In a 30‑year‑old HIV‑positive woman on tenofovir, lamivudine, and dolutegravir with a platelet count of 20 × 10⁹/L, how can immune thrombocytopenia, thrombotic thrombocytopenic purpura, and drug‑induced immune thrombocytopenia be differentiated?

Differentiating ITP, TTP, and Drug-Induced Thrombocytopenia in HIV-Positive Patients

In a 30-year-old HIV-positive woman on antiretroviral therapy with severe thrombocytopenia (platelet count 20 × 10⁹/L), the differentiation hinges on peripheral blood smear findings, temporal relationship to drug exposure, and presence or absence of microangiopathic hemolytic anemia—with HIV-associated ITP being the most likely diagnosis if the smear shows isolated thrombocytopenia without schistocytes and the patient has been on stable antiretroviral therapy. 1, 2

Immediate Diagnostic Algorithm

Step 1: Confirm True Thrombocytopenia

• Repeat platelet count in citrate or heparin tube to exclude EDTA-dependent pseudothrombocytopenia, which occurs in approximately 0.1% of samples 2
• Obtain manual peripheral blood smear review by a hematopathologist immediately—this single test is the most critical differentiating step 2

Step 2: Peripheral Blood Smear Interpretation

Findings that distinguish the three conditions:

Finding	Diagnosis Suggested	Mortality Risk
Normal-sized or mildly enlarged platelets, no schistocytes, normal RBC/WBC morphology	HIV-associated ITP	Low if platelet >10 × 10⁹/L [1,2]
Schistocytes present, fragmented RBCs, polychromasia	TTP	>90% if untreated [2]
Normal platelet size, no schistocytes, temporal correlation with new drug	Drug-induced thrombocytopenia	Low after drug withdrawal [3,4]

Step 3: Essential Laboratory Tests to Perform Simultaneously

For TTP exclusion (life-threatening—must be ruled out first):

• LDH (markedly elevated in TTP) 2
• Haptoglobin (undetectable in TTP) 2
• Indirect bilirubin (elevated in hemolysis) 2
• Creatinine (renal dysfunction in TTP) 2
• ADAMTS13 activity (severely deficient <10% in TTP)—send immediately but do not wait for results to treat 2

For HIV-associated ITP confirmation:

• HIV viral load and CD4 count (thrombocytopenia may worsen with higher viral loads) 5, 6
• Direct antiglobulin test (DAT) to exclude Evans syndrome 2

For drug-induced thrombocytopenia assessment:

• Review all medications started or dose-changed in the past 1-3 weeks, including over-the-counter drugs and herbal supplements 3, 4
• Common antiretroviral culprits: none of the current regimen (tenofovir, lamivudine, dolutegravir) are strongly associated with immune thrombocytopenia 3, 4

Clinical Features That Differentiate the Three Conditions

HIV-Associated ITP

• Presentation: Gradual or sudden onset of isolated thrombocytopenia; often asymptomatic until platelet count <20 × 10⁹/L 1, 5, 6
• Physical exam: Normal except for petechiae, purpura, or mucosal bleeding; absence of splenomegaly, hepatomegaly, or lymphadenopathy (their presence excludes primary ITP) 1, 2
• Mechanism: Antibody-mediated platelet destruction plus decreased platelet production from HIV-infected megakaryocytes 5, 6
• Timing: Can occur at any stage of HIV infection, may precede other HIV manifestations 1, 5
• Response to antiretroviral therapy: Platelet count typically improves with effective viral suppression over weeks to months 1, 6

Thrombotic Thrombocytopenic Purpura (TTP)

• Presentation: Acute onset with the classic pentad (present in only 40% of cases): thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal dysfunction, fever 2
• Physical exam: Altered mental status, focal neurologic deficits, fever; may have jaundice from hemolysis 2
• Mechanism: Platelet consumption through microvascular thrombosis due to ADAMTS13 deficiency 2
• Timing: Can occur at any time in HIV infection; HIV is a known risk factor for TTP 5
• Critical distinction: Presence of schistocytes on smear is pathognomonic—their absence effectively rules out TTP 2
• Mortality: >90% if untreated; requires immediate plasma exchange 2

Drug-Induced Immune Thrombocytopenia

• Presentation: Sudden, severe thrombocytopenia (often <20 × 10⁹/L) with petechiae, bruising, epistaxis occurring 5-14 days after drug initiation 3, 4, 7
• Physical exam: Normal except for bleeding manifestations; no organomegaly 2, 4
• Mechanism: Drug-dependent antibodies against platelet glycoproteins GPIIb/IIIa or GPIb/IX 3, 4
• Timing: Typically 5-14 days after first exposure; can occur within hours if prior sensitization 3, 4
• Most common culprits: Quinine, quinidine, sulfonamides (including trimethoprim-sulfamethoxazole), vancomycin, rifampin, carbamazepine, NSAIDs 3, 4
• Response to drug withdrawal: Platelet count begins rising within 1-3 days, normalizes within 7-10 days 3, 4, 7

Specific Considerations for This Patient

Why HIV-Associated ITP is Most Likely

• Patient is on stable antiretroviral therapy (tenofovir, lamivudine, dolutegravir)—none are strongly associated with drug-induced thrombocytopenia 3, 4
• HIV itself is a well-established cause of secondary ITP, occurring in up to 40% of untreated HIV patients 1, 5, 6
• The American Society of Hematology recommends treating the HIV infection with antiretroviral therapy as first-line management before other ITP treatments unless clinically significant bleeding is present 1

Red Flags That Would Change the Diagnosis

Immediate TTP work-up required if:

• Schistocytes on peripheral smear 2
• Neurologic symptoms (confusion, headache, focal deficits) 2
• Acute kidney injury 2
• Elevated LDH with low haptoglobin 2

Drug-induced thrombocytopenia more likely if:

• New medication started 5-14 days ago 3, 4
• History of prior thrombocytopenia with same drug 3, 4
• Rapid platelet recovery (within 7-10 days) after drug withdrawal 3, 4

Management Approach Based on Diagnosis

If HIV-Associated ITP is Confirmed

First-line management:

• Optimize antiretroviral therapy to achieve viral suppression—this is the most important intervention and should be done before other ITP treatments unless life-threatening bleeding is present 1
• Monitor platelet count weekly initially 1

Indications for additional ITP treatment (if bleeding is present or platelet count <10 × 10⁹/L with bleeding risk):

• Corticosteroids (prednisone 1-2 mg/kg/day for 2-4 weeks, then taper) 1
• OR IVIg 0.8-1 g/kg as single dose (preferred if rapid rise needed) 1
• OR Anti-D immunoglobulin 50-75 μg/kg (only if Rh(D)-positive and non-splenectomized) 1

Critical pitfall to avoid: Do not use prolonged corticosteroids in HIV patients due to immunosuppression risk; short courses only 1

If TTP is Suspected (Even Without Confirmed Diagnosis)

• Initiate plasma exchange immediately—do not wait for ADAMTS13 results 2
• Mortality exceeds 90% without treatment 2
• Platelet transfusions are contraindicated in TTP (may worsen thrombosis) 2

If Drug-Induced Thrombocytopenia is Suspected

• Immediately discontinue the suspected drug 3, 4, 7
• Avoid re-exposure permanently 3, 4
• Platelet transfusion only if life-threatening bleeding (effect is short-lived due to ongoing antibody-mediated destruction) 3, 4
• Platelet count should begin rising within 1-3 days and normalize within 7-10 days 3, 4

Common Diagnostic Pitfalls to Avoid

• Never diagnose ITP without hematopathologist review of the peripheral smear—automated counters miss pseudothrombocytopenia, schistocytes, and giant platelets 2
• Never assume isolated thrombocytopenia is ITP in an HIV patient without excluding TTP—the mortality difference is catastrophic 2, 5
• Never forget to review ALL medications, including over-the-counter drugs, herbal supplements, and quinine-containing beverages (tonic water) 3, 4
• Missing the diagnosis of TTP by failing to identify schistocytes has >90% mortality 2
• Assuming drug-induced thrombocytopenia when the patient has been on stable medications for months without prior thrombocytopenia 3, 4

Quality of Life and Bleeding Risk Considerations

• Platelet count of 20 × 10⁹/L carries moderate bleeding risk—avoid contact sports, intramuscular injections, and antiplatelet agents (aspirin, NSAIDs) 8
• Risk of intracranial hemorrhage is approximately 1.5% in adults with ITP 8
• Treatment decisions should be based on bleeding severity, not platelet count alone 1, 8
• Asymptomatic patients with platelet counts >30 × 10⁹/L can often be observed without treatment 1