17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T6726,## Summary Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy caused by severe acquired deficiency of ADAMTS13, usually from inhibitory or clearance-enhancing autoantibodies. The resulting persistence of ultra-large von Willebrand factor multimers drives platelet-rich microvascular thrombosis, producing thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and ischemic injury that often affects the brain and heart.[1-4] Suspect iTTP whenever otherwise unexplained thrombocytopenia and MAHA occur together, especially when coagulation studies are relatively preserved and kidney failure is not disproportionately severe. The historical pentad is neither sensitive nor required. A single absent schistocyte report early in disease does not safely exclude iTTP if the rest of the syndrome is compelling.[1-4] Draw ADAMTS13 activity, inhibitor, and/or anti-ADAMTS13 antibody testing **before plasma infusion or therapeutic plasma exchange (TPE)** whenever this can be done without delaying treatment. In the appropriate clinical setting, ADAMTS13 activity **<10 IU/dL or <10% of normal** strongly supports TTP. Activity ≥20% makes iTTP substantially less likely; 10–20% is an indeterminate zone requiring integration of assay timing, prior plasma exposure, phenotype, and competing diagnoses.[1,2] When pretest probability is high, start TPE plus corticosteroids without waiting for the ADAMTS13 result. Caplacizumab rapidly blocks von Willebrand factor–platelet interaction and should be incorporated early when iTTP is strongly suspected and timely ADAMTS13 testing is available. It does **not** correct the autoimmune ADAMTS13 deficiency, so immunosuppression remains essential.[1-4] Current U.S. labeling for caplacizumab in acquired TTP covers adults and patients aged ≥12 years. The regimen is **11 mg IV at least 15 minutes before the first plasma exchange, then 11 mg subcutaneously after that exchange; 11 mg subcutaneously after each subsequent daily exchange; then 11 mg subcutaneously once daily for 30 days after the final exchange**. Treatment may be extended for up to 28 additional days when the underlying disease remains active, including persistently suppressed ADAMTS13 activity.[5] Rituximab is commonly used early in iTTP to suppress the B-cell source of autoantibodies and reduce relapse risk. A widely used regimen is **375 mg/m² IV once weekly for 4 doses**, although accelerated schedules are used by some expert centers. Because plasma exchange removes circulating drug, administer rituximab after an exchange and maximize the interval before the next exchange when feasible.[3,6,7] Clinical response is not defined by the platelet count alone. Follow hemolysis, neurologic and cardiac status, creatinine, lactate dehydrogenase (LDH), platelet trajectory, and ADAMTS13 recovery. Continue TPE until sustained platelet recovery and resolution of active hemolysis and organ ischemia; do not stop treatment by elapsed time alone. Relapse risk persists after apparent clinical remission, and serial ADAMTS13 surveillance is central to long-term follow-up.[1-4,8] > **Caution:** Neurologic deterioration, troponin elevation, ischemic ECG changes, ventricular arrhythmia, hemodynamic instability, or refractory hemolysis should trigger immediate escalation to an intensive-care and specialist TTP pathway. Cardiac involvement may be clinically silent. ## Definition and classification ### Thrombotic microangiopathy Thrombotic microangiopathy (TMA) is a clinicopathologic syndrome characterized by microvascular thrombosis, thrombocytopenia, MAHA, and variable end-organ ischemia. TTP is one cause of TMA and must be differentiated from complement-mediated hemolytic uremic syndrome, Shiga toxin–associated HUS, pregnancy-related TMA, malignant hypertension, transplantation-associated TMA, drug-associated TMA, disseminated intravascular coagulation, and other mimics.[3,4] ### Immune TTP iTTP is acquired severe ADAMTS13 deficiency caused by autoantibodies that inhibit enzyme function and/or accelerate clearance. The hallmark is severe ADAMTS13 activity reduction in a compatible clinical syndrome.[1-4] ### Congenital TTP Congenital TTP results from biallelic pathogenic variants in **ADAMTS13**. It may present in childhood, adulthood, or pregnancy and requires a different long-term management strategy. The 2025 ISTH focused update changed recommendations for congenital disease, including support for recombinant ADAMTS13 where available, but did not materially change the established iTTP treatment recommendations.[8] ## Pathophysiology ADAMTS13 normally cleaves ultra-large von Willebrand factor (VWF) multimers released from endothelium. In iTTP, severe ADAMTS13 deficiency allows highly adhesive VWF multimers to persist under shear stress. This produces: 1. platelet adhesion and aggregation in the microcirculation; 2. platelet consumption and thrombocytopenia; 3. red-cell fragmentation through partially obstructed microvessels, causing schistocytes and MAHA; 4. tissue ischemia, particularly in the brain and myocardium.[2-4] This mechanism explains why PT, INR, aPTT, and fibrinogen may remain relatively preserved compared with disseminated intravascular coagulation. It also explains why platelet transfusion is generally avoided: the dominant threat is microvascular thrombosis rather than isolated bleeding from low platelet count. ### Therapeutic targets | Pathologic process | Therapy | Purpose | |---|---|---| | Severe ADAMTS13 deficiency | Plasma delivered through TPE | Replaces functional ADAMTS13 | | Circulating anti-ADAMTS13 antibodies | TPE | Removes pathogenic antibodies and other circulating mediators | | Autoantibody production | Corticosteroids | Broad immune suppression | | B-cell autoantibody source | Rituximab | Reduces autoantibody production and relapse risk | | VWF-mediated platelet adhesion | Caplacizumab | Rapidly interrupts microvascular platelet aggregation | | Persistent severe autoimmune activity | Additional specialist-directed immunotherapy | Reserved for refractory or multiply relapsing disease | ## Epidemiology and associated settings iTTP is rare. It occurs more often in women and has important population differences, including higher observed incidence in Black populations in several cohorts.[3,4] Episodes may occur without an obvious trigger or in association with: - pregnancy or the postpartum period; - systemic autoimmune disease, especially systemic lupus erythematosus; - infection; - surgery or major physiologic stress; - HIV; - selected medications associated with TMA; - prior iTTP relapse.[3,4] A trigger does not establish the TMA subtype. ADAMTS13 testing remains central. ## Clinical features ### Hematologic findings Typical findings include: - severe thrombocytopenia, often <30 ×10⁹/L; - anemia with reticulocytosis; - schistocytes; - elevated LDH; - low or undetectable haptoglobin; - indirect hyperbilirubinemia; - negative direct antiglobulin testing in most cases.[1-4] Petechiae and bruising may occur, but catastrophic spontaneous bleeding is less characteristic than the platelet count might imply. ### Neurologic involvement Neurologic abnormalities are common and may fluctuate: - headache; - confusion or encephalopathy; - transient focal deficits; - aphasia; - seizures; - stroke-like syndromes; - coma in severe disease.[3,4] ### Cardiac involvement Myocardial microvascular ischemia is a major prognostic concern and may be clinically silent. Manifestations include: - troponin elevation; - ischemic ECG abnormalities; - chest pain; - arrhythmia; - heart failure; - cardiogenic shock or sudden death.[3,4] Obtain an ECG and cardiac troponin during the acute episode. Escalate telemetry and critical-care monitoring when abnormalities are present. ### Kidney involvement Mild-to-moderate creatinine elevation, hematuria, and proteinuria can occur. Marked kidney failure does not exclude iTTP but should broaden the differential toward complement-mediated HUS, Shiga toxin–associated HUS, severe hypertension, pregnancy-related TMA, and other causes.[3,4] ### Gastrointestinal and constitutional features Abdominal pain, nausea, vomiting, fatigue, fever, and malaise can occur. Severe abdominal pain should also prompt consideration of mesenteric ischemia or an alternative TMA process. ## Initial stabilization ### Immediate priorities - Assess airway, breathing, perfusion, mental status, and active bleeding. - Obtain continuous cardiac monitoring when neurologic or cardiac involvement is present or disease is severe. - Establish IV access and obtain the ADAMTS13 specimen **before any plasma exposure** whenever feasible. - Contact hematology and the local apheresis/TTP service immediately when probability is high. - Do not delay TPE because confirmatory ADAMTS13 testing is pending.[1,2] ### Platelet transfusion Avoid routine prophylactic platelet transfusion. Consider platelets only for life-threatening hemorrhage or an unavoidable high-risk invasive procedure after specialist discussion. If a central venous catheter is urgently required for TPE, the decision should balance bleeding risk against the harm of delaying treatment.[3,4] ### Red-cell transfusion Red-cell transfusion can be used for clinically important anemia according to symptoms, hemodynamics, myocardial ischemia, and overall context. It does not treat the underlying microangiopathy. ## Diagnostic pathway ### Immediate laboratory studies Order urgently: - CBC with platelet count; - peripheral blood smear; - reticulocyte count; - LDH; - total and indirect bilirubin; - haptoglobin; - creatinine and electrolytes; - PT/INR, aPTT, fibrinogen; - direct antiglobulin test when immune hemolysis is plausible; - ECG and troponin; - urinalysis; - pregnancy testing when relevant; - blood group/type and screen; - targeted infection, autoimmune, pregnancy, or toxin studies guided by context.[1-4] ### Typical acute laboratory pattern | Test | Common iTTP pattern | Clinical meaning | |---|---|---| | Platelets | Markedly reduced | Microvascular platelet consumption | | Hemoglobin | Reduced or falling | MAHA ± bleeding | | Schistocytes | Present | Mechanical red-cell fragmentation | | LDH | Elevated | Hemolysis plus tissue ischemia | | Haptoglobin | Low or undetectable | Intravascular hemolysis | | Indirect bilirubin | Elevated | Hemoglobin breakdown | | Reticulocytes | Increased unless marrow response is impaired | Regenerative response | | PT/aPTT | Often near normal | Helps distinguish many cases from DIC | | Creatinine | Often normal to moderately elevated | Marked failure broadens the TMA differential | | Troponin | May be elevated | Myocardial microvascular injury | ### ADAMTS13 sampling and interpretation Draw ADAMTS13 activity plus inhibitor or antibody testing before TPE or plasma infusion whenever possible. Donor plasma can raise measurable activity and obscure severe deficiency.[1,2,9] Interpretation in the correct clinical setting: - **<10 IU/dL or <10%:** strongly supports TTP. - **10–20%:** indeterminate; integrate timing, assay characteristics, prior plasma exposure, and competing diagnoses. - **≥20%:** iTTP is substantially less likely; reassess the diagnosis and the need for caplacizumab.[1,2] Do not wait for a result in a patient with high clinical probability. ## PLASMIC score The PLASMIC score estimates the probability of severe ADAMTS13 deficiency in adults with suspected TMA while definitive testing is pending.[10,11] | Component | 1 point if present | |---|---| | Platelet count | <30 ×10⁹/L | | Hemolysis | Reticulocytes >2.5%, indirect bilirubin >2.0 mg/dL, or undetectable haptoglobin | | Active cancer | Absent | | Transplant history | Absent | | MCV | <90 fL | | INR | <1.5 | | Creatinine | <2.0 mg/dL | Interpretation: - **6–7:** high probability of severe ADAMTS13 deficiency; - **5:** intermediate probability; - **0–4:** low probability.[10,11] > **Clinical pearl:** PLASMIC is a bridge to definitive testing, not a substitute for ADAMTS13 measurement. A compelling syndrome can still warrant immediate treatment despite an imperfect score. ## Differential diagnosis | Condition | Clues favoring it over iTTP | Key next step | |---|---|---| | Complement-mediated HUS | Severe AKI, hypertension, less profound thrombocytopenia, ADAMTS13 not severely deficient | Complement/TMA specialist pathway; consider complement-directed therapy when appropriate | | Shiga toxin–associated HUS | Diarrheal prodrome, especially bloody diarrhea, significant AKI | Stool Shiga toxin/PCR and supportive renal care | | DIC | Prolonged coagulation studies, low fibrinogen, marked D-dimer elevation, sepsis/trauma/obstetric trigger | Treat cause; coagulation support as indicated | | Severe hypertension-associated TMA | Markedly elevated BP, hypertensive retinopathy, cardiac/renal target-organ injury | Controlled BP reduction and reassessment of hemolysis | | HELLP syndrome / preeclampsia | Pregnancy, hypertension, transaminase elevation, obstetric syndrome | Urgent obstetric evaluation and delivery planning | | Atypical postpartum TMA | Postpartum persistence or worsening, severe AKI | Distinguish iTTP from complement-mediated disease using ADAMTS13 and phenotype | | Drug-associated TMA | Exposure to implicated agent, temporal relationship | Stop suspected agent; disease-specific management | | Mechanical hemolysis | Prosthetic valve/device, less characteristic systemic TMA | Echocardiography/device assessment | | Severe B12 deficiency | Macrocytosis, low reticulocyte response, very high LDH, hypersegmented neutrophils | B12 testing and replacement | ## Definitive acute therapy ### Therapeutic plasma exchange TPE is the foundation of acute iTTP treatment. It both replaces ADAMTS13 and removes circulating autoantibodies.[1-4] A common acute regimen exchanges approximately **1–1.5 plasma volumes (about 40–60 mL/kg) every 24 hours** using plasma replacement.[8] Intensified exchange may be considered by expert centers in selected fulminant cases, but routine twice-daily treatment is not standard for every patient. Continue daily TPE until there is sustained clinical response, including: - platelet recovery to a stable near-normal or normal range; - resolution of active MAHA with falling/normalizing LDH and improving hemolysis markers; - no new ischemic organ injury; - overall clinical stability.[1-4] A clock-only stopping rule is unsafe. Persistent severe ADAMTS13 deficiency affects decisions about ongoing caplacizumab and immune therapy even after the platelet count normalizes. ### Corticosteroids ISTH recommends corticosteroids in addition to TPE for acute iTTP.[3] Exact regimens vary. Common specialist strategies include high-dose oral prednisone/prednisolone or IV methylprednisolone in severe disease, followed by tapering as clinical and ADAMTS13 response becomes established. Because comparative evidence does not establish one universally superior steroid schedule, follow the institutional TTP protocol rather than improvising prolonged therapy. ### Caplacizumab Caplacizumab binds the A1 domain of VWF and rapidly blocks VWF-mediated platelet adhesion. It shortens the period of active platelet consumption but does not suppress the anti-ADAMTS13 autoimmune process.[1-5] **Current U.S. regimen:**[5] 1. **11 mg IV** at least 15 minutes before the first plasma exchange. 2. **11 mg subcutaneously** after completion of the first exchange. 3. **11 mg subcutaneously once daily** after each subsequent plasma exchange during the exchange period. 4. After the final exchange, **11 mg subcutaneously once daily for 30 days**. 5. Continue for up to **28 additional days** when evidence of persistent underlying disease remains, including persistently suppressed ADAMTS13 activity.[5] Monitor for mucocutaneous and major bleeding. Withhold or stop when clinically important bleeding risk outweighs benefit, and coordinate any invasive procedure carefully.[5] > **Caution:** A normalized platelet count while ADAMTS13 remains severely deficient does not indicate immunologic remission. Premature caplacizumab discontinuation in that setting can be followed by recurrence. ### Rituximab Rituximab targets CD20-positive B cells and is commonly added early in acute iTTP, particularly when relapse risk is substantial or ADAMTS13 recovery is delayed.[3,6,7] A widely used regimen is: - **375 mg/m² IV once weekly for 4 doses**.[6] Some specialist protocols use accelerated four-dose schedules during acute disease. Because plasma exchange can remove rituximab, administer it after an exchange and, when feasible, allow at least several hours before the next exchange.[7] Before therapy, assess hepatitis B status and other infection risks according to the relevant biologic-therapy protocol. ## Monitoring during acute treatment ### At least daily while disease is active - platelet count; - hemoglobin; - LDH; - bilirubin and haptoglobin as needed; - creatinine and electrolytes; - neurologic status; - bleeding assessment; - cardiac rhythm in high-risk patients; - troponin when myocardial involvement is present or suspected.[3,4] ### ADAMTS13 Repeat ADAMTS13 during recovery according to local TTP-center practice. Persistent severe deficiency is a marker of continuing autoimmune disease and should influence caplacizumab duration and immune therapy.[1-4] ### Response terminology Clinical response requires correction of the acute TMA phenotype, not merely a transient platelet rise. Escalate when there is: - recurrent thrombocytopenia after initial improvement; - persistent or recurrent MAHA; - new neurologic or cardiac ischemia; - failure of platelet recovery despite adequate TPE and immune therapy; - persistently severe ADAMTS13 suppression with ongoing clinical activity. ## Refractory or worsening disease Confirm that the patient is receiving uninterrupted effective TPE, adequate immunosuppression, and caplacizumab when appropriate. Reassess for: - delayed or missed exchanges; - occult infection; - competing TMA diagnosis; - pregnancy-associated disease; - drug-associated TMA; - complement-mediated HUS; - severe hypertension; - ongoing autoimmune activity.[3,4] Specialist rescue strategies may include intensified B-cell/plasma-cell–directed therapy in selected cases. Such approaches are not routine first-line care and should be managed by an experienced TTP center. ## Pregnancy and postpartum disease Pregnancy can trigger either immune or congenital TTP and overlaps clinically with preeclampsia/HELLP and complement-mediated TMA. ADAMTS13 testing is crucial when thrombocytopenia and MAHA are disproportionate, occur early in pregnancy, persist after delivery, or are accompanied by neurologic features.[3,4] When iTTP is strongly suspected during pregnancy, urgent TPE and corticosteroid-based specialist therapy should not wait for final confirmatory testing. Caplacizumab and other immune therapies require individualized maternal-fetal risk assessment because pregnancy evidence is limited. A history of TTP warrants preconception hematology review and serial ADAMTS13 monitoring during pregnancy because biochemical relapse can precede overt hematologic recurrence. ## Pediatric patients iTTP is rare in children. Management should involve pediatric hematology and a center with TTP/apheresis expertise. U.S. caplacizumab labeling now includes acquired TTP in patients aged **≥12 years** in combination with plasma exchange and immunosuppression.[5] Younger children require specialist individualized therapy because regulatory labeling and evidence differ. ## Disposition Acute iTTP requires admission to a hospital capable of urgent plasma exchange and specialist hematology care. Intensive-care placement is favored for: - altered consciousness or seizure; - significant cardiac injury or arrhythmia; - hemodynamic instability; - major bleeding; - respiratory failure; - severe multiorgan dysfunction; - rapidly progressive disease.[3,4] Transfer should not create avoidable interruption in TPE. Coordinate plasma therapy, transport timing, and receiving-center readiness. ## Remission and long-term follow-up Clinical remission does not eliminate relapse risk. Follow-up should include:[1,3,8,9] - serial ADAMTS13 activity; - CBC when clinically indicated or when ADAMTS13 falls; - education regarding relapse symptoms; - cardiovascular risk assessment; - assessment for cognitive, mood, fatigue, and quality-of-life effects after severe disease; - pregnancy planning where relevant. Severe recurrent ADAMTS13 deficiency can precede clinical relapse. Preemptive rituximab during remission is supported as a conditional strategy in selected nonpregnant patients with persistently or recurrently low ADAMTS13 activity.[3,8] ## Complications | Complication | Recognition | Action | |---|---|---| | Ischemic stroke/seizure | Focal deficit, altered consciousness, seizure | Continue urgent TTP therapy; neurologic and critical-care support | | Myocardial injury | Troponin elevation, ECG change, arrhythmia, shock | Telemetry, cardiology/critical-care input; treat TTP urgently | | Major bleeding | Gastrointestinal, intracranial, procedural, or other significant hemorrhage | Reassess caplacizumab, hemostatic support, urgent specialist management | | Acute kidney injury | Rising creatinine, oliguria | Reassess TMA subtype, optimize perfusion, renal support if needed | | Exacerbation after apparent response | Falling platelets or recurrent MAHA soon after treatment change | Resume/intensify TTP therapy and reassess ADAMTS13 | | Later relapse | Recurrent thrombocytopenia/MAHA after remission | Treat as acute iTTP and reassess immune strategy | ## Acute management checklist - Recognize thrombocytopenia plus MAHA as a TTP emergency until an alternative is established. - Draw ADAMTS13 activity and antibody/inhibitor testing before plasma exposure when feasible. - Do not wait for the ADAMTS13 result when pretest probability is high. - Start TPE plus corticosteroids urgently. - Add caplacizumab early when iTTP is strongly suspected and the local pathway supports it. - Add rituximab early in the specialist treatment plan. - Obtain ECG and troponin; monitor neurologic status closely. - Avoid routine platelet transfusion. - Track platelet count, LDH, hemolysis, organ injury, and ADAMTS13 recovery. - Stop TPE only after sustained clinical response, not after a predetermined number of days. - Extend caplacizumab when autoimmune activity remains evident, including persistent severe ADAMTS13 suppression. - Arrange long-term ADAMTS13 surveillance after remission. ## Recent practice updates The **2025 ISTH focused update** reviewed newer evidence and retained the established 2020 treatment approach for iTTP; its major recommendation change involved congenital TTP.[8] Caplacizumab is now labeled in the United States for adults and pediatric patients aged ≥12 years with acquired TTP in combination with plasma exchange and immunosuppression.[5] In **August 2026**, the British Society for Haematology published updated laboratory guidance emphasizing standardized ADAMTS13 activity, antibody, antigen, and monitoring processes and the role of experienced laboratories in rapid TTP diagnosis.[9] ## Related library topics - [Systemic Lupus Erythematosus](../rheumatology/systemic-lupus-erythematosus.md) - [Preeclampsia and Eclampsia](../obstetrics-gynecology/preeclampsia-and-eclampsia.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Acute Ischemic Stroke](../neurology/acute-ischemic-stroke.md) ## References 1. Zheng XL, Vesely SK, Cataland SR, et al. **ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2020;18:2486-2495. DOI: 10.1111/jth.15006. PMID: 32914582. https://pmc.ncbi.nlm.nih.gov/articles/PMC8146131/ 2. Zheng XL. **The standard of care for immune thrombotic thrombocytopenic purpura today.** *J Thromb Haemost.* 2021;19:1866-1871. DOI: 10.1111/jth.15407. PMID: 34173673. 3. Zheng XL, Vesely SK, Cataland SR, et al. **ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2020;18:2496-2502. DOI: 10.1111/jth.15010. PMID: 32914581. https://pmc.ncbi.nlm.nih.gov/articles/PMC8091490/ 4. Joly BS, Coppo P, Veyradier A. **Thrombotic thrombocytopenic purpura.** *Blood.* 2017;129:2836-2846. DOI: 10.1182/blood-2016-10-709857. PMID: 28416507. 5. U.S. Food and Drug Administration. **Caplacizumab-yhdp injection: prescribing information.** Revised 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s010lbl.pdf 6. Scully M, McDonald V, Cavenagh J, et al. **A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.** *Blood.* 2011;118:1746-1753. DOI: 10.1182/blood-2011-03-341131. PMID: 21636861. 7. NHS England. **Rituximab for the treatment of acute thrombotic thrombocytopenic purpura: clinical commissioning policy.** 2022. https://www.england.nhs.uk/publication/rituximab-for-the-treatment-of-acute-thrombotic-thrombocytopenic-purpura/ 8. Zheng XL, Cataland SR, Coppo P, et al. **2025 focused update of the 2020 ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2025;23:3711-3732. DOI: 10.1016/j.jtha.2025.06.002. PMID: 40533296. https://pubmed.ncbi.nlm.nih.gov/40533296/ 9. British Society for Haematology. **Diagnosis and monitoring of thrombotic thrombocytopenic purpura: Guidance for laboratories and for clinical collaboration between laboratories and TTP specialist centres.** 2026. https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-monitoring-of-thrombotic-thrombocytopenic-purpura 10. Bendapudi PK, Hurwitz S, Fry A, et al. **Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies.** *Lancet Haematol.* 2017;4:e157-e164. DOI: 10.1016/S2352-3026(17)30026-1. PMID: 28259520. 11. Li A, Khalighi PR, Wu Q, Garcia DA. **External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment.** *J Thromb Haemost.* 2018;16:164-169. DOI: 10.1111/jth.13882. PMID: 29064619.19:T6746,## Summary Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy caused by severe acquired deficiency of ADAMTS13, usually from inhibitory or clearance-enhancing autoantibodies. The resulting persistence of ultra-large von Willebrand factor multimers drives platelet-rich microvascular thrombosis, producing thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and ischemic injury that often affects the brain and heart.[1-4] Suspect iTTP whenever otherwise unexplained thrombocytopenia and MAHA occur together, especially when coagulation studies are relatively preserved and kidney failure is not disproportionately severe. The historical pentad is neither sensitive nor required. A single absent schistocyte report early in disease does not safely exclude iTTP if the rest of the syndrome is compelling.[1-4] Draw ADAMTS13 activity, inhibitor, and/or anti-ADAMTS13 antibody testing **before plasma infusion or therapeutic plasma exchange (TPE)** whenever this can be done without delaying treatment. In the appropriate clinical setting, ADAMTS13 activity **<10 IU/dL or <10% of normal** strongly supports TTP. Activity ≥20% makes iTTP substantially less likely; 10–20% is an indeterminate zone requiring integration of assay timing, prior plasma exposure, phenotype, and competing diagnoses.[1,2] When pretest probability is high, start TPE plus corticosteroids without waiting for the ADAMTS13 result. Caplacizumab rapidly blocks von Willebrand factor–platelet interaction and should be incorporated early when iTTP is strongly suspected and timely ADAMTS13 testing is available. It does **not** correct the autoimmune ADAMTS13 deficiency, so immunosuppression remains essential.[1-4] Current U.S. labeling for caplacizumab in acquired TTP covers adults and patients aged ≥12 years. The regimen is **11 mg IV at least 15 minutes before the first plasma exchange, then 11 mg subcutaneously after that exchange; 11 mg subcutaneously after each subsequent daily exchange; then 11 mg subcutaneously once daily for 30 days after the final exchange**. Treatment may be extended for up to 28 additional days when the underlying disease remains active, including persistently suppressed ADAMTS13 activity.[5] Rituximab is commonly used early in iTTP to suppress the B-cell source of autoantibodies and reduce relapse risk. A widely used regimen is **375 mg/m² IV once weekly for 4 doses**, although accelerated schedules are used by some expert centers. Because plasma exchange removes circulating drug, administer rituximab after an exchange and maximize the interval before the next exchange when feasible.[3,6,7] Clinical response is not defined by the platelet count alone. Follow hemolysis, neurologic and cardiac status, creatinine, lactate dehydrogenase (LDH), platelet trajectory, and ADAMTS13 recovery. Continue TPE until sustained platelet recovery and resolution of active hemolysis and organ ischemia; do not stop treatment by elapsed time alone. Relapse risk persists after apparent clinical remission, and serial ADAMTS13 surveillance is central to long-term follow-up.[1-4,8] > **Caution:** Neurologic deterioration, troponin elevation, ischemic ECG changes, ventricular arrhythmia, hemodynamic instability, or refractory hemolysis should trigger immediate escalation to an intensive-care and specialist TTP pathway. Cardiac involvement may be clinically silent. ## Definition and classification ### Thrombotic microangiopathy Thrombotic microangiopathy (TMA) is a clinicopathologic syndrome characterized by microvascular thrombosis, thrombocytopenia, MAHA, and variable end-organ ischemia. TTP is one cause of TMA and must be differentiated from complement-mediated hemolytic uremic syndrome, Shiga toxin–associated HUS, pregnancy-related TMA, malignant hypertension, transplantation-associated TMA, drug-associated TMA, disseminated intravascular coagulation, and other mimics.[3,4] ### Immune TTP iTTP is acquired severe ADAMTS13 deficiency caused by autoantibodies that inhibit enzyme function and/or accelerate clearance. The hallmark is severe ADAMTS13 activity reduction in a compatible clinical syndrome.[1-4] ### Congenital TTP Congenital TTP results from biallelic pathogenic variants in **ADAMTS13**. It may present in childhood, adulthood, or pregnancy and requires a different long-term management strategy. The 2025 ISTH focused update changed recommendations for congenital disease, including support for recombinant ADAMTS13 where available, but did not materially change the established iTTP treatment recommendations.[8] ## Pathophysiology ADAMTS13 normally cleaves ultra-large von Willebrand factor (VWF) multimers released from endothelium. In iTTP, severe ADAMTS13 deficiency allows highly adhesive VWF multimers to persist under shear stress. This produces: 1. platelet adhesion and aggregation in the microcirculation; 2. platelet consumption and thrombocytopenia; 3. red-cell fragmentation through partially obstructed microvessels, causing schistocytes and MAHA; 4. tissue ischemia, particularly in the brain and myocardium.[2-4] This mechanism explains why PT, INR, aPTT, and fibrinogen may remain relatively preserved compared with disseminated intravascular coagulation. It also explains why platelet transfusion is generally avoided: the dominant threat is microvascular thrombosis rather than isolated bleeding from low platelet count. ### Therapeutic targets | Pathologic process | Therapy | Purpose | |---|---|---| | Severe ADAMTS13 deficiency | Plasma delivered through TPE | Replaces functional ADAMTS13 | | Circulating anti-ADAMTS13 antibodies | TPE | Removes pathogenic antibodies and other circulating mediators | | Autoantibody production | Corticosteroids | Broad immune suppression | | B-cell autoantibody source | Rituximab | Reduces autoantibody production and relapse risk | | VWF-mediated platelet adhesion | Caplacizumab | Rapidly interrupts microvascular platelet aggregation | | Persistent severe autoimmune activity | Additional specialist-directed immunotherapy | Reserved for refractory or multiply relapsing disease | ## Epidemiology and associated settings iTTP is rare. It occurs more often in women and has important population differences, including higher observed incidence in Black populations in several cohorts.[3,4] Episodes may occur without an obvious trigger or in association with: - pregnancy or the postpartum period; - systemic autoimmune disease, especially systemic lupus erythematosus; - infection; - surgery or major physiologic stress; - HIV; - selected medications associated with TMA; - prior iTTP relapse.[3,4] A trigger does not establish the TMA subtype. ADAMTS13 testing remains central. ## Clinical features ### Hematologic findings Typical findings include: - severe thrombocytopenia, often <30 ×10⁹/L; - anemia with reticulocytosis; - schistocytes; - elevated LDH; - low or undetectable haptoglobin; - indirect hyperbilirubinemia; - negative direct antiglobulin testing in most cases.[1-4] Petechiae and bruising may occur, but catastrophic spontaneous bleeding is less characteristic than the platelet count might imply. ### Neurologic involvement Neurologic abnormalities are common and may fluctuate: - headache; - confusion or encephalopathy; - transient focal deficits; - aphasia; - seizures; - stroke-like syndromes; - coma in severe disease.[3,4] ### Cardiac involvement Myocardial microvascular ischemia is a major prognostic concern and may be clinically silent. Manifestations include: - troponin elevation; - ischemic ECG abnormalities; - chest pain; - arrhythmia; - heart failure; - cardiogenic shock or sudden death.[3,4] Obtain an ECG and cardiac troponin during the acute episode. Escalate telemetry and critical-care monitoring when abnormalities are present. ### Kidney involvement Mild-to-moderate creatinine elevation, hematuria, and proteinuria can occur. Marked kidney failure does not exclude iTTP but should broaden the differential toward complement-mediated HUS, Shiga toxin–associated HUS, severe hypertension, pregnancy-related TMA, and other causes.[3,4] ### Gastrointestinal and constitutional features Abdominal pain, nausea, vomiting, fatigue, fever, and malaise can occur. Severe abdominal pain should also prompt consideration of mesenteric ischemia or an alternative TMA process. ## Initial stabilization ### Immediate priorities - Assess airway, breathing, perfusion, mental status, and active bleeding. - Obtain continuous cardiac monitoring when neurologic or cardiac involvement is present or disease is severe. - Establish IV access and obtain the ADAMTS13 specimen **before any plasma exposure** whenever feasible. - Contact hematology and the local apheresis/TTP service immediately when probability is high. - Do not delay TPE because confirmatory ADAMTS13 testing is pending.[1,2] ### Platelet transfusion Avoid routine prophylactic platelet transfusion. Consider platelets only for life-threatening hemorrhage or an unavoidable high-risk invasive procedure after specialist discussion. If a central venous catheter is urgently required for TPE, the decision should balance bleeding risk against the harm of delaying treatment.[3,4] ### Red-cell transfusion Red-cell transfusion can be used for clinically important anemia according to symptoms, hemodynamics, myocardial ischemia, and overall context. It does not treat the underlying microangiopathy. ## Diagnostic pathway ### Immediate laboratory studies Order urgently: - CBC with platelet count; - peripheral blood smear; - reticulocyte count; - LDH; - total and indirect bilirubin; - haptoglobin; - creatinine and electrolytes; - PT/INR, aPTT, fibrinogen; - direct antiglobulin test when immune hemolysis is plausible; - ECG and troponin; - urinalysis; - pregnancy testing when relevant; - blood group/type and screen; - targeted infection, autoimmune, pregnancy, or toxin studies guided by context.[1-4] ### Typical acute laboratory pattern | Test | Common iTTP pattern | Clinical meaning | |---|---|---| | Platelets | Markedly reduced | Microvascular platelet consumption | | Hemoglobin | Reduced or falling | MAHA ± bleeding | | Schistocytes | Present | Mechanical red-cell fragmentation | | LDH | Elevated | Hemolysis plus tissue ischemia | | Haptoglobin | Low or undetectable | Intravascular hemolysis | | Indirect bilirubin | Elevated | Hemoglobin breakdown | | Reticulocytes | Increased unless marrow response is impaired | Regenerative response | | PT/aPTT | Often near normal | Helps distinguish many cases from DIC | | Creatinine | Often normal to moderately elevated | Marked failure broadens the TMA differential | | Troponin | May be elevated | Myocardial microvascular injury | ### ADAMTS13 sampling and interpretation Draw ADAMTS13 activity plus inhibitor or antibody testing before TPE or plasma infusion whenever possible. Donor plasma can raise measurable activity and obscure severe deficiency.[1,2,9] Interpretation in the correct clinical setting: - **<10 IU/dL or <10%:** strongly supports TTP. - **10–20%:** indeterminate; integrate timing, assay characteristics, prior plasma exposure, and competing diagnoses. - **≥20%:** iTTP is substantially less likely; reassess the diagnosis and the need for caplacizumab.[1,2] Do not wait for a result in a patient with high clinical probability. ## PLASMIC score The PLASMIC score estimates the probability of severe ADAMTS13 deficiency in adults with suspected TMA while definitive testing is pending.[10,11] | Component | 1 point if present | |---|---| | Platelet count | <30 ×10⁹/L | | Hemolysis | Reticulocytes >2.5%, indirect bilirubin >2.0 mg/dL, or undetectable haptoglobin | | Active cancer | Absent | | Transplant history | Absent | | MCV | <90 fL | | INR | <1.5 | | Creatinine | <2.0 mg/dL | Interpretation: - **6–7:** high probability of severe ADAMTS13 deficiency; - **5:** intermediate probability; - **0–4:** low probability.[10,11] > **Clinical pearl:** PLASMIC is a bridge to definitive testing, not a substitute for ADAMTS13 measurement. A compelling syndrome can still warrant immediate treatment despite an imperfect score. ## Differential diagnosis | Condition | Clues favoring it over iTTP | Key next step | |---|---|---| | Complement-mediated HUS | Severe AKI, hypertension, less profound thrombocytopenia, ADAMTS13 not severely deficient | Complement/TMA specialist pathway; consider complement-directed therapy when appropriate | | Shiga toxin–associated HUS | Diarrheal prodrome, especially bloody diarrhea, significant AKI | Stool Shiga toxin/PCR and supportive renal care | | DIC | Prolonged coagulation studies, low fibrinogen, marked D-dimer elevation, sepsis/trauma/obstetric trigger | Treat cause; coagulation support as indicated | | Severe hypertension-associated TMA | Markedly elevated BP, hypertensive retinopathy, cardiac/renal target-organ injury | Controlled BP reduction and reassessment of hemolysis | | HELLP syndrome / preeclampsia | Pregnancy, hypertension, transaminase elevation, obstetric syndrome | Urgent obstetric evaluation and delivery planning | | Atypical postpartum TMA | Postpartum persistence or worsening, severe AKI | Distinguish iTTP from complement-mediated disease using ADAMTS13 and phenotype | | Drug-associated TMA | Exposure to implicated agent, temporal relationship | Stop suspected agent; disease-specific management | | Mechanical hemolysis | Prosthetic valve/device, less characteristic systemic TMA | Echocardiography/device assessment | | Severe B12 deficiency | Macrocytosis, low reticulocyte response, very high LDH, hypersegmented neutrophils | B12 testing and replacement | ## Definitive acute therapy ### Therapeutic plasma exchange TPE is the foundation of acute iTTP treatment. It both replaces ADAMTS13 and removes circulating autoantibodies.[1-4] A common acute regimen exchanges approximately **1–1.5 plasma volumes (about 40–60 mL/kg) every 24 hours** using plasma replacement.[8] Intensified exchange may be considered by expert centers in selected fulminant cases, but routine twice-daily treatment is not standard for every patient. Continue daily TPE until there is sustained clinical response, including: - platelet recovery to a stable near-normal or normal range; - resolution of active MAHA with falling/normalizing LDH and improving hemolysis markers; - no new ischemic organ injury; - overall clinical stability.[1-4] A clock-only stopping rule is unsafe. Persistent severe ADAMTS13 deficiency affects decisions about ongoing caplacizumab and immune therapy even after the platelet count normalizes. ### Corticosteroids ISTH recommends corticosteroids in addition to TPE for acute iTTP.[3] Exact regimens vary. Common specialist strategies include high-dose oral prednisone/prednisolone or IV methylprednisolone in severe disease, followed by tapering as clinical and ADAMTS13 response becomes established. Because comparative evidence does not establish one universally superior steroid schedule, follow the institutional TTP protocol rather than improvising prolonged therapy. ### Caplacizumab Caplacizumab binds the A1 domain of VWF and rapidly blocks VWF-mediated platelet adhesion. It shortens the period of active platelet consumption but does not suppress the anti-ADAMTS13 autoimmune process.[1-5] **Current U.S. regimen:**[5] 1. **11 mg IV** at least 15 minutes before the first plasma exchange. 2. **11 mg subcutaneously** after completion of the first exchange. 3. **11 mg subcutaneously once daily** after each subsequent plasma exchange during the exchange period. 4. After the final exchange, **11 mg subcutaneously once daily for 30 days**. 5. Continue for up to **28 additional days** when evidence of persistent underlying disease remains, including persistently suppressed ADAMTS13 activity.[5] Monitor for mucocutaneous and major bleeding. Withhold or stop when clinically important bleeding risk outweighs benefit, and coordinate any invasive procedure carefully.[5] > **Caution:** A normalized platelet count while ADAMTS13 remains severely deficient does not indicate immunologic remission. Premature caplacizumab discontinuation in that setting can be followed by recurrence. ### Rituximab Rituximab targets CD20-positive B cells and is commonly added early in acute iTTP, particularly when relapse risk is substantial or ADAMTS13 recovery is delayed.[3,6,7] A widely used regimen is: - **375 mg/m² IV once weekly for 4 doses**.[6] Some specialist protocols use accelerated four-dose schedules during acute disease. Because plasma exchange can remove rituximab, administer it after an exchange and, when feasible, allow at least several hours before the next exchange.[7] Before therapy, assess hepatitis B status and other infection risks according to the relevant biologic-therapy protocol. ## Monitoring during acute treatment ### At least daily while disease is active - platelet count; - hemoglobin; - LDH; - bilirubin and haptoglobin as needed; - creatinine and electrolytes; - neurologic status; - bleeding assessment; - cardiac rhythm in high-risk patients; - troponin when myocardial involvement is present or suspected.[3,4] ### ADAMTS13 Repeat ADAMTS13 during recovery according to local TTP-center practice. Persistent severe deficiency is a marker of continuing autoimmune disease and should influence caplacizumab duration and immune therapy.[1-4] ### Response terminology Clinical response requires correction of the acute TMA phenotype, not merely a transient platelet rise. Escalate when there is: - recurrent thrombocytopenia after initial improvement; - persistent or recurrent MAHA; - new neurologic or cardiac ischemia; - failure of platelet recovery despite adequate TPE and immune therapy; - persistently severe ADAMTS13 suppression with ongoing clinical activity. ## Refractory or worsening disease Confirm that the patient is receiving uninterrupted effective TPE, adequate immunosuppression, and caplacizumab when appropriate. Reassess for: - delayed or missed exchanges; - occult infection; - competing TMA diagnosis; - pregnancy-associated disease; - drug-associated TMA; - complement-mediated HUS; - severe hypertension; - ongoing autoimmune activity.[3,4] Specialist rescue strategies may include intensified B-cell/plasma-cell–directed therapy in selected cases. Such approaches are not routine first-line care and should be managed by an experienced TTP center. ## Pregnancy and postpartum disease Pregnancy can trigger either immune or congenital TTP and overlaps clinically with preeclampsia/HELLP and complement-mediated TMA. ADAMTS13 testing is crucial when thrombocytopenia and MAHA are disproportionate, occur early in pregnancy, persist after delivery, or are accompanied by neurologic features.[3,4] When iTTP is strongly suspected during pregnancy, urgent TPE and corticosteroid-based specialist therapy should not wait for final confirmatory testing. Caplacizumab and other immune therapies require individualized maternal-fetal risk assessment because pregnancy evidence is limited. A history of TTP warrants preconception hematology review and serial ADAMTS13 monitoring during pregnancy because biochemical relapse can precede overt hematologic recurrence. ## Pediatric patients iTTP is rare in children. Management should involve pediatric hematology and a center with TTP/apheresis expertise. U.S. caplacizumab labeling now includes acquired TTP in patients aged **≥12 years** in combination with plasma exchange and immunosuppression.[5] Younger children require specialist individualized therapy because regulatory labeling and evidence differ. ## Disposition Acute iTTP requires admission to a hospital capable of urgent plasma exchange and specialist hematology care. Intensive-care placement is favored for: - altered consciousness or seizure; - significant cardiac injury or arrhythmia; - hemodynamic instability; - major bleeding; - respiratory failure; - severe multiorgan dysfunction; - rapidly progressive disease.[3,4] Transfer should not create avoidable interruption in TPE. Coordinate plasma therapy, transport timing, and receiving-center readiness. ## Remission and long-term follow-up Clinical remission does not eliminate relapse risk. Follow-up should include:[1,3,8,9] - serial ADAMTS13 activity; - CBC when clinically indicated or when ADAMTS13 falls; - education regarding relapse symptoms; - cardiovascular risk assessment; - assessment for cognitive, mood, fatigue, and quality-of-life effects after severe disease; - pregnancy planning where relevant. Severe recurrent ADAMTS13 deficiency can precede clinical relapse. Preemptive rituximab during remission is supported as a conditional strategy in selected nonpregnant patients with persistently or recurrently low ADAMTS13 activity.[3,8] ## Complications | Complication | Recognition | Action | |---|---|---| | Ischemic stroke/seizure | Focal deficit, altered consciousness, seizure | Continue urgent TTP therapy; neurologic and critical-care support | | Myocardial injury | Troponin elevation, ECG change, arrhythmia, shock | Telemetry, cardiology/critical-care input; treat TTP urgently | | Major bleeding | Gastrointestinal, intracranial, procedural, or other significant hemorrhage | Reassess caplacizumab, hemostatic support, urgent specialist management | | [Acute kidney injury](/library/acute-kidney-injury) | Rising creatinine, oliguria | Reassess TMA subtype, optimize perfusion, renal support if needed | | Exacerbation after apparent response | Falling platelets or recurrent MAHA soon after treatment change | Resume/intensify TTP therapy and reassess ADAMTS13 | | Later relapse | Recurrent thrombocytopenia/MAHA after remission | Treat as acute iTTP and reassess immune strategy | ## Acute management checklist - Recognize thrombocytopenia plus MAHA as a TTP emergency until an alternative is established. - Draw ADAMTS13 activity and antibody/inhibitor testing before plasma exposure when feasible. - Do not wait for the ADAMTS13 result when pretest probability is high. - Start TPE plus corticosteroids urgently. - Add caplacizumab early when iTTP is strongly suspected and the local pathway supports it. - Add rituximab early in the specialist treatment plan. - Obtain ECG and troponin; monitor neurologic status closely. - Avoid routine platelet transfusion. - Track platelet count, LDH, hemolysis, organ injury, and ADAMTS13 recovery. - Stop TPE only after sustained clinical response, not after a predetermined number of days. - Extend caplacizumab when autoimmune activity remains evident, including persistent severe ADAMTS13 suppression. - Arrange long-term ADAMTS13 surveillance after remission. ## Recent practice updates The **2025 ISTH focused update** reviewed newer evidence and retained the established 2020 treatment approach for iTTP; its major recommendation change involved congenital TTP.[8] Caplacizumab is now labeled in the United States for adults and pediatric patients aged ≥12 years with acquired TTP in combination with plasma exchange and immunosuppression.[5] In **August 2026**, the British Society for Haematology published updated laboratory guidance emphasizing standardized ADAMTS13 activity, antibody, antigen, and monitoring processes and the role of experienced laboratories in rapid TTP diagnosis.[9] ## Related library topics - [Systemic Lupus Erythematosus](../rheumatology/systemic-lupus-erythematosus.md) - [Preeclampsia and Eclampsia](../obstetrics-gynecology/preeclampsia-and-eclampsia.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Acute Ischemic Stroke](../neurology/acute-ischemic-stroke.md) ## References 1. Zheng XL, Vesely SK, Cataland SR, et al. **ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2020;18:2486-2495. DOI: 10.1111/jth.15006. PMID: 32914582. https://pmc.ncbi.nlm.nih.gov/articles/PMC8146131/ 2. Zheng XL. **The standard of care for immune thrombotic thrombocytopenic purpura today.** *J Thromb Haemost.* 2021;19:1866-1871. DOI: 10.1111/jth.15407. PMID: 34173673. 3. Zheng XL, Vesely SK, Cataland SR, et al. **ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2020;18:2496-2502. DOI: 10.1111/jth.15010. PMID: 32914581. https://pmc.ncbi.nlm.nih.gov/articles/PMC8091490/ 4. Joly BS, Coppo P, Veyradier A. **Thrombotic thrombocytopenic purpura.** *Blood.* 2017;129:2836-2846. DOI: 10.1182/blood-2016-10-709857. PMID: 28416507. 5. U.S. Food and Drug Administration. **Caplacizumab-yhdp injection: prescribing information.** Revised 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761112s010lbl.pdf 6. Scully M, McDonald V, Cavenagh J, et al. **A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.** *Blood.* 2011;118:1746-1753. DOI: 10.1182/blood-2011-03-341131. PMID: 21636861. 7. NHS England. **Rituximab for the treatment of acute thrombotic thrombocytopenic purpura: clinical commissioning policy.** 2022. https://www.england.nhs.uk/publication/rituximab-for-the-treatment-of-acute-thrombotic-thrombocytopenic-purpura/ 8. Zheng XL, Cataland SR, Coppo P, et al. **2025 focused update of the 2020 ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.** *J Thromb Haemost.* 2025;23:3711-3732. DOI: 10.1016/j.jtha.2025.06.002. PMID: 40533296. https://pubmed.ncbi.nlm.nih.gov/40533296/ 9. British Society for Haematology. **Diagnosis and monitoring of thrombotic thrombocytopenic purpura: Guidance for laboratories and for clinical collaboration between laboratories and TTP specialist centres.** 2026. https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-monitoring-of-thrombotic-thrombocytopenic-purpura 10. Bendapudi PK, Hurwitz S, Fry A, et al. **Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies.** *Lancet Haematol.* 2017;4:e157-e164. DOI: 10.1016/S2352-3026(17)30026-1. PMID: 28259520. 11. Li A, Khalighi PR, Wu Q, Garcia DA. **External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment.** *J Thromb Haemost.* 2018;16:164-169. DOI: 10.1111/jth.13882. 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