Blood & Lymphoreticular

Thrombotic thrombocytopenic purpura: pentad and plasma exchange

Clinical Overview and When to Suspect TTP

— Loss of ADAMTS13 → ultralarge vWF multimers → platelet-rich microthrombi in arterioles/capillaries → mechanical RBC shearing, consumptive thrombocytopenia, ischemic end-organ injury.

— Immune TTP (iTTP, ~95%): autoantibody against ADAMTS13. Female predominance, peak age 30–50, often idiopathic but triggered by infection, pregnancy, HIV, lupus, drugs (clopidogrel, ticlopidine, quinine, gemcitabine, cyclosporine, tacrolimus).

— Congenital TTP (Upshaw-Schulman): ADAMTS13 gene mutation; presents in infancy or unmasked by pregnancy.

— Microangiopathic hemolytic anemia (MAHA) with schistocytes on smear, AND

— Thrombocytopenia (typically platelets 10–30 ×10⁹/L), AND

— No alternative explanation (DIC, malignant HTN, HELLP, mechanical valve hemolysis).

— MAHA, thrombocytopenia, neurologic changes, renal dysfunction, fever.

— Modern teaching: dyad of MAHA + thrombocytopenia without another cause = treat as TTP until proven otherwise.

Step 3 management: In the ED, a patient with new schistocytes + platelets <30k + altered mentation or focal neuro deficit gets hematology consult, ADAMTS13 level drawn before therapy, and emergent PLEX initiation within hours — do not wait for the assay to result. Empiric corticosteroids and caplacizumab are started concurrently in suspected iTTP. Delay to PLEX is the single strongest modifiable predictor of death.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) caused by severe deficiency (<10%) of ADAMTS13, the von Willebrand factor (vWF)-cleaving metalloprotease.

Two forms:

When to suspect — any adult with otherwise-unexplained:

Classic pentad (only ~5% have all five — do NOT wait for it):

Untreated mortality ~90%; with plasma exchange (PLEX), survival ~80–90%.

Presentation Patterns and Key History

— Headache, confusion, lethargy, transient aphasia, visual changes, seizures, TIA-like deficits, focal weakness, coma.

— Symptoms fluctuate hour-to-hour as microthrombi form and lyse — a key historical clue.

— Drugs: quinine (tonic water!), clopidogrel, ticlopidine, gemcitabine, mitomycin, calcineurin inhibitors, oral contraceptives, interferon, bevacizumab.

— Infection: recent viral illness, HIV status, E. coli O157:H7 exposure (points to HUS not TTP).

— Pregnancy/postpartum status — TTP can mimic HELLP/preeclampsia.

— Autoimmune: SLE, antiphospholipid syndrome, scleroderma.

— Family history of TTP/neonatal jaundice → congenital form.

— Prior episodes (iTTP relapses in 30–50% within years).

Board pearl: A woman in her 30s with fluctuating neuro deficits, bruising, and pallor after a viral URI is the prototypical stem. The exam writer wants you to act on MAHA + thrombocytopenia alone — do not be lured by the absence of fever or renal failure.

Onset: subacute over days; patients often "feel unwell" before catastrophic decompensation.

Constitutional: fatigue, malaise, low-grade fever (high fever suggests sepsis/DIC instead).

Neurologic (60–70%) — the most variable and dangerous feature:

Bleeding/petechiae: mucocutaneous bruising, epistaxis, menorrhagia, petechiae (especially lower extremities). Major hemorrhage is uncommon despite severe thrombocytopenia.

Renal: usually mild — proteinuria, hematuria, modest creatinine rise. Anuric/severe AKI argues against TTP and toward HUS or other TMA.

GI: abdominal pain, nausea, vomiting, diarrhea (mesenteric ischemia from microthrombi); pancreatitis can occur.

Cardiac: troponin elevation in up to 25%; chest pain, arrhythmia, sudden cardiac death from coronary microthrombi.

Targeted history (high-yield triggers):

Physical Exam Findings (and Hemodynamic Assessment)

— Often hemodynamically stable initially; tachycardia from anemia.

— Hypertension may occur (especially if renal involvement); profound hypotension suggests sepsis or hemorrhage and should redirect workup.

— Fever low-grade (<38.5°C); high fever + hypotension → consider DIC/sepsis/TMA mimics.

— Petechiae on lower extremities, oral mucosa, conjunctivae.

— Purpura, ecchymoses at venipuncture sites.

— No palpable purpura (would suggest vasculitis).

— Mental status fluctuations, dysarthria, hemiparesis, visual field cuts, ataxia.

— Findings can fully resolve and recur — "waxing and waning" focal deficits in a thrombocytopenic patient is TTP until proven otherwise.

— Place 2 large-bore IVs, continuous telemetry, pulse oximetry.

— Mean arterial pressure goal ≥65; cautious crystalloid — avoid volume overload before PLEX (large plasma volumes coming).

— Baseline weight, daily I/Os.

CCS pearl: Order in this sequence: CBC with smear, BMP, LDH, haptoglobin, total/indirect bilirubin, reticulocyte count, PT/PTT/fibrinogen, type & screen, troponin, urinalysis, pregnancy test, HIV, ADAMTS13 activity + inhibitor, then call hematology and the apheresis service. Document neuro exam every 2 hours. Avoid platelet transfusion unless life-threatening bleeding or pre-procedure — it can fuel thrombosis.

Vital signs:

General: pallor, jaundice (scleral icterus from hemolysis), ill-appearing but often alert between neurologic episodes.

Skin:

Neurologic exam — perform serially, document time-stamps:

Cardiopulmonary: tachycardia, flow murmur from anemia; new arrhythmia or chest pain warrants ECG + troponin.

Abdomen: mild diffuse tenderness; hepatosplenomegaly is uncommon (its presence suggests lymphoma/DIC).

Fundoscopy: retinal hemorrhages possible; absence of papilledema helps differentiate from malignant HTN.

Hemodynamic assessment in ED:

Diagnostic Workup — Initial Labs

— Thrombocytopenia, typically 10–30 ×10⁹/L (often <20); isolated — WBC usually normal.

— Anemia (Hgb often 7–9 g/dL), normocytic to mildly macrocytic from reticulocytosis.

— Schistocytes ≥1% (or >2 per high-power field) confirm MAHA.

— Helmet cells, polychromasia, nucleated RBCs, reduced platelets.

— Absence of schistocytes essentially excludes TTP — request the smear personally.

— LDH markedly elevated (often >1000; reflects both hemolysis and tissue ischemia).

— Haptoglobin undetectable.

— Indirect hyperbilirubinemia.

— Reticulocyte count elevated.

— Direct Coombs NEGATIVE (key distinguishing feature from autoimmune hemolytic anemia).

— PT, aPTT, fibrinogen normal; D-dimer mildly elevated.

— Key distinction: prolonged PT/PTT + low fibrinogen → DIC, not TTP.

— Creatinine usually <2 mg/dL in TTP; higher values suggest HUS or other TMA.

— UA: mild proteinuria, hematuria, granular casts.

— Pregnancy test (β-hCG) in all reproductive-age women.

— HIV, hepatitis B/C, ANA — screen for triggers.

— Blood cultures if febrile.

— Type & crossmatch (anticipating PRBC transfusion and PLEX volume).

Board pearl: The diagnostic quartet for TTP at presentation: thrombocytopenia + schistocytes + ↑LDH + normal coags. If fibrinogen is low, you are dealing with DIC; if Coombs is positive, you are dealing with Evans syndrome. Memorize this triage logic — it is the most common Step 3 distractor pattern.

CBC:

Peripheral smear — the cornerstone:

Hemolysis labs:

Coagulation panel — normal in TTP:

Renal/metabolic:

Cardiac: troponin (prognostic — elevation associated with worse outcome and need for intensified therapy), ECG.

Other essentials:

Diagnostic Workup — Confirmatory Studies

— <10% activity confirms TTP (essentially pathognomonic in the right clinical setting).

— Draw before PLEX or plasma infusion (exogenous plasma replenishes the enzyme and obscures results).

— Turnaround typically 1–5 days at reference labs — do not delay treatment waiting on it.

— Positive in immune TTP, negative in congenital.

— Guides duration of immunosuppression and relapse risk monitoring.

— Platelets <30, hemolysis (retic >2.5%, undetectable hapto, indirect bili >2), no active cancer, no transplant, MCV <90, INR <1.5, creatinine <2.

— Score 6–7 = high probability (>70%) → initiate PLEX empirically.

— Score 5 = intermediate; 0–4 = low.

— Stool studies for Shiga toxin / E. coli O157:H7 if diarrhea (HUS).

— Complement studies (C3, C4, CH50, factor H/I, MCP) if atypical HUS suspected.

— ANA, dsDNA, antiphospholipid antibodies (lupus-associated TMA).

— Blood cultures, procalcitonin (sepsis-DIC).

— Pregnancy-specific labs: LFTs, uric acid, urine protein:creatinine (HELLP/preeclampsia).

— CT head if focal neuro deficits — exclude hemorrhage before anticoagulation/PLEX line placement, but do not delay PLEX for non-essential imaging.

Step 3 management: Use PLASMIC + clinical gestalt to commit to PLEX within hours. Document ADAMTS13 draw time and pre-treatment sample storage. Send a peripheral smear with a hematologist's read — the report drives the apheresis call.

ADAMTS13 activity assay — the confirmatory test:

ADAMTS13 inhibitor titer / anti-ADAMTS13 IgG:

PLASMIC score (pretest probability tool) — 7 variables:

Additional testing to exclude mimics:

Imaging: generally not required for diagnosis; brain MRI may show punctate ischemic lesions.

Risk Stratification and First-Line Management Logic

— 1. Therapeutic plasma exchange (PLEX) — daily until platelets >150 ×10⁹/L for 2 consecutive days and LDH normalizing.

— 2. Corticosteroids — methylprednisolone 1 g IV daily × 3 days, then prednisone 1 mg/kg/day taper; or high-dose pulse for severe disease.

— 3. Caplacizumab — anti-vWF nanobody; reduces time to platelet recovery, exacerbations, refractory disease, and TTP-related mortality.

— Indicated for refractory/relapsing iTTP, persistent low ADAMTS13 despite remission, or upfront in high-risk patients.

— Reduces relapse rate; standard 375 mg/m² weekly × 4 doses.

— High-risk features: troponin elevation, severe neuro deficits (coma/seizure), age >60, LDH >10× ULN, very low ADAMTS13 with high inhibitor titer.

— These patients warrant ICU admission, twice-daily PLEX, and earlier rituximab/caplacizumab.

— Avoid prophylactic platelet transfusion — associated with worsened thrombosis and possible death; reserve for life-threatening hemorrhage or pre-line/procedure.

— Avoid antiplatelets/anticoagulants during severe thrombocytopenia.

— Do not delay PLEX waiting for ADAMTS13 results.

CCS pearl: On a CCS case, the high-yield order set is "plasma exchange daily, methylprednisolone IV, caplacizumab, hematology consult, ICU admit, hold platelet transfusion." Advancing the clock without PLEX initiated will tank your management score.

Treat empirically in any patient with MAHA + thrombocytopenia + no clear alternative — survival depends on rapid PLEX initiation.

The treatment triad for immune TTP:

Rituximab — anti-CD20:

Severity stratification:

What NOT to do:

If PLEX not immediately available: give plasma infusion (FFP 25–30 mL/kg/day) as a bridge until apheresis available — transfer to a center with apheresis.

Pharmacotherapy — First-Line Regimen Detail

— Methylprednisolone 1 g IV daily × 3 days for severe disease, then transition to prednisone 1 mg/kg/day (or 1.5 mg/kg for refractory).

— Taper over 4–8 weeks guided by platelet recovery and ADAMTS13.

— Monitor: glucose, BP, infection, mood, GI prophylaxis (PPI).

— Mechanism: humanized bivalent nanobody against vWF A1 domain → blocks platelet–vWF interaction.

— Dose: 11 mg IV bolus before first PLEX, then 11 mg SC daily during PLEX and 30 days after PLEX cessation (extend if ADAMTS13 still <10%).

— Reduces refractoriness, exacerbations, and TTP-related death (HERCULES trial).

— Adverse effects: mucocutaneous bleeding (epistaxis, gingival, menorrhagia) — hold for major procedures; reverse with vWF concentrate if life-threatening hemorrhage.

— 375 mg/m² IV weekly × 4 doses (frontline if severe, refractory, or relapsing).

— Premedicate with acetaminophen, diphenhydramine, methylprednisolone.

— Screen HBV (HBsAg, anti-HBc) before — risk of reactivation.

— Folate 1–5 mg PO daily (ongoing hemolysis depletes stores).

— PRBC transfusion for symptomatic anemia (Hgb <7 or symptomatic).

— VTE prophylaxis with mechanical devices while thrombocytopenic; pharmacologic once platelets >50.

— PPI while on high-dose steroids.

— Pneumocystis prophylaxis (TMP-SMX) if prolonged steroids + rituximab.

— Twice-daily PLEX, switch to cryosupernatant replacement, add/intensify rituximab, consider bortezomib, splenectomy in select cases.

Board pearl: The HERCULES-era standard of care for severe iTTP is the "PEX + steroids + caplacizumab + rituximab" quadruple regimen. Knowing caplacizumab's mucocutaneous bleeding profile and that it is held for surgery is a Step 3 favorite.

Corticosteroids:

Caplacizumab:

Rituximab:

Supportive:

Refractory disease (no platelet response after 4–7 days PLEX):

Procedural Therapy — Plasma Exchange Details

— Removes ultralarge vWF multimers and ADAMTS13 autoantibodies; replenishes functional ADAMTS13.

— Replacement fluid: plasma (FFP or solvent/detergent-treated plasma) — not albumin (lacks ADAMTS13).

— Volume: 1–1.5× total plasma volume per session (~40–60 mL/kg).

— Frequency: daily until platelets >150 ×10⁹/L for 2 consecutive days and LDH normalized, then taper or stop (no proven benefit to slow taper).

— Typically 7–14 sessions; refractory cases require twice-daily.

— Large-bore central venous catheter (dual-lumen apheresis catheter) — typically internal jugular or femoral.

— Use ultrasound guidance; correct severe thrombocytopenia risk with caution — generally proceed without platelet transfusion unless bleeding.

— Subclavian avoided (compressibility issues).

— Ionized calcium (citrate anticoagulant causes hypocalcemia — paresthesias, QT prolongation, tetany).

— Magnesium, potassium.

— Allergic/anaphylactoid reactions to plasma (urticaria, bronchospasm).

— TRALI, TACO, transfusion-transmitted infection.

— Catheter complications: pneumothorax, hematoma, infection, thrombosis.

— FFP infusion 25–30 mL/kg/day until transfer to apheresis-capable center.

— Useful for congenital TTP (provides ADAMTS13).

— Platelets >150 ×10⁹/L × 2 days, LDH near normal, resolved neuro/cardiac symptoms.

— Recurrence after stopping → restart PLEX immediately.

CCS pearl: When platelets are 12 and the patient needs an apheresis line, the right move is to proceed with US-guided IJ catheter placement, hold prophylactic platelets, and have transfusion ready for bleeding. Choosing "transfuse platelets prior to line" is a wrong-answer trap.

Therapeutic plasma exchange (PLEX) is the definitive intervention:

Prescription:

Vascular access:

Monitoring during PLEX:

Bridging when PLEX unavailable:

Discontinuation criteria:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher mortality, more cardiac involvement, more refractory disease.

— Lower threshold for ICU admission and twice-daily PLEX.

— Increased risk of steroid complications: hyperglycemia, delirium, osteoporosis, infection — start calcium/vitamin D, glucose monitoring, DEXA planning, PJP prophylaxis.

— Polypharmacy review — discontinue offending agents (clopidogrel, quinine, calcineurin inhibitors).

— Cognitive baseline often unclear → use family/collateral to gauge neuro recovery.

— Significant renal failure is atypical for TTP — reconsider diagnosis and evaluate for:

— Atypical HUS (complement-mediated): treat with eculizumab.

— Shiga toxin–HUS: supportive care, avoid antibiotics in children (increase toxin release).

— Malignant hypertension, scleroderma renal crisis, drug-induced TMA.

— If TTP confirmed with AKI: PLEX still indicated; dose-adjust adjunct drugs.

— Caplacizumab — no renal dose adjustment.

— Rituximab — no renal adjustment but monitor for tumor lysis-like cytokine release.

— Hemolysis-driven indirect hyperbilirubinemia is expected; transaminase elevation suggests ischemic hepatopathy or alternative TMA (HELLP).

— Coag factors usually preserved — abnormal coags should prompt reconsideration toward DIC.

— Steroid metabolism intact in mild–moderate disease; monitor for fluid retention in cirrhosis.

Key distinction: Cr >2 with anuria + bloody diarrhea = HUS, not TTP. Cr <2 + dominant neuro features = TTP. Both can have schistocytes; ADAMTS13 activity differentiates them and dictates whether PLEX or eculizumab is the right move.

Elderly (>60 years):

Renal impairment:

Hepatic impairment:

Dialysis patients: schedule PLEX and HD on alternating days; HD removes some anticoagulants and electrolytes affecting both procedures.

Special Populations — Pregnancy and Pediatrics

— Pregnancy is a recognized trigger (rising vWF + falling ADAMTS13 in 2nd/3rd trimester).

— Can present at any trimester or postpartum; often unmasks congenital TTP.

— Differential is critical: HELLP, preeclampsia, AFLP, aHUS, APS catastrophic, lupus flare.

— HELLP: hypertension, proteinuria, ↑LFTs, platelets usually >20k, ADAMTS13 mildly low but not <10%, resolves with delivery.

— TTP: severe ADAMTS13 deficiency, often before 20 weeks, neuro-dominant, does not resolve with delivery.

— Management: PLEX is safe and indicated; steroids safe; caplacizumab data limited but used; rituximab generally avoided in pregnancy (especially 1st trimester) — defer if possible.

— Continue PLEX prophylactically through pregnancy in congenital TTP; FFP infusions every 2–3 weeks in later pregnancy.

— Multidisciplinary care: hematology, MFM, neonatology, apheresis.

— Rare; congenital TTP more common in this age group.

— Present with neonatal jaundice, recurrent thrombocytopenia, strokes.

— Treatment: scheduled FFP infusions every 2–3 weeks (provides ADAMTS13); PLEX for acute episodes; recombinant ADAMTS13 (apadamtase alfa) FDA-approved for congenital TTP — replaces plasma infusions.

— In acquired pediatric iTTP, PLEX + steroids ± rituximab as adults.

Step 3 management: A 28-year-old at 18 weeks gestation with platelets 18k, schistocytes, ADAMTS13 <5%, no hypertension → diagnose TTP (not HELLP), initiate PLEX + steroids, continue pregnancy, MFM co-management. Do not deliver — TTP does not resolve with delivery.

Pregnancy-associated TTP:

Pediatrics:

Postpartum follow-up: ADAMTS13 monitoring, contraception counseling (avoid estrogens), pre-conception counseling for future pregnancies — high recurrence risk.

Complications and Adverse Outcomes

— Stroke / intracranial hemorrhage — leading cause of acute death.

— Cardiac: arrhythmia, MI from coronary microthrombi, sudden cardiac death; troponin elevation portends worse outcomes.

— Mesenteric ischemia, pancreatitis, acute kidney injury.

— Major hemorrhage — relatively uncommon despite low platelets unless trauma or invasive procedure.

— PLEX: citrate-induced hypocalcemia (paresthesias, tetany, QT prolongation), allergic/anaphylactic reactions to plasma, TRALI, TACO, transfusion-transmitted infection, catheter complications (pneumothorax, line infection, CLABSI, thrombosis).

— Steroids: hyperglycemia, hypertension, infection, mood/psychosis, osteoporosis, avascular necrosis, adrenal suppression.

— Caplacizumab: mucocutaneous bleeding (epistaxis, gum, GI, GU); held 7 days pre-elective surgery.

— Rituximab: infusion reactions, HBV reactivation, hypogammaglobulinemia, late neutropenia, PML (rare), increased infection risk.

— Cognitive dysfunction in 30–50% of survivors — memory, concentration, executive function; often unrecognized.

— Depression and PTSD common after ICU course.

— Hypertension, CKD, cardiovascular events elevated lifetime risk.

— Relapse in 30–50% of iTTP within 7–10 years; most within first 2 years.

Board pearl: Cognitive impairment after TTP is underdiagnosed — Step 3 stems may show a survivor returning with new concentration problems or fatigue and expect you to screen with MoCA, refer to neuropsychology, and re-check ADAMTS13 to exclude subclinical relapse.

Acute disease complications:

Treatment-related:

Long-term sequelae:

Mortality: ~10–20% acute mortality even with PLEX; predictors — age >60, troponin elevation, severe neuro deficits, delay to PLEX, refractoriness.

When to Escalate Care — ICU, Consult, Transfer

— Altered mental status, focal neuro deficit, seizure, coma.

— Cardiac involvement: troponin elevation, arrhythmia, hemodynamic instability.

— Severe thrombocytopenia <10 ×10⁹/L with bleeding.

— Need for central apheresis line and continuous monitoring.

— Pregnancy with TTP.

— Hematology — disease management, ADAMTS13 interpretation, immunosuppression decisions.

— Apheresis/transfusion medicine — PLEX prescription and line.

— ICU/critical care if any high-risk feature.

— Neurology for ongoing deficits or seizure.

— Cardiology if troponin/ECG abnormalities.

— Nephrology if AKI/HD overlap.

— MFM/OB in pregnancy.

— Receiving hospital lacks 24/7 apheresis capability — transfer immediately while infusing FFP as a bridge.

— Refractory disease needing tertiary expertise (rituximab, caplacizumab, recombinant ADAMTS13).

— Pediatric or pregnant patient at non-specialized center.

— Hemodynamic stability, resolved neuro deficits, platelets trending up (>50–100), tolerating PLEX without complication.

CCS pearl: When the CCS clock shows a deteriorating mental status during PLEX, the moves are: STAT CT head (rule out ICH), neurology consult, continue PLEX, optimize platelet count, hold caplacizumab if hemorrhage. Choosing "stop PLEX" without alternative cause is wrong — the disease itself is the threat.

ICU admission criteria:

Mandatory consults at presentation:

Transfer indications:

Discharge from ICU:

Step-down/floor monitoring: continuous telemetry until platelets >150 and troponin negative; daily CBC, LDH, BMP, ionized calcium, magnesium.

Key Differentials — Other Thrombotic Microangiopathies

— Children > adults; preceded by bloody diarrhea (E. coli O157:H7, Shigella).

— Dominant renal failure, often anuric; neuro features less prominent.

— ADAMTS13 normal; stool Shiga toxin / culture positive.

— Treatment: supportive care, dialysis; avoid antibiotics in children (increases toxin release); avoid antimotility agents. PLEX of unclear benefit.

— Dysregulation of alternative complement pathway (factor H, I, MCP, C3 mutations).

— Triggered by infection, pregnancy, transplant, drugs.

— Severe renal involvement; ADAMTS13 normal.

— Treatment: eculizumab or ravulizumab (anti-C5); vaccinate against meningococcus before initiation (or give prophylactic antibiotics).

— Immune (quinine, oxaliplatin) or dose-dependent toxicity (gemcitabine, mitomycin, calcineurin inhibitors, VEGF inhibitors).

— Discontinue offending agent; PLEX if severe; eculizumab in select cases.

Key distinction: ADAMTS13 <10% = TTP and PLEX. ADAMTS13 normal + renal-dominant = HUS (STEC = supportive; atypical = eculizumab). The choice of therapy is determined by this fork.

Shiga toxin–producing E. coli HUS (STEC-HUS):

Atypical HUS (aHUS, complement-mediated):

Drug-induced TMA:

Transplant-associated TMA (HSCT/SOT): often calcineurin inhibitor or GVHD related; switch immunosuppression, supportive care, ± eculizumab.

HELLP/preeclampsia: hypertension, proteinuria, ↑LFTs, mild thrombocytopenia, resolves with delivery; ADAMTS13 mildly reduced but not <10%.

Catastrophic antiphospholipid syndrome (CAPS): multi-organ thrombosis, +aPL antibodies; anticoagulate + steroids + PLEX/IVIG.

Scleroderma renal crisis: severe hypertension, AKI, MAHA; ACE inhibitors are treatment.

Key Differentials — Non-TMA Mimics

— Triggered by sepsis, malignancy, trauma, obstetric emergency.

— Prolonged PT/PTT, low fibrinogen, elevated D-dimer, thrombocytopenia, schistocytes.

— Treat the underlying cause; replace factors (FFP, cryoprecipitate, platelets) — opposite approach to TTP (which avoids platelets).

— Isolated thrombocytopenia; no MAHA, no schistocytes, normal LDH/haptoglobin.

— Treat with steroids, IVIG, TPO agonists.

— Autoimmune hemolytic anemia + ITP; Coombs POSITIVE, spherocytes (not schistocytes).

— Steroids, IVIG, rituximab.

— Platelet drop 5–10 days after heparin exposure, thrombosis (not bleeding).

— 4T score, anti-PF4 antibodies, serotonin release assay.

— Stop heparin, start argatroban/bivalirudin/fondaparinux.

Board pearl: The smear is your best friend. Schistocytes + low fibrinogen → DIC. Schistocytes + normal coags → TTP/HUS. Spherocytes + Coombs positive → AIHA/Evans. No schistocytes + isolated low platelets → ITP. This single-frame decision tree resolves most stems.

Disseminated intravascular coagulation (DIC):

Immune thrombocytopenia (ITP):

Evans syndrome:

Heparin-induced thrombocytopenia (HIT):

Sepsis with thrombocytopenia: fever, hypotension, lactate, positive cultures; treat with antibiotics + source control.

Vitamin B12/folate deficiency: pancytopenia, hypersegmented neutrophils, macrocytosis, elevated LDH and indirect bili — can mimic MAHA but smear lacks schistocytes.

Malignancy-associated: bone marrow infiltration, intravascular hemolysis from mucinous adenocarcinoma; staging workup.

Mechanical hemolysis: prosthetic valve dysfunction, severe AS — schistocytes present but platelets normal, ADAMTS13 normal.

Acute liver failure / HELLP: ↑LFTs, coagulopathy.

Secondary Prevention and Long-Term Plan

— Continue prednisone taper over 4–8 weeks guided by ADAMTS13 recovery and platelet stability.

— Caplacizumab for 30 days after PLEX cessation; extend if ADAMTS13 remains <10% (high relapse risk).

— Rituximab for relapse prevention if ADAMTS13 remains depressed (<20%) despite clinical remission — "preemptive rituximab" reduces relapse from 50% to <10%.

— Prednisone with taper schedule.

— Folate 1 mg daily while hemolysis resolves.

— Calcium/vitamin D + bisphosphonate consideration for prolonged steroids.

— PPI for GI prophylaxis on steroids.

— TMP-SMX prophylaxis for PJP if on rituximab + steroids.

— Avoid known triggers: quinine (tonic water!), clopidogrel/ticlopidine, gemcitabine, calcineurin inhibitors.

— Avoid estrogen-containing contraceptives in women — alternative contraception (progestin-only, IUD, barrier).

— Update inactivated vaccines before/2 weeks after immunosuppression peaks.

— Avoid live vaccines while on rituximab/high-dose steroids.

— Annual influenza, COVID-19, pneumococcal series.

— MedicAlert bracelet noting TTP history and steroid use.

— Patient education on relapse symptoms: fatigue, bruising, headache, neuro changes.

— Pregnancy planning: pre-conception ADAMTS13 check, MFM consultation.

Step 3 management: Discharge a TTP survivor with prednisone taper, folate, PPI, TMP-SMX (if rituximab), avoidance counseling on quinine and estrogen contraceptives, MedicAlert, hematology follow-up in 1–2 weeks, ADAMTS13 in 1 month. Missing the estrogen-OCP swap is a common exam trap.

Maintain remission:

Discharge medication checklist:

Vaccination:

Lifestyle and counseling:

Long-term cardiovascular and renal monitoring — annual BP, lipids, glucose, urine albumin:creatinine.

Follow-Up, Monitoring, and Rehabilitation

— 1–2 weeks post-discharge: CBC, LDH, BMP, smear; symptom review.

— Monthly × 3 months: same labs + ADAMTS13 activity to detect subclinical relapse.

— Every 3 months × 1 year, then every 6–12 months lifetime — relapse risk persists indefinitely.

— More frequent in pregnancy or with declining ADAMTS13.

— Platelet count: should remain >150; sustained drop triggers urgent evaluation.

— LDH: low and stable; rise heralds relapse.

— ADAMTS13: trend important — drop <20% predicts relapse months in advance and may trigger preemptive rituximab.

— Hemoglobin, haptoglobin, reticulocyte count for ongoing hemolysis.

— Steroid-related: glucose (HbA1c), BP, lipids, bone density (DEXA at 1 year).

— Cardiovascular: annual ECG, lipid panel, BP; lower thresholds for cardiac workup if chest pain.

— Screen with MoCA at 3 and 12 months — TTP survivors have high rates of cognitive impairment.

— Screen for depression (PHQ-9) and PTSD — refer to behavioral health.

— Neuropsychological evaluation if persistent dysfunction; cognitive rehab, vocational support.

— Physical therapy if deconditioned from ICU stay.

— Bruising, fatigue, headache, confusion, dark urine, scleral icterus → ED immediately.

— Provide written action plan and ED card with diagnosis history.

— Coordinate PCP for steroid taper, vaccinations, cardiovascular prevention.

— Pharmacist medication reconciliation — particularly important with rituximab and ongoing immunosuppression.

Board pearl: A drop in ADAMTS13 below 10% before clinical relapse is the strongest signal to act — preemptive rituximab prevents most relapses and is the modern standard of care.

Outpatient hematology follow-up cadence:

Monitoring parameters:

Cognitive and psychiatric rehabilitation:

Relapse recognition for patients:

Transition of care:

Ethical, Legal, and Patient Safety Considerations

— TTP patients frequently present with fluctuating mental status — capacity may be impaired at decision points (PLEX line, transfusion, ICU admission).

— Use surrogate decision-makers per state hierarchy when capacity lacking; document capacity assessment.

— For emergent PLEX, the "emergency exception" applies — life-threatening, time-sensitive — proceed and document; obtain consent retrospectively when capacity returns.

— Reassess capacity each shift; consent for new interventions when patient lucid.

— Avoid prophylactic platelet transfusion in suspected TTP — associated with worsened thrombosis and possibly death.

— When given for life-threatening bleeding or pre-procedure, document risk-benefit reasoning.

— Educate trainees and ED staff — this is a common pre-treatment error.

— Document indications, products used, reactions reported to transfusion service.

— Report TRALI/TACO/anaphylaxis to hemovigilance per institutional and FDA requirements.

— Document offending agent (quinine, clopidogrel, gemcitabine) in allergy list as "do not rechallenge" — rechallenge can be fatal.

— Report adverse drug reactions to FDA MedWatch.

— Hand-offs from ED → ICU → floor → outpatient carry high error rates; use structured tools (SBAR), explicit medication reconciliation.

— Ensure follow-up appointments arranged before discharge; verify pharmacy can fill specialty meds (rituximab, caplacizumab).

Step 3 management: A confused patient needs urgent PLEX; spouse is unavailable. Proceed under emergency exception, document, and contact next-of-kin promptly. Choosing "wait for family before initiating PLEX" is the wrong-answer trap.

Informed consent in altered patients:

Platelet transfusion controversy as a safety issue:

Mandatory blood product/transfusion reporting:

Drug-induced TTP:

Transitions of care risks:

Genetic counseling: congenital TTP is autosomal recessive — offer family screening and reproductive counseling.

Insurance/cost: caplacizumab is expensive (>$200,000/course) — engage social work, manufacturer access programs, prior authorization early.

High-Yield Associations and Rapid-Fire Facts

Board pearl: The single most life-saving action in suspected TTP is initiating PLEX within hours of recognition — every hour of delay measurably increases mortality.

Pentad (only 5% have all five): MAHA, thrombocytopenia, neuro changes, renal dysfunction, fever — act on the dyad.

ADAMTS13 <10% = TTP; >10% = consider other TMA.

Coombs NEGATIVE in TTP — distinguishes from AIHA/Evans.

Coags NORMAL in TTP — distinguishes from DIC.

Tonic water (quinine) is a classic drug trigger — patient may not consider it a "medication."

Clopidogrel, ticlopidine, gemcitabine, calcineurin inhibitors, oral contraceptives — known triggers.

HIV is associated with TTP — always test.

Pregnancy can unmask both immune and congenital TTP.

Avoid platelet transfusion unless life-threatening bleed.

PLEX with plasma replacement (not albumin).

HERCULES trial established caplacizumab benefit (faster platelet recovery, fewer exacerbations, lower TTP-related mortality).

Preemptive rituximab when ADAMTS13 drops <20% reduces relapse from ~50% to <10%.

Cognitive dysfunction in 30–50% of survivors — screen.

Congenital TTP (Upshaw-Schulman): autosomal recessive; treat with scheduled FFP infusions or recombinant ADAMTS13 (apadamtase alfa).

Splenectomy considered for refractory/relapsing disease.

STEC-HUS: bloody diarrhea, kids, anuric AKI, no antibiotics in children, supportive only.

Atypical HUS: complement-mediated; eculizumab; vaccinate against meningococcus.

HELLP: resolves with delivery; TTP does not.

Troponin elevation in TTP = high mortality predictor.

Schistocytes ≥1% on smear is diagnostic threshold for MAHA.

PLASMIC score ≥6 → empiric PLEX.

Caplacizumab adverse effect: mucocutaneous bleeding; hold 7 days before elective surgery.

Avoid estrogen-containing OCPs in TTP survivors.

Board Question Stem Patterns

— "32-year-old woman with 3 days of fatigue, headache, bruising. Hgb 8, platelets 14, creatinine 1.1, LDH 1450, haptoglobin undetectable, PT/PTT normal, smear shows schistocytes." → Answer: emergent PLEX + steroids; do not transfuse platelets.

— "Patient on quinine for leg cramps / clopidogrel after stent / gemcitabine for pancreatic cancer develops thrombocytopenia and schistocytes." → Stop the drug, initiate PLEX, document do-not-rechallenge.

— "26-year-old at 22 weeks gestation, normal BP, no proteinuria, platelets 18, schistocytes, ADAMTS13 <5%." → TTP (not HELLP); PLEX + steroids; continue pregnancy.

— "5-year-old with bloody diarrhea, anuric AKI, schistocytes, platelets 50." → STEC-HUS; supportive care, dialysis; avoid antibiotics.

— Sepsis or obstetric emergency with prolonged PT/PTT, low fibrinogen, ↑D-dimer + schistocytes → DIC, not TTP; treat underlying cause, transfuse products.

— Patient with TTP and platelets 8 needs a line; stem asks first step. Answer: ultrasound-guided line placement without prophylactic platelets.

— TTP survivor 14 months out with fatigue, headache; ADAMTS13 drops to 8%, platelets still normal → Preemptive rituximab.

— Survivor with concentration problems → MoCA, neuropsych referral, screen for depression.

— Adult, AKI dominant, ADAMTS13 normal, family history → aHUS; eculizumab + meningococcal vaccine.

— TTP survivor wants contraception → progestin-only or IUD; avoid estrogen.

Key distinction: Every TTP stem can be solved with one matrix — schistocytes? coags? Coombs? ADAMTS13? renal? trigger? Walk that matrix and the answer falls out.

Pattern 1 — The classic dyad stem:

Pattern 2 — The drug-induced stem:

Pattern 3 — The pregnancy stem:

Pattern 4 — The HUS distractor:

Pattern 5 — The DIC differentiator:

Pattern 6 — The platelet transfusion trap:

Pattern 7 — The relapse stem:

Pattern 8 — The cognitive sequela stem:

Pattern 9 — The atypical HUS stem:

Pattern 10 — The contraception stem:

One-Line Recap

TTP is a hematologic emergency defined by severe ADAMTS13 deficiency causing microangiopathic hemolytic anemia and thrombocytopenia, treated empirically with daily plasma exchange, corticosteroids, and caplacizumab within hours of recognition — do not wait for the pentad and do not transfuse platelets.

Board pearl: When in doubt, send the ADAMTS13, start the PLEX — survival in TTP is measured in hours, not days.

Recognize early: MAHA (schistocytes + ↑LDH + ↓haptoglobin) + thrombocytopenia + normal coags + negative Coombs = TTP until proven otherwise; PLASMIC score ≥6 commits you to empiric therapy.

Treat fast: PLEX daily with plasma replacement until platelets >150 ×10⁹/L × 2 days, plus high-dose steroids and caplacizumab; add rituximab upfront for severe/refractory disease or preemptively when ADAMTS13 drops <20%. Avoid prophylactic platelet transfusion — it can fuel microthrombi.

Differentiate correctly: ADAMTS13 <10% = TTP (PLEX); ADAMTS13 normal + renal-dominant = HUS (STEC supportive, atypical eculizumab); ↓fibrinogen = DIC; Coombs+ = AIHA/Evans; HELLP resolves with delivery, TTP does not.

Plan the long game: discharge with steroid taper, folate, PPI, PJP prophylaxis if on rituximab; avoid quinine and estrogen contraceptives; serial ADAMTS13 monitoring detects relapse months early; screen survivors with MoCA, PHQ-9, BP, lipids, glucose, DEXA; counsel on pre-conception MFM care given high pregnancy relapse risk.