Thrombocytopenia

Thrombocytopenia is a platelet count below the normal range (< 150,000/mm³) that is most commonly due to either impaired platelet production in the bone marrow or increased platelet turnover in the periphery. Common causes of impaired platelet production include bone marrow failure, infection, malignancy, and chemotherapy/radiation. Additional etiologies include hereditary syndromes, such as Wiskott-Aldrich syndrome and Alport syndrome. In contrast, increased peripheral platelet turnover may be caused by autoimmune conditions, (e.g., immune thrombocytopenia), drugs (e.g., heparin), and other conditions (e.g., TTP/HUS, DIC/sepsis). Thrombocytopenia is often asymptomatic and found incidentally on routine bloodwork. Patients may notice petechiae or mucosal bleeding (e.g., bleeding gums, epistaxis) at lower platelet counts. Other patients with thrombocytopenia are clinically ill and have multisystem findings (e.g., acute infection, liver disease, TTP/HUS, DIC). Diagnosis should be confirmed with repeat testing (to rule out pseudothrombocytopenia) and underlying causes should be investigated and treated. Patients with active bleeding or neurological symptoms require emergency platelet transfusion, and in cases of immune-mediated etiologies, IVIG. Observation may be sufficient for patients who have stable medium-low platelet levels and no serious underlying condition. Patients with suspected ITP and low platelet counts (e.g., < 30,000/mm³) are typically treated with corticosteroids, IVIG, or splenectomy.

See also “Immune thrombocytopenia”.

Impaired platelet production in bone marrow ^[1]

Bone marrow conditions → ↓ megakaryocytes → ↓ thrombopoiesis

• Bone marrow failure: aplastic anemia, paroxysmal nocturnal hemoglobinuria
• Bone marrow suppression: drugs (e.g., linezolid, daptomycin, valproic acid, valacyclovir), chemotherapy, radiation
• Congenital thrombocytopenias: Wiskott-Aldrich syndrome, Alport syndrome, Bernard-Soulier syndrome, Fanconi anemia, von Willebrand disease
• Other congenital conditions: Gaucher disease
• Infection: CMV, EBV, hepatitis C virus, HIV, mumps and rubella, parvovirus B19, rickettsia, VZV, dengue
• Malignancy: leukemia, lymphoma, bone marrow infiltration, myelodysplastic syndrome
• Nutritional deficiency: vitamin B12 deficiency and/or folate deficiency (e.g., in chronic alcohol abuse)
• Other: necrotizing enterocolitis

If platelet production is impaired, the number of megakaryocytes on bone marrow biopsy will also be decreased.

Increased platelet turnover in the periphery

• Immune thrombocytopenia; (ITP) and other autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis)
• Disseminated intravascular coagulation (DIC) and sepsis
• Thrombotic thrombocytopenic purpura; (TTP) and hemolytic uremic syndrome (HUS)
• Drug-induced immune thrombocytopenia (DITP): Platelet-activating antibodies cause a hypercoagulable state and simultaneous reduction in platelet count.
  • The following drugs are most likely to be associated with DITP: ^[2][3]
    • Sodium-channel blockers: quinine, class I antiarrhythmics (e.g., quinidine); , valproate, carbamazepine
    • Calcium-channel blockers: amlodipine
    • Antibiotics: linezolid, vancomycin, TMP-SMX, penicillin, ceftriaxone, rifampin
    • Antiviral agents: ganciclovir, protease inhibitors (e.g., indinavir); , zidovudine
    • Antithrombotic agents: glycoprotein IIb/IIIa inhibitors (e.g., abciximab), heparin
    • Others: oxaliplatin, suramin, ibuprofen, mirtazapine
  • See also Heparin-induced thrombocytopenia (HIT)
• Pregnancy: preeclampsia; and HELLP syndrome
• Infection (see above)
• Post-transfusion thrombocytopenia
• Mechanical damage due to artificial cardiac valves or extracorporeal circulation (e.g., dialysis)

Increased peripheral turnover also increases numbers of megakaryocytes on bone marrow biopsy!

Redistribution, dilution, and other causes

• Liver disease and chronic alcohol abuse (decreased production of thrombopoietin in the liver)
• Splenomegaly
• Gestational thrombocytopenia
• Thrombocytopenia following transfusion or fluid resuscitation
• Pulmonary embolism or pulmonary hypertension ^[1]

References:^{[1][4][4][5][5][6][7][8]}

• See also “Clinical features of bleeding disorders” (e.g., bleeding gums, epistaxis, petechiae).

References:^[1][5][7]

Approach ^[1]

• Confirm the diagnosis in all patients:
  • Repeat CBC and compare with previous platelet counts.
  • Consider peripheral blood smear to exclude pseudothrombocytopenia.
• Investigate for underlying causes with a thorough history and routine laboratory studies.
• If the etiology remains unclear:
  • Evaluate recent medication (see “Etiology”).
  • Order additional investigations based on clinical suspicion, e.g., evaluation for MDS or other malignancies in patients > 60 years old with new-onset thrombocytopenia.
• See “ITP” if isolated thrombocytopenia with no other underlying cause detected.
• Evaluate for complications:
  • Identify the source of hemorrhage in bleeding patients (e.g., see “GI bleeding”).
  • Obtain neuroimaging for patients with altered mental status.
  • See also “DIC”.

Do not delay treatment for diagnostic testing in patients with significant bleeding or new neurological symptoms.

Routine laboratory studies ^[1]

• CBC: ↓ platelet count (< 150,000/mm³); depending on the etiology, anemia or pancytopenia may be present.
• Coagulation studies: ↑ bleeding time
• Peripheral blood smear
  • Abnormal platelet morphologies and cells
  • Platelet clumping may be seen in pseudothrombocytopenia.
• Renal function tests
• Liver chemistries

A rapidly falling platelet count is worrisome, even if it is within the normal range (e.g., in HIT).

Additional investigations

Consider additional laboratory studies or imaging depending on clinical features and results of routine laboratory studies

See “Differential diagnosis of platelet disorders” for a comparison of findings in various etiologies of thrombocytopenia.

• Pseudothrombocytopenia: A spuriously low platelet count due to platelet clumping in vitro ^[1][12][13]
  • Platelet clumping can occur secondary to: ^[14]
    • Pre-analysis collection factors : e.g., sampling technique , choice of anticoagulant used in collection tubes , delays in analysis, improper storage
    • Disease factors : e.g., presence of antibodies to EDTA anticoagulant, autoimmune and inflammatory conditions (e.g., cold agglutinin disease), neoplastic disease (e.g., multiple myeloma), viral infections, drugs (e.g., chemotherapeutic agents)
• Dilutional thrombocytopenia: Falsely low platelet concentration due to volume overload; typically affects all other cell counts (i.e., associated dilutional anemia and leukopenia)

The differential diagnoses listed here are not exhaustive.

Patients with thrombocytopenia may be asymptomatic or acutely unwell if the thrombocytopenia is a feature of a wider syndrome such as DIC or TTP. Management depends on symptoms, initial platelet count, and the underlying condition.

Approach ^[1][15]

• All patients
  • Treat any significant bleeding (see “Emergency management of thrombocytopenia”).
  • Treat underlying cause (See “Etiology”).
    • Immediately treat serious or life-threatening underlying illnesses (See “Treatment” in “TTP”, “HIT”, “HUS”, and “DIC”).
    • Benign or mild illnesses may resolve spontaneously.
  • Consider empiric treatment for ITP (e.g., corticosteroids, IVIG) if platelet count < 30,000/mm³ without another apparent cause (see “Treatment” in “ITP”).
  • Consider stopping medications that impair platelet function and increase bleeding risk, e.g., NSAIDs. ^[15]
• Mildly symptomatic or asymptomatic patients with a platelet count < 50,000/mm³: Consult hematology.
• Asymptomatic patients with a platelet count > 50,000/mm³: Repeat CBC in 1–4 weeks or if the patient becomes symptomatic. ^[1]
  • Decreasing or unchanging platelet count: Consult hematology.
  • Increasing platelet count: Follow-up until platelet count has normalized.

Emergency management of thrombocytopenia ^[15][16]

• Indications
  • Neurological symptoms
  • Anticipated urgent surgery or invasive procedures
  • Significant bleeding
• Treatment
  • If there is bleeding: Attempt hemostatic control.
  • Urgently replace platelets.
    • Immediate platelet transfusion (e.g., 1 unit of platelets IV; repeat as needed)
    • If an immune cause is suspected: Administer IVIG (prior to transfusion).