How should I evaluate and manage a patient with new microangiopathic hemolytic anemia (MAHA), thrombocytopenia, elevated lactate dehydrogenase (LDH), low haptoglobin, schistocytes on peripheral smear, and impaired renal function suggestive of thrombotic microangiopathy?

Evaluation and Management of Thrombotic Microangiopathy

Immediately obtain ADAMTS13 activity level and initiate empiric plasma exchange without waiting for results if clinical suspicion is high, because untreated TTP carries >90% mortality while prompt plasma exchange raises survival to 80-90%. 1

Immediate Diagnostic Workup

The presence of MAHA (schistocytes, elevated LDH, low haptoglobin) plus thrombocytopenia plus renal dysfunction defines TMA and mandates urgent action. 2 Do not delay treatment while awaiting confirmatory tests—mortality increases with every hour of delayed plasma exchange in TTP. 1, 2

Essential First-Line Laboratory Tests (Order Stat)

• ADAMTS13 activity level and inhibitor titer – the single most critical test to differentiate TTP from other TMAs 3, 1, 2
• Complete blood count with manual peripheral smear – confirm thrombocytopenia and visualize schistocytes (>1% strongly supports TMA, but absence does not exclude early disease) 3, 2
• Hemolysis markers: reticulocyte count, indirect bilirubin, LDH (already elevated in your patient) 3, 1
• Direct antiglobulin test (Coombs) – must be negative to exclude autoimmune hemolytic anemia 3, 1
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) – must be normal or only mildly abnormal to exclude DIC 1, 2
• Complement testing (C3, C4, CH50) – low C3 with normal C4 suggests atypical HUS from alternative pathway activation 3, 2
• Creatinine and urinalysis – assess severity of renal involvement (creatinine ≥1.5 mg/dL in adults favors HUS over TTP) 1

Secondary Diagnostic Tests

• Stool culture for Shiga toxin and E. coli O157:H7 – if diarrheal prodrome present 3
• Blood pressure measurement and funduscopic examination – severe hypertension with Grade III/IV retinopathy (hemorrhages, cotton-wool spots, papilledema) indicates malignant hypertension-associated TMA 3
• Drug history review – tacrolimus, cyclosporine, sirolimus, chemotherapy agents, quinine can trigger TMA 3
• Infectious workup (EBV, CMV, HHV6, HIV) – if clinically indicated 3

Algorithmic Approach to Differential Diagnosis

Step 1: Confirm TMA Triad

• Microangiopathic hemolysis (schistocytes + elevated LDH + low haptoglobin + elevated indirect bilirubin + negative Coombs) 1, 2
• Thrombocytopenia (typically <30 × 10⁹/L in TTP, but any degree may occur) 1
• Organ dysfunction (renal, neurologic, or other) 2

Step 2: Exclude DIC

• Normal PT, aPTT, and fibrinogen exclude DIC (which shows prolonged times, low fibrinogen, markedly elevated D-dimer) 1, 2

Step 3: Determine TMA Subtype Based on ADAMTS13

ADAMTS13 Activity	Diagnosis	Key Distinguishing Features	Reference
<10%	TTP	Prominent neurologic symptoms (headache, confusion, seizures, focal deficits); renal dysfunction usually mild (Cr <1.5 mg/dL); no diarrheal prodrome	[1,4]
>10% with Cr ≥1.5 mg/dL + diarrhea	Shiga toxin HUS	Recent bloody diarrhea, more severe renal failure, less prominent neurologic features	[1,5]
>10% with low C3, normal C4	Atypical HUS	Complement dysregulation (genetic or acquired anti-factor H antibodies); no diarrhea; severe renal involvement	[1,2,4]
>10% with severe hypertension + retinopathy	Malignant hypertension TMA	BP-induced endothelial injury; only moderate thrombocytopenia and few schistocytes; improves within 24-48h with BP control	[3,2]
>10% with drug exposure	Drug-induced TMA	Recent chemotherapy, calcineurin inhibitors, or other causative drugs; no benefit from plasma exchange	[3,6]

Immediate Management Algorithm

For Suspected TTP (Before ADAMTS13 Results Available)

Grade 4 (Life-threatening: CNS hemorrhage/thrombosis, renal failure):

• Immediately initiate therapeutic plasma exchange – do not wait for ADAMTS13 results 3, 1
• Administer methylprednisolone 1 g IV daily for 3 days, with first dose given immediately after first plasma exchange 3, 2
• Urgent hematology consultation 3
• Consider rituximab for refractory cases 3
• Continue daily plasma exchange until platelet count >100-150 × 10⁹/L for 2 consecutive days 2

Grade 3 (Laboratory findings with clinical consequences: G3 thrombocytopenia, anemia, renal insufficiency):

• Hold any potentially causative drugs 3
• Hematology consultation 3
• Administer prednisone 1-2 mg/kg/day 2
• Consider hospital admission based on clinical stability 2

Grade 2 (RBC destruction with G2 anemia/thrombocytopenia but no clinical consequences):

• Hematology consultation 3
• Administer prednisone 0.5-1 mg/kg/day 3, 2
• Monitor hemoglobin weekly during steroid tapering 2

Once ADAMTS13 Results Return

If ADAMTS13 <10% (Confirmed TTP):

• Continue plasma exchange and corticosteroids as above 1, 2
• Plasma exchange is life-saving and must not be stopped prematurely 1

If ADAMTS13 >10% with severe renal dysfunction (Atypical HUS):

• Immediately initiate eculizumab: 900 mg IV weekly × 4 doses, then 1,200 mg week 5, then 1,200 mg every 2 weeks 3, 2
• Administer meningococcal vaccination and long-term penicillin prophylaxis (eculizumab increases meningococcal infection risk) 2
• Stop plasma exchange – it has no proven benefit in atypical HUS 4, 5

If ADAMTS13 >10% with severe hypertension + retinopathy:

• Initiate controlled blood pressure lowering 3, 2
• Monitor for TMA improvement within 24-48 hours – if TMA resolves with BP control, diagnosis is malignant hypertension-associated TMA 3, 2
• Do not perform plasma exchange – no benefit in hypertension-induced TMA 3

If ADAMTS13 >10% with recent drug exposure (chemotherapy, calcineurin inhibitors):

• Discontinue causative drug immediately 2, 6
• Supportive care only – plasma exchange has no known benefit in drug-induced TMA 6

Transfusion Management

Red Blood Cell Transfusion

• Transfuse only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients 2
• Do not transfuse more than the minimum necessary 2
• Use extended antigen-matched RBCs (C/c, E/e, K, Jkᵃ/Jkᵇ, Fyᵃ/Fyᵇ, S/s) if patient has sickle cell disease or prior alloimmunization 2

Platelet Transfusion

• Generally contraindicated in TTP unless life-threatening bleeding 2
• Platelet transfusion may worsen microvascular thrombosis in TTP 1

Monitoring During Acute Phase

• Daily CBC with differential, LDH, haptoglobin, creatinine 2
• Daily platelet count to guide duration of plasma exchange 2
• Neurologic examination for evolving CNS complications 1

Critical Pitfalls to Avoid

• Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically (thrombocytopenia + MAHA + schistocytes ± neurologic signs) – mortality increases with every hour of delay 1, 2
• Do not dismiss TMA based on "rare" schistocytes alone – low schistocyte counts can occur in early or evolving TMA due to low test sensitivity 2
• Do not perform plasma exchange for atypical HUS, drug-induced TMA, or malignant hypertension-associated TMA – it has no proven benefit and carries major complication risks 3, 6, 4
• Do not transfuse platelets in TTP unless life-threatening bleeding – may worsen thrombosis 1, 2
• Do not overlook malignant hypertension – always measure BP and perform funduscopy, as BP control alone can resolve TMA within 24-48 hours 3, 2