Thrombocytopenia (Harrison's Principles of Internal Medicine, 22nd Ed., Ch. 120)

Definition and Mechanisms

Thrombocytopenia results from one or more of three processes:

Decreased bone marrow production (inherited or acquired)
Sequestration - usually in an enlarged spleen
Increased platelet destruction

Key First Step: Rule Out Pseudothrombocytopenia

Before working up any low platelet count, review the peripheral blood smear to exclude pseudothrombocytopenia - an in vitro artifact from platelet agglutination caused by antibodies (usually IgG, sometimes IgM/IgA) when calcium is chelated by EDTA (the anticoagulant in purple-top CBC tubes). If a low count is found in EDTA blood, recheck with a citrate (blue-top) or heparin (green-top) tube, or examine a fresh unanticoagulated finger-stick smear.

Approach to the Patient

History, physical exam, CBC, and peripheral smear review are all essential in initial evaluation.
Overall health and medication history shape the differential - a healthy young adult has a much narrower differential than a hospitalized patient on multiple drugs.
Decreased production usually reflects a marrow disorder also affecting RBC/WBC lines. Because myelodysplasia can present with isolated thrombocytopenia, bone marrow exam is warranted in patients over 60 with isolated thrombocytopenia, or those who fail initial therapy.
Careful drug history (including OTC/herbal) is essential - drugs are the most common cause of thrombocytopenia.
Physical exam: assess for splenomegaly (may need abdominal ultrasound if subtle), chronic liver disease signs.
A platelet count of roughly 5,000-10,000/uL is needed to maintain microvascular integrity. Petechiae (pinpoint, nonblanching hemorrhages, reflecting low platelet number rather than dysfunction) appear first in dependent areas (ankles/feet). Wet purpura (oral mucosal blood blisters) signals increased risk of life-threatening hemorrhage.

Infection-Induced Thrombocytopenia

The most common noniatrogenic cause. Viral and bacterial infections cause thrombocytopenia with or without DIC (classically gram-negative sepsis, also seen in COVID-19). Mechanisms include impaired production, decreased survival, and immune-mediated destruction (e.g., infectious mononucleosis, early HIV). Late HIV infection tends toward pancytopenia with dysplastic production. In children, immune thrombocytopenia typically follows a viral illness and resolves spontaneously; this link is less clear in adults.

Drug-Induced Thrombocytopenia

Predictable dose-related suppression occurs with chemotherapy.
Classic drug-dependent antibodies react with platelet surface antigens only in the presence of the drug - notably associated with quinine and sulfonamides, though many drugs are implicated (Table 120-1 lists abciximab, acetaminophen, amiodarone, vancomycin, penicillin, quinidine, quinine, and many others).
Any suspect drug should be discontinued/substituted when a cause isn't otherwise apparent.

Heparin-Induced Thrombocytopenia (HIT)

Early recognition and prompt heparin discontinuation are key, with transition to an alternative anticoagulant if thrombotic risk outweighs bleeding risk.
Thrombosis (venous and arterial) is a major complication, even after stopping heparin - lower extremity duplex Doppler imaging is recommended to screen.
Argatroban (direct thrombin inhibitor) is effective; bivalirudin, fondaparinux, and DOACs (most experience with rivaroxaban) also appear effective, though none are FDA-approved specifically for HIT.
LMWH must not be used - HIT antibodies cross-react with it.
Anticoagulation should be considered even without documented thrombosis given the high thrombotic risk; continue 3-6 months if thrombosis occurred, otherwise at least until platelet recovery.
Warfarin should never be started alone during acute HIT/HITT - it can precipitate venous gangrene from reduced protein C/S; overlap with a DTI/fondaparinux/DOAC and start only after thrombocytopenia resolves.
VITT (vaccine-induced immune thrombotic thrombocytopenia): rare, high D-dimer, thrombosis in unusual sites (e.g., cerebral venous sinuses), ~20% fatality; treated with IVIG (to block Fc receptor-mediated platelet activation from anti-PF4 antibodies) plus a non-heparin anticoagulant.

Immune Thrombocytopenic Purpura (ITP)

Acquired immune-mediated platelet destruction, with possible impaired release from megakaryocytes.
Children: usually acute, post-infectious, self-limited.
Adults: more chronic course, though spontaneous remission can occur within months.
Secondary ITP is associated with autoimmune disease (especially SLE) or infections (HIV, hepatitis C); association with H. pylori is geographically variable.
Clinical picture: mucocutaneous bleeding (ecchymoses, petechiae, oral mucosal bleeding) or incidental finding on routine CBC, with an otherwise normal blood count and smear.

Peripheral Smear Findings (Fig. 120-1)

A: Normal peripheral blood
B: Platelet clumping (pseudothrombocytopenia)
C: Abnormal large platelet (autosomal dominant macrothrombocytopenia)
D: Schistocytes with decreased platelets (microangiopathic hemolytic anemia, e.g., TTP/HUS/DIC)
Harrison's Principles of Internal Medicine, 22nd Ed., p. 964-967

Let me know if you'd like me to go deeper into a specific subtype (e.g., TTP/HUS, immune thrombocytopenia treatment algorithms, or inherited thrombocytopenias) - the chapter continues beyond what's summarized here.

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