What is the diagnosis for a patient with difficulty breathing, severe anemia (low hemoglobin (Hb)), thrombocytopenia (low platelet (plt) count), fever, leukocytosis (high white blood cell (WBC) count), and bilateral edema in the legs and hands for 2 months, with no recent travel history?

Differential Diagnosis: Thrombotic Microangiopathy vs. Severe Malaria vs. Hematologic Malignancy

This patient most likely has thrombotic microangiopathy (TMA), specifically thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic uremic syndrome (aHUS), given the constellation of difficulty breathing, severe anemia, thrombocytopenia, leukocytosis, and bilateral edema lasting 2 months. 1

Primary Diagnostic Considerations

Thrombotic Microangiopathy (Most Likely)

The triad of non-immune microangiopathic hemolysis, thrombocytopenia, and organ involvement (respiratory distress, edema suggesting renal involvement) defines TMA and fits this presentation perfectly. 1

• The 2-month duration of bilateral hand and leg edema strongly suggests chronic renal involvement, which is characteristic of aHUS 1
• Difficulty breathing may indicate pulmonary edema from fluid overload (renal failure) or metabolic acidosis 1
• Recent fever with leukocytosis could represent infection triggering TMA or secondary infection from immunocompromised state 1
• The absence of travel history makes malaria significantly less likely, though not impossible 2

Critical Immediate Actions Required

Order ADAMTS13 activity level and inhibitor titer STAT, along with peripheral blood smear to look for schistocytes, lactate dehydrogenase (LDH), haptoglobin, direct antiglobulin test (DAT), creatinine, and urinalysis for hematuria/proteinuria. 1

• If ADAMTS13 activity is <10%, this confirms TTP and requires immediate therapeutic plasma exchange plus methylprednisolone 1g IV daily for 3 days 1
• If ADAMTS13 activity is >10% with renal involvement, this suggests aHUS requiring urgent eculizumab therapy and meningococcal vaccination with penicillin prophylaxis 1
• Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically, as mortality increases with delayed treatment 1

Alternative Diagnoses to Exclude

Severe malaria remains in the differential despite no travel history, as the combination of fever, thrombocytopenia, anemia, and respiratory distress is characteristic. 2

• Immediate blood smear examination and rapid diagnostic testing for malaria parasites must be performed to definitively exclude this diagnosis 2
• Thrombocytopenia and anemia without eosinophilia are characteristic of blood-borne parasites like Plasmodium species 2, 3
• However, the 2-month duration of edema is atypical for acute malaria, which typically presents more acutely 4

Hematologic malignancy (acute leukemia, plasma cell leukemia, or hairy cell leukemia) should be considered given leukocytosis with cytopenias. 4, 5, 6

• Bone marrow examination may be needed if TMA workup is negative 1
• The presence of bilateral edema for 2 months is less typical for acute leukemia, which usually presents more acutely 4

Diagnostic Algorithm

Step 1: Immediate Laboratory Evaluation

• Complete blood count with differential to quantify thrombocytopenia, anemia severity, and characterize leukocytosis 1
• Peripheral blood smear review for schistocytes (>1% supports TMA diagnosis, but absence does not exclude early TMA) 1
• ADAMTS13 activity level and inhibitor titer (critical for TTP vs aHUS differentiation) 1
• LDH, haptoglobin, indirect bilirubin (elevated in hemolysis) 1
• Direct antiglobulin test (DAT) to exclude immune-mediated hemolysis 1
• Creatinine and urinalysis for hematuria/proteinuria (assess renal involvement) 1
• Blood smear for malaria parasites and rapid diagnostic test 2

Step 2: Severity Assessment

• Check lactate, glucose, and blood gas analysis if respiratory distress present to evaluate for metabolic acidosis 2
• Assess for severe malaria criteria: respiratory distress, severe anemia, metabolic acidosis, altered consciousness, hypoglycemia 2
• Evaluate for TMA severity: hemoglobin <7 g/dL, platelet count, presence of bleeding, renal function 1

Step 3: Management Based on Diagnosis

If TTP confirmed (ADAMTS13 <10%):

• Immediately initiate therapeutic plasma exchange 1
• Administer methylprednisolone 1g IV daily for 3 days, with first dose after first plasma exchange 1
• Continue daily plasma exchange until platelet count exceeds 100-150 × 10⁹/L for 2 consecutive days 1
• Platelet transfusion is contraindicated unless life-threatening bleeding 1
• Monitor daily CBC with differential, LDH, haptoglobin, and creatinine 1

If aHUS suspected (ADAMTS13 >10% with renal involvement):

• Begin eculizumab therapy urgently: 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks 1
• Administer meningococcal vaccination and long-term penicillin prophylaxis 1
• Test complement levels (C3, C4, CH50) to confirm complement-mediated mechanism 1

If severe malaria confirmed:

• Admit to intensive care unit immediately 2
• Administer intravenous artesunate 2
• Provide supportive care including oxygen, fluid resuscitation, and glucose monitoring 2
• Monitor for delayed hemolysis on days 7,14,21, and 28 post-treatment 2

Critical Pitfalls to Avoid

• Do not dismiss TMA diagnosis based on "rare" schistocytes alone, as low schistocyte counts can occur in early or evolving TMA 1
• Do not transfuse platelets in suspected TTP unless life-threatening bleeding, as this may worsen thrombosis 1
• RBC transfusion should only be done to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients 1
• Do not delay treatment while awaiting confirmatory testing if clinical suspicion for TTP is high 1
• The presence of thrombocytopenia and anemia does not definitively prove parasitic infection; direct parasite visualization via blood smear remains the gold standard 3

Additional Considerations

Malignant hypertension should be evaluated with blood pressure measurement and funduscopic examination, as severe blood pressure elevation with advanced retinopathy can cause TMA. 1

• Malignant hypertension-associated TMA typically shows only moderate thrombocytopenia and few schistocytes compared to TTP/HUS 1
• Blood pressure lowering will improve TMA within 24-48 hours if this is the cause 1

Review all medications for potential TMA triggers and discontinue them if possible. 1