Acquired Thrombotic Thrombocytopenic Purpura

Autoimmune MONDO:0019740 Pathograph 25 Show in embeddings browser Autoimmune Disease Hematologic Disease Thrombotic Microangiopathy

Acquired, immune-mediated thrombotic thrombocytopenic purpura (iTTP/aTTP) is a medical emergency caused by autoantibody-mediated severe functional deficiency of ADAMTS13, the von Willebrand factor (VWF)-cleaving protease. Unprocessed ultralarge VWF multimers recruit platelets under shear and form disseminated platelet-VWF microthrombi, producing thrombocytopenia, microangiopathic hemolytic anemia with schistocytes, and ischemic organ injury. Acute treatment must address three distinct processes: plasma exchange restores ADAMTS13 and removes circulating pathogenic material, corticosteroids and rituximab suppress the autoimmune driver, and caplacizumab blocks VWF-platelet adhesion. Clinical remission does not always mean immunologic remission; persistent or recurrent low ADAMTS13 activity predicts relapse and stroke risk and requires longitudinal surveillance.

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1
Definitions
8
Pathophys.
9
Phenotypes
3
Gaps
25
Pathograph
7
Medical Actions
8
Differentials
3
Trials
25
References
📘

Definitions

1
Immune-mediated TTP disease definition
Immune TTP is severe ADAMTS13 deficiency caused by anti-ADAMTS13 autoantibodies, distinguished from congenital TTP caused by biallelic ADAMTS13 variants.
CASE_DEFINITION Disease-level distinction between immune-mediated and congenital TTP.
Show evidence (1 reference)
PMID:28416507 SUPPORT Other
"ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gene."
This review distinguishes immune acquired TTP from hereditary ADAMTS13 deficiency.
?

Discussions and Knowledge Gaps

3
Why do some people with severe ADAMTS13 deficiency remain clinically well while others develop an acute episode with a particular pattern of organ injury?
KNOWLEDGE GAP OPEN gap_ittp_second_hit_and_organ_tropism
Attached to
pathophysiology#Severe ADAMTS13 Activity Deficiency pathophysiology#Disseminated Platelet-VWF Microthrombosis
Severe deficiency is necessary for TTP but does not by itself explain the timing of attacks, infection and pregnancy triggers, or variable cerebral, cardiac, and renal involvement. Endothelial activation, VWF release, inflammation, and vascular susceptibility are candidate additional factors.
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."
Common triggers demonstrate that enzyme deficiency is embedded in a broader attack context.
Which ADAMTS13 activity threshold, antibody profile, and testing interval best identify patients who benefit from preemptive immunosuppression?
KNOWLEDGE GAP OPEN gap_ittp_remission_threshold_and_monitoring_interval
Attached to
pathophysiology#Anti-ADAMTS13 Autoantibody Production pathophysiology#Severe ADAMTS13 Activity Deficiency
Low activity and high antibody levels predict relapse, but cohorts use different thresholds and the ISTH guideline identifies no evidence-based universal monitoring interval.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"There is also no evidence on the appropriate interval for performing ADAMTS13 activity testing."
The guideline directly identifies the interval evidence gap.
Can selected acute episodes be treated safely without plasma exchange, and can FcRn blockade or other targeted therapies produce durable immunologic remission with less treatment burden?
KNOWLEDGE GAP OPEN gap_ittp_pex_free_and_novel_autoantibody_therapy
Attached to
treatment#Immediate therapeutic plasma exchange treatment#Rituximab for acute immune control
Active PEX-free and efgartigimod studies are small or single-arm and have no posted results. They should not be treated as established alternatives to current TPE, caplacizumab, corticosteroid, and rituximab care.
Show evidence (1 reference)
clinicaltrials:NCT06291025 SUPPORT Human Clinical
"However, it's considered that robust data are still lacking to completely remove plasmatherapy from iTTP management."
The study rationale itself states the unresolved evidence gap.
⚙

Pathophysiology

8
Anti-ADAMTS13 Autoantibody Production
Autoreactive B-lineage cells produce predominantly IgG antibodies against ADAMTS13. Antibodies can inhibit proteolytic activity and/or accelerate antigen clearance. This acquired immune response, rather than a germline ADAMTS13 defect, defines immune TTP.
B cell CL:0000236 plasma cell CL:0000786
Downstream
Severe ADAMTS13 Activity Deficiency Inhibition and immune clearance reduce circulating ADAMTS13 activity to the severe-deficiency range.
Show evidence (2 references)
PMID:9828246 SUPPORT Human Clinical
"The inhibitors were IgG antibodies."
The original human study identifies the inhibitor as IgG.
PMID:9828245 SUPPORT Human Clinical
"Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease"
This foundational study distinguishes acquired inhibitor-mediated TTP.
Severe ADAMTS13 Activity Deficiency
Functional ADAMTS13 activity below 10% is the defining biochemical lesion of TTP in the appropriate thrombotic-microangiopathy context. Severe deficiency can persist during apparent clinical remission, so it is a disease-state marker as well as an acute diagnostic marker.
proteolysis GO:0006508 ↓ DECREASED
Downstream
Persistence of Ultralarge VWF Multimers Loss of VWF-cleaving activity permits newly released ultralarge VWF multimers to remain uncleaved.
Show evidence (1 reference)
PMID:39161536 SUPPORT Other
"An ADAMTS13 activity of <10% is required to confirm the diagnosis of TTP"
This supports the severe-activity threshold stated for the node.
Persistence of Ultralarge VWF Multimers
Endothelial VWF remains in ultralarge, highly adhesive forms when ADAMTS13 cleavage is severely impaired. Under shear, these multimers bind platelet glycoprotein Ib and recruit platelets.
platelet aggregation GO:0070527 ↑ INCREASED
Downstream
Disseminated Platelet-VWF Microthrombosis Shear-dependent platelet adhesion to ultralarge VWF produces growing platelet-rich microthrombi.
Show evidence (1 reference)
PMID:9828245 SUPPORT Human Clinical
"Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress"
The foundational study identifies the shear-dependent platelet-adhesive substrate.
Disseminated Platelet-VWF Microthrombosis
Platelet-rich, VWF-rich thrombi disseminate through small vessels. This is not modeled as conventional fibrin/thrombin thrombogenesis: the defining lesion is VWF-mediated platelet adhesion.
blood microvessel UBERON:8410081
Downstream
Platelet Consumption Recruitment of circulating platelets into disseminated microthrombi depletes the circulating platelet pool.
Shear-Mediated Erythrocyte Fragmentation Erythrocytes are mechanically fragmented while traversing partially occluded microvessels.
Microvascular Occlusion and Ischemic Organ Injury Occlusion of small vessels reduces organ perfusion and produces ischemic tissue injury.
Show evidence (1 reference)
PMID:28768626 SUPPORT Other
"microthrombi that are composed of von Willebrand factor and platelets"
The review defines the material composition of TTP microthrombi.
Platelet Consumption
Platelet incorporation into microthrombi produces the characteristic severe thrombocytopenia.
Downstream
Thrombocytopenia Consumption of circulating platelets lowers the measured platelet count.
Show evidence (1 reference)
PMID:30625070 SUPPORT Human Clinical
"microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia"
The phase 3 report supports platelet consumption as the proximal basis of thrombocytopenia in the microthrombotic process.
Shear-Mediated Erythrocyte Fragmentation
Mechanical injury to erythrocytes in obstructed microvessels produces intravascular hemolysis and fragmented cells on the blood smear.
Downstream
Microangiopathic Hemolytic Anemia Ongoing mechanical erythrocyte destruction produces anemia and hemolysis.
Schistocytosis Fragmented erythrocytes appear as schistocytes on peripheral smear.
Show evidence (1 reference)
PMID:28768626 SUPPORT Other
"the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP"
The review supports erythrocyte fragmentation as the proximal mechanism yielding hemolytic anemia and schistocytes.
Microvascular Occlusion and Ischemic Organ Injury
Platelet-VWF microthrombi obstruct organ microcirculation. Neurologic injury is prominent, but cardiac and renal ischemic injury also occur; severe renal failure should increase consideration of another thrombotic microangiopathy.
blood microvessel UBERON:8410081
Downstream
Encephalopathy Cerebral microvascular ischemia can cause fluctuating or persistent encephalopathy and focal neurologic injury.
Myocardial infarction Cardiac microvascular ischemia can produce myocardial injury or infarction.
Acute kidney injury Renal microvascular injury can impair kidney function, although severe kidney failure is less typical than in hemolytic-uremic syndromes.
Post-Acute Neurovascular and Psychosocial Sequelae Survivors have excess neurologic, cognitive, psychiatric, and cardiovascular morbidity, but the contribution of acute microvascular injury versus persistent ADAMTS13 deficiency and other factors is not fully resolved.
Show evidence (1 reference)
PMID:26863353 SUPPORT Human Clinical
"This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications."
The study establishes the organ-injury branch.
Post-Acute Neurovascular and Psychosocial Sequelae
Clinical remission can be followed by stroke, cognitive impairment, depression, anxiety, and cardiovascular morbidity. These outcomes are observationally associated with surviving iTTP; causal pathways are heterogeneous and incompletely defined.
Downstream
Stroke in remission Stroke risk persists outside acute TTP episodes and is associated with lower remission ADAMTS13 activity.
Cognitive impairment Attention and memory deficits can persist after recovery, including in people without overt neurologic disability.
Depression Depression is frequent among survivors, but may reflect microvascular, autoimmune, critical-illness, and psychosocial factors.
Show evidence (1 reference)
PMID:34461629 SUPPORT Human Clinical
"Immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors experience high rates of adverse health sequelae and increased mortality over long-term follow-up."
This multicenter registry study establishes a substantial survivorship burden.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acquired 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

9
Blood 1
Thrombocytopenia Thrombocytopenia HP:0001873
Show evidence (1 reference)
PMID:30625070 SUPPORT Human Clinical
"unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia"
The phase 3 trial report identifies thrombocytopenia as a core result of microthrombosis.
Cardiovascular 2
Myocardial infarction Myocardial infarction HP:0001658
Show evidence (1 reference)
PMID:39161536 SUPPORT Other
"Damage to major organs may also result in transient ischemic attack, stroke, myocardial infarction, or acute kidney injury."
The systematic review identifies myocardial infarction among acute organ complications.
Stroke in remission OCCASIONAL Stroke HP:0001297
Show evidence (1 reference)
PMID:31431443 SUPPORT Human Clinical
"Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years"
This supports the occasional frequency band specifically in a survivor cohort.
Genitourinary 1
Acute kidney injury Acute kidney injury HP:0001919
Show evidence (1 reference)
PMID:39161536 SUPPORT Other
"Damage to major organs may also result in transient ischemic attack, stroke, myocardial infarction, or acute kidney injury."
The systematic review identifies acute kidney injury as an organ complication.
Nervous System 3
Encephalopathy Encephalopathy HP:0001298
Show evidence (1 reference)
PMID:28768626 SUPPORT Other
"some die or acquire irreversible neurological deficits before they can respond"
The review supports serious neurologic involvement without overextending the snippet to specific symptoms.
Cognitive impairment Cognitive impairment HP:0100543
Show evidence (1 reference)
PMID:25975932 SUPPORT Human Clinical
"The patients as a group performed significantly worse than standardized values provided by the test developers from neurologically normal individuals on both the MoCA and the RBANS."
Formal survivor testing supports cognitive impairment after recovery.
Depression FREQUENT Depression HP:0000716
Show evidence (1 reference)
PMID:25975932 SUPPORT Human Clinical
"31 (59%) patients screened positive for depression at least once; in 15 (29%), the results suggested severe depression at least once."
The longitudinal cohort supports the frequent band with an explicit denominator and follow-up context.
Other 2
Microangiopathic Hemolytic Anemia Microangiopathic hemolytic anemia HP:0001937
Show evidence (1 reference)
PMID:28768626 SUPPORT Other
"the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP"
The review names hemolytic anemia as a defining feature.
Schistocytosis Schistocytosis HP:0001981
Show evidence (1 reference)
PMID:28768626 SUPPORT Other
"the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP"
The review identifies schistocytes as characteristic.
💊

Medical Actions

7
Immediate therapeutic plasma exchange
Category: Therapeutic Action: Plasmapheresis NCIT:C15304
Begin daily therapeutic plasma exchange urgently in suspected acute iTTP. TPE supplies functional ADAMTS13 and removes circulating antibody and other pathogenic plasma components. It remains part of current guideline and regulatory standard care; PEX-free regimens are investigational.
Mechanism Target:
RESTORES Severe ADAMTS13 Activity Deficiency — Donor plasma replenishes missing or inhibited ADAMTS13 while exchange removes circulating pathogenic material.
Show evidence (2 references)
PMID:32914526 SUPPORT Other
"replacing the missing and/or inhibited ADAMTS13"
The ISTH guideline identifies ADAMTS13 replacement as a principal treatment mechanism.
url:https://clinicaltrials.gov/api/v2/studies/NCT05468320 SUPPORT Human Clinical
"TPE replenishes the ADAMTS13 enzyme and removes anti-ADAMTS13 antibodies, and ultra-large von Willebrand factor multimers gradually from the circulation."
The registry outcome definition explicitly states the replacement and removal mechanisms attributed to TPE.
Show evidence (2 references)
PMID:32914526 SUPPORT Other
"For patients with iTTP experiencing a first acute event, the panel recommends the addition of corticosteroids to therapeutic plasma exchange (TPE) over TPE alone."
The guideline establishes TPE as the acute-care backbone while recommending corticosteroid addition.
PMID:40533296 SUPPORT Other
"For patients with iTTP, no change to 2020's recommendations."
The 2025 focused update retained the immune-TTP recommendations.
Corticosteroids with plasma exchange
Category: Therapeutic Action: Pharmacotherapy NCIT:C15986
Agent: corticosteroid CHEBI:50858
Add systemic corticosteroids to TPE for a first acute episode or relapse. The ISTH recommendation is strong because iTTP is life-threatening, but the supporting certainty is very low and no preferred steroid or dose is established.
Mechanism Target:
INHIBITS Anti-ADAMTS13 Autoantibody Production — Corticosteroids suppress inflammation and are intended to reduce the anti-ADAMTS13 autoimmune response.
Show evidence (1 reference)
PMID:32914526 PARTIAL Other
"The presumptive rationales for the use of corticosteroids are to reduce acute inflammation and inhibit the production of ADAMTS13 autoantibodies, although high-quality data are not available."
The guideline states the intended mechanism while explicitly qualifying the evidence.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"For patients with iTTP experiencing a first acute event, the panel recommends the addition of corticosteroids to therapeutic plasma exchange (TPE) over TPE alone."
This is a strong recommendation in the context of very low-certainty evidence.
Rituximab for acute immune control
Category: Therapeutic Action: Pharmacotherapy NCIT:C15986
Agent: rituximab NCIT:C1702
Rituximab is added to TPE and corticosteroids to control the anti-ADAMTS13 autoimmune response and reduce relapse risk. The acute first-event and relapse recommendations are conditional because evidence certainty is very low.
Mechanism Target:
INHIBITS Anti-ADAMTS13 Autoantibody Production — Anti-CD20 B-cell depletion reduces the B-cell compartment sustaining the pathogenic autoantibody response; mature plasma cells are not directly targeted.
Show evidence (1 reference)
PMID:28416507 PARTIAL Other
"Additional immune modulators targeting ADAMTS13 autoantibodies are mainly based on steroids and the humanized anti-CD20 monoclonal antibody rituximab."
The review supports B-cell-directed immune modulation while the detailed cellular route remains indirect.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"For patients with iTTP experiencing their first acute event, the panel suggests the addition of rituximab to corticosteroids and TPE over corticosteroids and TPE alone."
The guideline conditionally supports rituximab in acute first events.
Caplacizumab with plasma exchange and immunosuppression
Category: Therapeutic Action: Pharmacotherapy NCIT:C15986
Agent: caplacizumab NCIT:C128625
Caplacizumab is an anti-VWF single-domain antibody that blocks VWF A1-domain binding to platelet glycoprotein Ib. It rapidly suppresses new microthrombus formation but does not correct ADAMTS13 deficiency or remove the autoantibody. The approved United States regimen combines it with plasma exchange and immunosuppression; plasma-exchange-free use remains selected and investigational. Current labeling covers adults and pediatric patients aged 12 years or older. Bleeding is the principal risk. Pregnancy use requires individualized expert risk-benefit assessment because human data are unavailable and maternal and fetal bleeding are concerns.
Mechanism Target:
INHIBITS Disseminated Platelet-VWF Microthrombosis — Caplacizumab blocks VWF A1-domain binding to platelet glycoprotein Ib and thereby suppresses VWF-platelet microthrombus formation without restoring ADAMTS13.
Show evidence (1 reference)
PMID:26863353 SUPPORT Human Clinical
"Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets."
The phase 2 trial defines the molecular treatment mechanism.
Target Phenotypes: Thrombocytopenia HP:0001873
Show evidence (5 references)
PMID:30625070 SUPPORT Human Clinical
"The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001)."
This supports reduction of the prespecified composite outcome, not each component independently.
PMID:30625070 SUPPORT Human Clinical
"The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group."
The randomized trial establishes the common bleeding liability.
url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf SUPPORT Other
"indicated for the treatment of adult and pediatric patients 12 years of age and older with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy."
The current FDA label establishes the approved age range and combination regimen in the United States.
+ 2 more references
Preemptive rituximab during high-risk remission
Category: Therapeutic Action: Pharmacotherapy NCIT:C15986
Agent: rituximab NCIT:C1702
In asymptomatic nonpregnant patients with falling or severely reduced ADAMTS13 activity, preemptive rituximab may be used to restore immunologic remission and reduce clinical relapse risk. This is conditional and depends on reliable serial ADAMTS13 testing.
Mechanism Target:
INHIBITS Anti-ADAMTS13 Autoantibody Production — Preemptive B-cell depletion is intended to reverse the autoimmune relapse before thrombocytopenia and hemolysis recur.
Show evidence (1 reference)
PMID:30201758 SUPPORT Human Clinical
"Preemptive rituximab reduces clinical relapses by maintaining a detectable ADAMTS13 activity with an advantageous risk-benefit balance."
The 92-patient cohort supports the preemptive strategy.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"For patients with iTTP who are in remission, but still have low plasma ADAMTS13 activity with no clinical signs/symptoms, the panel suggests the use of rituximab over nonuse of rituximab for prophylaxis."
The ISTH guideline conditionally supports preemptive rituximab outside pregnancy.
Prophylactic treatment for high-risk pregnancy
Category: Therapeutic Action: Plasmapheresis NCIT:C15304
Pregnancy with a history of iTTP and reduced ADAMTS13 activity requires expert prophylactic treatment rather than observation alone. The ISTH guideline supports prophylactic therapy to raise ADAMTS13, but does not establish one universal immune-suppressive or plasma regimen.
Mechanism Target:
RESTORES Severe ADAMTS13 Activity Deficiency — Plasma-based prophylaxis can raise ADAMTS13 activity during a high-risk pregnancy; regimen choice is individualized.
Show evidence (1 reference)
PMID:32914526 PARTIAL Other
"Although no specific prophylactic immune suppressive or plasma treatment regimen is recommended, the panel made a strong recommendation for the use of prophylactic treatment to increase the ADAMTS13 activity to prevent both maternal and fetal mortality and morbidity."
The guideline supports prophylaxis while explicitly leaving regimen selection unresolved.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"Patients with a history of iTTP in remission that are pregnant with reduced levels of ADAMTS13 activity have more recently been recognized to have poor clinical outcomes with close monitoring alone."
This supports active expert management rather than surveillance alone.
Serial ADAMTS13 activity monitoring
Category: Monitoring Action: ADAMTS13 activity monitoring Ontology label: von Willebrand Coagulation Factor Cleaving Protease Measurement NCIT:C187684
Continue ADAMTS13 activity monitoring after clinical recovery and during pregnancy planning. Results guide relapse-risk assessment, preemptive immunosuppression, and the safe duration of caplacizumab; the optimal fixed testing interval is not established.
Show evidence (1 reference)
PMID:32914526 SUPPORT Other
"The panel raised practical issues around the cost, resource utilization, and patient commitment necessary for monitoring during remission, such as continued monitoring of plasma ADAMTS13 activity and starting rituximab in a timely fashion."
The guideline explicitly links serial monitoring with timely preemptive treatment.
🔬

Biochemical Markers

2
Severely Reduced ADAMTS13 Activity (DECREASED)
Context: Plasma ADAMTS13 activity below 10% in an appropriate thrombotic microangiopathy context confirms the defining enzyme defect. Anti-ADAMTS13 IgG or inhibitor supports immune etiology. Samples should be obtained before plasma therapy when feasible, but emergency treatment must not be delayed.
Pathograph Readouts
Readout Of Severe ADAMTS13 Activity Deficiency Negative Diagnostic
Lower measured activity is the direct biochemical readout of functional ADAMTS13 deficiency.
Show evidence (1 reference)
PMID:32914582 SUPPORT Other
"importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor)"
The diagnosis guideline establishes the measurement and immune assays as central readouts.
Show evidence (1 reference)
PMID:39161536 SUPPORT Other
"An ADAMTS13 activity of <10% is required to confirm the diagnosis of TTP"
The systematic review states the severe-deficiency diagnostic threshold.
Anti-ADAMTS13 IgG or Functional Inhibitor (Increased)
Context: Detectable anti-ADAMTS13 IgG or an inhibitor supports immune-mediated rather than congenital TTP. A negative assay does not by itself establish congenital disease; clinical context, repeat testing, recovery pattern, and genetic analysis may be needed.
Pathograph Readouts
Readout Of Anti-ADAMTS13 Autoantibody Production Positive Diagnostic
Higher or detectable anti-ADAMTS13 antibody supports the acquired immune mechanism.
Show evidence (1 reference)
PMID:9828246 SUPPORT Human Clinical
"Inhibitory antibodies against von Willebrand factor-cleaving protease occur in patients with acute thrombotic thrombocytopenic purpura."
The original study establishes the inhibitor as a mechanistic biomarker.
Show evidence (1 reference)
PMID:32914582 SUPPORT Other
"importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor)"
The guideline explicitly includes antibody and inhibitor assays.
🔀

Differential Diagnoses

8

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

Congenital thrombotic thrombocytopenic purpura
Overlapping Features Congenital TTP also has severe ADAMTS13 deficiency but results from biallelic ADAMTS13 variants rather than an acquired inhibitor. Childhood onset, pregnancy-associated presentation, absent antibody, and failure of activity to recover after immunosuppression should prompt genetic evaluation.
Show evidence (1 reference)
PMID:28416507 SUPPORT Other
"ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gene."
The review distinguishes immune and inherited ADAMTS13 deficiency.
Complement-mediated atypical hemolytic-uremic syndrome MONDO:0016244
Overlapping Features Complement-mediated HUS causes thrombotic microangiopathy, often with more severe kidney injury, but does not usually produce severe ADAMTS13 deficiency. Complement evaluation should not delay empiric TTP treatment when pretest probability is high.
Shiga toxin-associated hemolytic-uremic syndrome
Overlapping Features Diarrheal prodrome, Shiga-toxin evidence, and predominant renal injury favor Shiga toxin HUS; severe ADAMTS13 deficiency favors TTP.
Disseminated intravascular coagulation Not Yet Curated MONDO:0001243
Overlapping Features DIC can produce thrombocytopenia and fragmented erythrocytes but usually has systemic coagulation activation with abnormal clotting studies and a precipitating critical illness; TTP microthrombi are platelet-VWF rich.
HELLP syndrome and severe preeclampsia Not Yet Curated MONDO:0008585
Overlapping Features Pregnancy-associated hypertension, liver-enzyme elevation, and obstetric context favor HELLP or preeclampsia. Persistent thrombotic microangiopathy postpartum or severe ADAMTS13 deficiency supports TTP.
Catastrophic antiphospholipid syndrome
Overlapping Features Widespread thrombosis, antiphospholipid antibodies, and coagulation-related manifestations can mimic TTP; severe ADAMTS13 deficiency with immune inhibition favors iTTP.
Malignant hypertension-associated thrombotic microangiopathy
Overlapping Features Severe hypertension with target-organ injury can cause secondary microangiopathy. ADAMTS13 is generally not severely deficient, and the clinical sequence and response to blood-pressure control help distinguish it from iTTP.
Secondary thrombotic microangiopathy
Overlapping Features Sepsis, malignancy, transplantation, autoimmune disease, and certain drugs can cause thrombocytopenia and microangiopathic hemolysis without the severe ADAMTS13 deficiency that defines TTP.
🔬

Clinical Trials

3
NCT05468320 PHASE_III COMPLETED
Completed open-label, single-arm study of caplacizumab plus immunosuppressive therapy without first-line therapeutic plasma exchange in selected adults with iTTP. Actual enrollment was 51. Among evaluable participants, 93.5% achieved remission without TPE and 4.3% required TPE.
Target Phenotypes: Thrombocytopenia HP:0001873
Show evidence (6 references)
clinicaltrials:NCT05468320 SUPPORT Human Clinical
"This is a single group, treatment, Phase 3, open-label, single-arm study to evaluate the efficacy and safety of caplacizumab and immunosuppressive therapy"
The registry summary establishes the phase, single-arm design, and treatment combination.
url:https://clinicaltrials.gov/api/v2/studies/NCT05468320 SUPPORT Human Clinical
""statusVerifiedDate":"2025-12","overallStatus":"COMPLETED""
The registry API establishes completed status and its verification date.
url:https://clinicaltrials.gov/api/v2/studies/NCT05468320 SUPPORT Human Clinical
""enrollmentInfo":{"count":51,"type":"ACTUAL"}"
The registry API establishes actual enrollment.
+ 3 more references
NCT06831058 PHASE_II RECRUITING
Open-label pilot study of weekly intravenous efgartigimod in adults with prior iTTP who are in clinical remission but have ADAMTS13 activity above 30% and below 70%. Estimated enrollment is 15, completion is estimated for May 2028, and no results are posted.
Show evidence (3 references)
clinicaltrials:NCT06831058 SUPPORT Human Clinical
"It is expected that following efgartigimod therapy, there will be a rise in ADAMTS13 activity to the normal range that will be sustained during the treatment period."
The trial summary states the hypothesized biochemical effect of the investigational intervention.
url:https://clinicaltrials.gov/api/v2/studies/NCT06831058 SUPPORT Human Clinical
""statusVerifiedDate":"2026-06","overallStatus":"RECRUITING""
The live registry API establishes current recruiting status and verification date.
url:https://clinicaltrials.gov/api/v2/studies/NCT06831058 SUPPORT Human Clinical
""enrollmentInfo":{"count":15,"type":"ESTIMATED"}"
The registry provides the estimated enrollment.
NCT06291025 NOT_APPLICABLE RECRUITING
Prospective single-arm French PEX-FREE study testing plasma infusion, caplacizumab, corticosteroids, and rituximab without therapeutic plasma exchange in selected adults with acute clinical iTTP. Estimated enrollment is 131 and completion is estimated for August 2026; no results are posted.
Show evidence (3 references)
clinicaltrials:NCT06291025 SUPPORT Human Clinical
"Based on these statements, the objective is to address the efficacy and safety of a PEX-free regimen, combining PI only (15 ml/kg/day), corticosteroids/rituximab, and caplacizumab."
The registry summary defines the PEX-free experimental strategy.
url:https://clinicaltrials.gov/api/v2/studies/NCT06291025 SUPPORT Human Clinical
""statusVerifiedDate":"2026-02","overallStatus":"RECRUITING""
The live registry API establishes current recruiting status.
url:https://clinicaltrials.gov/api/v2/studies/NCT06291025 SUPPORT Human Clinical
""enrollmentInfo":{"count":131,"type":"ESTIMATED"}"
The registry provides the planned sample size.
{ }

Source YAML

click to show 
name: Acquired Thrombotic Thrombocytopenic Purpura
creation_date: "2026-07-05T00:00:00Z"
category: Autoimmune
parents:
- Autoimmune Disease
- Hematologic Disease
- Thrombotic Microangiopathy
disease_term:
  preferred_term: Acquired Thrombotic Thrombocytopenic Purpura
  term:
    id: MONDO:0019740
    label: acquired thrombotic thrombocytopenic purpura
description: >-
  Acquired, immune-mediated thrombotic thrombocytopenic purpura (iTTP/aTTP) is
  a medical emergency caused by autoantibody-mediated severe functional
  deficiency of ADAMTS13, the von Willebrand factor (VWF)-cleaving protease.
  Unprocessed ultralarge VWF multimers recruit platelets under shear and form
  disseminated platelet-VWF microthrombi, producing thrombocytopenia,
  microangiopathic hemolytic anemia with schistocytes, and ischemic organ
  injury. Acute treatment must address three distinct processes: plasma
  exchange restores ADAMTS13 and removes circulating pathogenic material,
  corticosteroids and rituximab suppress the autoimmune driver, and
  caplacizumab blocks VWF-platelet adhesion. Clinical remission does not always
  mean immunologic remission; persistent or recurrent low ADAMTS13 activity
  predicts relapse and stroke risk and requires longitudinal surveillance.
definitions:
- name: Immune-mediated TTP disease definition
  definition_type: CASE_DEFINITION
  description: >-
    Immune TTP is severe ADAMTS13 deficiency caused by anti-ADAMTS13
    autoantibodies, distinguished from congenital TTP caused by biallelic
    ADAMTS13 variants.
  scope: Disease-level distinction between immune-mediated and congenital TTP.
  evidence:
  - reference: PMID:28416507
    reference_title: Thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADAMTS13 deficiency is most frequently acquired via ADAMTS13
      autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13
      gene.
    explanation: >-
      This review distinguishes immune acquired TTP from hereditary ADAMTS13
      deficiency.
epidemiology:
- name: Rare relapsing autoimmune thrombotic microangiopathy
  description: >-
    General-population studies estimate 1.81 to 3.93 acute iTTP episodes per
    million people annually. Reported prevalence varies substantially with
    geography, ascertainment, and diagnostic method. The first episode usually
    occurs in adulthood; women are overrepresented, and Black people have a
    markedly higher reported incidence in United States cohorts.
  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: >-
      The incidence rate of acute episodes ranged from 0.19-0.35 person-years
      in adult patients with cTTP, and 1.81-3.93 per million persons per year
      for iTTP in the general population.
    explanation: >-
      The systematic review provides the general-population incidence range
      for immune TTP.
  - 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: >-
      Compared with cTTP, the onset of symptoms in patients with iTTP occurred
      later in life
    explanation: >-
      This supports typical adult onset while not excluding pediatric disease.
  - 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: >-
      A female predominance was reported for both cTTP and iTTP
    explanation: >-
      The review consistently found female predominance across immune-TTP
      studies.
  - 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: >-
      Black race is an established risk factor for iTTP,3,133with a sevenfold
      higher incidence reported among individuals who are Black vs non-Black.
    explanation: >-
      This reports a major population disparity while the review cautions that
      access and registry participation affect estimates.
prevalence:
- population: Spain
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.144
  notes: >-
    Nationwide registry survey estimate among people aged 16 years and older;
    it should not be generalized as a worldwide prevalence.
  evidence:
  - reference: PMID:33780553
    reference_title: "Incidence, diagnosis, and outcome of immune-mediated thrombotic thrombocytopenic purpura: A nationwide survey by the Spanish registry of thrombotic thrombocytopenic purpura."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incidence was 2.67 (95% CI 1.90-3.45) patients per million inhabitants
      per year and prevalence 21.44 (95% CI% 19.10-23.73) patients per million
      inhabitants.
    explanation: >-
      The Spanish registry supplies a denominator-based population estimate.
progression:
- phase: Acute immune-TTP episode
  age_range: Usually adulthood; pediatric and adolescent disease also occurs
  notes: >-
    A first or relapsed episode presents as a thrombotic microangiopathy and can
    progress rapidly to irreversible neurologic, cardiac, renal, or other organ
    injury. Treatment should begin on strong clinical suspicion rather than
    waiting for untreated natural progression or delayed ADAMTS13 results.
  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: >-
      Acute episodes are considered a true medical emergency and are associated
      with a mortality rate of >90% if left untreated.
    explanation: >-
      The systematic review documents the lethality of untreated acute TTP.
- phase: Clinical remission with residual relapse and survivorship risk
  notes: >-
    Platelet recovery and resolution of acute hemolysis define clinical
    response, but ADAMTS13 activity may remain suppressed or later fall again.
    Relapse timing is unpredictable, and survivors remain at risk for stroke,
    cardiovascular disease, cognitive impairment, depression, and reduced
    quality of life.
  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: >-
      Relapses can occur in up to 50% of patients who survive their initial
      episode, and the timing may be unpredictable, occurring close to
      achievement of remission or months later.
    explanation: >-
      This supports a chronic relapsing disease model rather than a single
      resolved acute event.
- phase: Pregnancy-associated risk
  age_range: Reproductive age
  notes: >-
    Pregnancy can precipitate a first or recurrent TTP episode. Congenital and
    immune TTP must be distinguished, and subsequent pregnancies require
    expert planning and ADAMTS13-guided monitoring.
  evidence:
  - reference: PMID:24859360
    reference_title: "Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP).
    explanation: >-
      The UK pregnancy cohort establishes pregnancy as a clinically important
      precipitant.
pathophysiology:
- name: Anti-ADAMTS13 Autoantibody Production
  description: >-
    Autoreactive B-lineage cells produce predominantly IgG antibodies against
    ADAMTS13. Antibodies can inhibit proteolytic activity and/or accelerate
    antigen clearance. This acquired immune response, rather than a germline
    ADAMTS13 defect, defines immune TTP.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  evidence:
  - reference: PMID:9828246
    reference_title: Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The inhibitors were IgG antibodies.
    explanation: >-
      The original human study identifies the inhibitor as IgG.
  - reference: PMID:9828245
    reference_title: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of
      von Willebrand factor-cleaving protease
    explanation: >-
      This foundational study distinguishes acquired inhibitor-mediated TTP.
  downstream:
  - target: Severe ADAMTS13 Activity Deficiency
    causal_link_type: DIRECT
    description: >-
      Inhibition and immune clearance reduce circulating ADAMTS13 activity to
      the severe-deficiency range.
    evidence:
    - reference: PMID:30625070
      reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an immune-mediated deficiency of the von Willebrand factor-cleaving
        protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor
        multimers to platelets and microthrombosis
      explanation: >-
        The phase 3 report states that immune-mediated ADAMTS13 deficiency is
        upstream of VWF-platelet microthrombosis.
- name: Severe ADAMTS13 Activity Deficiency
  description: >-
    Functional ADAMTS13 activity below 10% is the defining biochemical lesion
    of TTP in the appropriate thrombotic-microangiopathy context. Severe
    deficiency can persist during apparent clinical remission, so it is a
    disease-state marker as well as an acute diagnostic marker.
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
    modifier: DECREASED
  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: >-
      An ADAMTS13 activity of <10% is required to confirm the diagnosis of TTP
    explanation: >-
      This supports the severe-activity threshold stated for the node.
  downstream:
  - target: Persistence of Ultralarge VWF Multimers
    causal_link_type: DIRECT
    description: >-
      Loss of VWF-cleaving activity permits newly released ultralarge VWF
      multimers to remain uncleaved.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Inherited or acquired ADAMTS13 deficiency allows the unrestrained
        growth of microthrombi that are composed of von Willebrand factor and
        platelets
      explanation: >-
        Review evidence links ADAMTS13 deficiency to the VWF-platelet
        microthrombotic process.
- name: Persistence of Ultralarge VWF Multimers
  description: >-
    Endothelial VWF remains in ultralarge, highly adhesive forms when ADAMTS13
    cleavage is severely impaired. Under shear, these multimers bind platelet
    glycoprotein Ib and recruit platelets.
  biological_processes:
  - preferred_term: platelet aggregation
    term:
      id: GO:0070527
      label: platelet aggregation
    modifier: INCREASED
  evidence:
  - reference: PMID:9828245
    reference_title: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unusually large multimers of von Willebrand factor, capable of
      agglutinating circulating platelets under high shear stress
    explanation: >-
      The foundational study identifies the shear-dependent platelet-adhesive
      substrate.
  downstream:
  - target: Disseminated Platelet-VWF Microthrombosis
    causal_link_type: DIRECT
    description: >-
      Shear-dependent platelet adhesion to ultralarge VWF produces growing
      platelet-rich microthrombi.
    evidence:
    - reference: PMID:26863353
      reference_title: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acquired thrombotic thrombocytopenic purpura (TTP) is caused by
        aggregation of platelets on ultralarge von Willebrand factor multimers.
      explanation: >-
        The phase 2 report describes the direct VWF-platelet aggregation step.
- name: Disseminated Platelet-VWF Microthrombosis
  description: >-
    Platelet-rich, VWF-rich thrombi disseminate through small vessels. This is
    not modeled as conventional fibrin/thrombin thrombogenesis: the defining
    lesion is VWF-mediated platelet adhesion.
  locations:
  - preferred_term: blood microvessel
    term:
      id: UBERON:8410081
      label: blood microvessel
  evidence:
  - reference: PMID:28768626
    reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      microthrombi that are composed of von Willebrand factor and platelets
    explanation: >-
      The review defines the material composition of TTP microthrombi.
  downstream:
  - target: Platelet Consumption
    causal_link_type: DIRECT
    description: >-
      Recruitment of circulating platelets into disseminated microthrombi
      depletes the circulating platelet pool.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        which account for the thrombocytopenia, hemolytic anemia, schistocytes,
        and tissue injury that characterize TTP
      explanation: >-
        Review evidence attributes thrombocytopenia to the VWF-platelet
        microthrombi.
  - target: Shear-Mediated Erythrocyte Fragmentation
    causal_link_type: DIRECT
    description: >-
      Erythrocytes are mechanically fragmented while traversing partially
      occluded microvessels.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        which account for the thrombocytopenia, hemolytic anemia, schistocytes,
        and tissue injury that characterize TTP
      explanation: >-
        This links the microthrombotic process to hemolysis and schistocytes.
  - target: Microvascular Occlusion and Ischemic Organ Injury
    causal_link_type: DIRECT
    description: >-
      Occlusion of small vessels reduces organ perfusion and produces ischemic
      tissue injury.
    evidence:
    - reference: PMID:26863353
      reference_title: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This microvascular thrombosis causes multiorgan ischemia with
        potentially life-threatening complications.
      explanation: >-
        The trial report directly connects microvascular thrombosis with
        multiorgan ischemia.
- name: Platelet Consumption
  description: >-
    Platelet incorporation into microthrombi produces the characteristic severe
    thrombocytopenia.
  evidence:
  - reference: PMID:30625070
    reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microthrombosis, which result in thrombocytopenia, hemolytic anemia, and
      tissue ischemia
    explanation: >-
      The phase 3 report supports platelet consumption as the proximal basis of
      thrombocytopenia in the microthrombotic process.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Consumption of circulating platelets lowers the measured platelet count.
    evidence:
    - reference: PMID:30625070
      reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        unrestrained adhesion of von Willebrand factor multimers to platelets
        and microthrombosis, which result in thrombocytopenia, hemolytic anemia,
        and tissue ischemia
      explanation: >-
        The phase 3 report connects VWF-platelet microthrombosis to
        thrombocytopenia.
- name: Shear-Mediated Erythrocyte Fragmentation
  description: >-
    Mechanical injury to erythrocytes in obstructed microvessels produces
    intravascular hemolysis and fragmented cells on the blood smear.
  evidence:
  - reference: PMID:28768626
    reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury
      that characterize TTP
    explanation: >-
      The review supports erythrocyte fragmentation as the proximal mechanism
      yielding hemolytic anemia and schistocytes.
  downstream:
  - target: Microangiopathic Hemolytic Anemia
    causal_link_type: DIRECT
    description: >-
      Ongoing mechanical erythrocyte destruction produces anemia and hemolysis.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury
        that characterize TTP
      explanation: >-
        Review evidence supports hemolytic anemia as a consequence of the
        microthrombotic process.
  - target: Schistocytosis
    causal_link_type: DIRECT
    description: >-
      Fragmented erythrocytes appear as schistocytes on peripheral smear.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury
        that characterize TTP
      explanation: >-
        The review explicitly includes schistocytes among the consequences.
- name: Microvascular Occlusion and Ischemic Organ Injury
  description: >-
    Platelet-VWF microthrombi obstruct organ microcirculation. Neurologic injury
    is prominent, but cardiac and renal ischemic injury also occur; severe renal
    failure should increase consideration of another thrombotic
    microangiopathy.
  locations:
  - preferred_term: blood microvessel
    term:
      id: UBERON:8410081
      label: blood microvessel
  evidence:
  - reference: PMID:26863353
    reference_title: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This microvascular thrombosis causes multiorgan ischemia with potentially
      life-threatening complications.
    explanation: >-
      The study establishes the organ-injury branch.
  downstream:
  - target: Encephalopathy
    causal_link_type: DIRECT
    description: >-
      Cerebral microvascular ischemia can cause fluctuating or persistent
      encephalopathy and focal neurologic injury.
    evidence:
    - reference: PMID:28768626
      reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        some die or acquire irreversible neurological deficits before they can
        respond
      explanation: >-
        The review documents severe neurologic injury without over-specifying
        individual presentations.
  - target: Myocardial infarction
    causal_link_type: DIRECT
    description: >-
      Cardiac microvascular ischemia can produce myocardial injury or
      infarction.
    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: >-
        Damage to major organs may also result in transient ischemic attack,
        stroke, myocardial infarction, or acute kidney injury.
      explanation: >-
        The systematic review identifies myocardial infarction among acute
        organ complications.
  - target: Acute kidney injury
    causal_link_type: DIRECT
    description: >-
      Renal microvascular injury can impair kidney function, although severe
      kidney failure is less typical than in hemolytic-uremic syndromes.
    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: >-
        Damage to major organs may also result in transient ischemic attack,
        stroke, myocardial infarction, or acute kidney injury.
      explanation: >-
        The systematic review identifies acute kidney injury as a complication.
  - target: Post-Acute Neurovascular and Psychosocial Sequelae
    causal_link_type: UNKNOWN
    description: >-
      Survivors have excess neurologic, cognitive, psychiatric, and
      cardiovascular morbidity, but the contribution of acute microvascular
      injury versus persistent ADAMTS13 deficiency and other factors is not
      fully resolved.
    evidence:
    - reference: PMID:31558667
      reference_title: Long-term neuropsychological sequelae, emotional wellbeing and quality of life in patients with acquired thrombotic thrombocytopenic purpura.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients with TTP suffer from long term neurological sequelae even
        years after the acute phase.
      explanation: >-
        The survivor cohort supports long-term sequelae but not a single causal
        route.
- name: Post-Acute Neurovascular and Psychosocial Sequelae
  description: >-
    Clinical remission can be followed by stroke, cognitive impairment,
    depression, anxiety, and cardiovascular morbidity. These outcomes are
    observationally associated with surviving iTTP; causal pathways are
    heterogeneous and incompletely defined.
  evidence:
  - reference: PMID:34461629
    reference_title: Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors
      experience high rates of adverse health sequelae and increased mortality
      over long-term follow-up.
    explanation: >-
      This multicenter registry study establishes a substantial survivorship
      burden.
  downstream:
  - target: Stroke in remission
    causal_link_type: UNKNOWN
    description: >-
      Stroke risk persists outside acute TTP episodes and is associated with
      lower remission ADAMTS13 activity.
    evidence:
    - reference: PMID:31431443
      reference_title: Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, stroke is common after recovery from TTP and is
        associated with reduced ADAMTS13 activity during remission.
      explanation: >-
        The cohort supports an association but does not prove the precise
        causal mechanism.
  - target: Cognitive impairment
    causal_link_type: UNKNOWN
    description: >-
      Attention and memory deficits can persist after recovery, including in
      people without overt neurologic disability.
    evidence:
    - reference: PMID:25975932
      reference_title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patients as a group performed significantly worse than standardized
        values provided by the test developers from neurologically normal
        individuals on both the MoCA and the RBANS.
      explanation: >-
        Formal testing in survivors documents cognitive impairment.
  - target: Depression
    causal_link_type: UNKNOWN
    description: >-
      Depression is frequent among survivors, but may reflect microvascular,
      autoimmune, critical-illness, and psychosocial factors.
    evidence:
    - reference: PMID:25975932
      reference_title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        31 (59%) patients screened positive for depression at least once; in 15
        (29%), the results suggested severe depression at least once.
      explanation: >-
        The longitudinal survivor cohort quantifies depressive symptoms.
phenotypes:
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Severe consumptive thrombocytopenia caused by platelet incorporation into
    VWF-rich microthrombi.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:30625070
    reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      unrestrained adhesion of von Willebrand factor multimers to platelets and
      microthrombosis, which result in thrombocytopenia, hemolytic anemia, and
      tissue ischemia
    explanation: >-
      The phase 3 trial report identifies thrombocytopenia as a core result of
      microthrombosis.
- name: Microangiopathic Hemolytic Anemia
  category: Hematologic
  description: >-
    Coombs-independent intravascular hemolysis from mechanical erythrocyte
    fragmentation in the microcirculation.
  phenotype_term:
    preferred_term: Microangiopathic hemolytic anemia
    term:
      id: HP:0001937
      label: Microangiopathic hemolytic anemia
  evidence:
  - reference: PMID:28768626
    reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury
      that characterize TTP
    explanation: >-
      The review names hemolytic anemia as a defining feature.
- name: Schistocytosis
  category: Hematologic
  description: >-
    Fragmented erythrocytes on peripheral smear, supporting microangiopathic
    hemolysis.
  phenotype_term:
    preferred_term: Schistocytosis
    term:
      id: HP:0001981
      label: Schistocytosis
  evidence:
  - reference: PMID:28768626
    reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury
      that characterize TTP
    explanation: >-
      The review identifies schistocytes as characteristic.
- name: Encephalopathy
  category: Neurologic
  description: >-
    Acute cerebral involvement can produce fluctuating mental status or other
    neurologic deficits; the cited evidence does not establish the frequency of
    each individual manifestation.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:28768626
    reference_title: Pathophysiology of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      some die or acquire irreversible neurological deficits before they can
      respond
    explanation: >-
      The review supports serious neurologic involvement without overextending
      the snippet to specific symptoms.
- name: Myocardial infarction
  category: Cardiac
  description: >-
    Cardiac microvascular ischemia can cause myocardial injury or infarction
    during acute TTP.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  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: >-
      Damage to major organs may also result in transient ischemic attack,
      stroke, myocardial infarction, or acute kidney injury.
    explanation: >-
      The systematic review identifies myocardial infarction among acute organ
      complications.
- name: Acute kidney injury
  category: Renal
  description: >-
    Renal microvascular injury can cause acute loss of kidney function, although
    severe renal failure is less typical of TTP than of hemolytic-uremic
    syndromes.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  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: >-
      Damage to major organs may also result in transient ischemic attack,
      stroke, myocardial infarction, or acute kidney injury.
    explanation: >-
      The systematic review identifies acute kidney injury as an organ
      complication.
- name: Stroke in remission
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Stroke can occur after recovery, outside an acute TTP episode. One
    137-survivor cohort observed stroke in 13.1% over a median 3.08 years; this
    cohort-specific estimate should not be treated as lifetime population risk.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:31431443
    reference_title: Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to
      an acute TTP episode over a median observation period of 3.08 years
    explanation: >-
      This supports the occasional frequency band specifically in a survivor
      cohort.
- name: Cognitive impairment
  category: Neurologic
  description: >-
    Survivors may have persistent or progressive deficits in memory, attention,
    processing speed, and related cognitive domains.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:25975932
    reference_title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients as a group performed significantly worse than standardized
      values provided by the test developers from neurologically normal
      individuals on both the MoCA and the RBANS.
    explanation: >-
      Formal survivor testing supports cognitive impairment after recovery.
- name: Depression
  category: Psychiatric
  frequency: FREQUENT
  description: >-
    Depressive symptoms are common after recovery. The frequency band derives
    from one longitudinal survivor cohort in which 59% screened positive at
    least once; it is not a universal point-prevalence estimate.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:25975932
    reference_title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      31 (59%) patients screened positive for depression at least once; in 15
      (29%), the results suggested severe depression at least once.
    explanation: >-
      The longitudinal cohort supports the frequent band with an explicit
      denominator and follow-up context.
biochemical:
- name: Severely Reduced ADAMTS13 Activity
  presence: DECREASED
  context: >-
    Plasma ADAMTS13 activity below 10% in an appropriate thrombotic
    microangiopathy context confirms the defining enzyme defect. Anti-ADAMTS13
    IgG or inhibitor supports immune etiology. Samples should be obtained before
    plasma therapy when feasible, but emergency treatment must not be delayed.
  biomarker_term:
    preferred_term: ADAMTS13
    term:
      id: NCIT:C118327
      label: A Disintegrin and Metalloproteinase with Thrombospondin Motifs 13
  readouts:
  - target: Severe ADAMTS13 Activity Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Lower measured activity is the direct biochemical readout of functional
      ADAMTS13 deficiency.
    evidence:
    - reference: PMID:32914582
      reference_title: ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or
        inhibitor)
      explanation: >-
        The diagnosis guideline establishes the measurement and immune assays
        as central readouts.
  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: >-
      An ADAMTS13 activity of <10% is required to confirm the diagnosis of TTP
    explanation: >-
      The systematic review states the severe-deficiency diagnostic threshold.
- name: Anti-ADAMTS13 IgG or Functional Inhibitor
  presence: Increased
  context: >-
    Detectable anti-ADAMTS13 IgG or an inhibitor supports immune-mediated rather
    than congenital TTP. A negative assay does not by itself establish
    congenital disease; clinical context, repeat testing, recovery pattern, and
    genetic analysis may be needed.
  readouts:
  - target: Anti-ADAMTS13 Autoantibody Production
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Higher or detectable anti-ADAMTS13 antibody supports the acquired immune
      mechanism.
    evidence:
    - reference: PMID:9828246
      reference_title: Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Inhibitory antibodies against von Willebrand factor-cleaving protease
        occur in patients with acute thrombotic thrombocytopenic purpura.
      explanation: >-
        The original study establishes the inhibitor as a mechanistic biomarker.
  evidence:
  - reference: PMID:32914582
    reference_title: ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or
      inhibitor)
    explanation: >-
      The guideline explicitly includes antibody and inhibitor assays.
diagnosis:
- name: Urgent recognition of thrombotic microangiopathy
  description: >-
    Suspect TTP in thrombocytopenia with microangiopathic hemolytic anemia and
    no better explanation. Evaluate the blood count, peripheral smear,
    hemolysis markers, renal function, cardiac injury, and neurologic status
    urgently. The historical fever-neurologic-renal pentad is not required.
  diagnosis_term:
    preferred_term: Blood Cell Count
    term:
      id: NCIT:C28133
      label: Blood Cell Count
  results: >-
    Thrombocytopenia plus schistocyte-associated hemolysis should trigger an
    emergency TTP pathway and collection of ADAMTS13 samples.
  evidence:
  - reference: PMID:28416507
    reference_title: Thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TTP is a rare and life-threatening thrombotic microangiopathy
      characterized by microangiopathic hemolytic anemia, severe
      thrombocytopenia, and organ ischemia linked to disseminated microvascular
      platelet rich-thrombi.
    explanation: >-
      The review defines the urgent clinical syndrome.
- name: ADAMTS13 activity and immune-assay confirmation
  description: >-
    Measure ADAMTS13 activity and anti-ADAMTS13 IgG or functional inhibitor,
    ideally on blood drawn before plasma exchange. Severe activity deficiency
    confirms TTP in the proper clinical context; antibody/inhibitor evidence
    supports the immune acquired subtype.
  diagnosis_term:
    preferred_term: von Willebrand Coagulation Factor Cleaving Protease Measurement
    term:
      id: NCIT:C187684
      label: von Willebrand Coagulation Factor Cleaving Protease Measurement
  results: >-
    Activity below 10% supports TTP. Detectable anti-ADAMTS13 IgG or inhibitor
    supports immune TTP; absent antibody requires cautious interpretation and
    may prompt repeat or genetic evaluation.
  evidence:
  - reference: PMID:32914582
    reference_title: ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The panel agreed on three recommendations covering the initial diagnosis
      with emphasis on the importance of ADAMTS13 testing (eg, activity,
      anti-ADAMTS13 IgG or inhibitor)
    explanation: >-
      The ISTH guideline supports the confirmatory testing strategy.
- name: PLASMIC or French-score pretest assessment
  description: >-
    When rapid ADAMTS13 results are unavailable, use clinical judgment and a
    validated score such as PLASMIC or the French score to estimate the
    probability of severe ADAMTS13 deficiency. Scores aid urgent decisions but
    do not replace ADAMTS13 testing.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  results: >-
    High pretest probability supports immediate TTP-directed treatment while
    ADAMTS13 testing is pending; intermediate or low probability increases the
    need to assess alternative thrombotic microangiopathies.
  evidence:
  - reference: PMID:32914582
    reference_title: ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      assessment of the pretest probability of TTP by clinical assessment
      and/or the risk assessment models like the PLASMIC or French score.
    explanation: >-
      The diagnosis guideline explicitly supports clinical or score-based
      pretest assessment.
- name: Serial ADAMTS13 surveillance during remission
  description: >-
    Monitor ADAMTS13 activity longitudinally after clinical recovery because a
    falling or persistently low result identifies elevated relapse and stroke
    risk and can trigger specialist consideration of preemptive therapy.
  diagnosis_term:
    preferred_term: von Willebrand Coagulation Factor Cleaving Protease Measurement
    term:
      id: NCIT:C187684
      label: von Willebrand Coagulation Factor Cleaving Protease Measurement
  results: >-
    Activity at or below 20% together with a high anti-ADAMTS13 antibody titer
    identifies a higher-risk remission state; no universally proven optimal
    testing interval exists.
  evidence:
  - reference: PMID:32350923
    reference_title: "Low levels of ADAMTS-13 with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: A multi-institutional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with ADAMTS-13 activity ≤20% plus anti-ADAMTS13 antibody titer
      ≥15 U/mL at remission had an increased risk of relapse
    explanation: >-
      The multicenter cohort supports risk-stratified remission monitoring.
- name: Neuropsychological and depression surveillance
  description: >-
    Ask survivors about cognition, mood, anxiety, work function, and quality of
    life. Positive screening or functional concerns should prompt appropriate
    neurologic, neuropsychological, primary-care, or mental-health evaluation.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  results: >-
    Depression or cognitive impairment may persist despite hematologic
    remission and should not be dismissed as evidence that the acute episode
    has fully resolved.
  evidence:
  - reference: PMID:25975932
    reference_title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations emphasize the importance of screening evaluations for
      depression and cognitive impairment.
    explanation: >-
      The survivor study directly recommends screening.
- name: Cardiovascular risk and survivorship follow-up
  description: >-
    Long-term follow-up should include blood-pressure and cardiovascular-risk
    assessment, attention to recurrent neurologic symptoms, and prompt
    evaluation of possible stroke or cardiac events.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  results: >-
    Identified hypertension, vascular risk, stroke symptoms, or cardiac disease
    should receive guideline-directed evaluation and management.
  evidence:
  - reference: PMID:34461629
    reference_title: Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study highlights the need for survivorship care and investigation
      focused on cardiovascular disease and early mortality in TTP survivors.
    explanation: >-
      The multicenter survivor cohort supports cardiovascular-focused follow-up.
- name: Pregnancy planning and ADAMTS13-guided monitoring
  description: >-
    People with prior iTTP should receive expert preconception counseling and
    close hematology-obstetric monitoring through pregnancy and postpartum,
    including serial ADAMTS13 activity.
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  results: >-
    Falling or low ADAMTS13 activity in pregnancy identifies a high-risk state
    requiring individualized prophylactic management.
  evidence:
  - reference: PMID:24859360
    reference_title: "Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Careful diagnosis, monitoring, and treatment in congenital and acquired
      TTP have assisted in excellent pregnancy outcomes.
    explanation: >-
      The pregnancy cohort supports structured monitoring and management.
differential_diagnoses:
- name: Congenital thrombotic thrombocytopenic purpura
  description: >-
    Congenital TTP also has severe ADAMTS13 deficiency but results from biallelic
    ADAMTS13 variants rather than an acquired inhibitor. Childhood onset,
    pregnancy-associated presentation, absent antibody, and failure of activity
    to recover after immunosuppression should prompt genetic evaluation.
  evidence:
  - reference: PMID:28416507
    reference_title: Thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADAMTS13 deficiency is most frequently acquired via ADAMTS13
      autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13
      gene.
    explanation: >-
      The review distinguishes immune and inherited ADAMTS13 deficiency.
- name: Complement-mediated atypical hemolytic-uremic syndrome
  description: >-
    Complement-mediated HUS causes thrombotic microangiopathy, often with more
    severe kidney injury, but does not usually produce severe ADAMTS13
    deficiency. Complement evaluation should not delay empiric TTP treatment
    when pretest probability is high.
  disease_term:
    preferred_term: atypical hemolytic-uremic syndrome
    term:
      id: MONDO:0016244
      label: atypical hemolytic-uremic syndrome
- name: Shiga toxin-associated hemolytic-uremic syndrome
  description: >-
    Diarrheal prodrome, Shiga-toxin evidence, and predominant renal injury favor
    Shiga toxin HUS; severe ADAMTS13 deficiency favors TTP.
- name: Disseminated intravascular coagulation
  description: >-
    DIC can produce thrombocytopenia and fragmented erythrocytes but usually has
    systemic coagulation activation with abnormal clotting studies and a
    precipitating critical illness; TTP microthrombi are platelet-VWF rich.
  disease_term:
    preferred_term: disseminated intravascular coagulation
    term:
      id: MONDO:0001243
      label: disseminated intravascular coagulation
- name: HELLP syndrome and severe preeclampsia
  description: >-
    Pregnancy-associated hypertension, liver-enzyme elevation, and obstetric
    context favor HELLP or preeclampsia. Persistent thrombotic microangiopathy
    postpartum or severe ADAMTS13 deficiency supports TTP.
  disease_term:
    preferred_term: HELLP syndrome
    term:
      id: MONDO:0008585
      label: HELLP syndrome
- name: Catastrophic antiphospholipid syndrome
  description: >-
    Widespread thrombosis, antiphospholipid antibodies, and coagulation-related
    manifestations can mimic TTP; severe ADAMTS13 deficiency with immune
    inhibition favors iTTP.
- name: Malignant hypertension-associated thrombotic microangiopathy
  description: >-
    Severe hypertension with target-organ injury can cause secondary
    microangiopathy. ADAMTS13 is generally not severely deficient, and the
    clinical sequence and response to blood-pressure control help distinguish
    it from iTTP.
- name: Secondary thrombotic microangiopathy
  description: >-
    Sepsis, malignancy, transplantation, autoimmune disease, and certain drugs
    can cause thrombocytopenia and microangiopathic hemolysis without the severe
    ADAMTS13 deficiency that defines TTP.
treatments:
- name: Immediate therapeutic plasma exchange
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Begin daily therapeutic plasma exchange urgently in suspected acute iTTP.
    TPE supplies functional ADAMTS13 and removes circulating antibody and other
    pathogenic plasma components. It remains part of current guideline and
    regulatory standard care; PEX-free regimens are investigational.
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: Severe ADAMTS13 Activity Deficiency
    treatment_effect: RESTORES
    description: >-
      Donor plasma replenishes missing or inhibited ADAMTS13 while exchange
      removes circulating pathogenic material.
    evidence:
    - reference: PMID:32914526
      reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        replacing the missing and/or inhibited ADAMTS13
      explanation: >-
        The ISTH guideline identifies ADAMTS13 replacement as a principal
        treatment mechanism.
    - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
      reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TPE replenishes the ADAMTS13 enzyme and removes anti-ADAMTS13
        antibodies, and ultra-large von Willebrand factor multimers gradually
        from the circulation.
      explanation: >-
        The registry outcome definition explicitly states the replacement and
        removal mechanisms attributed to TPE.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with iTTP experiencing a first acute event, the panel
      recommends the addition of corticosteroids to therapeutic plasma exchange
      (TPE) over TPE alone.
    explanation: >-
      The guideline establishes TPE as the acute-care backbone while
      recommending corticosteroid addition.
  - reference: PMID:40533296
    reference_title: 2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with iTTP, no change to 2020's recommendations.
    explanation: >-
      The 2025 focused update retained the immune-TTP recommendations.
- name: Corticosteroids with plasma exchange
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Add systemic corticosteroids to TPE for a first acute episode or relapse.
    The ISTH recommendation is strong because iTTP is life-threatening, but the
    supporting certainty is very low and no preferred steroid or dose is
    established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Anti-ADAMTS13 Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Corticosteroids suppress inflammation and are intended to reduce the
      anti-ADAMTS13 autoimmune response.
    evidence:
    - reference: PMID:32914526
      reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        The presumptive rationales for the use of corticosteroids are to reduce
        acute inflammation and inhibit the production of ADAMTS13
        autoantibodies, although high-quality data are not available.
      explanation: >-
        The guideline states the intended mechanism while explicitly qualifying
        the evidence.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with iTTP experiencing a first acute event, the panel
      recommends the addition of corticosteroids to therapeutic plasma exchange
      (TPE) over TPE alone.
    explanation: >-
      This is a strong recommendation in the context of very low-certainty
      evidence.
- name: Rituximab for acute immune control
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Rituximab is added to TPE and corticosteroids to control the anti-ADAMTS13
    autoimmune response and reduce relapse risk. The acute first-event and
    relapse recommendations are conditional because evidence certainty is very
    low.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-ADAMTS13 Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Anti-CD20 B-cell depletion reduces the B-cell compartment sustaining the
      pathogenic autoantibody response; mature plasma cells are not directly
      targeted.
    evidence:
    - reference: PMID:28416507
      reference_title: Thrombotic thrombocytopenic purpura.
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        Additional immune modulators targeting ADAMTS13 autoantibodies are
        mainly based on steroids and the humanized anti-CD20 monoclonal antibody
        rituximab.
      explanation: >-
        The review supports B-cell-directed immune modulation while the detailed
        cellular route remains indirect.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with iTTP experiencing their first acute event, the panel
      suggests the addition of rituximab to corticosteroids and TPE over
      corticosteroids and TPE alone.
    explanation: >-
      The guideline conditionally supports rituximab in acute first events.
- name: Caplacizumab with plasma exchange and immunosuppression
  action_category: THERAPEUTIC
  therapeutic_modality: NANOBODY
  description: >-
    Caplacizumab is an anti-VWF single-domain antibody that blocks VWF A1-domain
    binding to platelet glycoprotein Ib. It rapidly suppresses new
    microthrombus formation but does not correct ADAMTS13 deficiency or remove
    the autoantibody. The approved United States regimen combines it with
    plasma exchange and immunosuppression; plasma-exchange-free use remains
    selected and investigational. Current labeling covers adults and pediatric
    patients aged 12 years or older. Bleeding is the principal risk. Pregnancy
    use requires individualized expert risk-benefit assessment because human
    data are unavailable and maternal and fetal bleeding are concerns.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: caplacizumab
      term:
        id: NCIT:C128625
        label: Caplacizumab
  target_mechanisms:
  - target: Disseminated Platelet-VWF Microthrombosis
    treatment_effect: INHIBITS
    description: >-
      Caplacizumab blocks VWF A1-domain binding to platelet glycoprotein Ib and
      thereby suppresses VWF-platelet microthrombus formation without restoring
      ADAMTS13.
    evidence:
    - reference: PMID:26863353
      reference_title: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Caplacizumab, an anti-von Willebrand factor humanized
        single-variable-domain immunoglobulin (Nanobody), inhibits the
        interaction between ultralarge von Willebrand factor multimers and
        platelets.
      explanation: >-
        The phase 2 trial defines the molecular treatment mechanism.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:30625070
    reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of patients with a composite outcome event was 74% lower
      with caplacizumab than with placebo (12% vs. 49%, P<0.001).
    explanation: >-
      This supports reduction of the prespecified composite outcome, not each
      component independently.
  - reference: PMID:30625070
    reference_title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common adverse event was mucocutaneous bleeding, which was
      reported in 65% of the patients in the caplacizumab group and in 48% in
      the placebo group.
    explanation: >-
      The randomized trial establishes the common bleeding liability.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      indicated for the treatment of adult and pediatric patients 12 years of
      age and older with acquired thrombotic thrombocytopenic purpura (aTTP), in
      combination with plasma exchange and immunosuppressive therapy.
    explanation: >-
      The current FDA label establishes the approved age range and combination
      regimen in the United States.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There are no available data on CABLIVI use in pregnant women to inform a
      drug-associated risk of major birth defects and miscarriage. However,
      there are potential risks of hemorrhage in the mother and fetus
      associated with use of CABLIVI
    explanation: >-
      The current label supports cautious individualized pregnancy use because
      human exposure data are absent and bleeding may affect mother and fetus.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment after plasma exchange period: 11 mg subcutaneous injection once
      daily continuing for 30 days following the last daily plasma exchange.
    explanation: >-
      The label supplies the post-exchange treatment duration; extension is
      considered when underlying disease remains active.
- name: Preemptive rituximab during high-risk remission
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    In asymptomatic nonpregnant patients with falling or severely reduced
    ADAMTS13 activity, preemptive rituximab may be used to restore immunologic
    remission and reduce clinical relapse risk. This is conditional and depends
    on reliable serial ADAMTS13 testing.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-ADAMTS13 Autoantibody Production
    treatment_effect: INHIBITS
    description: >-
      Preemptive B-cell depletion is intended to reverse the autoimmune relapse
      before thrombocytopenia and hemolysis recur.
    evidence:
    - reference: PMID:30201758
      reference_title: Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Preemptive rituximab reduces clinical relapses by maintaining a
        detectable ADAMTS13 activity with an advantageous risk-benefit balance.
      explanation: >-
        The 92-patient cohort supports the preemptive strategy.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with iTTP who are in remission, but still have low plasma
      ADAMTS13 activity with no clinical signs/symptoms, the panel suggests the
      use of rituximab over nonuse of rituximab for prophylaxis.
    explanation: >-
      The ISTH guideline conditionally supports preemptive rituximab outside
      pregnancy.
- name: Prophylactic treatment for high-risk pregnancy
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Pregnancy with a history of iTTP and reduced ADAMTS13 activity requires
    expert prophylactic treatment rather than observation alone. The ISTH
    guideline supports prophylactic therapy to raise ADAMTS13, but does not
    establish one universal immune-suppressive or plasma regimen.
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: Severe ADAMTS13 Activity Deficiency
    treatment_effect: RESTORES
    description: >-
      Plasma-based prophylaxis can raise ADAMTS13 activity during a high-risk
      pregnancy; regimen choice is individualized.
    evidence:
    - reference: PMID:32914526
      reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        Although no specific prophylactic immune suppressive or plasma
        treatment regimen is recommended, the panel made a strong
        recommendation for the use of prophylactic treatment to increase the
        ADAMTS13 activity to prevent both maternal and fetal mortality and
        morbidity.
      explanation: >-
        The guideline supports prophylaxis while explicitly leaving regimen
        selection unresolved.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with a history of iTTP in remission that are pregnant with
      reduced levels of ADAMTS13 activity have more recently been recognized to
      have poor clinical outcomes with close monitoring alone.
    explanation: >-
      This supports active expert management rather than surveillance alone.
- name: Serial ADAMTS13 activity monitoring
  action_category: MONITORING
  description: >-
    Continue ADAMTS13 activity monitoring after clinical recovery and during
    pregnancy planning. Results guide relapse-risk assessment, preemptive
    immunosuppression, and the safe duration of caplacizumab; the optimal fixed
    testing interval is not established.
  treatment_term:
    preferred_term: ADAMTS13 activity monitoring
    term:
      id: NCIT:C187684
      label: von Willebrand Coagulation Factor Cleaving Protease Measurement
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The panel raised practical issues around the cost, resource utilization,
      and patient commitment necessary for monitoring during remission, such as
      continued monitoring of plasma ADAMTS13 activity and starting rituximab
      in a timely fashion.
    explanation: >-
      The guideline explicitly links serial monitoring with timely preemptive
      treatment.
clinical_trials:
- name: NCT05468320
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Completed open-label, single-arm study of caplacizumab plus
    immunosuppressive therapy without first-line therapeutic plasma exchange in
    selected adults with iTTP. Actual enrollment was 51. Among evaluable
    participants, 93.5% achieved remission without TPE and 4.3% required TPE.
  notes: >-
    The study completed on 2024-12-26 and posted results in December 2025.
    Severe neurologic or cardiac presentations were excluded, and there was no
    randomized comparator; these findings therefore do not establish
    equivalence or replace current guideline-based TPE care.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT05468320
    reference_title: "An Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a single group, treatment, Phase 3, open-label, single-arm study
      to evaluate the efficacy and safety of caplacizumab and immunosuppressive
      therapy
    explanation: >-
      The registry summary establishes the phase, single-arm design, and
      treatment combination.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"statusVerifiedDate":"2025-12","overallStatus":"COMPLETED"'
    explanation: >-
      The registry API establishes completed status and its verification date.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"enrollmentInfo":{"count":51,"type":"ACTUAL"}'
    explanation: >-
      The registry API establishes actual enrollment.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"value":"93.5","lowerLimit":"82.5","upperLimit":"97.8"'
    explanation: >-
      The posted primary outcome reports the percentage of evaluable
      participants achieving remission without TPE and its 95% confidence
      interval.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"value":"4.3","lowerLimit":"1.2","upperLimit":"14.5"'
    explanation: >-
      The posted secondary outcome reports the percentage requiring TPE during
      treatment and its 95% confidence interval.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Those presenting with severe neurological or cardiac disease.
    explanation: >-
      The exclusion criterion limits generalization to the most severe acute
      presentations.
- name: NCT06831058
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Open-label pilot study of weekly intravenous efgartigimod in adults with
    prior iTTP who are in clinical remission but have ADAMTS13 activity above
    30% and below 70%. Estimated enrollment is 15, completion is estimated for
    May 2028, and no results are posted.
  notes: >-
    ClinicalTrials.gov API record retrieved 2026-07-17; registry status was
    RECRUITING and sponsor verification was 2026-06. This is investigational
    FcRn-directed IgG reduction, not established remission therapy.
  evidence:
  - reference: clinicaltrials:NCT06831058
    reference_title: A Pilot Study of Efgartigimod for Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is expected that following efgartigimod therapy, there will be a rise
      in ADAMTS13 activity to the normal range that will be sustained during the
      treatment period.
    explanation: >-
      The trial summary states the hypothesized biochemical effect of the
      investigational intervention.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06831058
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT06831058
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "statusVerifiedDate":"2026-06","overallStatus":"RECRUITING"
    explanation: >-
      The live registry API establishes current recruiting status and
      verification date.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06831058
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT06831058
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "enrollmentInfo":{"count":15,"type":"ESTIMATED"}
    explanation: >-
      The registry provides the estimated enrollment.
- name: NCT06291025
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Prospective single-arm French PEX-FREE study testing plasma infusion,
    caplacizumab, corticosteroids, and rituximab without therapeutic plasma
    exchange in selected adults with acute clinical iTTP. Estimated enrollment
    is 131 and completion is estimated for August 2026; no results are posted.
  notes: >-
    ClinicalTrials.gov API record retrieved 2026-07-17; status was RECRUITING
    and verified 2026-02. This design is experimental and does not replace the
    current TPE-based guideline regimen.
  evidence:
  - reference: clinicaltrials:NCT06291025
    reference_title: "Efficacy and Safety of Immunosuppression, Caplacizumab and Plasma Infusion Without Therapeutic Plasma Exchange in Immune-mediated Thrombotic Thrombocytopenic Purpura: Multicentric Non-inferiority Single-arm Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on these statements, the objective is to address the efficacy and
      safety of a PEX-free regimen, combining PI only (15 ml/kg/day),
      corticosteroids/rituximab, and caplacizumab.
    explanation: >-
      The registry summary defines the PEX-free experimental strategy.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06291025
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT06291025
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "statusVerifiedDate":"2026-02","overallStatus":"RECRUITING"
    explanation: >-
      The live registry API establishes current recruiting status.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06291025
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT06291025
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "enrollmentInfo":{"count":131,"type":"ESTIMATED"}
    explanation: >-
      The registry provides the planned sample size.
discussions:
- discussion_id: gap_ittp_second_hit_and_organ_tropism
  prompt: >-
    Why do some people with severe ADAMTS13 deficiency remain clinically well
    while others develop an acute episode with a particular pattern of organ
    injury?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Severe ADAMTS13 Activity Deficiency
  - pathophysiology#Disseminated Platelet-VWF Microthrombosis
  rationale: >-
    Severe deficiency is necessary for TTP but does not by itself explain the
    timing of attacks, infection and pregnancy triggers, or variable cerebral,
    cardiac, and renal involvement. Endothelial activation, VWF release,
    inflammation, and vascular susceptibility are candidate additional factors.
  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: >-
      Common triggers demonstrate that enzyme deficiency is embedded in a
      broader attack context.
- discussion_id: gap_ittp_remission_threshold_and_monitoring_interval
  prompt: >-
    Which ADAMTS13 activity threshold, antibody profile, and testing interval
    best identify patients who benefit from preemptive immunosuppression?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Anti-ADAMTS13 Autoantibody Production
  - pathophysiology#Severe ADAMTS13 Activity Deficiency
  rationale: >-
    Low activity and high antibody levels predict relapse, but cohorts use
    different thresholds and the ISTH guideline identifies no evidence-based
    universal monitoring interval.
  evidence:
  - reference: PMID:32914526
    reference_title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is also no evidence on the appropriate interval for performing
      ADAMTS13 activity testing.
    explanation: >-
      The guideline directly identifies the interval evidence gap.
- discussion_id: gap_ittp_pex_free_and_novel_autoantibody_therapy
  prompt: >-
    Can selected acute episodes be treated safely without plasma exchange, and
    can FcRn blockade or other targeted therapies produce durable immunologic
    remission with less treatment burden?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatment#Immediate therapeutic plasma exchange
  - treatment#Rituximab for acute immune control
  rationale: >-
    Active PEX-free and efgartigimod studies are small or single-arm and have no
    posted results. They should not be treated as established alternatives to
    current TPE, caplacizumab, corticosteroid, and rituximab care.
  evidence:
  - reference: clinicaltrials:NCT06291025
    reference_title: "Efficacy and Safety of Immunosuppression, Caplacizumab and Plasma Infusion Without Therapeutic Plasma Exchange in Immune-mediated Thrombotic Thrombocytopenic Purpura: Multicentric Non-inferiority Single-arm Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it's considered that robust data are still lacking to completely
      remove plasmatherapy from iTTP management.
    explanation: >-
      The study rationale itself states the unresolved evidence gap.
references:
- reference: PMID:24859360
  title: "Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes."
- reference: PMID:25975932
  title: Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
- reference: PMID:26863353
  title: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
- reference: PMID:28416507
  title: Thrombotic thrombocytopenic purpura.
- reference: PMID:28768626
  title: Pathophysiology of thrombotic thrombocytopenic purpura.
- reference: PMID:30201758
  title: Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura.
- reference: PMID:30625070
  title: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
- reference: PMID:31431443
  title: Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors.
- reference: PMID:31558667
  title: Long-term neuropsychological sequelae, emotional wellbeing and quality of life in patients with acquired thrombotic thrombocytopenic purpura.
- reference: PMID:32350923
  title: "Low levels of ADAMTS-13 with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: A multi-institutional study."
- reference: PMID:32914526
  title: ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
- reference: PMID:32914582
  title: ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
- reference: PMID:33780553
  title: "Incidence, diagnosis, and outcome of immune-mediated thrombotic thrombocytopenic purpura: A nationwide survey by the Spanish registry of thrombotic thrombocytopenic purpura."
- reference: PMID:34461629
  title: Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission.
- reference: PMID:39161536
  title: A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
- reference: PMID:40533296
  title: 2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura.
- reference: PMID:9828245
  title: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
- reference: PMID:9828246
  title: Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
- reference: clinicaltrials:NCT06291025
  title: "Efficacy and Safety of Immunosuppression, Caplacizumab and Plasma Infusion Without Therapeutic Plasma Exchange in Immune-mediated Thrombotic Thrombocytopenic Purpura: Multicentric Non-inferiority Single-arm Study"
- reference: clinicaltrials:NCT05468320
  title: "An Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura"
- reference: clinicaltrials:NCT06831058
  title: A Pilot Study of Efgartigimod for Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06291025
  title: https://clinicaltrials.gov/api/v2/studies/NCT06291025
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
  title: https://clinicaltrials.gov/api/v2/studies/NCT05468320
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT06831058
  title: https://clinicaltrials.gov/api/v2/studies/NCT06831058
- reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
  title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
notes: >-
  This entry models acquired immune TTP, not congenital ADAMTS13 deficiency or
  secondary thrombotic microangiopathy. Severe ADAMTS13 deficiency is central,
  but attack timing and organ tropism require additional incompletely defined
  factors. Caplacizumab suppresses VWF-platelet thrombosis without curing the
  autoimmune disease; platelet recovery therefore does not replace ADAMTS13
  surveillance or immunosuppressive control.
📚

References & Deep Research

References

25
PMID:24859360
Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.
No top-level findings curated for this source.
PMID:25975932
Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:26863353
Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.
No top-level findings curated for this source.
PMID:28416507
Thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:28768626
Pathophysiology of thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:30201758
Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:30625070
Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.
No top-level findings curated for this source.
PMID:31431443
Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors.
No top-level findings curated for this source.
PMID:31558667
Long-term neuropsychological sequelae, emotional wellbeing and quality of life in patients with acquired thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:32350923
Low levels of ADAMTS-13 with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: A multi-institutional study.
No top-level findings curated for this source.
PMID:32914526
ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:32914582
ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:33780553
Incidence, diagnosis, and outcome of immune-mediated thrombotic thrombocytopenic purpura: A nationwide survey by the Spanish registry of thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:34461629
Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission.
No top-level findings curated for this source.
PMID:39161536
A Systematic Review of the Epidemiology and Disease Burden of Congenital and Immune-Mediated Thrombotic Thrombocytopenic Purpura.
No top-level findings curated for this source.
PMID:40533296
2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
PMID:9828245
von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
No top-level findings curated for this source.
PMID:9828246
Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
No top-level findings curated for this source.
clinicaltrials:NCT06291025
Efficacy and Safety of Immunosuppression, Caplacizumab and Plasma Infusion Without Therapeutic Plasma Exchange in Immune-mediated Thrombotic Thrombocytopenic Purpura: Multicentric Non-inferiority Single-arm Study
No top-level findings curated for this source.
clinicaltrials:NCT05468320
An Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura
No top-level findings curated for this source.
clinicaltrials:NCT06831058
A Pilot Study of Efgartigimod for Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT06291025
https://clinicaltrials.gov/api/v2/studies/NCT06291025
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT05468320
https://clinicaltrials.gov/api/v2/studies/NCT05468320
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT06831058
https://clinicaltrials.gov/api/v2/studies/NCT06831058
No top-level findings curated for this source.
url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s018lbl.pdf
No top-level findings curated for this source.