A 42-year-old man with a 10-year history of rheumatoid arthritis on methotrexate and sulfasalazine presents with acute-onset severe mucosal bleeding (epistaxis, hemoptysis, hematuria) and petechial rash over lower extremities. He denies recent infections or medication changes. Vital signs: BP 95/60, HR 110/min. Laboratory findings: Hb 8.5 g/dL, WBC 7,200/μL, platelet count 8,000/μL, reticulocyte count 4.2%, PT 13 sec (control 12 sec), aPTT 32 sec (control 28 sec), fibrinogen 280 mg/dL (normal 200–400), D-dimer 2.8 μg/mL (normal

Question

A 42-year-old man with a 10-year history of rheumatoid arthritis on methotrexate and sulfasalazine presents with acute-onset severe mucosal bleeding (epistaxis, hemoptysis, hematuria) and petechial rash over lower extremities. He denies recent infections or medication changes. Vital signs: BP 95/60, HR 110/min. Laboratory findings: Hb 8.5 g/dL, WBC 7,200/μL, platelet count 8,000/μL, reticulocyte count 4.2%, PT 13 sec (control 12 sec), aPTT 32 sec (control 28 sec), fibrinogen 280 mg/dL (normal 200–400), D-dimer 2.8 μg/mL (normal <0.5). Peripheral blood smear shows schistocytes. Direct antiglobulin test (DAT) is positive. What is the most likely diagnosis?

Accepted Answer

C. Thrombotic thrombocytopenic purpura (TTP). ## Clinical Presentation & Pentad Recognition

**Key Point:** Thrombotic thrombocytopenic purpura (TTP) classically presents with a pentad: (1) microangiopathic hemolytic anemia (MAHA), (2) thrombocytopenia, (3) neurological symptoms, (4) renal dysfunction, and (5) fever. However, only 5% of patients present with all five; the diagnosis rests on MAHA + thrombocytopenia [cite:Harrison 21e Ch 180].

### Why TTP?

This patient demonstrates the diagnostic triad for TTP:

1. **Microangiopathic hemolytic anemia (MAHA)**
   - Hemoglobin 8.5 g/dL (anemia)
   - Reticulocyte count 4.2% (elevated, indicating hemolysis)
   - Schistocytes on blood smear (fragmented RBCs from mechanical shearing)
   - Positive DAT (hemolysis confirmed; note: DAT may be negative in TTP but positive here, consistent with immune-mediated component or concurrent autoimmune hemolysis)

2. **Severe thrombocytopenia**
   - Platelet count 8,000/μL (severe, <30,000/μL defines severe thrombocytopenia)
   - Petechial rash and mucosal bleeding (consequences of severe thrombocytopenia)

3. **Elevated D-dimer with mild coagulopathy**
   - D-dimer 2.8 μg/mL (markedly elevated, indicating microthrombi formation)
   - Slightly prolonged PT and aPTT (consumptive coagulopathy from platelet-rich microthrombi)
   - Fibrinogen normal (rules out overt DIC, where fibrinogen is typically <100 mg/dL)

**Clinical Pearl:** The combination of schistocytes + severe thrombocytopenia + elevated D-dimer is virtually diagnostic of a thrombotic microangiopathy (TTP or hemolytic uremic syndrome [HUS]). The absence of diarrheal prodrome and presence of neurological/systemic features favor TTP over HUS.

### Pathophysiology of TTP

TTP results from deficiency of ADAMTS13 (a von Willebrand factor-cleaving protease), leading to:
1. Accumulation of ultra-large vWF multimers
2. Platelet aggregation and microthrombi formation in microvasculature
3. Mechanical RBC fragmentation (schistocytes)
4. Consumption of platelets and coagulation factors
5. Tissue ischemia (neurological, renal, cardiac manifestations)

### Differential Diagnosis Table

| Feature | TTP | HUS | DIC | ITP |
|---------|-----|-----|-----|-----|
| **Schistocytes** | **Yes** | **Yes** | **Yes** | No |
| **Thrombocytopenia** | Severe | Severe | Severe | Severe |
| **Hemolysis** | **MAHA** | **MAHA** | **MAHA** | No |
| **Coagulopathy** | Mild/absent | Absent | **Severe** | Absent |
| **Fibrinogen** | Normal/↑ | Normal | **↓↓** | Normal |
| **D-dimer** | **↑↑** | ↑ | **↑↑↑** | Normal |
| **Renal dysfunction** | Variable | **Prominent** | Variable | No |
| **Neurological symptoms** | **Common** | Rare | Possible | No |
| **Prodrome** | Viral/diarrheal | **Diarrheal (Shiga toxin)** | Sepsis/malignancy | Autoimmune |
| **Treatment** | **Plasma exchange** | Supportive | Treat underlying cause | Steroids/IVIG |

**High-Yield:** The **pentad mnemonic** for TTP is **MAHA-T**: **M**icroangiopathic hemolytic anemia, **A**cute renal dysfunction, **T**hrombocytopenia, **A**bdominal pain/neurological symptoms, **T**emperature (fever). However, diagnosis requires only MAHA + thrombocytopenia + elevated LDH + low haptoglobin + schistocytes.

### Why Not the Other Options?

**ITP:** Presents with isolated thrombocytopenia and no hemolysis (no schistocytes, normal Hb, normal reticulocyte count, negative DAT in typical ITP). Coagulation studies are normal.

**Drug-induced thrombocytopenia:** Methotrexate can cause thrombocytopenia, but it does not cause hemolytic anemia, schistocytes, or elevated D-dimer. The acute presentation with MAHA is inconsistent.

**DIC:** While DIC also presents with thrombocytopenia, schistocytes, and elevated D-dimer, it is distinguished by **severe coagulopathy** (markedly prolonged PT/aPTT, fibrinogen <100 mg/dL, low platelets). This patient has mild coagulopathy and normal fibrinogen, making DIC less likely. DIC typically follows sepsis, malignancy, or obstetric catastrophe; this patient has no such trigger.

**Mnemonic:** **MAHA-T = TTP** (Microangiopathic hemolytic anemia + Acute renal dysfunction + Thrombocytopenia + Abdominal pain/neuro + Temperature).

### Management Implication

**Urgent action:** Plasma exchange (PEX) is the definitive treatment for TTP and must be initiated immediately upon suspicion. Platelet transfusions are contraindicated (worsen microthrombi formation). ADAMTS13 activity testing (if available) confirms the diagnosis but should not delay PEX initiation.

Answer

A. Disseminated intravascular coagulation (DIC)

Answer

B. Immune thrombocytopenia (ITP)

Answer

D. Drug-induced thrombocytopenia from methotrexate

Explanation

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