Differential Diagnosis

Priority Differential Diagnoses

1. Thrombotic Thrombocytopenic Purpura (TTP) - TOP PRIORITY

• TTP is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia (MAHA) + thrombocytopenia as the core dyad
• The pentad is: MAHA, thrombocytopenia, renal failure, neurologic findings, and fever - but the full pentad is now rarely required for diagnosis
• PBS should show schistocytes (fragmented RBCs) alongside polychromasia and reticulocytosis
• Pathogenesis involves deficiency of or antibodies to ADAMTS13, causing persistence of ultra-large VWF multimers that trigger platelet aggregation and microvascular thrombosis
• PT and aPTT are characteristically normal in TTP (unlike DIC)
• The leukocytosis seen here can be a reactive/stress response

2. Evans Syndrome

• Evans syndrome = autoimmune hemolytic anemia (AIHA) + immune thrombocytopenia (ITP), occurring together or sequentially
• PBS shows spherocytes (not schistocytes) with polychromasia and reticulocytosis
• Direct Coombs test is positive - this is the key differentiating feature from TTP
• Can occur in isolation or in the setting of SLE, other autoimmune diseases, or lymphoma
• The high reticulocyte count and borderline macrocytic MCV fit perfectly (large reticulocytes skew MCV up)

3. Systemic Lupus Erythematosus (SLE)

• SLE can cause hemolytic anemia, thrombocytopenia, and leukocytosis/leukopenia - all three cytopenias are part of the classification criteria
• The thrombotic microangiopathy of SLE can mimic TTP
• Antiphospholipid syndrome (APS) within SLE context can cause both thrombocytopenia and hemolysis
• Young woman of reproductive age is the classic SLE demographic
• Menorrhagia in SLE can be driven by thrombocytopenia

4. Hemolytic Uremic Syndrome (HUS)

• Like TTP, HUS is a TMA with MAHA + thrombocytopenia
• Classic HUS is preceded by bloody diarrhea (Shiga toxin-producing E. coli)
• Atypical HUS involves complement dysregulation
• Renal involvement (oliguria, elevated creatinine) is more prominent than in TTP

5. Disseminated Intravascular Coagulation (DIC)

• DIC causes thrombocytopenia and microangiopathic hemolysis from fibrin strand shearing
• Unlike TTP/HUS, DIC shows elevated PT and aPTT, low fibrinogen, elevated D-dimer
• Must look for an underlying trigger: sepsis, malignancy, obstetric complication
• The leukocytosis here could indicate sepsis as a DIC trigger

6. Megaloblastic Anemia with Immune Thrombocytopenia

• Vitamin B12 or folate deficiency causes macrocytic anemia (MCV >100), and can occasionally cause thrombocytopenia via ineffective thrombopoiesis
• However, severe megaloblastic anemia is typically a hypoproliferative state with LOW reticulocytes (not 8%)
• The high reticulocyte count here makes pure megaloblastic anemia unlikely as a primary diagnosis, though a coexisting deficiency is possible
• Could contribute to the MCV of 98 if B12/folate deficiency is mild

Summary Table

Recommended Initial Workup

1. Peripheral blood smear - look for schistocytes vs. spherocytes (this single step narrows things most)
2. Direct Coombs (DAT) - separates autoimmune (Evans, SLE) from microangiopathic (TTP, HUS)
3. LDH, unconjugated bilirubin, haptoglobin - confirm hemolysis
4. PT, aPTT, fibrinogen, D-dimer - exclude DIC
5. ADAMTS13 activity - if TTP is suspected (schistocytes + normal coags)
6. ANA, anti-dsDNA, complement - screen for SLE
7. Serum B12, folate - especially if hypersegmented neutrophils on smear
8. Renal function, urinalysis - renal involvement points to HUS or SLE

TTP is a medical emergency - if the PBS shows schistocytes and ADAMTS13 is pending, plasma exchange should not wait for the result. Early treatment reduces mortality from 85-100% to 10-30%. (Harrison's 22E)

Clinical Summary & Key Interpretation

Differential Diagnoses - Prioritized

🔴 #1 - Thrombotic Thrombocytopenic Purpura (TTP)

• Microangiopathic hemolytic anemia (MAHA) - fragmented RBCs (schistocytes) on PBS
• Severe thrombocytopenia (typically <30,000/µL)
• The classic pentad also includes: fever, neurological symptoms, renal failure - but the full pentad is not required for diagnosis

• Platelets 3,000 (below 30,000 threshold)
• Anemia with polychromasia and reticulocytosis = hemolysis
• Leukocytosis is a reactive stress response
• Reproductive-age female (TTP has a female predominance)

• Platelet count <30,000 ✓
• Evidence of hemolysis ✓
• Absence of active cancer ✓ (likely)
• Absence of transplant ✓ (likely)
• MCV <90 fL - not met here (MCV 98) - but MCV elevation is from reticulocytosis, not megaloblastic disease
• INR <1.5 ✓ (likely)
• Creatinine <2.0 ✓ (likely)

TTP is a medical emergency. If schistocytes are seen on PBS, do not wait for ADAMTS13 result. Start plasma exchange immediately. Mortality falls from 85-100% to 10-30% with treatment. (Symptom to Diagnosis 4E)

🔴 #2 - Evans Syndrome

• Primary (idiopathic)
• Secondary to: SLE, lymphoma, CLL, other autoimmune diseases

• Severe anemia with active hemolysis (reticulocytes 8%, polychromasia)
• Severe thrombocytopenia
• Leukocytosis is reactive (can also have leukocytosis in Evans)
• Young woman of reproductive age

• Warm AIHA: IgG positive ± C3
• Cold AIHA: IgG negative, C3 positive

"TTP may be distinguished from autoimmune causes of thrombocytopenia, such as Evans' syndrome (ITP and autoimmune hemolytic anemia) or SLE, by a negative result on Coombs' test." (Schwartz's Principles of Surgery 11E)

🟡 #3 - Systemic Lupus Erythematosus (SLE)

• Autoimmune hemolytic anemia (positive Coombs)
• Immune thrombocytopenia
• Lupus-associated TMA (mimics TTP)
• Antiphospholipid Syndrome (APS) causing thrombocytopenia

• Young woman (peak SLE incidence in reproductive years)
• Multi-system cytopenia
• Menorrhagia as presenting complaint

🟡 #4 - Hemolytic Uremic Syndrome (HUS)

• Also a TMA, with schistocytes on PBS
• Typical HUS: Shiga-toxin-producing E. coli (O157:H7), preceded by bloody diarrhea
• Atypical HUS: complement pathway dysregulation
• More prominent acute kidney injury than TTP
• ADAMTS13 activity is normal (unlike TTP)

🟡 #5 - Disseminated Intravascular Coagulation (DIC)

• PT and aPTT are elevated (normal in TTP/HUS)
• Low fibrinogen, high D-dimer
• Requires a trigger: sepsis (leukocytosis here could indicate infection), malignancy, obstetric complication

🟢 #6 - Vitamin B12 / Folate Deficiency with Concurrent ITP

• B12/folate deficiency causes MCV >100, pancytopenia via ineffective hematopoiesis
• However, in pure megaloblastic anemia, reticulocytes are LOW (hypoproliferative)
• An 8% reticulocyte count argues strongly against this being the primary cause
• Could co-exist (e.g., mild B12 deficiency contributing to the MCV of 98)
• PBS would show hypersegmented neutrophils and macro-ovalocytes

Summary Comparison Table

Recommended Initial Workup

1. Peripheral blood smear (PBS) - look for schistocytes vs. spherocytes vs. hypersegmented neutrophils - this is the single most informative next step
2. Direct Coombs test (DAT) - separates autoimmune from microangiopathic causes
3. LDH, unconjugated bilirubin, haptoglobin - confirm hemolysis
4. PT, aPTT, fibrinogen, D-dimer - exclude DIC
5. ADAMTS13 activity + inhibitor assay - for TTP diagnosis (do not wait for result before treating if TTP suspected)
6. ANA, anti-dsDNA, complement C3/C4 - screen for SLE
7. Serum B12, folate - particularly if hypersegmented neutrophils seen
8. Renal function, urinalysis - HUS vs TTP distinction
9. Blood culture - if sepsis/DIC considered given leukocytosis

If PBS shows schistocytes and PT/aPTT are normal, treat for TTP with plasma exchange without waiting for ADAMTS13 results. This is a time-critical decision. (Symptom to Diagnosis 4E; Harrison's 22E)