Thrombotic microangiopathies (TTP, HUS) and PNH

TMA, definition and approach

• Definition: MAHA + thrombocytopenia + organ ischemia from microvascular thrombi.
• Hallmarks: schistocytes on smear, ↑ LDH, ↓ haptoglobin, ↑ indirect bilirubin, ↑ retic, plt <150K, ↑ Cr or other end-organ injury.
• Critical first step: identify treatable causes (TTP, complement-mediated, drug-induced) early. MAHA and thrombocytopenia without an obvious cause are enough to start empiric plasma exchange while awaiting ADAMTS13 if TTP is suspected.

TMA differential, distinguishing features

• Scores (PLASMIC score, 7 items; French score, 3 items): predict severe ADAMTS13 deficiency. Schistocytes are not included in the PLASMIC or French scores because they are considered a precondition for applying the scores. A high score plus MAHA and thrombocytopenia without an obvious cause is enough to start plasmapheresis.

Thrombotic thrombocytopenic purpura (TTP)

• Epidemiology and course: if untreated, mortality is 98%. More common in females and African-Americans, ~3 per million, peak age 30. Do not wait for the classic pentad to treat.
• Renal and coags: Cr is normal in ~50% and rarely >2.2; coags are almost always normal.
• Workup adjuncts: consider MRI brain if neurologic symptoms; stool studies if bloody diarrhea (Shiga toxin).
• Pathophysiology: vWF is secreted from endothelium as long (ultra-large) multimers, and ADAMTS13 is the enzyme that cleaves these multimers. In TTP ADAMTS13 is absent or very low (congenital, or due to an autoantibody), so vWF complexes accumulate and form clots with platelets, leading to tissue ischemia and thrombocytopenia (from platelet consumption in the clots).
• ADAMTS13 caveat: blood transfusion can falsely elevate ADAMTS13, so a level >10% does not exclude TTP; if ADAMTS13 is normal or only mildly low, consider an alternative diagnosis.
• Acquired (immune) TTP: autoantibody to ADAMTS13. Female-predominant, African-American predominance. Triggers: pregnancy, infection, drugs (ticlopidine), autoimmune disease. Clopidogrel causes TMA usually with ADAMTS13 >10%, not autoantibody TTP. Note: quinine, gemcitabine, and calcineurin inhibitors cause drug-induced TMA with ADAMTS13 usually >10%, not autoantibody TTP.
• Congenital TTP (Upshaw-Schulman): ADAMTS13 mutations; recurrent episodes triggered by stress or pregnancy.
• Classic pentad (often incomplete, do not wait for all 5): MAHA with schistocytes; thrombocytopenia; neurologic abnormalities (confusion, headache, focal deficits, seizure, coma); renal dysfunction (usually mild vs HUS); fever.
• Modern diagnostic approach: MAHA + thrombocytopenia without an alternative explanation + ADAMTS13 <10%.

TTP, initial treatment

• 1. Plasma exchange (PEX): the cornerstone. Goal is to remove anti-ADAMTS13 autoantibodies, replace ADAMTS13 (present in FFP), and remove large vWF multimers. Daily until platelets >150K for 2 consecutive days.
  • Jehovah's Witness: if the patient cannot accept plasma, consider factor VIII concentrates that are plasma-derived and contain sufficient ADAMTS13 (e.g., Koate-DVI). If PEX cannot be used at all, give caplacizumab, high-dose steroids, and rituximab.
• 2. Immunosuppression (corticosteroids + rituximab): targets anti-ADAMTS13 antibody production.
  • Corticosteroids: prednisone 1 mg/kg daily if no high-risk features. If no platelet response in 3 to 4 days (refractory), switch to methylprednisolone 1000 mg/day until response is seen (or for 3 days). If high-risk TTP (neurologic or cardiac abnormalities, elevated troponin), start with methylprednisolone 1000 mg/day and switch to prednisone 1 mg/kg once platelets or neurologic symptoms respond (or give 3 days of methylprednisolone). Continue prednisone 1 mg/kg after platelets improve, then taper over 2 to 3 weeks once ADAMTS13 is >20 to 30% (check ADAMTS13 weekly in the acute phase).
  • Rituximab: depletes B cells producing anti-ADAMTS13 antibody. Dose 375 mg/m2 weekly x4 (some data support lower or biweekly dosing).
    • De novo TTP (upfront): rituximab with daily PEX started within 3 days of presentation lowered relapse (10% vs 57%, p=0.011) and inpatient stay (-7 days, p=0.04, ICU patients excluded) (Scully et al). PEX can remove ~60% of rituximab, but rituximab still raises ADAMTS13; to maximize benefit, give it 24 hours before the next plasma exchange.
    • R/R TTP: ORR 80 to 100%, relapse 12.5% vs 42.8% (Page, 2016).
    • During remission with an ADAMTS13 relapse: see clinical course below.
  • Other immunosuppression: cyclosporine, vincristine, cyclophosphamide, splenectomy (very effective but high morbidity, especially in the acute phase), bortezomib (plasma-cell-directed). Adjuncts (not immunosuppressants): N-acetylcysteine (vWF-modifying) and recombinant ADAMTS13 (enzyme replacement, investigational in immune TTP).
• 3. Caplacizumab: binds the A1 domain of vWF and blocks its interaction with the platelet GPIb-IX-V glycoprotein. Faster resolution of thrombocytopenia and prevents end-organ ischemia.
  • HERCULES (Scully et al): 10 mg (US labeled dose 11 mg) IV bolus on day 1 before plasma exchange, then 10 mg SQ daily from day 1 until 30 days after the last plasma exchange. Can be extended 28 days beyond the 30 if recurrence risk is high (low ADAMTS13). With PEX and immunosuppression it shortens time to platelet recovery and decreases the composite of TTP-related death, recurrence, or major thromboembolism (12% vs 49%), driven mainly by fewer recurrences. Major adverse event is bleeding. Projected cost ~$270,000 for 4 weeks.
• Avoid platelet transfusions unless there is life-threatening bleeding (theoretical risk of fueling thrombosis).

TTP, clinical course

• Clinical response: goal is platelets >150K x 2 days and LDH <1.5x ULN. Continue PEX until platelets >150K x 2 days; most need ~7 to 10 days. Stop PEX abruptly (do not taper, no benefit) and continue immunosuppression. Monitor daily CBC for 3 to 5 days after stopping PEX; if no exacerbation, remove the catheter and monitor CBC every 2 to 3 days while continuing immunosuppression. Monitor ADAMTS13 weekly; once >20 to 30%, taper prednisone over 2 to 3 weeks and stop caplacizumab (the package insert states to continue it for 30 days after the last PEX). Give rituximab 375 mg/m2 weekly x4 regardless of response. Clinical remission = clinical response for ≥30 days after stopping PEX and caplacizumab, or partial (>20%) or complete (>60% or >LLN) ADAMTS13 remission. Once in remission, monitor ADAMTS13 monthly, then less often if >60% and more often if 40 to 60% or <40%.
• Refractory TTP (no clinical response): no platelet recovery and ADAMTS13 <10% despite treatment. Continue PEX, increase steroids to methylprednisolone 1000 mg daily for 3 days (or until response), and continue or start rituximab and caplacizumab (give other immunosuppression if caplacizumab cannot be used). Reevaluate for other causes (infection, malignancy, drug-induced TMA), especially if ADAMTS13 was >10% before PEX.
• TTP exacerbation: platelet drop (often with rising LDH) within 30 days of stopping PEX or anti-vWF therapy (caplacizumab), after response but before remission, usually 3 to 5 days after. Restart PEX (same volume), continue steroids, and add rituximab and caplacizumab if not already given. Caplacizumab is the only treatment shown to prevent exacerbation.
• Clinical relapse: recurrence of thrombocytopenia (platelets <150K) ≥30 days out with ADAMTS13 <10%. About 50% of relapses occur in the first year, but relapse can be very remote (median 5 to 9 years), so monitor indefinitely. Before 2004 ~50% of TTP relapsed; with rituximab and more aggressive immunosuppression this dropped to ~20%, and with upfront rituximab to ~10% (Scully et al). If symptomatic with platelets <100K, start PEX, steroids, rituximab, and caplacizumab. If asymptomatic with platelets 100 to 150K, consider further workup before treating. Rituximab can be omitted if the patient previously responded poorly to it, did well on PEX and steroids alone, recently completed rituximab, is in the 2nd or 3rd trimester, is on other immunosuppression, or has HBV.
• Multiple clinical relapses: maintenance rituximab 375 mg/m2 every 3 months for 2 to 3 years, and consider splenectomy.
• ADAMTS13 relapse: ADAMTS13 <20% (or <10%) after an ADAMTS13 remission, with a normal platelet count and no symptoms. Use a preemptive rituximab strategy: a single dose of rituximab 375 mg/m2, and if ADAMTS13 recovers to >40% within one month, no further doses; if it remains <40% after the first dose, give 3 more weekly doses. Relapse is lower with preemptive rituximab than historical controls (15% vs 74%) (Jestin et al, Blood 2018).

TTP, severe features and survivorship

• Severe features of TTP (any one): neurologic abnormalities (seizures, focal weakness, aphasia, dysarthria, confusion, coma); symptoms suggesting encephalopathy; high serum troponin; or thrombocytopenia due to TTP that does not improve after 2 to 3 days of TPE, glucocorticoids, and rituximab.
• Survivor morbidity: TTP survivors have high rates of hypertension, obesity and lupus, stroke (13.1% vs 2.6% expected in an age- and sex-matched population), depression and PTSD, neurocognitive deficits, and impaired quality of life.
• Silent cerebral infarcts: the NeST study (Johns Hopkins) showed that 50% of patients with TTP in remission develop silent cerebral infarcts, which were associated with cognitive impairment and depression.
• Congenital TTP: plasma infusion (replaces ADAMTS13). Apadamtase alfa (Adzynma), recombinant ADAMTS13, FDA-approved November 2023.

Hemolytic uremic syndrome (HUS)

• Typical (STEC) HUS: Shiga toxin-producing E. coli (O157:H7 most common; other STEC strains; rarely Shigella). Bloody diarrhea, then MAHA + thrombocytopenia + AKI about 5 to 7 days later.
• Pediatric predominance (children, especially <5).
• Treatment: supportive (fluids, transfusion, dialysis if needed). Avoid antibiotics in children, which may worsen disease by increasing Shiga toxin release.
• Eculizumab: role in STEC-HUS is controversial but considered if severe or atypical features.

Atypical HUS (aHUS)

• Pathophysiology: complement dysregulation, mutations in CFH (most common), CFI, MCP, C3, CFB, or anti-CFH antibodies.
• Triggers: pregnancy, infection, surgery, malignancy, organ transplantation.
• Diagnosis of exclusion: MAHA + thrombocytopenia + AKI after excluding severe ADAMTS13 deficiency, STEC, and secondary TMAs; normal complement or negative genetics do not exclude aHUS and are not required before treatment. Genetic and complement panel.
• Treatment:
  • Eculizumab (Soliris): anti-C5 mAb. IV 900 mg weekly x4, then 1200 mg q2wk.
  • Ravulizumab (Ultomiris): long-acting anti-C5, q8wk. FDA-approved for aHUS 2019.
  • Vaccinate against Neisseria meningitidis (ACWY + B) at least 2 weeks before starting eculizumab (pneumococcus and Hib by age or risk); penicillin prophylaxis x2 weeks after vaccination.
  • Duration: lifelong vs monitored discontinuation per recent data; relapse risk is highest with CFH mutations.

Paroxysmal nocturnal hemoglobinuria (PNH)

• Pathophysiology: somatic PIGA mutation in a hematopoietic stem cell, loss of GPI-anchored proteins (CD55, CD59) on the cell surface, uncontrolled complement activation, intravascular hemolysis and thrombosis.
• Triad: intravascular hemolysis (LDH markedly up, hemoglobinuria, low haptoglobin), thrombosis (especially hepatic vein / Budd-Chiari, splenic, mesenteric, cerebral), and bone marrow failure (overlap with aplastic anemia).
• Diagnosis: flow cytometry: RBCs with CD59 (+/- CD55, CD235a gating); granulocytes/monocytes with FLAER (fluorescent aerolysin binds the GPI anchor) plus CD24/CD14.
• Clones: clone size predicts severity; >50% PNH granulocytes increases thrombosis risk.
• Classical PNH: hemolysis and thrombosis without overt marrow failure. PNH with aplastic anemia: often a small subclinical clone not needing complement inhibition, but clone size varies; use complement inhibition if clinically significant hemolysis or PNH-related thrombosis. Subclinical PNH: clone detected without clinical hemolysis.

PNH, complement inhibitor therapies

• Before any complement inhibitor: meningococcal ACWY + B (at least 2 weeks prior, with boosters). Pneumococcal and Hib are required for proximal inhibitors (pegcetacoplan, iptacopan, danicopan) and given by age or risk for C5 inhibitors. Antibiotic prophylaxis x2 weeks post-vaccination. Educate patients on infection signs.
• Clinically significant extravascular hemolysis on a C5 inhibitor: consider switching to a C3 inhibitor (pegcetacoplan), oral Factor B inhibitor (iptacopan), or adding a Factor D inhibitor (danicopan).
• Thrombosis prophylaxis: controversial; do not use aspirin for PNH thromboprophylaxis; prior thrombosis requires therapeutic anticoagulation plus complement inhibition; primary anticoagulant prophylaxis is individualized (large clone) when complement inhibition is unavailable. Complement inhibition significantly reduces thrombosis risk.
• Curative: allogeneic HSCT (younger patients with severe disease, especially with concurrent marrow failure).

High yield

• TTP: severe ADAMTS13 deficiency (<10%); immune TTP has an anti-ADAMTS13 autoantibody, congenital TTP has biallelic ADAMTS13 mutations. Start PEX before the ADAMTS13 result. ADAMTS13 >10% does not exclude TTP (transfusion can falsely raise it).
• Modern TTP quad: PEX + steroids + caplacizumab + rituximab. Give rituximab 24 hours before the next PEX.
• Preemptive rituximab for an ADAMTS13 relapse cuts clinical relapse (15% vs 74%).
• Caplacizumab is the only agent shown to prevent exacerbation.
• Avoid platelet transfusions in TTP unless life-threatening bleeding.
• STEC-HUS in children: supportive only; antibiotics can worsen it by increasing Shiga toxin release.
• aHUS: complement dysregulation, eculizumab/ravulizumab, vaccinate against meningococcus.
• PNH triad: hemolysis + thrombosis (atypical sites) + cytopenia/aplasia overlap; splanchnic vein thrombosis with hemolysis should prompt PNH testing.
• Apadamtase alfa (Adzynma), first recombinant ADAMTS13, FDA November 2023 for congenital TTP. Iptacopan (Dec 2023) first oral monotherapy for PNH; crovalimab (Piasky, Jun 2024) SC monthly anti-C5; danicopan (Mar 2024) add-on to ravulizumab or eculizumab for extravascular hemolysis.