Thrombotic Thrombocytopenic Purpura

• ADAMTS13 Deficiency and Ultra-Large vWF Accumulation: ADAMTS13 normally cleaves unusually large multimers of von Willebrand factor (UL-vWF) released from endothelial cells into smaller, less thrombogenic fragments. When ADAMTS13 activity falls below 10% of normal (critical threshold), UL-vWF multimers accumulate persistently on the endothelial surface and in the circulation. These massive multimers have extraordinarily high platelet-binding affinity—orders of magnitude greater than normal vWF—and spontaneously trigger platelet aggregation even without prior vessel injury. In acquired TTP (most common, 95% of cases), autoimmune IgG antibodies against ADAMTS13 block enzymatic activity or promote immune clearance; in congenital TTP (rare, 5% of cases), mutations in the ADAMTS13 gene reduce protein production or cause functional deficiency. The degree of ADAMTS13 activity correlates inversely with disease severity and prognosis.

• Platelet Microthrombi Formation and Consumption: The accumulated UL-vWF multimers cause spontaneous platelet aggregation in the microcirculation, particularly in the brain, kidneys, and heart where shear stress is highest. This platelet consumption exceeds bone marrow production capacity, resulting in severe thrombocytopenia (typically <30,000/μL, often <10,000/μL). Platelet aggregates lodge in arterioles and capillaries, mechanically obstructing blood flow and causing tissue ischemia. Importantly, platelet aggregation occurs without preceding endothelial damage in TTP, contrasting with disseminated intravascular coagulation (DIC) where platelet consumption is secondary to tissue factor activation and thrombin generation. The platelet count correlates with thrombotic burden and organ involvement—patients with counts <10,000/μL have higher risk of neurologic and cardiac events.

• Mechanical Hemolysis and Endothelial Injury: As red blood cells traverse microvasculature partially occluded by platelet thrombi and fibrin strands, mechanical shearing forces fragment erythrocytes, producing schistocytes (helmet cells, fragmented RBCs). This mechanical hemolysis accounts for the microangiopathic hemolytic anemia (MAHA) component of the pentad. Simultaneously, vWF-platelet aggregates directly injure the endothelium by triggering inflammatory responses, complement activation (particularly the alternative pathway), and apoptosis of endothelial cells. Endothelial injury further exposes tissue factor and generates additional prothrombotic surfaces, perpetuating the cycle. The severity of endothelial damage correlates with the degree of organ dysfunction—particularly neurologic involvement (from cerebral vessel thrombosis and inflammation) and acute kidney injury (from glomerular capillary obstruction).

• Shear-Stress-Induced Platelet Activation: UL-vWF multimers have unique propensity for causing platelet activation under high shear stress, a phenomenon distinct from normal hemostasis. The A1 domain of vWF binds directly to platelet glycoprotein Ib-IX-V under pathologic shear conditions without requiring von Willebrand factor's normal cofactor (ristocetin). Additionally, UL-vWF provides simultaneous binding to fibrinogen and other adhesion molecules on platelets, creating cross-links that stabilize platelet aggregates. These shear-activated platelet aggregates are highly resistant to physiologic inhibitors (prostacyclin, nitric oxide, adenosine) and require direct removal by ADAMTS13 or clearance by the reticuloendothelial system.

• Organ-Specific Microvascular Injury: Different organs show varying susceptibility to microvascular thrombosis based on vascular anatomy and hemodynamic forces. The brain has dense capillary networks with high shear stress, making it particularly vulnerable to microthrombi formation; thrombosis in parietal, temporal, and occipital cortices produces the characteristic neurologic manifestations. The kidneys, particularly the glomerular capillaries, experience high shear stress and show platelet deposition; however, true acute kidney injury requiring dialysis occurs in only 10-15% of TTP cases (contrasting with hemolytic uremic syndrome where renal involvement is dominant). Cardiac involvement through coronary microvascular thrombosis or myocardial microvascular injury accounts for troponin elevation in up to 50% of patients and contributes significantly to mortality. The lungs can develop diffuse alveolar hemorrhage from capillary injury, and the gastrointestinal tract may show mucosal bleeding and ischemia.

• Acquired Autoimmune TTP (95% of cases): The predominant form results from development of IgG autoantibodies (most commonly) or less frequently IgM antibodies directed against ADAMTS13. These antibodies either directly block the catalytic domain of ADAMTS13 (inhibitory antibodies) or target epitopes that promote immune complex formation and complement-mediated clearance. Autoimmune TTP typically occurs in previously healthy individuals without constitutional ADAMTS13 mutations and may be triggered by infections (particularly bacterial infections like pneumococcal sepsis, HIV, or viral infections), medications (especially ticlopidine, clopidogrel, quinine, and rarely other drug classes), malignancy, systemic lupus erythematosus or other autoimmune conditions, pregnancy or postpartum period (likely due to placental microparticles or endothelial injury), or prior transfusion/alloimmunization. In many patients, no clear trigger is identified. Importantly, patients with acquired TTP frequently have positive ADAMTS13 inhibitor assays that distinguish them from congenital forms and guide treatment decisions.

• Congenital TTP (5% of cases): Results from inherited mutations in the ADAMTS13 gene with severely reduced or absent protease activity. Congenital cases typically present earlier in life (infancy through childhood), with episodes triggered by relatively minor stressors including febrile infections, vaccinations, pregnancy, or stress. Unlike acquired TTP which usually presents acutely in adulthood, congenital TTP often has a chronic-relapsing course with recurrent episodes throughout life. Patients with congenital TTP have negative ADAMTS13 inhibitor assays and can be treated with prophylactic plasma infusions or regular plasma exchange to prevent episodes, distinguishing their management from acquired cases.

• Drug-Associated TTP: Certain medications carry well-established risk for TTP development. Ticlopidine and clopidogrel (thienopyridines) historically accounted for 1-2% of TTP cases, though incidence has decreased with increased awareness; these antiplatelet agents likely trigger an immune response against ADAMTS13. Quinine causes immune-mediated TTP through formation of quinine-dependent antibodies that cross-react with ADAMTS13. Other drugs implicated include mitomycin C (chemotherapy agent causing dose-related endothelial injury), calcineurin inhibitors (tacrolimus, cyclosporine), rifampin, valproic acid, and interferon-alpha. Drug-associated TTP typically resolves with discontinuation of the offending agent, though this alone is rarely sufficient and plasma exchange is required.

• Infection-Associated TTP: Bacterial sepsis, particularly from Streptococcus pneumoniae, can trigger TTP through endotoxin-induced endothelial damage and potentially through autoimmune mechanisms against ADAMTS13. Acute HIV infection is associated with TTP development, though modern antiretroviral therapy has reduced incidence dramatically. Viral infections including influenza, EBV, and parvovirus B19 have been reported as triggers. Infection-associated TTP may have somewhat better prognosis than idiopathic cases, possibly because removal of the infectious trigger allows for resolution of the underlying microangiopathy.

• Malignancy-Associated TTP: Various solid tumors and hematologic malignancies can precipitate TTP through mechanisms including release of cancer procoagulant, endothelial injury from malignant infiltration or paraneoplastic phenomena, or development of anti-ADAMTS13 antibodies. Gastric adenocarcinoma, breast cancer, and lymphoproliferative disorders are most commonly reported. Cancer-associated TTP carries worse prognosis than idiopathic disease, reflecting both the underlying malignancy and potentially more aggressive microangiopathy.

• Pregnancy and Postpartum-Associated TTP: TTP can develop during pregnancy, particularly in the third trimester, or in the immediate postpartum period (typically within 2-4 weeks of delivery). Preeclampsia/eclampsia can coexist with or masquerade as TTP, and distinguishing between these entities is clinically challenging but essential as management differs significantly. Postpartum TTP may represent a spectrum with preeclampsia and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. The mechanism is incompletely understood but likely involves endothelial injury from placental factors and possibly anti-ADAMTS13 autoimmunity triggered by pregnancy.

• SLE and Systemic Autoimmune Conditions: Patients with systemic lupus erythematosus and other autoimmune vasculitides have increased TTP risk, possibly through generation of anti-ADAMTS13 antibodies as part of their broader autoimmune dysregulation. TTP occurring in SLE patients may represent lupus microangiopathy or true concomitant TTP.

• Prior Solid Organ or Hematopoietic Stem Cell Transplantation: Post-transplant TTP can develop acutely (within days to weeks) related to calcineurin inhibitors, endothelial injury from conditioning regimens, or chronic graft-versus-host disease. Incidence is higher with more intense conditioning regimens and calcineurin inhibitor use.

• Thrombocytopenia: Profound thrombocytopenia (typically <30,000/μL and often <10,000/μL) is the hallmark laboratory finding and usually the first manifestation. Patients develop petechiae and purpura, most notably over lower extremities, buttocks, and oral mucosa, reflecting spontaneous platelet-mediated microthrombi rather than vasculitis (petechiae are generally non-blanching but non-inflammatory in character). Severe thrombocytopenia increases bleeding risk—petechiae and purpura are most common hemorrhagic manifestations, but frank mucosal bleeding (epistaxis, gingival bleeding), menorrhagia, or intracranial hemorrhage can occur. The thrombocytopenia is immune-mediated (consumption-type) with elevated thrombopoietin levels and adequate or elevated bone marrow megakaryocytes.

• Microangiopathic Hemolytic Anemia (MAHA): Mechanical fragmentation of erythrocytes navigating through platelet-fibrin-occluded capillaries produces schistocytes on blood smear (fragmented RBCs, helmet cells, keratocytes, triangular cells) visible on peripheral blood examination. Hemolysis manifests as elevated reticulocyte count (typically >3%), elevated indirect hyperbilirubinemia (usually <3 mg/dL), elevated LDH (often >1000 IU/L, sometimes >2000), low haptoglobin, elevated urobilinogen, and hemoglobinuria. Anemia may range from mild to severe (Hgb 6-10 g/dL typical at presentation). The presence of MAHA distinguished from immune hemolytic anemia by negative direct antiglobulin test (Coombs)—if Coombs is positive, consider concurrent autoimmune hemolytic anemia (Evans syndrome) or an alternative diagnosis.

• Neurologic Manifestations (Present in 60% of cases): Neurologic involvement is the most common non-hematologic manifestation and ranges from subtle cognitive changes to catastrophic stroke. Fluctuating mental status and confusion are classic early signs, reflecting multiple microinfarcts in cerebral cortex and white matter. Headache occurs in 15-20% and may be severe. Focal neurologic deficits including hemiparesis, aphasia, visual field defects, ataxia, or cranial nerve palsies occur when microthrombi occlude major vessel territories. Seizures develop in 10-15% of cases from cortical involvement. Coma indicates severe cerebral involvement and is an ominous sign. Transient ischemic attack-like episodes that wax and wane over hours to days are characteristic of fluctuating microangiopathy. Posterior reversible encephalopathy syndrome (PRES) pattern on MRI can occur. Importantly, neurologic manifestations can evolve rapidly—a patient may present with mild confusion and progress to seizures and coma within hours without treatment. Neurologic involvement correlates with worse prognosis and higher mortality if untreated. The fluctuating nature of neurologic symptoms is a key distinguishing feature—worsening symptoms with falling platelets strongly suggests TTP over other etiologies.

• Renal Dysfunction (Present in 50%, with dialysis-requiring AKI in 10-15%): Acute kidney injury results from glomerular capillary microthrombi obstructing glomerular filtration and tubular injury. Serum creatinine elevation is usually modest (1.5-3.0 mg/dL) and occurs without significant proteinuria or RBC casts (distinguishing TTP from post-infectious glomerulonephritis or vasculitis). Hematuria is common but mild. Oliguria or anuria requiring dialysis occurs in minority of cases but carries poor prognosis. Importantly, severe renal dysfunction is atypical of classic TTP and suggests alternative diagnoses such as Shiga toxin-producing E. coli hemolytic uremic syndrome (STEC-HUS) or other etiologies. Renal biopsy shows characteristic platelet-rich thrombi in arterioles and glomeruli with minimal inflammation—the "black thrombi" appearance is pathognomonic.

• Cardiac Manifestations (Present in 50%, clinically evident in 10-30%): Coronary microvascular thrombosis causes troponin elevation in approximately 50% of patients, often without diagnostic ST-segment changes on ECG. Acute heart failure from diffuse myocardial microvascular injury, arrhythmias from myocardial infarction or electrolyte derangement, and sudden cardiac death can occur. Takotsubo cardiomyopathy pattern (stress-induced cardiomyopathy) has been reported in association with severe stress of TTP. Cardiac involvement significantly worsens prognosis and can necessitate intensive supportive care including mechanical support.

• Pulmonary Involvement: Diffuse alveolar hemorrhage from capillary injury manifests as hemoptysis, progressive dyspnea, and diffuse bilateral infiltrates on chest imaging. Acute respiratory distress syndrome (ARDS) pattern can develop. Pulmonary hemorrhage indicates severe systemic endothelial injury and carries poor prognosis.

• Gastrointestinal Manifestations: Abdominal pain, nausea and vomiting, and diarrhea occur in 15-20% and result from mesenteric microthrombi causing mucosal ischemia. Occult or overt GI bleeding can occur but frank melena or hematochezia is uncommon. Severe GI ischemia with perforation is

Initial testing (obtain before any plasma is given)

• CBC with peripheral smear: severe thrombocytopenia plus schistocytes (helmet cells, keratocytes) are the entry criteria. A smear read by an experienced observer is the single most informative early test.
• Hemolysis panel: markedly elevated LDH, undetectable/low haptoglobin, indirect hyperbilirubinemia, reticulocytosis.
• Direct antiglobulin (Coombs) test — negative. A positive DAT points to autoimmune hemolysis or Evans syndrome instead.
• Coagulation studies — normal or near-normal PT, aPTT, fibrinogen, and D-dimer. This is the pivotal discriminator from DIC, where consumption of clotting factors prolongs PT/aPTT and consumes fibrinogen. TTP is a platelet–vWF disease, not a thrombin-driven one.
• Creatinine, troponin, ECG, pregnancy test, HIV and hepatitis serologies, stool studies if diarrhea to capture triggers and organ injury.

Risk stratification

• PLASMIC score (7 points, each scored 1): Platelet count <30 ×10⁹/L; Lysis (reticulocytes >2.5%, undetectable haptoglobin, or indirect bilirubin >2 mg/dL); no active cancer; no solid-organ or stem-cell transplant; MCV <90 fL; INR <1.5; Creatinine <2.0 mg/dL. Scores of 6–7 indicate high probability of severe ADAMTS13 deficiency and justify immediate plasma exchange; 0–4 is low risk; 5 is intermediate. The French score is an accepted alternative.

Confirmatory/gold standard

• ADAMTS13 activity <10% (severe deficiency) confirms TTP. Send with an anti-ADAMTS13 IgG inhibitor/antibody assay: detectable inhibitor establishes immune TTP; absent antibody with persistently low activity after recovery suggests congenital (Upshaw–Schulman) disease and warrants gene sequencing.

First-line therapy (ISTH 2020 guideline for immune TTP)

• Therapeutic plasma exchange (TPE): daily 1–1.5 plasma-volume exchanges with plasma replacement. It simultaneously removes anti-ADAMTS13 autoantibody and ultralarge vWF multimers and replaces functional ADAMTS13. Continue until platelet count normalizes for at least two consecutive days with resolving LDH.
• If apheresis is not immediately available, plasma infusion is a bridge — it supplies enzyme but does not remove inhibitor.
• Corticosteroids: high-dose glucocorticoid (methylprednisolone or prednisone) to suppress autoantibody production.
• Caplacizumab, an anti-vWF A1-domain nanobody that blocks the GPIb–vWF interaction, is recommended by ISTH in combination with TPE and steroids; it produces faster platelet recovery and fewer exacerbations.

Escalation / second-line

• Rituximab (anti-CD20 monoclonal antibody) depletes autoantibody-producing B cells; ISTH favors adding it in the acute immune episode and in relapse.
• Refractory disease: intensify to twice-daily TPE and add immunosuppression — calcineurin inhibitor, cyclophosphamide, or bortezomib. Splenectomy is reserved for multiply refractory or frequently relapsing disease.

Contraindicated / cautions

• Platelet transfusion — avoid; it fuels ongoing microvascular thrombosis. Reserve for life-threatening hemorrhage or an invasive procedure that cannot be deferred.
• Hold caplacizumab for major bleeding.
• Give folate; withhold iron unless documented deficiency, and discontinue any implicated drug (thienopyridine, quinine, calcineurin inhibitor).

Disease-related — emergencies

• Intracranial hemorrhage or ischemic stroke: profound thrombocytopenia plus cerebral microthrombi. Signaled by a new focal deficit, seizure, or abrupt decline in consciousness. Emergent head CT; this is the leading neurologic cause of death.
• Myocardial microvascular infarction, arrhythmia, sudden cardiac death: coronary microthrombi. Signaled by rising troponin, often without ST-segment elevation, or by new heart failure. Serial troponin and telemetry are mandatory — cardiac involvement is a major driver of early mortality.
• Mesenteric or pancreatic ischemia: abdominal pain with rising lipase or lactate.

Disease-related — subacute

• Acute kidney injury: glomerular capillary thrombi; usually modest creatinine rise, dialysis rarely needed. Severe renal failure should prompt reconsideration of STEC-HUS or complement-mediated HUS.
• Exacerbation (platelet fall within 30 days of stopping TPE) versus relapse (recurrence later); driven by persistent autoantibody. Falling platelets with rising LDH is the signal — monitor ADAMTS13 activity in remission, as a fall below normal predicts relapse and can prompt preemptive rituximab.
• Long-term neurocognitive impairment, depression, and hypertension after apparent recovery.

Treatment-related

• Central venous catheter complications: pneumothorax, catheter-related bloodstream infection, and catheter thrombosis — placement in a severely thrombocytopenic patient is high-risk.
• Citrate anticoagulation during apheresis: chelates calcium, producing perioral/acral paresthesias, tetany, and QT prolongation. Check ionized calcium; treat with calcium repletion.
• Plasma exposure: allergic/anaphylactic reactions, TRALI, volume overload, transfusion-transmitted infection.
• Caplacizumab: mucocutaneous bleeding (epistaxis, gingival, menorrhagia) from vWF-axis blockade — an emergency if intracranial or GI.
• Rituximab: infusion reactions, hypogammaglobulinemia, hepatitis B reactivation (screen HBsAg/anti-HBc first), and rarely PML.
• Corticosteroids: hyperglycemia, psychosis, infection, and with prolonged use, osteoporosis.
• Post-splenectomy: lifelong risk of encapsulated-organism sepsis; vaccinate.

• The dyad, not the pentad, makes the diagnosis: unexplained MAHA (schistocytes, high LDH, low haptoglobin, negative Coombs) plus thrombocytopenia is enough. The classic pentad is present in a minority and waiting for it is a trap.
• Single best next step in a stem with schistocytes and platelets <30 ×10⁹/L: send ADAMTS13 activity, then start urgent therapeutic plasma exchange with corticosteroids — never delay apheresis for the assay result.
• Normal PT, aPTT, and fibrinogen distinguish TTP from DIC. TTP is platelet–vWF driven; DIC is thrombin driven with prolonged coags, low fibrinogen, and high D-dimer.
• The one association examiners test: severe ADAMTS13 deficiency (<10%) from an inhibitory IgG autoantibody, allowing ultralarge vWF multimers to persist. Congenital cases lack the antibody.
• Do not transfuse platelets for the thrombocytopenia alone — the classic distractor. Platelets feed ongoing microthrombosis; reserve for life-threatening hemorrhage.
• Distinguish from HUS: a child with bloody diarrhea, prominent oliguric renal failure, and normal ADAMTS13 has STEC-HUS — plasma exchange is not the answer; supportive care and avoidance of antibiotics/antimotility agents are. Adults with dialysis-requiring AKI and normal ADAMTS13 suggest complement-mediated HUS (eculizumab).
• Know the PLASMIC score as the named tool; a score of 6–7 predicts severe ADAMTS13 deficiency and justifies immediate apheresis.
• Drug triggers worth memorizing: ticlopidine and clopidogrel, quinine, calcineurin inhibitors, and mitomycin C. Stopping the drug alone is insufficient.
• Falling platelets with rising LDH after stopping exchange = exacerbation; recurrent low ADAMTS13 activity in remission predicts relapse and prompts preemptive rituximab.