A 34-Year-Old with Microangiopathic Hemolysis and a Normal ADAMTS13
A 34-year-old previously healthy woman presents with 4 days of fever, confusion, and petechiae. Labs: hemoglobin 7.8 g/dL, platelets 18 x10^9/L, WBC 12.4 x10^9/L, creatinine 2.1 mg/dL, LDH 1,240 U/L, haptoglobin <10 mg/dL, total bilirubin 2.8 mg/dL (indirect 2.2), INR 1.0, fibrinogen 310 mg/dL. Peripheral smear shows numerous schistocytes (estimated 6-8 per high-power field) and no platelet clumps. ADAMTS13 activity returns at 42% (ref >10%). Direct antiglobulin test is negative. Blood cultures are pending. She has no diarrhea and no known family history. The team is debating TTP versus HUS versus DIC versus a complement-mediated process.
1. How do you interpret the ADAMTS13 result, and what is your leading diagnosis? Justify using the smear, coagulation studies, and clinical picture.
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The picture is a thrombotic microangiopathy (TMA): MAHA (schistocytes, high LDH, low haptoglobin, indirect hyperbilirubinemia) plus thrombocytopenia and acute kidney injury. Key discriminators:
- ADAMTS13 42% is above the diagnostic threshold for TTP (typically <10%). A value of 42% does not exclude TTP in a partially treated or early case, but it makes severe ADAMTS13 deficiency unlikely and shifts the differential.
- Normal INR and fibrinogen with modest platelet count argue against DIC; DIC usually shows prolonged PT/INR, low fibrinogen, and elevated D-dimer.
- No diarrhea and adult age make STEC-HUS less likely, though STEC testing should still be sent (stool PCR for Shiga toxin).
- Negative DAT excludes autoimmune hemolysis and supports a microangiopathic process.
The leading diagnosis is a complement-mediated TMA (atypical HUS) or a secondary TMA (infection, drug, malignancy, autoimmune). Atypical HUS is driven by alternative complement pathway dysregulation (factor H/I, MCP, C3, or anti-factor H antibodies). The normal ADAMTS13 and prominent renal injury with MAHA fit this better than TTP. Send C3, C4, factor H, factor I, and anti-factor H antibody testing, and consider genetic complement panel. Treat empirically with plasma exchange while awaiting results if TTP cannot be excluded, but eculizumab is the targeted therapy for complement-mediated TMA once TTP is excluded.
2. The patient is started on plasma exchange. On day 3 her platelets are 45 x10^9/L and creatinine is 2.6 mg/dL. What is your next step and why?
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Platelet count rising from 18 to 45 with stable-to-worsening creatinine on plasma exchange is a partial response. In TTP, the expected response is a platelet count >150 x10^9/L and normalization of LDH; a partial rise may indicate inadequate exchange volume, need for twice-daily exchange, or an alternative diagnosis.
Given the ADAMTS13 of 42% and the renal-predominant picture, the working diagnosis remains complement-mediated TMA. Next steps:
- Confirm ADAMTS13 with a repeat and inhibitor assay if not already done; a single value can be misleading.
- Send complement studies (C3, C4, factor H/I, anti-factor H) and STEC stool PCR if not done.
- Escalate to eculizumab (meningococcal vaccination/prophylaxis first) if complement-mediated TMA is suspected and TTP is excluded. Eculizumab is effective in atypical HUS and can be started while awaiting genetic results.
- Continue supportive care: avoid platelet transfusion unless life-threatening bleeding, manage volume status, and consider renal replacement therapy if uremia or hyperkalemia develops.
- Reassess for secondary causes (drugs, malignancy, autoimmune disease, HIV, pregnancy).
3. What laboratory finding would most strongly support a diagnosis of atypical HUS over TTP in this patient, and what is the pitfall of relying on it?
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The most supportive finding is low C3 with normal C4 (isolated alternative pathway activation) or a pathogenic variant in a complement gene (CFH, CFI, MCP, C3, CFB) or anti-factor H antibodies. Low C3 with normal C4 suggests alternative pathway dysregulation, the hallmark of atypical HUS.
Pitfall: Complement levels are normal in 30-50% of atypical HUS cases, so a normal C3/C4 does not exclude the diagnosis. Genetic testing is also slow (weeks) and variants of uncertain significance are common. Conversely, ADAMTS13 activity can be >10% in TTP if the sample is drawn after plasma exchange or in mild cases, so a single value must be interpreted with timing. The decision to treat should rest on the clinical phenotype (renal-predominant TMA, no severe ADAMTS13 deficiency, no DIC) and response to therapy, not on any single test.