A 28-year-old man from endemic Assam presents with fever, headache, and myalgia for 4 days. Thick and thin blood smears confirm Plasmodium vivax malaria. He is started on chloroquine 600 mg base stat, then 300 mg at 6 hours, then 300 mg daily for 2 days, followed by primaquine 15 mg base daily for 14 days to prevent relapse. On day 5 of primaquine therapy, he develops dark urine, jaundice, and pallor. Hemoglobin drops from 13.5 g/dL to 10.2 g/dL. Reticulocyte count is elevated at 8%. What is the most likely diagnosis and the immediate next step?

Explanation

## Clinical Presentation Analysis The patient develops: - **Dark urine** (hemoglobinuria) - **Jaundice** (unconjugated hyperbilirubinemia from hemolysis) - **Pallor** (anemia) - **Rapid Hb drop** (13.5 → 10.2 g/dL in 5 days) - **Elevated reticulocyte count** (8% — appropriate bone marrow response to hemolysis) - **Temporal relationship** — symptoms appear on day 5 of primaquine therapy These findings are pathognomonic for **acute hemolytic anemia**, not hepatitis or hepatotoxicity. ## Primaquine-Induced Hemolysis in G6PD Deficiency **Key Point:** Primaquine causes **dose-dependent oxidative hemolysis** in patients with **glucose-6-phosphate dehydrogenase (G6PD) deficiency**. This is the most common pharmacogenetic adverse reaction to antimalarials worldwide. **High-Yield:** G6PD deficiency prevalence: - **Africa and Mediterranean:** 5–15% of population - **Southeast Asia (including India):** 2–10% - **Assam (Northeast India):** Higher prevalence due to genetic drift - Hemolysis occurs in ~10% of G6PD-deficient patients on standard primaquine (15 mg/day) ## Mechanism of Primaquine-Induced Hemolysis ```mermaid flowchart TD A[Primaquine metabolized to quinoneimine]:::action --> B[Oxidative stress in RBC]:::outcome B --> C{G6PD deficiency?}:::decision C -->|Yes| D[↓ NADPH production]:::outcome D --> E[↓ Glutathione reduction]:::outcome E --> F[RBC membrane oxidative damage]:::outcome F --> G[Hemolysis]:::urgent C -->|No| H[No hemolysis]:::outcome G --> I[Dark urine, jaundice, anemia]:::urgent ``` **Mnemonic for primaquine hemolysis:** **OXIDIZE** - **O** — Oxidative stress (primaquine metabolite) - **X** — X-linked (most G6PD variants are X-linked) - **I** — Immediate hemolysis (within days of starting) - **D** — Deficiency of G6PD enzyme - **I** — Intravascular hemolysis (hemoglobinuria, jaundice) - **Z** — Zero tolerance — stop drug immediately - **E** — Enzyme assay confirms diagnosis ## Immediate Management | Step | Action | Rationale | | --- | --- | --- | | **1. Stop primaquine** | Discontinue immediately | Prevent further hemolysis and RBC destruction | | **2. Supportive care** | IV fluids, monitor urine output | Prevent acute kidney injury from hemoglobinuria | | **3. Perform G6PD assay** | Spectrophotometric or fluorescent spot test | Confirm diagnosis; guides future antimalarial choice | | **4. Monitor Hb, reticulocyte, LDH, bilirubin** | Serial labs daily × 3–5 days | Track hemolysis severity and recovery | | **5. Blood transfusion** | If Hb < 7 g/dL or symptomatic | Rare; most cases self-limited | | **6. Relapse prevention** | Primaquine 45 mg base weekly × 8 weeks (low-dose regimen) after recovery, if G6PD normal; OR atovaquone-proguanil or artemisinin-based therapy if G6PD-deficient | Avoid standard 15 mg/day regimen in G6PD-deficient patients | **Clinical Pearl:** Hemolysis is **self-limited** in most cases because older RBCs (which have lower G6PD activity) are preferentially lysed, while younger RBCs (reticulocytes, with higher G6PD) survive. This is why reticulocytosis is a good prognostic sign. **Warning:** Do NOT continue primaquine with supportive care alone. The drug must be stopped to halt hemolysis. Continuing it "with monitoring" risks severe anemia, acute kidney injury, and death. [cite:KD Tripathi 8e Ch 51; Harrison 21e Ch 218]