Thrombocytopenia

Overview

Definition

Thrombocytopenia is a deficiency of platelets, typically defined as < 150,000 platelets per microliter of whole blood.

Epidemiology

• Platelet counts are naturally slightly higher in:
  • Females
  • Younger persons 
  • Non-Hispanic Black persons (as compared with White persons)
• Most common cause: immune-mediated thrombocytopenia 
• Second most common cause: infection-induced thrombocytopenia
• Epidemiologic statistics are related to the underlying etiology.

Classification

Thrombocytopenia can be classified as mild, moderate, or severe on the basis of platelet counts:

• Mild: 100,000–150,000/μL 
• Moderate: 50,000–99,000/μL
• Severe: < 50,000/μL

Etiology

Thrombocytopenia can be caused by decreased production, increased destruction, or sequestration of platelets.

Causes of thrombocytopenia

Drugs definitively associated with isolated thrombocytopenia

Review of Normal Physiology

Platelet production

Under normal physiologic conditions, platelets are produced from the fragmentation of megakaryocytes in the bone marrow.

• Upon release from the bone marrow:
  •  ⅔ of platelets will circulate in the blood for 8–10 days.
  • Remaining ⅓ are sequestered in the spleen.
  • Senescent platelets are removed by phagocytic cells in the spleen (monocytes, macrophages).
  • No platelets are stored in the bone marrow.
• Decreased platelet counts stimulate megakaryocytes to release platelets.
• Thrombopoietin (TPO):
  • Regulates platelet levels
  • Stimulates multipotent hematopoietic stem cells
  • Produced in the liver and kidneys
  • Binds megakaryocytes:
    • Prevents apoptosis
    • Stimulates their number, size, ploidy, and maturation
  • Binds platelets: lowers their threshold for activation
• Cytokines:
  • Stimulates megakaryocytes and platelet production independently of TPO
  • Platelets ↑ during acute infection or inflammation.
  • Exact mechanism unknown but thought to include IL-6 and IL-11.

Platelet function

Platelets are the principle cells involved in formation of the initial platelet plug (i.e., primary hemostasis).

• Disrupted endothelial surface exposes von Willebrand factor (VWF) to the passing blood. 
• Platelets bind to the VWF via their glycoprotein (Gp) Ib receptors and are activated. 
• Platelet activation triggers them to secrete ADP, which stimulates the expression of the GpIIb/IIIa receptors on the platelets. 
• GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing platelets to aggregate. 
• As more platelets are bound to one another, the platelet plug is generated. 
• As the coagulation cascade is activated, thrombin converts the weaker fibrinogen into the stronger fibrin, creating a much more stable clot.

Pathophysiology

Pathophysiology of platelet deficiency

In thrombocytopenia, a platelet deficiency results in:

• Decreased ability to produce the platelet plug after a vessel wall injury
• Requirement for the coagulation cascade to form a clot
• End results:
  • Prolonged bleeding time (> 7 minutes)
  • Petechiae and purpura
  • Spontaneous or severe bleeding

Drug-induced thrombocytopenia

Drug-induced thrombocytopenia may be due to direct toxic effects on the bone marrow (e.g., chemotherapy) or to drug-dependent antibodies. Drug-dependent antibodies:

• React with specific platelet surface antigens
• Result in thrombocytopenia only when the drug is present
• More common with quinine and sulfonamides
• Thrombocytopenia typically occurs after an initial exposure.
• Typically resolves 7–10 days after discontinuation of the drug

Heparin-induced thrombocytopenia

Unlike most drug-induced thrombocytopenias, HIT is associated with a markedly increased risk of thrombosis rather than bleeding.

• Antibodies form against the complex of platelet factor 4 + heparin
• These antibodies activate platelets and endothelial cells → thrombosis
• More common with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH)
• Begins within 5–10 days after heparin exposure

HIV-associated thrombocytopenia

• Early in an HIV infection: antibodies against HIV Gp120 antigen can cross-react with GpIIb/IIIa antigens on platelets (molecular mimicry) → ↑ destruction
• Later in HIV infection: ↓ production (often associated with pancytopenia)

Clinical Presentation

• Bleeding symptoms:
  • Petechiae: pinpoint hemorrhages (< 2 mm)
  • Purpura: coalesced petechiae 
  • Ecchymoses (bruises): bleeding into the skin
  • Clinical bleeding:
    • Epistaxis
    • Gingival bleeding
    • GI bleeding: hematemesis, melena
    • Heavy menstrual bleeding
    • Internal bleeding (e.g., stroke)
• Expected bleeding based on platelet count:
  • > 50,000/μL: often asymptomatic
  • 20,000–50,000/μL: excessive bleeding with trauma
  • < 20,000/μL: ↑ risk of spontaneous bleeding (e.g., mucosal, intracrainal, GI, genitourinary)
  • < 5000/μL: hematologic emergency
• Other potential exam findings: helpful in determining the underlying etiology
  • Hepatomegaly → liver disease
  • Splenomegaly → liver disease, infectious disease
  • Lymphadenopathy → recent infection, HIV, malignancy, autoimmune/inflammatory conditions
• Heparin-induced thrombocytopenia (HIT):
  • Thrombocytopenia beginning 5–10 days after beginning heparin
  • Skin necrosis around injection site (due to local thrombosis)

Diagnosis

The diagnosis of thrombocytopenia itself is made with laboratory evaluations. Clues to the underlying etiology can be obtained from the history and exam, and additional lab testing can further aid in diagnosis.

Routine testing

The following tests should be ordered for all patients with thrombocytopenia:

• CBC: 
  • Evaluate platelet count: establishes the diagnosis of thrombocytopenia
  • Determine if there are other cytopenias: presence suggests a bone marrow issue
• Peripheral blood smear: 
  • Microscopic evaluation of the number and appearance of blood cells, including platelets
  • Excludes pseudothrombocytopenias (falsely low platelet counts)
  • Schistocytes: suggest a microangiopathic process (e.g., DIC, TTP, HUS)
  • Teardrop cells and nucleated RBCs: suggest an infiltrative process in the bone marrow
  • Immature or dysplastic WBCs: suggest leukemia or myelodysplasia
  • Multilobed/hypersegmented neutrophils: suggest deficiency of vitamin B₁₂ or folate
• HIV test
• Hepatitis C

Additional testing

The following tests should be ordered only as clinically indicated to help identify the underlying etiology.

• Coagulation studies: 
  • Evaluate the function of the coagulation cascade
  • Key tests: PT, PTT
• Bleeding time: 
  • Measures the time for bleeding to stop after a lancet incision
  • An indirect measure of platelet function
• CMP: 
  • Evaluates metabolic health and organ function 
  • ↑ Liver function tests: suggests liver disease
  • ↑ Creatinine and BUN: suggests renal disease
• Bone marrow aspiration and/or biopsy:
  • Normal or ↑ megakaryocytes:  thrombocytopenia is due to ↑ destruction (e.g., ITP or drug-induced)
  • ↓ Megakaryocytes + ↓ cellularity overall: ↓ production (e.g., aplastic anemia)
  • ↓ Megakaryocytes with otherwise normal cellularity: most commonly seen in SLE
  • Dysplasia: myelodysplastic disorder
• Platelet factor 4 antibody assays (HIT antibody)
• ANA
• Vitamin B₁₂ and folate levels
• Blood cultures

Management

Management of thrombocytopenia depends mainly on addressing the underlying cause, monitoring platelet counts, and preventing/controlling any bleeding complications.

• Routine monitoring of the platelet count for stable patients
• Consider activity restrictions (generally for severe thrombocytopenia only).
• Treatment of the underlying cause:
  • Discontinue medications known to induce immune-mediated platelet destruction.
  • Discontinue cytotoxic medications.
  • Antibiotics to treat bacterial infections/sepsis
  • Antiretrovirals to manage HIV
  • Administration of glucocorticoids and/or IV immunoglobulin (IVIG) is indicated for symptomatic ITP.
  • Treatment of neoplastic, autoimmune, or inflammatory diseases
• Platelet transfusions:
  • Indications:
    • Life-threatening bleeding: intracranial hemorrhage or massive GI bleed
    • Prophylactic prevention of bleeding if platelets < 10,000/μL (afebrile) or < 20,000/μL (febrile) 
    • Prophylactic treatment in severe thrombocytopenia prior to invasive procedures
  • Goal platelet counts for prophylactic transfusions depend on the procedure to be performed; examples include:
    • Neurosurgery: 100,000/μL
    • Most other major surgery: 50,000/μL
    • Central line placement: 20,000/μL
• Consider splenectomy for sequestration.

Clinical Relevance

• Immune thrombocytopenic purpura (ITP): condition that develops secondary to immune-mediated destruction of platelets: IgG antibodies target the platelets, which are then cleared by the spleen. Immune thrombocytopenic purpura may be primary or secondary and is usually a diagnosis of exclusion. Severity of thrombocytopenia in patients with ITP is variable. Treatment includes platelet transfusion, steroids, IVIG, and sometimes splenectomy.
• Thrombotic thrombocytopenic purpura (TTP): life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of VWF: These large multimers then aggregate excessive platelets, resulting in microvascular thrombosis and an increase in consumption of platelets. Clinical presentation can consist of thrombocytopenia, hemolytic anemia, hematuria, GI symptoms, neurologic symptoms, and renal involvement.
• Disseminated intravascular coagulation (DIC): a condition characterized by systemic body-wide activation of the coagulation cascade. This activation results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. DIC is always triggered by another (often serious) condition, including severe sepsis, trauma, malignancy, or obstetric complications.
• Hemolytic uremic syndrome (HUS): clinical phenomenon most commonly seen in children: Hemolytic uremic syndrome consists of the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI and is most commonly associated with a prodrome of diarrheal illness caused by Shiga-like toxin–producing bacteria.
• Aplastic anemia (AA): rare life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow: Aplastic anemia is due to damaged hematopoietic stem cells (HSCs). It can be acquired or inherited. Most cases are acquired and caused by autoimmune damage to HSCs. Other causes include medications and chemicals, high doses of whole-body radiation, viral infections, immune diseases, pregnancy, Fanconi anemia, and Down syndrome.