Thrombotic microangiopathies — TTP from ADAMTS13 deficiency, HUS classically from Shiga toxin; both produce microangiopathic hemolysis with thrombocytopenia.
Also known as: TTP, HUS, thrombotic microangiopathy, TMA, STEC-HUS, atypical HUS, aHUS
Overview
Thrombotic microangiopathies (TMAs) — disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. TTP is caused by ADAMTS13 deficiency (acquired autoantibody or hereditary). HUS is most often caused by Shiga toxin (STEC-HUS, especially E. coli O157:H7); atypical HUS (aHUS) results from dysregulated complement activation.
Epidemiology
TTP: incidence ~3 per million; female:male 2:1; peak ages 30-50; Black patients overrepresented. STEC-HUS: most common cause of acute kidney injury in young children; outbreaks linked to undercooked ground beef, unpasteurized milk/juice, contaminated produce. aHUS: rare, may present at any age, often genetic complement mutations.
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Question 1HematologyMedium
A 38-year-old woman presents with a 3-day history of fatigue, scattered bruising, and intermittent confusion noted by her family. She has no recent illness, trauma, or new medications. On exam she is febrile and has petechiae over both shins; she is oriented only to person. Labs show hemoglobin 7.8 g/dL, platelets 18,000/uL, LDH 1,420 U/L, haptoglobin undetectable, and creatinine 1.4 mg/dL. PT, aPTT, and fibrinogen are normal, and the direct antiglobulin (Coombs) test is negative. A peripheral smear shows numerous schistocytes. Which of the following is the most likely diagnosis?
AWarm-type autoimmune hemolytic anemia
BThrombotic thrombocytopenic purpura
CDisseminated intravascular coagulation
DPrimary immune thrombocytopenic purpura
Reveal answer & full explanation
Correct answer: B — Thrombotic thrombocytopenic purpura
AWarm-type autoimmune hemolytic anemia
BThrombotic thrombocytopenic purpura✓
CDisseminated intravascular coagulation
DPrimary immune thrombocytopenic purpura
Why Thrombotic thrombocytopenic purpura is correct
The combination of microangiopathic hemolytic anemia (anemia, markedly elevated LDH, undetectable haptoglobin, schistocytes) plus severe thrombocytopenia with NORMAL coagulation studies and a NEGATIVE direct Coombs is the defining picture of a thrombotic microangiopathy, and the prominent neurologic involvement (confusion) with only mild renal injury points to TTP.
TTP results from severe ADAMTS13 deficiency (usually an acquired autoantibody); ultralarge vWF multimers drive platelet-rich microthrombi, causing red-cell shear and organ ischemia.
The classic pentad (hemolytic anemia, thrombocytopenia, neurologic changes, renal dysfunction, fever) is rarely complete — microangiopathic hemolytic anemia plus thrombocytopenia alone warrants treating as TTP until proven otherwise. Emergent plasma exchange plus glucocorticoids should begin before the ADAMTS13 result returns, and platelet transfusion is avoided unless there is life-threatening bleeding.
Why the others are wrong
Disseminated intravascular coagulation — also causes thrombocytopenia and schistocytes, but it prolongs the PT and aPTT, consumes fibrinogen, and raises D-dimer; the normal coagulation panel here excludes it.
Primary immune thrombocytopenic purpura — produces isolated thrombocytopenia without hemolysis, schistocytes, or organ dysfunction; the anemia, elevated LDH, and fragmented red cells are inconsistent with it.
Warm-type autoimmune hemolytic anemia — causes immune (not mechanical) hemolysis with a POSITIVE direct Coombs and spherocytes rather than schistocytes; the negative Coombs and fragmented red cells here argue against it.
Question 2HematologyMedium
A 38-year-old woman presents with fatigue, confusion, and scattered bruising over 3 days. She has had no recent diarrhea and takes no medications. Temperature is 38.1°C (100.6°F) and blood pressure is 128/78 mm Hg. Examination shows pallor, petechiae, and mild disorientation. Laboratory studies show hemoglobin 8.2 g/dL, platelet count 18,000/µL, lactate dehydrogenase 1,150 U/L, elevated indirect bilirubin, and undetectable haptoglobin. The peripheral smear shows numerous schistocytes. Which of the following laboratory findings would best support the diagnosis of thrombotic thrombocytopenic purpura?
AADAMTS13 activity level of 60 percent
BProlonged PT and PTT with low fibrinogen
CNormal PT, PTT, and fibrinogen levels
DPositive direct antiglobulin (Coombs) test
Reveal answer & full explanation
Correct answer: C — Normal PT, PTT, and fibrinogen levels
AADAMTS13 activity level of 60 percent
BProlonged PT and PTT with low fibrinogen
CNormal PT, PTT, and fibrinogen levels✓
DPositive direct antiglobulin (Coombs) test
Why Normal PT, PTT, and fibrinogen levels is correct
TTP is a thrombotic microangiopathy driven by ADAMTS13 deficiency, not by consumption of the coagulation cascade, so PT, PTT, and fibrinogen are characteristically normal.
This normal-coagulation pattern, combined with microangiopathic hemolytic anemia (schistocytes, high LDH, low haptoglobin, indirect hyperbilirubinemia) and thrombocytopenia, is the classic profile that distinguishes TTP/HUS from DIC; confirmation is ADAMTS13 activity <10%.
Per ASH 2020 TTP guidance, plasma exchange should be started on clinical suspicion (often using the PLASMIC score) without waiting for the ADAMTS13 result.
Why the others are wrong
Prolonged PT and PTT with low fibrinogen — this is the picture of DIC, where the coagulation cascade is consumed; in TTP the coagulation studies are normal, so this finding argues against TTP.
Positive direct antiglobulin (Coombs) test — indicates immune-mediated hemolysis such as autoimmune hemolytic anemia or Evans syndrome; TTP causes mechanical (shear) hemolysis, so the DAT is negative.
ADAMTS13 activity level of 60 percent — TTP is confirmed by severely deficient ADAMTS13 activity, below 10 percent; an activity of 60 percent effectively excludes TTP and redirects the workup toward HUS, DIC, or another cause of microangiopathic hemolysis.
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TTP: ADAMTS13 (von Willebrand factor-cleaving protease) deficient — acquired autoantibody (most common) or congenital (Upshaw-Schulman). Ultralarge vWF multimers accumulate, bind platelets, and form microvascular thrombi causing organ ischemia and red cell shear (schistocytes). STEC-HUS: Shiga toxin from E. coli O157:H7 (or Shigella dysenteriae) damages endothelial cells, especially in renal glomeruli, triggering platelet activation and microvascular thrombosis. aHUS: uncontrolled alternative complement activation on endothelial surfaces.
Clinical presentation
Symptoms
Classic TTP pentad (rarely all 5; even 2 of 5 in correct context warrants treatment): microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms (confusion, headache, focal deficits, seizures), renal dysfunction, fever
STEC-HUS: bloody diarrhea 3-10 days prior, then triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (often oliguric)
aHUS: similar to TTP but with more prominent renal failure and less neurologic involvement; family history
TTP/aHUS may present in pregnancy or postpartum — must differentiate from HELLP, severe preeclampsia
DAT (direct Coombs) NEGATIVE (mechanical, not immune, hemolysis)
Normal PT, PTT, fibrinogen — distinguishes from DIC
BUN/creatinine elevated, especially in HUS
ADAMTS13 activity — <10% diagnostic of TTP (send before starting plasma exchange when feasible); inhibitor assay if acquired TTP suspected
Stool culture for E. coli O157:H7 and Shiga toxin testing (STEC-HUS)
Complement studies, genetic testing for aHUS in atypical/refractory cases
Pregnancy test in any reproductive-age woman
PLASMIC score for TTP probability (ADAMTS13 deficiency likelihood)
Imaging
Head CT/MRI if neurologic symptoms (exclude hemorrhage before plasma exchange line placement)
Renal ultrasound if persistent AKI
Diagnostic algorithm
Feature
TTP
STEC-HUS
aHUS
Mechanism
ADAMTS13 deficiency
Shiga toxin (E. coli O157)
Complement dysregulation
Typical patient
Adult, F>M
Child after bloody diarrhea
Any age, often genetic
Neurologic
Prominent
Less common
Less common
Renal
Variable
Severe AKI
Severe AKI (recurrent)
Diarrhea prodrome
No
Yes (bloody)
No
Schistocytes
Yes
Yes
Yes
Coagulation
Normal PT/PTT
Normal PT/PTT
Normal PT/PTT
Diagnostic test
ADAMTS13 <10%
Stool Shiga toxin/E. coli O157
Complement studies, genetics
First-line treatment
Plasma exchange + steroids + caplacizumab
Supportive (no abx)
Eculizumab
Distinguishing the three major thrombotic microangiopathies.
Treatment
First-line
TTP (acquired): EMERGENCY plasma exchange (PLEX) — initiate as soon as TTP suspected; do not wait for ADAMTS13 result. Replaces deficient ADAMTS13 and removes autoantibody. Daily until platelet count >150K for ≥2 days
TTP: high-dose glucocorticoids (methylprednisolone 1 g IV × 3 days or prednisone 1 mg/kg) to suppress autoantibody
TTP: caplacizumab (anti-vWF nanobody) — added to PLEX + immunosuppression per HERCULES trial; reduces refractoriness and time to platelet normalization
TTP: rituximab — early addition for refractory or relapsed disease; standard adjunct in many centers
STEC-HUS: SUPPORTIVE CARE — fluid/electrolyte management, dialysis if needed, transfusion as required. AVOID ANTIBIOTICS (may increase Shiga toxin release) and AVOID antimotility agents
aHUS: eculizumab (anti-C5 complement inhibitor) — first-line; rapid response; requires meningococcal vaccination and antibiotic prophylaxis; ravulizumab (longer-acting) alternative
Avoid platelet transfusion in TTP unless life-threatening bleeding — may exacerbate microvascular thrombosis
Second-line / adjunct
TTP refractory to PLEX: increase PLEX frequency (twice daily), rituximab, vincristine, cyclophosphamide, bortezomib, splenectomy (rare)
Hereditary TTP (Upshaw-Schulman): plasma infusion (not exchange) prophylactically every 2-3 weeks; recombinant ADAMTS13 (apadamtase alfa) FDA approved 2023
aHUS refractory: continue eculizumab/ravulizumab indefinitely if genetic mutation; consider kidney transplant with continued complement blockade
Maintenance immunosuppression for relapsed acquired TTP
Complications
TTP untreated: ~90% mortality; with PLEX ~10-20% mortality
Microangiopathic hemolytic anemia + thrombocytopenia = treat as TTP/HUS until proven otherwise. Do not wait for the full pentad — most patients have only 2 or 3 features.
Plasma exchange must be initiated within hours of suspicion in TTP — mortality halves with prompt treatment.
DO NOT give platelet transfusion in TTP unless life-threatening bleeding — fuels thrombosis. (Contrast with ITP where platelet transfusion is acceptable for severe bleeding.)
PLASMIC score: high probability of severe ADAMTS13 deficiency predicts TTP — useful when ADAMTS13 result delayed.
STEC-HUS: AVOID ANTIBIOTICS — may worsen outcomes by triggering Shiga toxin release from dying bacteria. Aggressive IV fluids early reduce HUS risk in confirmed STEC infection.
Eculizumab (aHUS) requires meningococcal vaccination 2 weeks before initiation plus penicillin prophylaxis — patients are at high risk of meningococcal sepsis.
Pregnancy can precipitate both TTP and aHUS, and HELLP/severe preeclampsia mimic them — ADAMTS13 testing and delivery trial distinguish.
Caplacizumab (HERCULES trial) is a relatively new agent — anti-vWF nanobody — that reduces time to platelet normalization and refractoriness when added to standard TTP therapy.
References
ISTH 2020 — ISTH guidelines for the diagnosis and treatment of thrombotic thrombocytopenic purpura (Zheng et al., J Thromb Haemost 2020)
HERCULES Trial — Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura (Scully et al., NEJM 2019)
ASH 2020 — American Society of Hematology 2020 guidelines on thrombotic thrombocytopenic purpura (Zheng et al.)
Tarr et al. — Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome (Tarr, Lancet 2005)
Legendre et al. — Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome (NEJM 2013)
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