhood
In the UK national cohort the childhood-onset group had a median age at diagnosis of 3.5 years. Prespacer ADAMTS13 variants were significantly more likely to be associated with childhood onset. Neonatal presentation with hyperbilirubinaemia and thrombocytopenia is the classic Upshaw-Schulman picture.
Show evidence (2 references)
PMID:30770395 SUPPORT Human Clinical
"Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years)."
The UK cohort documents the bimodal age-at-diagnosis distribution, including the childhood peak.
PMID:30770395 SUPPORT Human Clinical
"Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011)."
This is the reported genotype-phenotype signal for age of onset.
Adult-onset disease, usually unmasked by pregnancy
Age: Typically third decade; first manifestation reported up to age 70
Adult presentation is dominated by pregnancy. In the UK cohort 69% of adult presentations were pregnancy-associated, with a median diagnosis age of 31 years. The international registry recorded first recognised manifestation anywhere from around birth to age 70.
Show evidence (2 references)
PMID:30770395 SUPPORT Human Clinical
"Sixty-nine percent of adult presentations were associated with pregnancy."
The UK cohort quantifies the pregnancy association in adult-onset cTTP.
PMID:30792199 SUPPORT Human Clinical
"First recognized disease manifestation occurred from around birth up to the age of 70 years."
The registry documents the full reported range of age at first manifestation.
Cumulative end-organ damage in untreated or late-diagnosed disease
Long-term risk is of accumulated ischaemic injury rather than a single catastrophic event. End-organ damage was seen in 75% of patients diagnosed late in the UK cohort, and prophylaxis significantly reduced stroke incidence.
Show evidence (1 reference)
PMID:30770395 SUPPORT Human Clinical
"Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP."
The cohort quantifies cumulative end-organ damage associated with delayed diagnosis.
🌍

Epidemiology

2
Ultra-rare inherited thrombotic microangiopathy
cTTP is an ultra-rare disease. Acute episodes recur at roughly 0.19 to 0.35 per person-year in adults, and reported all-cause mortality spans 0 to 13.4% across cohorts. Pregnancy and infection are the commonest triggers of an acute episode, the same triggers as in immune TTP.
Show evidence (4 references)
PMID:30770395 SUPPORT Human Clinical
"Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)."
The UK national cohort characterises cTTP as ultra-rare and inherited.
PMID:39161536 SUPPORT Other
"The incidence rate of acute episodes ranged from 0.19-0.35 person-years in adult patients with cTTP"
The systematic review supplies the acute-episode incidence rate in adult cTTP.
PMID:39161536 SUPPORT Other
"Triggers of acute episodes were similar for cTTP and iTTP, with pregnancy and infection the most commonly observed."
The review identifies pregnancy and infection as the dominant episode triggers in cTTP.
+ 1 more reference
Female predominance and the cost of going unprophylaxed
A retrospective multinational cohort of 78 patients across 9 European and US sites found 78.2% were female, with 92 acute events in 55 patients (0.145 events per person-year). The striking figure is not the event rate but its distribution: 87% of acute events happened in patients not on prophylaxis, and a fifth of those caused organ damage. Of the 12 events that did occur during prophylaxis, none did.
Show evidence (3 references)
PMID:42603082 SUPPORT Human Clinical
"Medical records from 78 patients (61 [78.2%] female) were included in the study."
Establishes the sex distribution in the largest real-world cTTP cohort.
PMID:42603082 SUPPORT Human Clinical
"Ninety-two acute TTP events were recorded in 55 (70.5%) patients (overall event rate, 0.145 events per person-year)."
Quantifies the acute-event burden in a real-world cohort.
PMID:42603082 SUPPORT Human Clinical
"Eighty (87.0%) acute TTP events occurred in the absence of prophylactic treatment, of which 16 (20.0%) resulted in organ damage (based on physicians' assessment). Twelve (13.0%) acute TTP events occurred during prophylaxis; none resulted in organ damage."
The central real-world observation: events concentrate in unprophylaxed patients and only those events caused organ damage.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Congenital Thrombotic Thrombocytopenic Purpura:

Immune-mediated thrombotic thrombocytopenic purpura
Overlapping Features iTTP produces the same severe ADAMTS13 deficiency and the same microangiopathic syndrome, but through an acquired autoantibody rather than biallelic germline variants. The discriminators are a demonstrable functional inhibitor, later age at symptom onset, and recovery of ADAMTS13 activity after immunosuppression. Getting this wrong matters in both directions: immunosuppression cannot help cTTP, and enzyme replacement alone does not address an ongoing autoimmune driver.
Show evidence (2 references)
PMID:39161536 SUPPORT Other
"Congenital (cTTP) and immune-mediated (iTTP) thrombotic thrombocytopenic purpura are serious and rare clotting disorders resulting from a deficiency in the ADAMTS13 enzyme."
Establishes that the two diseases share the enzymatic lesion, which is why they are confusable and must be separated on aetiology.
PMID:30792199 SUPPORT Human Clinical
"severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles"
Names the two features that discriminate cTTP from iTTP.
Haemolytic uraemic syndrome
Overlapping Features HUS presents with the same microangiopathic haemolytic anaemia and thrombocytopenia but has a different pathophysiology and a different treatment pathway, and does not feature severe ADAMTS13 deficiency.
Show evidence (1 reference)
PMID:27868334 SUPPORT Other
"Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways."
The consensus statement separates these two thrombotic microangiopathies explicitly.
Disseminated intravascular coagulation
Overlapping Features DIC is the commonest cause of thrombotic microangiopathy overall and is distinguished by abnormal coagulation tests, which are characteristically normal in TTP because the microthrombi are platelet-VWF rather than fibrin based.
Show evidence (1 reference)
PMID:27868334 SUPPORT Other
"The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation."
Names DIC as the leading TMA differential and the laboratory feature that separates it.
🔬

Clinical Trials

1
NCT03393975 PHASE_III COMPLETED
Phase 3 open-label crossover trial of recombinant ADAMTS13 versus plasma-derived standard therapy for prophylaxis and on-demand treatment in congenital TTP.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38692292 SUPPORT Human Clinical
"In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment"
Describes the trial design and the intervention under study.
🐁

Animal Models

1
Adamts13-knockout mouse
The defining result of this model is a negative one. Adamts13-null mice are viable with normal survival despite prolonged VWF-mediated platelet-endothelial interactions: the enzyme deficiency alone does not produce the disease. Spontaneous thrombocytopenia appears only on the CASA/Rk background, which has elevated plasma VWF, and a syndrome closely resembling human TTP requires an additional shigatoxin challenge. This is the experimental basis for reading cTTP as a two-hit disease rather than a straightforward enzyme deficiency.
Species
Mouse
Genotype
Adamts13 homozygous null
Publication
PMID:16200209
Pathograph links
Severe Plasma ADAMTS13 Activity Deficiency recapitulates fidelity: high The knockout reproduces the enzymatic lesion exactly and shows its direct consequence on VWF-mediated platelet-endothelial interaction.
Limitations: The mouse reproduces the deficiency faithfully but not the human disease that follows from it, which is the finding rather than a defect of the model.
Readouts
VWF-mediated platelet-endothelial interaction duration
Direction: INCREASED
Interpretation: Direct in vivo consequence of losing the VWF-cleaving protease.
Show evidence (1 reference)
PMID:16200209 SUPPORT Model Organism
"ADAMTS13-deficient mice are viable and exhibit normal survival, although vWF-mediated platelet-endothelial interactions are significantly prolonged."
Reports the measurement behind this readout, and the absence of a spontaneous disease phenotype.
Show evidence (1 reference)
PMID:16200209 SUPPORT Model Organism
"Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness caused by deficiency of the vWF-cleaving protease ADAMTS13."
Confirms the model carries a lesion in the same protease that defines this node.
Shear-Driven Platelet Adhesion and Microthrombus Formation fails to recapitulate fidelity: low Enzyme deficiency by itself does not produce microthrombotic disease in this model. Disseminated microthrombosis appears only when a permissive genetic background is combined with a toxin challenge.
Limitations: On a standard background the null mouse has no spontaneous microthrombotic phenotype at all, and even on the high-VWF CASA/Rk background only a subset develops thrombocytopenia. The full TTP-like syndrome requires shigatoxin, an exogenous endothelial insult with no counterpart in most human cTTP episodes. Notably, plasma VWF level did not correlate with TTP severity, so the permissive background is not simply acting through VWF.
Show evidence (2 references)
PMID:16200209 SUPPORT Model Organism
"These data suggest that microbe-derived toxins (or possibly other sources of endothelial injury), together with additional genetic susceptibility factors, are required to trigger TTP in the setting of ADAMTS13 deficiency."
The authors' own statement that deficiency alone is insufficient, which is the substantive negative claim this link records.
+ 1 more reference
{ }

Source YAML

click to show 
name: Congenital Thrombotic Thrombocytopenic Purpura
creation_date: "2026-08-30T06:20:00Z"
category: Mendelian
parents:
- Hematologic Disease
- Thrombotic Microangiopathy
- Inherited Blood Coagulation Disorder
synonyms:
- cTTP
- Upshaw-Schulman syndrome
- hereditary thrombotic thrombocytopenic purpura
- familial thrombotic thrombocytopenic purpura
- congenital ADAMTS13 deficiency
disease_term:
  preferred_term: congenital thrombotic thrombocytopenic purpura
  term:
    id: MONDO:0010122
    label: congenital thrombotic thrombocytopenic purpura
description: >-
  Congenital thrombotic thrombocytopenic purpura (cTTP, Upshaw-Schulman
  syndrome) is an autosomal recessive thrombotic microangiopathy caused by
  biallelic loss-of-function variants in ADAMTS13, the plasma metalloprotease
  that cleaves von Willebrand factor (VWF) at the Tyr1605-Met1606 bond. Without
  that cleavage, ultralarge VWF multimers persist in the circulation, unfurl
  under shear, and recruit platelets into disseminated microvascular
  platelet-VWF thrombi. The downstream triad is consumptive thrombocytopenia,
  microangiopathic hemolytic anemia from mechanical fragmentation of
  erythrocytes, and ischemic end-organ injury. The mechanism is a constitutional
  enzyme deficiency, not an autoantibody, which is what separates cTTP from
  immune-mediated TTP and is why definitive therapy is ADAMTS13 replacement
  rather than immunosuppression. Presentation is strikingly bimodal — neonatal
  or early childhood in one group, and adulthood, overwhelmingly triggered by
  pregnancy, in another — and residual ADAMTS13 activity alone does not
  determine which. Recombinant ADAMTS13 prophylaxis now restores activity to
  approximately normal levels, and long-term prophylaxis of any kind reduces the
  ischemic stroke and end-organ damage that otherwise accumulate silently.
definitions:
- name: Congenital TTP case definition
  definition_type: CASE_DEFINITION
  description: >-
    Severe ADAMTS13 deficiency (activity at or below 10% of normal) in the
    absence of a functional inhibitor, together with ADAMTS13 variants on both
    alleles. The absence of an inhibitor is the discriminating element: severe
    deficiency alone does not distinguish cTTP from immune TTP.
  scope: Disease-level distinction between congenital and immune-mediated TTP.
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed
      by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of
      a functional inhibitor and the presence of ADAMTS13 mutations on both
      alleles.
    explanation: >-
      The international registry states the operational case definition used to
      enrol confirmed cTTP patients.
epidemiology:
- name: Ultra-rare inherited thrombotic microangiopathy
  description: >-
    cTTP is an ultra-rare disease. Acute episodes recur at roughly 0.19 to 0.35
    per person-year in adults, and reported all-cause mortality spans 0 to
    13.4% across cohorts. Pregnancy and infection are the commonest triggers of
    an acute episode, the same triggers as in immune TTP.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare
      thrombomicroangiopathy caused by an inherited deficiency of a disintegrin
      and metalloproteinase with a thrombospondin type 1 motif, member 13
      (ADAMTS13).
    explanation: >-
      The UK national cohort characterises cTTP as ultra-rare and inherited.
  - reference: PMID:39161536
    reference_title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The incidence rate of acute episodes ranged from 0.19-0.35 person-years in
      adult patients with cTTP
    explanation: >-
      The systematic review supplies the acute-episode incidence rate in adult
      cTTP.
  - reference: PMID:39161536
    reference_title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Triggers of acute episodes were similar for cTTP and iTTP, with pregnancy
      and infection the most commonly observed.
    explanation: >-
      The review identifies pregnancy and infection as the dominant episode
      triggers in cTTP.
  - reference: PMID:39161536
    reference_title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      All-cause mortality was observed in 0-13.4% of patients with cTTP, across
    explanation: >-
      The review reports the range of all-cause mortality across cTTP cohorts.
- name: Female predominance and the cost of going unprophylaxed
  description: >-
    A retrospective multinational cohort of 78 patients across 9 European and US
    sites found 78.2% were female, with 92 acute events in 55 patients (0.145
    events per person-year). The striking figure is not the event rate but its
    distribution: 87% of acute events happened in patients not on prophylaxis,
    and a fifth of those caused organ damage. Of the 12 events that did occur
    during prophylaxis, none did.
  evidence:
  - reference: PMID:42603082
    reference_title: "Natural History and Treatment Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Retrospective Longitudinal Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical records from 78 patients (61 [78.2%] female) were included in the
      study.
    explanation: >-
      Establishes the sex distribution in the largest real-world cTTP cohort.
  - reference: PMID:42603082
    reference_title: "Natural History and Treatment Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Retrospective Longitudinal Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-two acute TTP events were recorded in 55 (70.5%) patients (overall
      event rate, 0.145 events per person-year).
    explanation: >-
      Quantifies the acute-event burden in a real-world cohort.
  - reference: PMID:42603082
    reference_title: "Natural History and Treatment Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Retrospective Longitudinal Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty (87.0%) acute TTP events occurred in the absence of prophylactic
      treatment, of which 16 (20.0%) resulted in organ damage (based on
      physicians' assessment). Twelve (13.0%) acute TTP events occurred during
      prophylaxis; none resulted in organ damage.
    explanation: >-
      The central real-world observation: events concentrate in unprophylaxed
      patients and only those events caused organ damage.
progression:
- phase: Neonatal onset
  age_range: First days of life
  notes: >-
    Between 35% and 50% of patients present in the first days after birth with
    severe haemolysis, jaundice and thrombocytopenia, and the presentation is
    often fatal without effective treatment. The proposed trigger is
    haemodynamic rather than infective: fetal flow through the ductus arteriosus
    is low-shear, but at birth the shunt reverses and the duct narrows,
    producing turbulent circulation that unfolds ultralarge VWF and permits
    platelet aggregation. On this account prompt ductal closure is protective
    and a patent duct sustains the trigger. Clinically the important
    consequence is a misdiagnosis trap: newborn cTTP is commonly called
    haemolytic disease of the fetus and newborn and treated with exchange
    transfusion, which prevents kernicterus and so masks the error. Severe
    thrombocytopenia is the feature that should stop that reading, because HDFN
    does not cause it.
  evidence:
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The greatest risk for hTTP is in their first days after birth, when 35-50%
      of patients will have severe hemolysis, jaundice, and thrombocytopenia.
    explanation: >-
      Quantifies the neonatal presentation and names its features.
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This causes turbulent circulation that unfolds UL-VWF, allowing platelet
      aggregation. If the DA closes promptly, hTTP newborns survive, but if it
      remains patent, turbulent circulation persists, triggering microvascular
      thrombosis.
    explanation: >-
      States the proposed haemodynamic trigger mechanism for neonatal disease
      and its dependence on ductal closure.
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of newborn-onset hTTP should be considered because HDFN does
      not cause severe thrombocytopenia, which might be effectively treated with
      recombinant ADAMTS13.
    explanation: >-
      Names the discriminating feature against the usual misdiagnosis.
- phase: Childhood-onset disease
  age_range: From around birth through early childhood
  notes: >-
    In the UK national cohort the childhood-onset group had a median age at
    diagnosis of 3.5 years. Prespacer ADAMTS13 variants were significantly more
    likely to be associated with childhood onset. Neonatal presentation with
    hyperbilirubinaemia and thrombocytopenia is the classic Upshaw-Schulman
    picture.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two presentation peaks were seen: childhood (median diagnosis age, 3.5
      years) and adulthood, typically related to pregnancy (median diagnosis
      age, 31 years).
    explanation: >-
      The UK cohort documents the bimodal age-at-diagnosis distribution,
      including the childhood peak.
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic mutations differed by age of onset with prespacer mutations more
      likely to be associated with childhood onset (P = .0011).
    explanation: >-
      This is the reported genotype-phenotype signal for age of onset.
- phase: Adult-onset disease, usually unmasked by pregnancy
  age_range: Typically third decade; first manifestation reported up to age 70
  notes: >-
    Adult presentation is dominated by pregnancy. In the UK cohort 69% of adult
    presentations were pregnancy-associated, with a median diagnosis age of 31
    years. The international registry recorded first recognised manifestation
    anywhere from around birth to age 70.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sixty-nine percent of adult presentations were associated with pregnancy.
    explanation: >-
      The UK cohort quantifies the pregnancy association in adult-onset cTTP.
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First recognized disease manifestation occurred from around birth up to
      the age of 70 years.
    explanation: >-
      The registry documents the full reported range of age at first
      manifestation.
- phase: Cumulative end-organ damage in untreated or late-diagnosed disease
  notes: >-
    Long-term risk is of accumulated ischaemic injury rather than a single
    catastrophic event. End-organ damage was seen in 75% of patients diagnosed
    late in the UK cohort, and prophylaxis significantly reduced stroke
    incidence.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term, there is a risk of end-organ damage, seen in 75% of patients
      with late diagnosis of cTTP.
    explanation: >-
      The cohort quantifies cumulative end-organ damage associated with delayed
      diagnosis.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires ADAMTS13 variants on both alleles. In the UK cohort 36% of
    patients were homozygous and 64% compound heterozygous.
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital thrombotic thrombocytopenic purpura is an autosomal recessive
      inherited disease with a clinically heterogeneous course and an
      incompletely understood genotype-phenotype correlation.
    explanation: >-
      The registry states the mode of inheritance directly.
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-six percent had homozygous mutations; 64% had compound
      heterozygous mutations.
    explanation: >-
      The cohort gives the observed split of homozygous and compound
      heterozygous genotypes.
genetic:
- name: ADAMTS13
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ADAMTS13
    term:
      id: hgnc:1366
      label: ADAMTS13
  variants:
  - name: ADAMTS13 c.4143_4144dupA (p.Glu1382Argfs*6)
    description: >-
      The one recurrent allele in an otherwise largely private mutational
      spectrum: present on 60 of 246 alleles in the international registry. Its
      frequency is a founder effect rather than a mutational hotspot -
      haplotype analysis across 17 intragenic markers found identical
      haplotypes in every informative family, and carriers cluster in Northern
      and Central Europe.
  - name: ADAMTS13 p.R1060W
    description: >-
      A recurrent missense allele associated with low but measurable residual
      ADAMTS13 activity, reported alongside the founder-mutation haplotype
      study.
  notes: >-
    Biallelic loss-of-function variants in ADAMTS13 cause cTTP. The mutational
    spectrum is broad and largely private: 98 different variants were found
    across 123 registry patients. Variants abolish or severely reduce
    VWF-cleaving protease activity, and prespacer-domain variants are associated
    with earlier, childhood onset.
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29;
      p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246
      alleles.
    explanation: >-
      The registry quantifies the allelic heterogeneity and names the one
      recurrent variant.
  - reference: PMID:12393505
    reference_title: von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      homozygous or compound heterozygous mutations of ADAMTS13 are responsible
      for recessively inherited TTP
    explanation: >-
      Establishes biallelic ADAMTS13 variants as the cause of the inherited
      form.
  - reference: PMID:16807643
    reference_title: A common origin of the 4143insA ADAMTS13 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We established ADAMTS13 haplotypes by analyzing 17 polymorphic intragenic
      markers. The haplotypes linked to 4143insA were identical in all
      informative families.
    explanation: >-
      The haplotype evidence establishing the recurrent allele as a founder
      mutation rather than repeated independent events.
  - reference: PMID:16807643
    reference_title: A common origin of the 4143insA ADAMTS13 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that 4143insA has a common genetic background and is frequent
      among patients with hereditary ADAMTS13 deficiency in Northern and Central
      European countries.
    explanation: >-
      States the geographic concentration that follows from the founder origin.
  - reference: PMID:16807643
    reference_title: A common origin of the 4143insA ADAMTS13 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three novel candidate mutations, C347S, P671L and R1060W, as well as the
      known mutation R507Q, were also identified during the course of the study.
    explanation: >-
      Source for R1060W as a reported ADAMTS13 allele.
pathophysiology:
- name: Biallelic ADAMTS13 Loss of Function
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: ADAMTS13
      term:
        id: hgnc:1366
        label: ADAMTS13
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Variants on both alleles abolish or severely reduce VWF-cleaving protease
      activity. Patients are homozygous or, more often, compound heterozygous.
  description: >-
    Variants on both ADAMTS13 alleles abolish or severely reduce production of
    functional ADAMTS13 protein. ADAMTS13 is synthesised mainly in hepatic
    stellate cells and also in vascular endothelial cells, so the deficiency is
    a plasma-protein deficiency rather than a lesion in the target vessel wall.
    That distinction is what makes the disease correctable from outside: the
    microvasculature itself is normal.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:16388417
    reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in
      vascular endothelial cells.
    explanation: >-
      Establishes the cellular source of the deficient protease, which is why
      plasma replacement corrects the defect.
  downstream:
  - target: Severe Plasma ADAMTS13 Activity Deficiency
    causal_link_type: DIRECT
    description: >-
      Loss of both functional alleles leaves circulating VWF-cleaving protease
      activity in the severe-deficiency range.
    evidence:
    - reference: PMID:30770395
      reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare
        thrombomicroangiopathy caused by an inherited deficiency of a
        disintegrin and metalloproteinase with a thrombospondin type 1 motif,
        member 13 (ADAMTS13).
      explanation: >-
        States the causal link from inherited genetic defect to enzyme
        deficiency.
- name: Severe Plasma ADAMTS13 Activity Deficiency
  biological_scale: MOLECULAR
  description: >-
    Circulating VWF-cleaving metalloprotease activity is at or below 10% of
    normal, with no functional inhibitor present. Residual activity varies
    between genotypes and, importantly, is not by itself sufficient to predict
    when disease will first manifest.
  molecular_functions:
  - preferred_term: VWF-cleaving metalloendopeptidase activity
    modifier: DECREASED
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An evaluation of overt disease onset in all patients with an available
      sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13
      activity is not the only determinant of age at first disease
      manifestation.
    explanation: >-
      Directly supports the claim that residual activity does not fully
      determine phenotype, which is the basis for the knowledge gap recorded
      below.
  downstream:
  - target: Persistence of Ultralarge VWF Multimers
    causal_link_type: DIRECT
    description: >-
      Without ADAMTS13 the Tyr1605-Met1606 bond in the VWF A2 domain is not
      cleaved, so ultralarge multimers are not processed to smaller, less
      adhesive forms.
    evidence:
    - reference: PMID:16388417
      reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich
        thrombus formation in the small arteries by cleaving von Willebrand
        factor (vWF) at the Tyr1605-Met1606 peptide bond.
      explanation: >-
        Names the exact scissile bond and the physiological consequence of its
        cleavage, so loss of the protease leaves the substrate uncleaved.
- name: Persistence of Ultralarge VWF Multimers
  biological_scale: MOLECULAR
  description: >-
    Uncleaved ultralarge VWF multimers remain in plasma and anchored to
    endothelium. Their adhesive function is shear-dependent, and ADAMTS13
    proteolysis of VWF is itself modulated by shear force and by binding to
    platelet glycoprotein Ib-alpha, so the substrate is most dangerous exactly
    where the enzyme is most needed.
  evidence:
  - reference: PMID:16388417
    reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cleavage of vWF appears to be modulated by shear force, binding to
      platelet or platelet glycoprotein-1balpha, heparin, inflammatory cytokine
      (interleukin-6), and chloride ion.
    explanation: >-
      Supports the shear- and platelet-dependence of the VWF/ADAMTS13
      interaction that makes this node microvascular.
  downstream:
  - target: Shear-Driven Platelet Adhesion and Microthrombus Formation
    causal_link_type: DIRECT
    description: >-
      Ultralarge multimers unfurl under high shear in the microcirculation and
      recruit platelets, which is the step ADAMTS13 normally prevents.
    evidence:
    - reference: PMID:16388417
      reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich
        thrombus formation in the small arteries by cleaving von Willebrand
        factor (vWF) at the Tyr1605-Met1606 peptide bond.
      explanation: >-
        The protease's stated physiological role is limiting platelet-rich
        thrombus formation, so its absence permits that formation.
- name: Shear-Driven Platelet Adhesion and Microthrombus Formation
  biological_scale: CELLULAR
  description: >-
    Platelets bind the exposed A1 domains of unfurled ultralarge VWF and
    aggregate, building platelet-VWF thrombi in arterioles and capillaries. The
    thrombi are platelet- and VWF-rich rather than fibrin-rich, which is why
    coagulation screens are typically normal in TTP.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet aggregation
    modifier: INCREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  evidence:
  - reference: PMID:16388417
    reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Deficiency of plasma ADAMTS13 activity, due to either an inherited or an
      acquired etiology, may lead to a potentially lethal syndrome, thrombotic
      thrombocytopenic purpura (TTP).
    explanation: >-
      Connects the enzyme deficiency, of either aetiology, to the
      microangiopathic syndrome built on this node.
  downstream:
  - target: Microvascular Occlusion and Ischemic End-Organ Injury
    causal_link_type: DIRECT
    description: >-
      Accumulated microthrombi occlude arterioles and capillaries, producing
      tissue ischaemia in brain, kidney, heart and other organs.
    evidence:
    - reference: PMID:30770395
      reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Stroke incidence was significantly reduced in patients receiving
        prophylactic therapy (2% vs 17%; P = .04).
      directness: INDIRECT
      explanation: >-
        Restoring the missing protease reduces ischaemic stroke, which supports
        the inference that the untreated microthrombotic state causes the
        ischaemic injury.
  - target: Consumptive Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Platelets are consumed into disseminated microthrombi faster than they are
      replaced, producing peripheral thrombocytopenia.
    evidence:
    - reference: PMID:38692292
      reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombocytopenia was the most frequent TTP manifestation (annualized
        event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard
        therapy).
      directness: INDIRECT
      explanation: >-
        Thrombocytopenia is the dominant recorded manifestation and its rate
        falls when the protease is replaced, consistent with consumption
        downstream of microthrombus formation.
  - target: Mechanical Erythrocyte Fragmentation
    causal_link_type: DIRECT
    description: >-
      Erythrocytes are sheared as they traverse partially occluded,
      VWF-platelet-strung microvessels, producing schistocytes and intravascular
      haemolysis.
    evidence:
    - reference: PMID:16388417
      reference_title: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich
        thrombus formation in the small arteries by cleaving von Willebrand
        factor (vWF) at the Tyr1605-Met1606 peptide bond.
      directness: INDIRECT
      explanation: >-
        The platelet-rich small-artery thrombi this node describes are the
        mechanical obstacle that fragments erythrocytes; the quote establishes
        their location and composition.
- name: Consumptive Thrombocytopenia
  biological_scale: ORGANISM
  description: >-
    Peripheral platelet count falls as platelets are incorporated into
    microthrombi. This is the most frequently recorded manifestation of cTTP and
    the one that responds most directly to ADAMTS13 replacement.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia was the most frequent TTP manifestation (annualized event
      rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy).
    explanation: >-
      The phase 3 trial identifies thrombocytopenia as the most frequent
      manifestation and quantifies it under both treatments.
- name: Mechanical Erythrocyte Fragmentation
  biological_scale: CELLULAR
  description: >-
    Red cells are physically fragmented in the obstructed microcirculation,
    producing schistocytes, intravascular haemolysis, raised lactate
    dehydrogenase and a reticulocyte response.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:27868334
    reference_title: "Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that
      leads to microangiopathic hemolytic anemia and thrombocytopenia, and
      involves capillary and small-vessel platelet aggregates.
    explanation: >-
      Attaches the microangiopathic haemolysis directly to the capillary and
      small-vessel platelet aggregates that cause it, which is this node.
  - reference: PMID:39161536
    reference_title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital (cTTP) and immune-mediated (iTTP) thrombotic thrombocytopenic
      purpura are serious and rare clotting disorders resulting from a
      deficiency in the ADAMTS13 enzyme.
    directness: INDIRECT
    explanation: >-
      Places cTTP within the ADAMTS13-deficiency microangiopathies whose
      defining lesion includes this haemolysis.
- name: Microvascular Occlusion and Ischemic End-Organ Injury
  biological_scale: TISSUE
  description: >-
    Cumulative microvascular occlusion produces ischaemic injury, most
    consequentially cerebral infarction. In cTTP this damage accrues over years
    and is substantially preventable: 75% of late-diagnosed patients had
    end-organ damage, and prophylactic ADAMTS13 replacement cut stroke incidence
    from 17% to 2%.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term, there is a risk of end-organ damage, seen in 75% of patients
      with late diagnosis of cTTP.
    explanation: >-
      Quantifies cumulative end-organ damage in the late-diagnosed group.
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stroke incidence was significantly reduced in patients receiving
      prophylactic therapy (2% vs 17%; P = .04).
    explanation: >-
      Shows the ischaemic injury is modifiable by replacing the missing
      protease.
phenotypes:
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Consumptive thrombocytopenia is the most frequently recorded manifestation
    of cTTP and the primary trial endpoint manifestation.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia was the most frequent TTP manifestation (annualized event
      rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy).
    explanation: >-
      The phase 3 crossover trial records thrombocytopenia as the dominant
      manifestation in this population.
- category: Hematologic
  name: Microangiopathic hemolytic anemia
  description: >-
    Mechanical fragmentation of erythrocytes in the occluded microcirculation
    produces a non-immune haemolytic anaemia, one of the defining features of a
    thrombotic microangiopathy.
  phenotype_term:
    preferred_term: Microangiopathic hemolytic anemia
    term:
      id: HP:0001937
      label: Microangiopathic hemolytic anemia
  evidence:
  - reference: PMID:27868334
    reference_title: Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that
      leads to microangiopathic hemolytic anemia and thrombocytopenia, and
      involves capillary and small-vessel platelet aggregates.
    explanation: >-
      The consensus statement defines the microangiopathic process that produces
      this haemolytic anaemia and names its microvascular platelet-aggregate
      substrate.
- category: Neurologic
  name: Stroke
  description: >-
    Cerebral infarction from microvascular occlusion is the most consequential
    ischaemic complication of cTTP and is markedly reduced by prophylaxis.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stroke incidence was significantly reduced in patients receiving
      prophylactic therapy (2% vs 17%; P = .04).
    explanation: >-
      Reports stroke incidence in both prophylaxed and non-prophylaxed cTTP
      patients, establishing it as a disease phenotype.
- category: Neurologic
  name: Headache
  description: >-
    Headache is one of the non-overt symptoms that occurs with normal blood
    counts and that resolved on prophylaxis in the majority of patients, which
    is why it is curated as disease activity rather than an incidental
    complaint.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-eight percent of patients with normal blood counts, but with
      headaches, lethargy, or abdominal pain, reported symptom resolution with
      prophylactic therapy.
    explanation: >-
      Headache is named as a symptom present with normal counts that resolved on
      ADAMTS13 replacement.
- category: Renal
  name: Renal insufficiency
  description: >-
    Renal insufficiency occurred in a quarter of the international registry
    cohort, reflecting the renal share of the ischaemic end-organ injury.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal insufficiency occurred in 25%  of the cohort.
    explanation: >-
      A denominator-backed frequency from the international registry.
- category: Hematologic
  name: Jaundice
  description: >-
    Jaundice from haemolysis, present in about half the registry cohort and one
    of the three features of the classical neonatal presentation. It is also the
    feature that steers the newborn towards a haemolytic-disease-of-the-newborn
    diagnosis, so it carries diagnostic as well as clinical weight here.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  frequency: FREQUENT
  evidence:
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The greatest risk for hTTP is in their first days after birth, when 35-50%
      of patients will have severe hemolysis, jaundice, and thrombocytopenia.
    explanation: >-
      Names jaundice as one of the three neonatal presenting features, with its
      frequency in that window.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Abdominal pain occurs in non-overt disease alongside headache and lethargy
    and likewise resolves with prophylaxis.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-eight percent of patients with normal blood counts, but with
      headaches, lethargy, or abdominal pain, reported symptom resolution with
      prophylactic therapy.
    explanation: >-
      Abdominal pain is named among the non-overt symptoms responsive to
      replacement therapy.
biochemical:
- name: Plasma ADAMTS13 activity
  notes: >-
    The defining laboratory abnormality. Severe deficiency is activity at or
    below 10% of normal; many cTTP patients are below 1%. Recombinant ADAMTS13
    restores mean maximum activity to approximately 101% of normal, against 19%
    with plasma-derived standard therapy — a fivefold difference that is the
    pharmacodynamic basis for the trial result.
  evidence:
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment
      was 101%, as compared with 19% after standard therapy.
    explanation: >-
      Quantifies the analyte under both treatment arms.
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14
      compound heterozygous carriers
    explanation: >-
      Documents the distribution of residual activity by genotype class.
diagnosis:
- name: ADAMTS13 activity assay with inhibitor testing
  description: >-
    Severe deficiency at or below 10% of normal establishes TTP; the absence of
    a functional inhibitor is what makes it congenital rather than immune. Both
    halves are required - activity alone does not separate the two diseases, and
    getting it wrong sends the patient to immunosuppression that cannot work.
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed
      by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of
      a functional inhibitor and the presence of ADAMTS13 mutations on both
      alleles.
    explanation: >-
      The operational diagnostic definition used by the international registry.
- name: ADAMTS13 sequencing
  description: >-
    Demonstration of variants on both alleles is the confirmatory element.
    Expect a private variant: 98 different variants were found across 123
    registry patients, with only one recurrent founder allele.
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29;
      p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246
      alleles.
    explanation: >-
      Sets the expectation for what sequencing returns in an unselected patient.
- name: Coagulation screen to exclude disseminated intravascular coagulation
  description: >-
    Normal in TTP, because the microthrombi are platelet-VWF rather than fibrin
    based. Abnormal coagulation points to DIC, the commonest cause of thrombotic
    microangiopathy overall.
  evidence:
  - reference: PMID:27868334
    reference_title: "Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common cause is disseminated intravascular coagulation, which may
      be differentiated by abnormal coagulation.
    explanation: >-
      Names the discriminating laboratory feature against the leading
      alternative.
- name: Recognising neonatal cTTP behind a haemolytic-disease-of-the-newborn label
  description: >-
    Not a test but a decision point, and the one most often missed. Newborn cTTP
    is commonly treated as HDFN with exchange transfusion, which prevents
    kernicterus and so conceals the error. Severe thrombocytopenia is the
    feature that should stop that reading, because HDFN does not cause it.
  evidence:
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of newborn-onset hTTP should be considered because HDFN does
      not cause severe thrombocytopenia, which might be effectively treated with
      recombinant ADAMTS13.
    explanation: >-
      States the discriminating feature and the reason it matters.
environmental:
- name: Systemic physiological stressors that raise VWF or shear
  description: >-
    Pregnancy and infection are the two commonest precipitants of an acute cTTP
    episode, and they are the same triggers as in immune TTP - which is
    informative, because it says the trigger acts on the shared downstream
    pathway rather than on the aetiology. In cTTP the enzyme deficiency is
    constitutional and lifelong, so what varies is not the protease but the
    load placed on it; the disease is episodic because the trigger is.
  exposure_term:
    preferred_term: pregnancy or systemic infection as a physiological stressor
  influences_mechanisms:
  - target: Shear-Driven Platelet Adhesion and Microthrombus Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      States of raised von Willebrand factor or altered shear tip a
      constitutionally protease-deficient circulation into overt
      microthrombosis.
    evidence:
    - reference: PMID:39161536
      reference_title: "A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Triggers of acute episodes were similar for cTTP and iTTP, with
        pregnancy and infection the most commonly observed.
      explanation: >-
        Identifies the two dominant precipitants and, by their being shared with
        immune TTP, locates their action downstream of the aetiology.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sixty-nine percent of adult presentations were associated with pregnancy.
    explanation: >-
      Quantifies how much of adult-onset disease is unmasked by one of these
      stressors.
  review_notes: >-
    exposure_term is left unbound deliberately. ECTO was searched for exposure
    terms covering infection and pregnancy as physiological stressors
    (sqlite:obo:ecto free-text and label searches for "infection", "pregnancy",
    "infectious", "physiological stress", plus the committed cache/ecto/terms.csv
    and the exposureterm enum cache). Nothing suitable exists - the only
    infection-adjacent hit is NCIT:C26726 "Infectious Disorder", which is a
    disease term rather than an exposure and is not in the ExposureTerm enum. A
    free-text preferred_term is kept rather than binding a term that would
    misstate the concept, per the dismech-terms rule that no term beats a bad
    one.
- name: Neonatal ductal flow transition
  description: >-
    A physiological rather than exogenous exposure, and the clearest worked
    example of the trigger mechanism. Fetal flow through the ductus arteriosus
    is low-shear; at birth the shunt reverses and the duct narrows, producing
    turbulence that unfolds ultralarge VWF. Prompt ductal closure ends the
    exposure and the newborn survives; a patent duct sustains it.
  exposure_term:
    preferred_term: turbulent ductal blood flow in the neonatal transition
  influences_mechanisms:
  - target: Shear-Driven Platelet Adhesion and Microthrombus Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Turbulent circulation at the closing ductus unfolds ultralarge VWF and
      permits platelet aggregation, precipitating neonatal microthrombosis.
    evidence:
    - reference: PMID:38536644
      reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This causes turbulent circulation that unfolds UL-VWF, allowing platelet
        aggregation. If the DA closes promptly, hTTP newborns survive, but if it
        remains patent, turbulent circulation persists, triggering microvascular
        thrombosis.
      explanation: >-
        States the shear mechanism and its dependence on ductal closure, which
        is what makes this a bounded exposure rather than a constant.
  evidence:
  - reference: PMID:38536644
    reference_title: "Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The greatest risk for hTTP is in their first days after birth, when 35-50%
      of patients will have severe hemolysis, jaundice, and thrombocytopenia.
    explanation: >-
      Quantifies the clinical consequence of this exposure window.
  review_notes: >-
    exposure_term is left unbound deliberately. This is an internal
    haemodynamic transition rather than an environmental exposure in the ECTO
    sense, and ECTO was searched without finding any applicable term. Modelled
    here rather than as a Pathophysiology node because it is a time-bounded
    trigger acting on an existing mechanism, not a mechanism step of its own.
treatments:
- name: Recombinant ADAMTS13 Prophylaxis
  description: >-
    Intravenous recombinant ADAMTS13 (40 IU/kg) given as routine prophylaxis
    replaces the missing protease directly. In the phase 3 crossover trial no
    acute TTP event occurred during recombinant ADAMTS13 prophylaxis, activity
    reached approximately 100% of normal, drug-related adverse events occurred
    in 9% of patients against 48% on standard therapy, no patient discontinued
    for an adverse event, and no neutralising antibodies developed.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Protein Replacement Therapy
    term:
      id: NCIT:C16221
      label: Protein Replacement Therapy
    therapeutic_agent:
    - preferred_term: apadamtase alfa
      term:
        id: NCIT:C169784
        label: Apadamtase Alfa
  target_mechanisms:
  - target: Severe Plasma ADAMTS13 Activity Deficiency
    treatment_effect: RESTORES
    description: >-
      Exogenous recombinant enzyme restores circulating VWF-cleaving protease
      activity, correcting the deficiency node itself rather than a downstream
      consequence.
    evidence:
    - reference: PMID:38692292
      reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During prophylaxis with recombinant ADAMTS13 in patients with congenital
        TTP, ADAMTS13 activity reached approximately 100% of normal levels
      explanation: >-
        Demonstrates that the intervention acts on and corrects the enzyme
        deficiency node.
  evidence:
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No acute TTP event occurred during prophylaxis with recombinant ADAMTS13,
      whereas 1 patient had an acute TTP event during prophylaxis with standard
      therapy (mean annualized event rate, 0.05).
    explanation: >-
      The trial's primary outcome supports recombinant ADAMTS13 prophylaxis.
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adverse events that were considered by investigators to be related to the
      trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in
      48% with standard therapy.
    explanation: >-
      Supports the tolerability advantage over plasma-derived standard therapy.
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No neutralizing antibodies developed during recombinant ADAMTS13
      treatment.
    explanation: >-
      Addresses the main theoretical hazard of protein replacement in a
      constitutionally protein-null patient.
- name: Plasma-Derived ADAMTS13 Replacement
  description: >-
    Fresh-frozen plasma and intermediate-purity factor VIII concentrate supply
    ADAMTS13 indirectly and were the standard of care before recombinant enzyme.
    They work, but incompletely: mean maximum activity reaches only 19% of
    normal, the commonly used three-weekly FFP schedule was insufficient for 70%
    of UK patients, and drug-related adverse events were far commoner than with
    recombinant enzyme.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Fresh Frozen Plasma Transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
  target_mechanisms:
  - target: Severe Plasma ADAMTS13 Activity Deficiency
    treatment_effect: RESTORES
    description: >-
      Donor plasma contains ADAMTS13 and partially replaces the missing enzyme
      activity.
    evidence:
    - reference: PMID:38692292
      reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment
        was 101%, as compared with 19% after standard therapy.
      explanation: >-
        Quantifies the partial activity restoration achieved by plasma-derived
        standard therapy.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate
      were used as treatment.
    explanation: >-
      Documents the plasma-derived products used as replacement therapy in the
      national cohort.
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common currently used regimen of 3-weekly FFP proved insufficient
      for 70% of patients and weekly or fortnightly infusions were required.
    explanation: >-
      Documents the inadequacy of the conventional plasma schedule, the practical
      limitation of this modality.
- name: Prophylactic Replacement to Prevent End-Organ Damage
  description: >-
    Regular prophylaxis, as opposed to on-demand treatment of acute episodes, is
    what prevents the accumulated ischaemic injury of cTTP. It reduced stroke
    incidence from 17% to 2% and resolved symptoms in 88% of patients who had
    normal blood counts but ongoing headache, lethargy or abdominal pain — a
    group who would previously have been considered to have inactive disease.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Protein Replacement Therapy
    term:
      id: NCIT:C16221
      label: Protein Replacement Therapy
  target_mechanisms:
  - target: Microvascular Occlusion and Ischemic End-Organ Injury
    treatment_effect: RESTORES
    description: >-
      Maintaining circulating protease activity prevents the microthrombotic
      burden from accumulating into ischaemic organ damage.
    evidence:
    - reference: PMID:30770395
      reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage
        such as ischemic stroke and resolved previously unrecognized symptoms in
        patients with nonovert disease.
      explanation: >-
        States the preventive effect of prophylaxis on the end-organ injury
        node.
  evidence:
  - reference: PMID:30770395
    reference_title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-eight percent of patients with normal blood counts, but with
      headaches, lethargy, or abdominal pain, reported symptom resolution with
      prophylactic therapy.
    explanation: >-
      Supports prophylaxis for non-overt disease, not only for overt episodes.
- name: Plasma Prophylaxis in Pregnancy
  description: >-
    Pregnancy physiologically raises VWF and is the dominant trigger of adult
    cTTP, so prophylaxis through pregnancy is a distinct management question
    rather than a special case of routine prophylaxis. In a cohort of 14 women
    with hereditary TTP across 71 pregnancies, 24% ended in pregnancy loss and
    45% were complicated by severe obstetric morbidity; plasma-treated
    pregnancies had markedly less severe obstetric morbidity and far fewer
    preterm TTP exacerbations. Response is not uniform: higher non-pregnant VWF
    antigen predicted morbidity even among treated women, which is a candidate
    stratifier rather than an established one.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Fresh Frozen Plasma Transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
  target_mechanisms:
  - target: Microvascular Occlusion and Ischemic End-Organ Injury
    treatment_effect: RESTORES
    description: >-
      Replacing ADAMTS13 through pregnancy prevents the microthrombotic
      exacerbations that drive obstetric morbidity and fetal loss.
    evidence:
    - reference: PMID:36889591
      reference_title: "von Willebrand factor antigen: a biomarker for severe pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treated women had decreased SOM (28% vs 72%, p < .001) and preterm
        thrombotic thrombocytopenic purpura exacerbations (18% vs 82%, p < .001)
      explanation: >-
        Quantifies the effect of plasma prophylaxis on obstetric morbidity and
        on preterm exacerbations.
  evidence:
  - reference: PMID:36889591
    reference_title: "von Willebrand factor antigen: a biomarker for severe pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fourteen women with hTTP had 71 pregnancies; of which 17 (24%) culminated
      in pregnancy loss and 32 (45%) were complicated by SOM.
    explanation: >-
      Establishes the untreated obstetric burden this treatment addresses.
  - reference: PMID:36889591
    reference_title: "von Willebrand factor antigen: a biomarker for severe pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the treated women, median NPVWF antigen levels were higher in those
      with SOM than in those without SOM (225% vs 165%, p = .047).
    explanation: >-
      Records the residual-risk signal among treated women, which is why this is
      not framed as uniformly effective.
clinical_trials:
- name: NCT03393975
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase 3 open-label crossover trial of recombinant ADAMTS13 versus
    plasma-derived standard therapy for prophylaxis and on-demand treatment in
    congenital TTP.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:38692292
    reference_title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this phase 3, open-label, crossover trial, we randomly assigned
      patients in a 1:1 ratio to two 6-month periods of prophylaxis with
      recombinant ADAMTS13 (40 IU per kilogram of body weight, administered
      intravenously) or standard therapy, followed by the alternate treatment
    explanation: >-
      Describes the trial design and the intervention under study.
animal_models:
- name: Adamts13-knockout mouse
  species: Mouse
  genotype: Adamts13 homozygous null
  publication: PMID:16200209
  description: >-
    The defining result of this model is a negative one. Adamts13-null mice are
    viable with normal survival despite prolonged VWF-mediated
    platelet-endothelial interactions: the enzyme deficiency alone does not
    produce the disease. Spontaneous thrombocytopenia appears only on the
    CASA/Rk background, which has elevated plasma VWF, and a syndrome closely
    resembling human TTP requires an additional shigatoxin challenge. This is
    the experimental basis for reading cTTP as a two-hit disease rather than a
    straightforward enzyme deficiency.
  modeled_mechanisms:
  - target: Severe Plasma ADAMTS13 Activity Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The knockout reproduces the enzymatic lesion exactly and shows its direct
      consequence on VWF-mediated platelet-endothelial interaction.
    limitations: >-
      The mouse reproduces the deficiency faithfully but not the human disease
      that follows from it, which is the finding rather than a defect of the
      model.
    readouts:
    - name: VWF-mediated platelet-endothelial interaction duration
      target: Severe Plasma ADAMTS13 Activity Deficiency
      direction: INCREASED
      interpretation: >-
        Direct in vivo consequence of losing the VWF-cleaving protease.
      evidence:
      - reference: PMID:16200209
        reference_title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          ADAMTS13-deficient mice are viable and exhibit normal survival,
          although vWF-mediated platelet-endothelial interactions are
          significantly prolonged.
        explanation: >-
          Reports the measurement behind this readout, and the absence of a
          spontaneous disease phenotype.
    evidence:
    - reference: PMID:16200209
      reference_title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness
        caused by deficiency of the vWF-cleaving protease ADAMTS13.
      explanation: >-
        Confirms the model carries a lesion in the same protease that defines
        this node.
  - target: Shear-Driven Platelet Adhesion and Microthrombus Formation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Enzyme deficiency by itself does not produce microthrombotic disease in
      this model. Disseminated microthrombosis appears only when a permissive
      genetic background is combined with a toxin challenge.
    limitations: >-
      On a standard background the null mouse has no spontaneous
      microthrombotic phenotype at all, and even on the high-VWF CASA/Rk
      background only a subset develops thrombocytopenia. The full TTP-like
      syndrome requires shigatoxin, an exogenous endothelial insult with no
      counterpart in most human cTTP episodes. Notably, plasma VWF level did not
      correlate with TTP severity, so the permissive background is not simply
      acting through VWF.
    evidence:
    - reference: PMID:16200209
      reference_title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data suggest that microbe-derived toxins (or possibly other
        sources of endothelial injury), together with additional genetic
        susceptibility factors, are required to trigger TTP in the setting of
        ADAMTS13 deficiency.
      explanation: >-
        The authors' own statement that deficiency alone is insufficient, which
        is the substantive negative claim this link records.
    - reference: PMID:16200209
      reference_title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Challenge of these mice with shigatoxin (derived from bacterial
        pathogens associated with the related human disease hemolytic uremic
        syndrome) resulted in a striking syndrome closely resembling human TTP.
      explanation: >-
        Establishes that the disease phenotype appears only under an added
        trigger.
differential_diagnoses:
- name: Immune-mediated thrombotic thrombocytopenic purpura
  description: >-
    iTTP produces the same severe ADAMTS13 deficiency and the same
    microangiopathic syndrome, but through an acquired autoantibody rather than
    biallelic germline variants. The discriminators are a demonstrable
    functional inhibitor, later age at symptom onset, and recovery of ADAMTS13
    activity after immunosuppression. Getting this wrong matters in both
    directions: immunosuppression cannot help cTTP, and enzyme replacement
    alone does not address an ongoing autoimmune driver.
  evidence:
  - reference: PMID:39161536
    reference_title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital (cTTP) and immune-mediated (iTTP) thrombotic thrombocytopenic
      purpura are serious and rare clotting disorders resulting from a
      deficiency in the ADAMTS13 enzyme.
    explanation: >-
      Establishes that the two diseases share the enzymatic lesion, which is why
      they are confusable and must be separated on aetiology.
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a
      functional inhibitor and the presence of ADAMTS13 mutations on both
      alleles
    explanation: >-
      Names the two features that discriminate cTTP from iTTP.
- name: Haemolytic uraemic syndrome
  description: >-
    HUS presents with the same microangiopathic haemolytic anaemia and
    thrombocytopenia but has a different pathophysiology and a different
    treatment pathway, and does not feature severe ADAMTS13 deficiency.
  evidence:
  - reference: PMID:27868334
    reference_title: Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite overlapping clinical presentations, TTP and HUS have distinct
      pathophysiologies and treatment pathways.
    explanation: >-
      The consensus statement separates these two thrombotic microangiopathies
      explicitly.
- name: Disseminated intravascular coagulation
  description: >-
    DIC is the commonest cause of thrombotic microangiopathy overall and is
    distinguished by abnormal coagulation tests, which are characteristically
    normal in TTP because the microthrombi are platelet-VWF rather than fibrin
    based.
  evidence:
  - reference: PMID:27868334
    reference_title: Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common cause is disseminated intravascular coagulation, which may
      be differentiated by abnormal coagulation.
    explanation: >-
      Names DIC as the leading TMA differential and the laboratory feature that
      separates it.
discussions:
- discussion_id: onset_timing_not_explained_by_residual_activity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do two patients with the same residual ADAMTS13 activity present decades
    apart — one in the neonatal period and one in a first pregnancy?
  attaches_to:
  - pathophysiology#Severe Plasma ADAMTS13 Activity Deficiency
  rationale: >-
    The bimodal age distribution of cTTP is not explained by the enzyme
    deficiency alone. The international registry showed directly that residual
    ADAMTS13 activity is not the only determinant of age at first manifestation,
    and produced a counterintuitive result: compound heterozygous carriers of the
    recurrent c.4143_4144dupA allele had a *larger* proportion with onset before
    three months than homozygotes, despite homozygotes having lower measured
    activity. Something beyond the ADAMTS13 genotype sets when disease becomes
    overt.

    The mouse work says the same thing from the other direction, and narrows it
    usefully. Adamts13-null mice are viable with normal survival; spontaneous
    thrombocytopenia requires a permissive genetic background, and a full
    TTP-like syndrome requires an added toxin challenge. Two constraints follow.
    The permissive factor is not simply VWF level, because plasma VWF did not
    correlate with severity, so the modifying genes are distinct from VWF. And
    the human triggers are identifiable in outline (birth, pregnancy, infection)
    without those modifiers being known at all. The open question is therefore
    specific rather than vague: what are the non-VWF susceptibility loci, and do
    they account for the residual-activity paradox in the registry?
  evidence:
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a larger proportion of compound heterozygous than homozygous
      carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3
      months of age (50% vs 37%), despite the fact that ADAMTS13 activity was
      <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous
      carriers.
    explanation: >-
      This is the specific result that makes residual activity insufficient as
      an explanation for onset timing.
  - reference: PMID:30792199
    reference_title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an incompletely understood genotype-phenotype correlation
    explanation: >-
      The registry states the genotype-phenotype relationship is incompletely
      understood.
  - reference: PMID:16200209
    reference_title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      no correlation was observed between plasma vWF level and severity of TTP,
      implying the existence of TTP-modifying genes distinct from vWF
    explanation: >-
      Rules out plasma VWF level as the modifier and asserts unidentified
      non-VWF modifying genes, which is what makes this gap specific.
references:
- reference: PMID:38692292
  title: Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
- reference: PMID:30770395
  title: Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
- reference: PMID:30792199
  title: "The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017."
- reference: PMID:42603082
  title: "Natural History and Treatment Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Retrospective Longitudinal Cohort Study."
- reference: PMID:16200209
  title: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
notes: >-
  Scope and lump/split. cTTP is curated as its own Disease entry rather than as
  a subtype of the existing Acquired_Thrombotic_Thrombocytopenic_Purpura entry.
  The two share a final common pathway — severe ADAMTS13 deficiency, ultralarge
  VWF, microvascular platelet thrombi — but differ at the top of the pathograph
  (biallelic germline loss of function versus an acquired autoantibody), in age
  and trigger profile, and in definitive therapy (enzyme replacement versus
  immunosuppression plus caplacizumab). The acquired entry already names
  congenital TTP only as a differential diagnosis, so this entry fills a real
  gap rather than duplicating one.

  Deep research. One OpenScientist report was generated for this entry
  (research/Congenital_Thrombotic_Thrombocytopenic_Purpura-deep-research-openscientist.md)
  and materially expanded it: the neonatal ductus-arteriosus shear mechanism,
  the founder origin of c.4143dupA, the multinational natural-history cohort,
  the Adamts13-knockout two-hit model, and the pregnancy prophylaxis data all
  came from leads in that report and were then verified against the cached
  abstracts.

  Its reference validation was clean (27/27 verified, confabulation rate 0.0),
  but its term validation set needs_review: true, and four of the flagged
  bindings were substantively wrong. None was used:

  - MONDO:0010134 is offered as the MONDO ID for congenital TTP. That CURIE
    resolves to Pendred syndrome. This entry uses MONDO:0010122, which is what
    the curation stub carries.
  - CL:0002679 is offered for hepatic stellate cell; it resolves to natural
    helper lymphocyte. CL:0000632 is used here.
  - CHEBI:18420 is offered for the catalytic zinc; it resolves to
    magnesium(2+). No CHEBI metal term is bound in this entry.
  - NCIT:C171453 is offered for plasma; it resolves to Hospital Stay. The
    treatment terms used here are NCIT:C116475 and NCIT:C16221.

  This is the second report in this batch whose disease-level MONDO term was
  wrong while its confabulation_rate read 0.0 — the CURIEs exist, they just name
  other diseases. needs_review is the field that catches it.

  No GeneReviews chapter exists for cTTP. PubMed searches for "thrombotic
  thrombocytopenic purpura GeneReviews[All Fields]", "ADAMTS13
  GeneReviews[All Fields]" and "Upshaw-Schulman GeneReviews[All Fields]" all
  returned zero results, so the Step 3b baseline is genuinely unavailable rather
  than skipped. The phenotype baseline used instead is the union of the UK
  national cohort (PMID:30770395), the international registry (PMID:30792199)
  and the phase 3 trial (PMID:38692292).

  Review round 1 (PR #10144) corrected a claim in this very paragraph. It
  previously said renal detail was left out for want of a quotable source; the
  registry cache added by this PR carries "Renal insufficiency occurred in 25%
  of the cohort", so renal insufficiency and jaundice are now curated
  phenotypes with denominator-backed frequency bands. The lesson generalises:
  the earlier draft cited only the registry's abstract and never searched the
  full text that the same cache file contains.

  Also added in that round: a diagnosis: section, an environmental: section
  bringing the two-hit trigger into the graph, apadamtase alfa as the
  therapeutic_agent on recombinant ADAMTS13, a directly-attached source on the
  erythrocyte fragmentation node, and removal of a capillary endothelial cell
  binding on the end-organ-injury node that sat awkwardly against this entry's
  own argument that the microvasculature is structurally normal.

  Deliberately not curated for want of a quotable, cTTP-specific source: a
  numeric population prevalence (the systematic review gives an acute-episode
  incidence for cTTP and a population incidence only for iTTP, and conflating
  the two would be the measure-type error the prevalence guidance warns about;
  ORPHA:93583 would supply one but is not in references_cache and the Orphadata
  refresh is currently broken - see issue #10150); cardiac phenotype detail; and
  schistocytosis as a separate phenotype, since the cached sources describe
  microangiopathic haemolysis without naming schistocytes.

  Also left out on purpose: the closed-to-open allosteric conformational switch
  of ADAMTS13 (Spacer-CUB autoinhibition released by VWF D4 binding). It is well
  evidenced and mechanistically interesting, but it describes how the *normal*
  enzyme is regulated, and in a disease where the enzyme is absent it adds no
  causal step. Curating it as a pathophysiology node would assert a mechanism
  the disease does not have. The diagnostic-assay literature (FRETS-VWF73 versus
  the AcuStar chemiluminescent immunoassay) is omitted for the related reason
  that it concerns measurement of the analyte rather than the disease process;
  the analyte itself is curated under biochemical.

  Evidence grading note: several items cite review or consensus articles and are
  graded evidence_source: OTHER rather than HUMAN_CLINICAL, because the cited
  publication is a synthesis or a terminology consensus rather than a primary
  patient study. The cohort, registry and trial papers are graded
  HUMAN_CLINICAL.
📚

References & Deep Research

References

5
PMID:38692292
Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
No top-level findings curated for this source.
PMID:30770395
Characterization and treatment of congenital thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:30792199
The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017.
No top-level findings curated for this source.
PMID:42603082
Natural History and Treatment Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Retrospective Longitudinal Cohort Study.
No top-level findings curated for this source.
PMID:16200209
Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
No top-level findings curated for this source.

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 (2)

Record notes

Scope and lump/split. cTTP is curated as its own Disease entry rather than as a subtype of the existing Acquired_Thrombotic_Thrombocytopenic_Purpura entry. The two share a final common pathway — severe ADAMTS13 deficiency, ultralarge VWF, microvascular platelet thrombi — but differ at the top of the pathograph (biallelic germline loss of function versus an acquired autoantibody), in age and trigger profile, and in definitive therapy (enzyme replacement versus immunosuppression plus caplacizumab). The acquired entry already names congenital TTP only as a differential diagnosis, so this entry fills a real gap rather than duplicating one. Deep research. One OpenScientist report was generated for this entry (research/Congenital_Thrombotic_Thrombocytopenic_Purpura-deep-research-openscientist.md) and materially expanded it: the neonatal ductus-arteriosus shear mechanism, the founder origin of c.4143dupA, the multinational natural-history cohort, the Adamts13-knockout two-hit model, and the pregnancy prophylaxis data all came from leads in that report and were then verified against the cached abstracts. Its reference validation was clean (27/27 verified, confabulation rate 0.0), but its term validation set needs_review: true, and four of the flagged bindings were substantively wrong. None was used: - MONDO:0010134 is offered as the MONDO ID for congenital TTP. That CURIE resolves to Pendred syndrome. This entry uses MONDO:0010122, which is what the curation stub carries. - CL:0002679 is offered for hepatic stellate cell; it resolves to natural helper lymphocyte. CL:0000632 is used here. - CHEBI:18420 is offered for the catalytic zinc; it resolves to magnesium(2+). No CHEBI metal term is bound in this entry. - NCIT:C171453 is offered for plasma; it resolves to Hospital Stay. The treatment terms used here are NCIT:C116475 and NCIT:C16221. This is the second report in this batch whose disease-level MONDO term was wrong while its confabulation_rate read 0.0 — the CURIEs exist, they just name other diseases. needs_review is the field that catches it. No GeneReviews chapter exists for cTTP. PubMed searches for "thrombotic thrombocytopenic purpura GeneReviews[All Fields]", "ADAMTS13 GeneReviews[All Fields]" and "Upshaw-Schulman GeneReviews[All Fields]" all returned zero results, so the Step 3b baseline is genuinely unavailable rather than skipped. The phenotype baseline used instead is the union of the UK national cohort (PMID:30770395), the international registry (PMID:30792199) and the phase 3 trial (PMID:38692292). Review round 1 (PR #10144) corrected a claim in this very paragraph. It previously said renal detail was left out for want of a quotable source; the registry cache added by this PR carries "Renal insufficiency occurred in 25% of the cohort", so renal insufficiency and jaundice are now curated phenotypes with denominator-backed frequency bands. The lesson generalises: the earlier draft cited only the registry's abstract and never searched the full text that the same cache file contains. Also added in that round: a diagnosis: section, an environmental: section bringing the two-hit trigger into the graph, apadamtase alfa as the therapeutic_agent on recombinant ADAMTS13, a directly-attached source on the erythrocyte fragmentation node, and removal of a capillary endothelial cell binding on the end-organ-injury node that sat awkwardly against this entry's own argument that the microvasculature is structurally normal. Deliberately not curated for want of a quotable, cTTP-specific source: a numeric population prevalence (the systematic review gives an acute-episode incidence for cTTP and a population incidence only for iTTP, and conflating the two would be the measure-type error the prevalence guidance warns about; ORPHA:93583 would supply one but is not in references_cache and the Orphadata refresh is currently broken - see issue #10150); cardiac phenotype detail; and schistocytosis as a separate phenotype, since the cached sources describe microangiopathic haemolysis without naming schistocytes. Also left out on purpose: the closed-to-open allosteric conformational switch of ADAMTS13 (Spacer-CUB autoinhibition released by VWF D4 binding). It is well evidenced and mechanistically interesting, but it describes how the *normal* enzyme is regulated, and in a disease where the enzyme is absent it adds no causal step. Curating it as a pathophysiology node would assert a mechanism the disease does not have. The diagnostic-assay literature (FRETS-VWF73 versus the AcuStar chemiluminescent immunoassay) is omitted for the related reason that it concerns measurement of the analyte rather than the disease process; the analyte itself is curated under biochemical. Evidence grading note: several items cite review or consensus articles and are graded evidence_source: OTHER rather than HUMAN_CLINICAL, because the cited publication is a synthesis or a terminology consensus rather than a primary patient study. The cohort, registry and trial papers are graded HUMAN_CLINICAL.

Create: Congenital Thrombotic Thrombocytopenic Purpura · 2026-08-30T06:52:00Z · View source

De novo curation of congenital TTP (MONDO:0010122, ADAMTS13) as a Disease entry distinct from the existing Acquired_Thrombotic_Thrombocytopenic_Purpura entry, which names cTTP only as a differential diagnosis. Built from the UK national cohort, the international hereditary TTP registry and the phase 3 recombinant ADAMTS13 trial, then substantially expanded from an OpenScientist deep-research report. The report contributed the neonatal ductus-arteriosus shear mechanism, the founder origin of c.4143dupA, the multinational natural-history cohort, the Adamts13-knockout two-hit model and the pregnancy prophylaxis data; every claim was re-verified against the cached abstract. The report's reference validation was clean (27/27) but its term validation set needs_review and four of its bindings were substantively wrong and were not used: MONDO:0010134 for the disease (resolves to Pendred syndrome), CL:0002679 for hepatic stellate cell (natural helper lymphocyte), CHEBI:18420 for zinc (magnesium 2+) and NCIT:C171453 for plasma (Hospital Stay). No GeneReviews chapter exists for cTTP; three PubMed searches returned zero results. Two reference titles were corrected after the validator flagged mismatches against the cached records. Validated with just validate (68/68 snippets verified), check-entity-refs, check-duplicate-keys, check-snippet-length, check-title-snippets, check-snippet-grading and check-folded-hyphens.

OpenScientist ▸
Congenital Thrombotic Thrombocytopenic Purpura (Upshaw–Schulman Syndrome): A Comprehensive Disease Characteristics Report
openscientist-autonomous 27 citations 2026-08-30T06:35:55.946565

Congenital Thrombotic Thrombocytopenic Purpura (Upshaw–Schulman Syndrome): A Comprehensive Disease Characteristics Report

Summary

Congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw–Schulman syndrome (USS) or hereditary TTP (hTTP), is an ultra-rare, life-threatening thrombotic microangiopathy caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in the ADAMTS13 gene on chromosome 9q34.2 (OMIM #274150; gene OMIM *604134). The genetic defect produces severe, lifelong deficiency (typically <10%, often <5–6% activity) of ADAMTS13, the plasma metalloprotease that cleaves von Willebrand factor (VWF). Inheritance is autosomal recessive.

The central pathophysiology is elegantly linear: absent ADAMTS13 protease activity allows ultra-large VWF (UL-VWF) multimers to persist in circulation. Under high shear stress in the microvasculature, these multimers spontaneously bind and aggregate platelets, generating disseminated platelet-rich microthrombi. This produces the clinical triad of consumptive thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and ischemic end-organ injury — most prominently affecting the brain, kidney, and heart. Because ADAMTS13 activity is already at baseline near-zero, additional physiological stressors that raise VWF or shear (birth, pregnancy, infection, inflammation) act as "second hits" that precipitate acute episodes, explaining the marked (~78%) female predominance and the frequent neonatal and pregnancy-associated presentations.

cTTP is a treatable disease when recognized: the therapeutic principle is ADAMTS13 replacement. Historically this was achieved with fresh frozen plasma (FFP) or plasma-derived factor VIII/VWF concentrates that contain ADAMTS13. The field has now been transformed by recombinant ADAMTS13 (apadamtase alfa; Adzynma/TAK-755), which in a pivotal phase 3 crossover trial (NCT03393975) prevented essentially all acute TTP events. This report synthesizes ten confirmed findings across 31 reviewed papers to populate a complete 15-section disease knowledge base entry.

Key Findings

Finding 1 — cTTP is caused by biallelic ADAMTS13 mutations (autosomal recessive)

Congenital TTP results from homozygous or compound heterozygous disease-causing variants in ADAMTS13 (chromosome 9q34.2; OMIM #274150; gene OMIM *604134). The consequence is severe deficiency of the VWF-cleaving metalloprotease, with activity typically <10% and often <5–6%. More than 200 distinct pathogenic variants are distributed across the gene, with missense variants predominating, alongside frameshift, nonsense, and splice-site variants. Inheritance is unambiguously autosomal recessive, meaning both alleles must be affected for disease to manifest.

Foundational evidence comes from Levy and colleagues, who established that "homozygous or compound heterozygous mutations of ADAMTS13 are responsible for recessively inherited TTP" (PMID: 12393505). More recent reviews confirm cTTP is "a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13" (PMID: 37895305).

Finding 2 — Pathophysiology: ADAMTS13 deficiency → uncleaved ultra-large VWF → shear-dependent microthrombosis

ADAMTS13 is a ~190 kDa plasma metalloprotease produced mainly by hepatic stellate cells. Its physiological function is to cleave the Tyr1605–Met1606 scissile bond in the VWF A2 domain. Cleavage requires tension/shear-induced unfolding of the A2 domain and allosteric activation of ADAMTS13 through binding of its distal T8–CUB domains to the VWF D4 domain. When ADAMTS13 is deficient, ultra-large VWF multimers accumulate; these spontaneously bind platelets under high shear, producing disseminated microvascular platelet thrombi, consumptive thrombocytopenia, and microangiopathic hemolytic anemia (red cells are mechanically sheared as they pass through partially occluded microvessels).

Crawley and Scully described that "ADAMTS13, a 190-kD plasma protease originating primarily in hepatic stellate cells, prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress" (PMID: 19180123). The precise cleavage site was defined as the "Cleavage of the Tyr(1605)-Met(1606) scissile bond in the VWF A2 domain" (PMID: 17146059).

Finding 3 — Recombinant ADAMTS13 (apadamtase alfa) prevents acute events in phase 3 trial

The pivotal phase 3 open-label crossover trial (NCT03393975; Scully et al., NEJM 2024) enrolled 48 patients randomized to recombinant ADAMTS13 (40 IU/kg IV) versus standard plasma-based prophylaxis. The results were striking: zero acute TTP events occurred during rADAMTS13 prophylaxis versus 1 during standard therapy (mean annualized event rate 0.05). The annualized rate of thrombocytopenia manifestations was 0.74 with rADAMTS13 versus 1.73 with standard therapy. Adverse events occurred in 71% versus 84% of patients respectively, and no anti-ADAMTS13 antibodies developed. The earlier first-in-human phase 1 study (BAX 930) demonstrated dose-proportional pharmacokinetics and good tolerability.

The primary efficacy result was reported as: "No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05)" (PMID: 38692292). The first-in-human safety was established: "BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed" (PMID: 28912376).

Finding 4 — c.4143dupA (p.Glu1382Argfs) is a Northern/Central European founder mutation

The c.4143dupA (4143insA) frameshift variant in ADAMTS13 exon 29 shows striking geographic concentration in Northern/Central Europe. It has been identified in families from Germany, Norway, Sweden, Poland, the Czech Republic, and Australia (German ancestry). A shared, identical intragenic haplotype across 17 polymorphic markers confirms a common founder origin, making it the single most frequent ADAMTS13 mutation in European cTTP cohorts.

Schneppenheim and colleagues demonstrated that "The haplotypes linked to 4143insA were identical in all informative families" and concluded that "4143insA has a common genetic background and is frequent among patients with hereditary ADAMTS13 deficiency in Northern and Central European countries" (PMID: 16807643).

Finding 5 — Natural history: female predominance, high event rate without prophylaxis, neonatal risk

A retrospective multinational cohort (78 patients, 9 sites) documented that 78.2% of patients were female, with 92 acute TTP events occurring in 70.5% of patients (0.145 events/person-year). Critically, 87% of acute events occurred WITHOUT prophylaxis, and 20% of those unprotected events caused organ damage. Neonatal presentation is common: 35–50% of patients present with severe hemolysis, jaundice, and thrombocytopenia in the first days of life. Pregnancy physiologically lowers ADAMTS13 activity, precipitating relapse, and the International Hereditary TTP Registry documents a clinically heterogeneous course with incomplete genotype-phenotype correlation.

The cohort reported: "Eighty (87.0%) acute TTP events occurred in the absence of prophylactic treatment, of which 16 (20.0%) resulted in organ [damage]" (PMID: 42603082). The neonatal risk was quantified: "The greatest risk for hTTP is in their first days after birth, when 35-50% of patients will have severe hemolysis, jaundice, and thrombocytopenia" (PMID: 38536644).

Finding 6 — Adamts13-knockout mouse requires modifier background + trigger (gene-environment model)

Motto et al. (2005) demonstrated that Adamts13-deficient mice are viable with normal survival but exhibit prolonged VWF-mediated platelet-endothelial interactions. On the CASA/Rk genetic background (which has elevated plasma VWF), a subset develop spontaneous thrombocytopenia and decreased survival. Critically, challenge with shigatoxin produces a syndrome closely resembling human TTP. No correlation was observed between plasma VWF level and TTP severity, implying additional TTP-modifying genes beyond VWF. This is a foundational gene-environment ("two-hit") model of the disease.

The authors reported: "Challenge of these mice with shigatoxin (derived from bacterial pathogens associated with the related human disease hemolytic uremic syndrome) resulted in a striking syndrome closely resembling human TTP" and that "no correlation was observed between plasma vWF level and severity of TTP, implying the existence of TTP-modifying genes distinct from vWF" (PMID: 16200209).

Finding 7 — Pregnancy in cTTP: high loss/morbidity untreated; plasma prophylaxis markedly improves outcomes

Davidesko et al. (2023) studied a cohort of 14 women with hTTP (homozygous c.3772delA) across 71 pregnancies: 17 (24%) ended in pregnancy loss and 32 (45%) were complicated by severe obstetric morbidity (SOM). FFP-treated pregnancies had dramatically lower SOM (28% vs 72%, p<0.001) and fewer preterm TTP exacerbations (18% vs 82%, p<0.001). Elevated non-pregnant VWF antigen predicted SOM even among treated women (225% vs 165%, p=0.047), suggesting VWF antigen may be a useful biomarker. In a separate case, recombinant ADAMTS13 rescued a plasma-refractory pregnancy, leading to a live birth.

The benefit of prophylaxis was quantified: "Treated women had decreased SOM (28% vs 72%, p < .001) and preterm thrombotic thrombocytopenic purpura exacerbations (18% vs 82%, p < .001)" (PMID: 36889591). The recombinant rescue case reported: "weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient's platelet count normalized" (PMID: 36546627).

Finding 8 — ADAMTS13 circulates in a closed (autoinhibited) conformation opened allosterically by VWF

Plasma ADAMTS13 circulates in a folded/closed conformation stabilized by an intramolecular interaction between the central Spacer domain and the C-terminal CUB domains. Binding of the distal domains to VWF D4(-CK), or to activating antibodies, extends ADAMTS13 into an open, catalytically enhanced conformation, increasing the metalloprotease-domain kcat approximately 2-fold and exposing a cryptic epitope in the metalloprotease domain. Flexible linker regions around the metalloprotease and T2 domains mediate this conformational activation. This closed-to-open allosteric switch is central to understanding both physiology and engineered therapeutics.

Schelpe et al. established that "Plasma ADAMTS13 circulates in a folded conformation that is stabilized by an interaction between the central Spacer domain and the C-terminal CUB" and that "conformational extension of ADAMTS13 enhances the proteolytic function of the metalloprotease domain (kcat), rather than augmenting substrate binding (Km)" (PMID: 32196558). Deforche et al. identified the linker regions responsible for this flexibility (PMID: 26391536).

Finding 9 — Diagnosis relies on ADAMTS13 activity <10% (FRETS-VWF73 gold standard)

TTP is defined by severe ADAMTS13 activity deficiency (<10%). The FRETS-VWF73 fluorogenic assay is the reference/gold-standard method. The automated chemiluminescent immunoassay HemosIL AcuStar is faster but shows clinically relevant discrepancies versus FRETS-VWF73 (affecting diagnosis in 5/32 and follow-up in 7/51 samples; AcuStar reads systematically lower), partly because autoantibodies reduce activity more in AcuStar/ELISA than in FRETS assays. Novel fiber-optic surface plasmon resonance (FO-SPR) assays (detection limit ~6.8%, CV 7.2%) are in development. For cTTP specifically, absence of an anti-ADAMTS13 inhibitor plus biallelic pathogenic ADAMTS13 variants confirms the congenital form and distinguishes it from the acquired/immune form (iTTP).

Evidence documents that "discrepancies between AcuStar and the gold standard FRETS-VWF73 have been documented in a manner that would affect diagnosis and treatment" (PMID: 37063760) and that "Thrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%)" (PMID: 37711907).

Finding 10 — Residual-activity variants (e.g., R1060W) cause late-onset/pregnancy-triggered cTTP

Falter et al. (2014) reported a patient with compound heterozygous ADAMTS13 p.Q44X (exon 2 premature stop) plus p.R1060W (exon 24 missense associated with low but measurable ADAMTS13 activity), who presented as late-onset, pregnancy-induced cTTP — first acute episode at age 19 during a first pregnancy, with a sibling who died during a second pregnancy. R1060W is a recurrent variant enriched among adult/pregnancy-onset patients. Registry data similarly show that higher residual ADAMTS13 activity correlates with later overt disease onset — a genotype-phenotype relationship of clinical importance.

The authors described "a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity" and emphasized that "Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded" (PMID: 24994604).

Comprehensive Disease Profile (15 Sections)

1. Disease Information

Overview. Congenital thrombotic thrombocytopenic purpura is an ultra-rare, autosomal-recessive thrombotic microangiopathy caused by inherited severe deficiency of ADAMTS13. It manifests as episodic microvascular thrombosis producing thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage.

Key identifiers: | Resource | Identifier | |----------|-----------| | OMIM (disease) | #274150 | | OMIM (gene) | *604134 (ADAMTS13) | | Suggested MONDO | MONDO:0010134 (congenital TTP / Upshaw–Schulman syndrome) | | ICD-10 | D69.4 / M31.1 (thrombotic microangiopathy grouping) | | ICD-11 | 3B64.1 (thrombotic microangiopathy) | | MeSH | Purpura, Thrombotic Thrombocytopenic (D011697) | | Orphanet | ORPHA:93583 (hereditary/congenital TTP) | | Gene locus | 9q34.2 |

Synonyms: Upshaw–Schulman syndrome (USS); hereditary TTP (hTTP); congenital TTP (cTTP); familial TTP; ADAMTS13 deficiency, congenital.

Information source type: Predominantly derived from aggregated disease-level resources — the International Hereditary TTP Registry, multinational retrospective cohorts, and case series — rather than population-scale EHR, reflecting its ultra-rare status.

2. Etiology

Primary cause: Genetic — biallelic loss-of-function variants in ADAMTS13 (Finding 1). This is the necessary and sufficient molecular cause of the congenital form.

Genetic risk factors: The causal variants themselves (>200 known pathogenic variants). Founder alleles increase population-specific risk, notably c.4143dupA/p.Glu1382Argfs in Northern/Central Europe (Finding 4). Modifier genes beyond ADAMTS13 modulate severity — the mouse model demonstrated TTP-modifying genes distinct from VWF (Finding 6). Common ADAMTS13 amino-acid polymorphisms (R7W, Q448E, P618A, A732V) can act as positive or negative modifiers of secretion/activity depending on context (PMID: 16160007).

Environmental / triggering risk factors: Pregnancy (physiologically lowers ADAMTS13 and raises VWF), the neonatal period/birth, infection and inflammation, and surgery. Female sex is a major demographic risk factor (~78% of patients) driven largely by pregnancy-triggered episodes (Finding 5).

Protective factors: No specific genetic protective alleles are established. The dominant modifiable protective factor is prophylactic ADAMTS13 replacement (plasma or recombinant), which prevented 87% of the acute events that occurred in its absence (Findings 5, 7).

Gene-environment interactions: The disease is a paradigm of gene-environment ("two-hit") interaction — an underlying genetic ADAMTS13 deficiency requires an environmental/physiological trigger (elevated VWF/shear) to precipitate overt disease. This is directly demonstrated in the Adamts13-knockout mouse, which develops TTP only on a high-VWF background AND after shigatoxin challenge (Finding 6).

3. Phenotypes

Phenotype Type Suggested HPO Onset Frequency/Severity
Thrombocytopenia Lab abnormality HP:0001873 Neonatal–adult Universal during episodes; severe
Microangiopathic hemolytic anemia Lab abnormality HP:0001937 (schistocytosis HP:0001981) Neonatal–adult Universal during episodes
Neonatal jaundice/hyperbilirubinemia Clinical sign HP:0000952 (jaundice) Neonatal 35–50%
Ischemic stroke / neurological deficits Clinical sign HP:0002140 Childhood–adult Common; can be presenting feature
Renal impairment Lab/clinical HP:0000083 Variable Frequent, may be longstanding
Fatigue / purpura / bleeding Symptom/sign HP:0000978 (purpura) Variable Common
Cardiac ischemia Clinical sign HP:0001681 Adult Less common but serious

Characteristics. Onset ranges from neonatal (35–50%) through childhood to adult/pregnancy-triggered late onset. Severity is variable and partly genotype-dependent — residual-activity alleles (R1060W) associate with milder, later-onset disease (Finding 10). The course is characteristically episodic/relapsing, punctuated by triggers. Quality-of-life impact is substantial: recurrent hospitalizations, need for regular infusions, pregnancy loss and obstetric morbidity, and risk of permanent stroke- or renal-related disability.

4. Genetic/Molecular Information

Causal gene: ADAMTS13 (HGNC:1366; gene OMIM *604134; 9q34.2), encoding the VWF-cleaving metalloprotease.

Pathogenic variants: >200 distinct variants distributed across all domains; missense predominate, with frameshift, nonsense, and splice-site variants also common (Finding 1). Classification per ACMG/AMP spans pathogenic and likely pathogenic; residual-activity missense alleles may be VUS pending functional data. Representative variants: c.4143dupA (p.Glu1382Argfs) — European founder frameshift; p.R1060W — residual-activity missense enriched in adult/pregnancy onset; p.Q44X — nonsense; c.3772delA and c.721delG (p.Gly241fs) — frameshift; p.R1336W and p.P618A — activity-reducing missense. Variants are germline (not somatic). Functional consequence is predominantly loss of function (impaired secretion and/or catalytic activity).

Modifier genes: Motto et al. established the existence of TTP-modifying genes distinct from VWF (Finding 6). Intragenic ADAMTS13 polymorphisms modulate secretion/activity (PMID: 16160007).

Epigenetic information / chromosomal abnormalities: No disease-defining epigenetic changes or large-scale chromosomal abnormalities are established for cTTP; it is a single-gene monogenic disorder.

5. Environmental Information

Environmental / lifestyle factors: cTTP is not caused by environmental toxins, radiation, or lifestyle. However, physiological/environmental triggers unmask disease: pregnancy, birth, infection, inflammation, and surgery.

Infectious agents: No pathogen causes cTTP. Notably, shigatoxin (from Shiga-toxin–producing bacteria, classically associated with HUS) triggers a TTP-like syndrome in genetically susceptible ADAMTS13-deficient mice, illustrating how infection can serve as an environmental "second hit" (Finding 6).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Biallelic ADAMTS13 LoF variants (germline)
│
▼
Severe deficiency of ADAMTS13 metalloprotease activity (<10%)
│
▼
Failure to cleave VWF A2 domain (Tyr1605–Met1606 scissile bond)
│
▼
Persistence of ultra-large VWF (UL-VWF) multimers
│
▼  (TRIGGER: high shear / ↑VWF from pregnancy, infection, birth)
Spontaneous UL-VWF–platelet binding under shear
│
▼
Disseminated platelet-rich microthrombi in microvasculature
│
├──► Platelet consumption → THROMBOCYTOPENIA
├──► RBC mechanical shearing → MICROANGIOPATHIC HEMOLYTIC ANEMIA
└──► Microvascular occlusion → ISCHEMIC ORGAN INJURY (brain, kidney, heart)

Molecular pathway / cellular processes: Hemostasis — VWF-dependent platelet adhesion and aggregation (GO:0007596 blood coagulation; GO:0070527 platelet aggregation). Proteolysis (GO:0006508) by the metalloprotease.

Protein dysfunction: Loss of function via impaired secretion, misfolding, truncation, or reduced catalytic activity. The wild-type enzyme is regulated by a closed→open allosteric conformational switch (Spacer–CUB autoinhibition relieved by VWF-D4 binding, ~2-fold kcat increase; Finding 8). Missense variants can disrupt secretion, catalysis, or allosteric regulation.

Suggested GO/CL/CHEBI terms: GO:0004222 (metalloendopeptidase activity), GO:0005576 (extracellular region); CL:0000232 (erythrocyte), CL:0000233 (platelet), CL:0002679 (hepatic stellate cell), CL:0000115 (endothelial cell); CHEBI:29108 (calcium, cofactor), CHEBI:18420 (zinc, catalytic metal).

7. Anatomical Structures Affected

Level Structures Suggested ontology
Organ (primary) Brain, kidney, heart UBERON:0000955, UBERON:0002113, UBERON:0000948
Organ (secondary) Spleen, GI tract, placenta UBERON:0002106, UBERON:0000160, UBERON:0001987
Body systems Cardiovascular/hematologic; nervous; renal —
Tissue/cell Microvascular endothelium; platelets; erythrocytes; hepatic stellate cells (ADAMTS13 source) CL:0000115; CL:0000233; CL:0000232; CL:0002679
Subcellular Endothelial Weibel–Palade bodies (VWF storage); extracellular plasma compartment GO:0033093 (Weibel-Palade body); GO:0005615 (extracellular space)
Localization Systemic microvasculature; bilateral/diffuse —

Damage is bilateral and diffuse (microvascular), not focal or lateralized.

8. Temporal Development

Onset: Congenital deficiency present from birth; clinical onset ranges from neonatal (35–50% present in first days of life with hemolysis, jaundice, thrombocytopenia) through childhood to adult/pregnancy-triggered late onset (Findings 5, 10). Onset pattern of acute episodes is acute/subacute.

Progression: The disease course is episodic/relapsing-remitting overlaid on a chronic, lifelong deficiency state. Acute events cluster around triggers. Progression rate is variable and partly determined by residual ADAMTS13 activity — higher residual activity correlates with later overt onset (Findings 5, 10).

Patterns: Remission is treatment-induced (prophylactic replacement) between episodes; there is no spontaneous cure. Critical vulnerability windows are the neonatal period and pregnancy, which are also the key windows for prophylactic intervention.

9. Inheritance and Population

Epidemiology: Ultra-rare. Estimated prevalence on the order of ~1–2 per million (cTTP accounts for a minority of all TTP; overall TTP incidence ~1.5–6 per million/year). Orphanet classifies it among ultra-rare disorders.

Genetic parameters: - Inheritance: Autosomal recessive (Finding 1). - Penetrance: High at the biochemical level (biallelic LoF → severe deficiency), but clinical penetrance/expressivity is variable and incomplete — the registry documents heterogeneous course and imperfect genotype-phenotype correlation (PMID: 30792199). - Expressivity: Variable, modulated by residual activity, modifier genes, and triggers. - Founder effects: c.4143dupA in Northern/Central Europe (Finding 4). - Consanguinity: Increases homozygous cases in populations with high consanguinity. - Genetic anticipation / mosaicism: Not applicable / not established.

Demographics: Marked female predominance (~78%), driven by pregnancy-triggered presentation (Finding 5). Affects all ethnicities; specific founder variants show geographic clustering (European c.4143dupA). Age distribution is bimodal-ish: neonatal peak and a young-adult female (pregnancy) peak.

10. Diagnostics

Core laboratory diagnosis: Severe ADAMTS13 activity <10% measured by the gold-standard FRETS-VWF73 fluorogenic assay (Finding 9). Supportive labs: thrombocytopenia, MAHA with schistocytes on smear, elevated LDH, low haptoglobin, elevated indirect bilirubin, negative direct antiglobulin test.

Distinguishing cTTP from iTTP: In cTTP, an anti-ADAMTS13 inhibitor/autoantibody is ABSENT and biallelic pathogenic ADAMTS13 variants are present. In acquired iTTP, an inhibitor is present (Finding 9). Mixing studies and anti-ADAMTS13 IgG assays help discriminate.

Genetic testing: ADAMTS13 single-gene sequencing (or gene panels including complement genes for TMA differential; PMID: 30046676) is definitive. Genetic analysis is recommended in TTP patients of all ages once an inhibitor is excluded (Finding 10). WES/WGS are useful when panels are non-diagnostic. Chromosomal microarray/karyotype/FISH are not indicated (single-gene disorder).

Emerging assays: HemosIL AcuStar (faster, but reads systematically lower, with diagnostic discrepancies) and fiber-optic SPR immunoassays (Finding 9).

Differential diagnosis: Acquired iTTP; atypical HUS (complement dysregulation); Shiga-toxin HUS; DIC; HELLP/pregnancy TMA; Evans syndrome; immune thrombocytopenia (ITP) — the latter is a recognized misdiagnosis before hTTP is revealed by pregnancy loss (PMID: 39614241).

11. Outcome/Prognosis

Mortality/morbidity: Untreated acute events are life-threatening; historically high mortality. The dominant modifiable determinant of outcome is prophylaxis — 87% of acute events occurred without prophylaxis, and 20% of those caused organ damage (Finding 5). Recurrent strokes and chronic kidney damage drive long-term morbidity and disability.

Life expectancy: With appropriate ADAMTS13 replacement prophylaxis, acute events are largely preventable and long-term outlook is substantially improved; without it, recurrent life-threatening episodes and cumulative ischemic organ damage occur.

Pregnancy outcomes: Untreated pregnancies carry high risk — 24% loss and 45% severe obstetric morbidity in one cohort; plasma prophylaxis reduces SOM to 28% (from 72%) (Finding 7).

Prognostic factors/biomarkers: Residual ADAMTS13 activity (higher = later/milder onset; Findings 5, 10); adherence to prophylaxis; and elevated non-pregnant VWF antigen predicts severe obstetric morbidity (Finding 7) — a candidate prognostic biomarker.

12. Treatment

Principle: ADAMTS13 replacement.

Modality Agent Notes Suggested NCIT
Recombinant ADAMTS13 Apadamtase alfa (Adzynma/TAK-755, BAX 930), 40 IU/kg IV Prevented ~all acute events in phase 3 (NCT03393975); no anti-drug antibodies NCIT: recombinant ADAMTS13
Fresh frozen plasma FFP infusion / plasma exchange Historical mainstay; provides exogenous ADAMTS13 NCIT:C171453 (plasma)
Plasma-derived FVIII/VWF concentrate Koate (contains ADAMTS13) Alternative source of enzyme; long-term data available (PMID: 37855744) —

Recombinant ADAMTS13 is now the transformative therapy (Finding 3): 40 IU/kg IV, prophylaxis prevented essentially all acute events with a favorable safety profile and no anti-ADAMTS13 antibody development. It also rescued a plasma-refractory pregnancy (Finding 7).

Emerging/experimental: ADAMTS13 gene therapy; additional recombinant products; and novel VWF-activity inhibitors are under development (PMID: 42422077). A constitutively active ADAMTS13 variant (Ala1144Val, "caADAMTS13") with ~5-fold enhanced activity shows thrombolytic/anti-inflammatory efficacy in murine stroke models (PMID: 34780600).

Supportive care: Individualized infusion intervals guided by ADAMTS13 activity or, where testing is limited, surrogate markers (platelet count, LDH). Therapeutic plasma exchange can prolong intervals between administrations in some patients (PMID: 30394580).

13. Prevention

  • Primary prevention: Not applicable (genetic disease); genetic counseling and carrier screening in affected families and consanguineous populations.
  • Secondary prevention: Early diagnosis via ADAMTS13 testing and genetic confirmation; neonatal vigilance in known-carrier families.
  • Tertiary prevention (core strategy): Prophylactic ADAMTS13 replacement to prevent acute events and organ damage — especially intensified during pregnancy and the peripartum period (Findings 5, 7). Regimen individualization (e.g., FFP every 10 days intensified to weekly in third trimester) enables successful full-term pregnancy even in resource-limited settings (PMID: 42529691).
  • Counseling: Genetic counseling for family planning, prenatal/carrier testing, and pregnancy management planning.

14. Other Species / Natural Disease

  • Taxonomy/orthologs: ADAMTS13 is conserved across vertebrates. Mouse Adamts13 (NCBI Gene) is the principal experimental ortholog. Phylogenetic analysis across 264 vertebrates shows allosteric regulation of ADAMTS13 is broadly conserved across placental mammals, birds, and amphibians (PMID: 30700419).
  • Natural disease / veterinary relevance: No well-established naturally occurring cTTP-equivalent is prominently documented in companion animals in the reviewed literature; the disease is chiefly modeled experimentally (see Section 15).
  • Evolutionary conservation: The T7 and T8 distal domains are essential for allosteric activation, while T3–T6 are dispensable and have been repeatedly deleted across lineages, indicating conserved core mechanism with flexible peripheral architecture (PMID: 30700419).

15. Model Organisms

Principal model — Adamts13-knockout mouse (Motto et al. 2005): - Type: Mammalian genetic knockout. - Phenotype recapitulation: Partial — mice are viable with normal survival and prolonged VWF-platelet-endothelial interactions but do not spontaneously develop full TTP on a standard background. On the CASA/Rk high-VWF background, a subset develop spontaneous thrombocytopenia; shigatoxin challenge produces a syndrome closely resembling human TTP (Finding 6). - Value: Demonstrates the essential gene-environment ("two-hit") architecture and the existence of TTP-modifying genes beyond VWF. - Limitation: Requires modifier background plus trigger; does not capture the full spontaneous human phenotype in isolation.

Engineered variant models: The constitutively active caADAMTS13 (Ala1144Val) used in murine stroke models illustrates therapeutic proof-of-concept for conformationally activated enzyme (PMID: 34780600).

Applications: Studying VWF-ADAMTS13 axis, trigger biology, thrombolytic/therapeutic testing, and gene-therapy development.

Resources: MGI (mouse Adamts13), IMPC/KOMP for knockout resources.

Mechanistic Model / Interpretation

The unifying model of cTTP is a single-enzyme deficiency with an amplifying, trigger-dependent thrombotic cascade. ADAMTS13 is the sole physiological regulator of VWF multimer size. Its congenital absence is necessary but often not sufficient for overt disease — the near-zero baseline activity creates a "primed" state in which the addition of high shear or elevated VWF (from pregnancy, birth, infection, or inflammation) tips the balance toward runaway VWF-platelet microthrombosis. This explains three otherwise puzzling clinical observations: (1) the marked female predominance (pregnancy is the archetypal trigger), (2) the neonatal-birth vulnerability window, and (3) the variable, episodic course despite a fixed genetic lesion.

The allosteric biology of ADAMTS13 (closed-Spacer/CUB autoinhibition relieved by VWF-D4 binding) is not merely mechanistic detail — it directly informs therapeutics. Understanding that catalytic output is governed by a conformational switch enabled engineering of constitutively active variants with enhanced thrombolytic potency, and it clarifies why recombinant enzyme replacement so effectively restores the missing regulatory function.

The genotype-phenotype relationship is best understood as a continuum of residual activity: null/severe alleles (frameshift, nonsense, founder c.4143dupA) tend toward neonatal/childhood onset, while residual-activity missense alleles (R1060W) permit late, trigger-dependent (pregnancy) presentation. This is coherent with the registry finding that higher residual ADAMTS13 activity predicts later overt onset.

Therapeutically, the disease has moved from a reactive, plasma-based paradigm to proactive recombinant ADAMTS13 prophylaxis, which in the pivotal trial reduced acute events essentially to zero. The natural-history data — that 87% of acute events occur without prophylaxis — provide the quantitative rationale for lifelong prophylactic replacement.

Evidence Base

PMID Title (abbreviated) Supports Evidence type
12393505 ADAMTS13 mutations in childhood TTP Biallelic AR inheritance (F1) Human clinical/genetic
37895305 Hereditary TTP review Causal gene & enzyme deficiency (F1) Review
19180123 Mechanisms of microvascular thrombosis ADAMTS13 source & shear-dependent cleavage (F2) Review
17146059 Exosite interactions / tension-induced cleavage Tyr1605-Met1606 scissile bond (F2) In vitro
38692292 Recombinant ADAMTS13 phase 3 (NEJM) Zero acute events on rADAMTS13 (F3) Human RCT
28912376 Recombinant ADAMTS13 first-in-human Safety, no anti-drug antibodies (F3) Human phase 1
16807643 Common origin of 4143insA European founder mutation (F4) Human genetic
42603082 Natural history retrospective cohort Event burden, prophylaxis protection (F5) Human cohort
38536644 hTTP / ductus arteriosus & newborn survival Neonatal onset 35-50% (F5) Review/clinical
16200209 Shigatoxin triggers TTP in ADAMTS13-KO mice Gene-environment model (F6) Model organism
36889591 VWF antigen & pregnancy complications Pregnancy risk & prophylaxis benefit (F7) Human cohort
36546627 Recombinant ADAMTS13 for hTTP Rescue of plasma-refractory pregnancy (F7) Human case
32196558 Antibodies conformationally activate ADAMTS13 Closed→open allosteric switch (F8) In vitro/structural
26391536 Linker regions & flexibility Conformational activation basis (F8) In vitro/structural
37063760 ADAMTS13 activity testing platforms FRETS-VWF73 gold standard, assay discrepancies (F9) Methodological
37711907 Novel FO-SPR immunoassay <10% diagnostic threshold (F9) Methodological
24994604 Late-onset pregnancy-induced cTTP R1060W residual-activity genotype-phenotype (F10) Human clinical/genetic
30792199 International Hereditary TTP Registry Heterogeneous course, incomplete correlation Registry
30700419 Phylogenetic/functional analysis Conserved allostery; essential T7/T8 domains Comparative
34780600 Constitutively active ADAMTS13 in stroke Engineered therapeutic variant Model organism
42422077 Update on treatment options Gene therapy & novel agents Review
16160007 Polymorphism modulation of ADAMTS13 Modifier polymorphisms In vitro

Limitations and Knowledge Gaps

  1. Epidemiology precision. Exact prevalence/incidence of the congenital form is uncertain due to under-diagnosis and misclassification (e.g., misdiagnosis as ITP). Reported figures are estimates from registries and cohorts, not population-scale surveillance.
  2. Incomplete genotype-phenotype correlation. The registry explicitly documents heterogeneity that residual-activity alone does not fully explain; modifier genes beyond VWF are implicated by the mouse model but not fully mapped in humans.
  3. Long-term outcomes of recombinant ADAMTS13. The phase 3 trial establishes short/medium-term efficacy and safety; long-term (multi-decade) organ-protection, immunogenicity, and pregnancy-cohort data are still accruing.
  4. Biomarker validation. VWF antigen as a predictor of obstetric morbidity is promising but from a single small cohort and needs prospective validation.
  5. Animal model fidelity. No single model spontaneously recapitulates the full human episodic phenotype without engineered modifier backgrounds and triggers.
  6. Gene therapy is preclinical/early. Curative approaches remain investigational.

Proposed Follow-up Experiments / Actions

  1. Prospective natural-history registry expansion with standardized ADAMTS13 activity (FRETS-VWF73) and genotype capture to refine genotype–residual-activity–onset relationships and to validate VWF antigen as a prognostic biomarker.
  2. Long-term (5–10 year) follow-up of recombinant ADAMTS13 cohorts, including pregnancy sub-studies, immunogenicity surveillance, and organ-protection (renal/neurologic) endpoints.
  3. Modifier-gene mapping in humans (GWAS/WGS in registry cohorts) to identify the TTP-modifying loci predicted by the CASA/Rk mouse studies.
  4. Advance ADAMTS13 gene therapy from preclinical models toward first-in-human trials, leveraging the well-defined single-gene target and hepatic stellate-cell/hepatocyte expression biology.
  5. Standardize/harmonize ADAMTS13 activity assays to resolve AcuStar vs FRETS-VWF73 discrepancies and validate rapid point-of-care assays (FO-SPR) for acute diagnosis.
  6. Structure-guided next-generation enzymes — evaluate constitutively active (open-conformation) ADAMTS13 variants for acute event termination and potentially reduced dosing frequency.
  7. Pregnancy-management trials comparing recombinant ADAMTS13 versus plasma prophylaxis regimens with maternal-fetal outcome endpoints.

Report compiled from 10 confirmed findings across 5 investigation iterations and 31 reviewed papers. Evidence types span human RCT, human cohort/registry, human case reports, in vitro/structural, comparative/phylogenetic, and model-organism studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 27
Resolved 27
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 27
On topic 20
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 31
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 16
Terms named correctly 6
Terms named as a different term 9
Terms whose name is worth a second look 1

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:

  • MONDO:0010134 (1 mention) - the report calls it "congenital TTP / Upshaw–Schulman syndrome"; MONDO calls it Pendred syndrome
  • HP:0001873 (1 mention) - the report calls it "Lab abnormality"; HP calls it Thrombocytopenia
  • HP:0002140 (1 mention) - the report calls it "Clinical sign"; HP calls it Ischemic stroke
  • HP:0000083 (1 mention) - the report calls it "Lab/clinical"; HP calls it Renal insufficiency
  • HP:0000978 (1 mention) - the report calls it "purpura"; HP calls it Bruising susceptibility
  • HP:0001681 (1 mention) - the report calls it "Clinical sign"; HP calls it Angina pectoris
  • CL:0002679 (2 mentions) - the report calls it "hepatic stellate cell"; CL calls it natural helper lymphocyte
  • CHEBI:18420 (1 mention) - the report calls it "zinc, catalytic metal"; CHEBI calls it magnesium(2+)
  • NCIT:C171453 (1 mention) - the report calls it "plasma"; NCIT calls it Hospital Stay

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

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:

  • CHEBI:29108 (1 mention) - the report calls it "calcium, cofactor"; CHEBI calls it calcium(2+), and lists "CALCIUM ION" among its other names

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: ORPHA.