Thrombocytopenia in Adults

Background

• Thrombocytopenia is defined as a platelet count that is < the 2.5th percentile of normal platelet count range, with the traditional cutoff for the lower limit being 150 × 10⁹/L.
• The incidence of thrombocytopenia varies according to the clinical context. For example, it occurs in about 1% of patients admitted to an acute care hospital, 8%-68% of patients at time of admission to intensive care unit (ICU), up to 50% of patients during an ICU stay, 77%-85% of patients with cirrhosis, and 7%-10% of pregnancies.

Table 1. Most Common Causes of Thrombocytopenia Depend on the Clinical Setting

• Pathogenic mechanisms of thrombocytopenia include decreased platelet production (for example, due to chronic alcohol use disorder, infection or bone marrow infiltration), increased platelet destruction (for example, due to immune-mediated causes such as immune thrombocytopenia, drug-induced immune thrombocytopenia or posttransfusion purpura, and nonimmune causes such as infection, disseminated intravascular coagulopathy or thrombotic microangiopathy), splenic sequestration (for example, due to portal hypertension) and hemodilution (for example, due to massive transfusion).
• Clinically significant spontaneous bleeding does not typically occur until the platelet count is < 10-20 × 10⁹, unless there is concomitant platelet dysfunction or abnormalities in secondary hemostasis.
• Thrombocytopenia may indicate presence of an underlying disorder that represents a greater risk than the thrombocytopenia itself.

General Workup

• Patients with new-onset thrombocytopenia should be evaluated:
  • to determine the risk of bleeding
  • to rule out life-threatening causes of thrombocytopenia, including those that are associated with thrombosis and acute leukemia
  • to determine the underlying cause
• The differential diagnosis of thrombocytopenia and the nature of the work up vary according to clinical context, including:
  • where the thrombocytopenia is first detected (in ambulatory clinic, urgent care, medical or surgical wards, or the intensive care unit)
  • whether thrombocytopenia is isolated or is associated with other cytopenias
  • whether the thrombocytopenia is associated with bleeding (for example, immune thrombocytopenia and drug-induced immune thrombocytopenia) or paradoxical thrombosis (for example, heparin-induced thrombocytopenia, disseminated intravascular coagulopathy, and thrombotic microangiopathy)
  • whether or not the patient is pregnant
• History includes assessment of any family history, review of bleeding symptoms (especially in mucocutaneous sites), neurological symptoms (may indicate central nervous system bleeding or underlying thrombotic microangiopathy), drugs, vaccines, diet, alcohol intake, recent transfusions, recent travel, known or possible pregnancy, and history of liver disease, autoimmune disorders, or malignancy.
• Physical exam includes evaluation of skin and palate for bruising and petechiae and signs associated with underlying causes of thrombocytopenia such as skeletal and skin abnormalities (congenital thrombocytopenia); stigmata of chronic liver disease; splenomegaly; skin rash (systemic lupus erythematosus, viral infection); skin necrosis, venous limb gangrene, necrotizing skin lesions at injection sites (heparin-induced thrombocytopenia); and neurological manifestations, fever, hypertension (thrombotic thrombocytopenic purpura [TTP]).
• Diagnostic testing
  • Measure complete blood cell count (CBC) with white blood cell differential. The degree of thrombocytopenia may provide clues about the underlying diagnosis, though there is significant overlap and the platelet count itself is not specific for any one diagnosis.

Table 2.

• Examine peripheral blood smear for platelet clumping and for morphological findings in all 3 cell lines (red blood cells, white blood cells, and platelets).
• If platelet clumping is observed, repeat CBC in citrated or heparinized blood; improvement of normalization of platelet count suggests pseudothrombocytopenia, which is an in vitro artifact with no clinical consequence.
• Additional tests depend on the clinical context and the results of the CBC and peripheral smear.

Table 3. Summary of Ancillary Tests for Work-up of Patient with Thrombocytopenia

Evaluation by Clinical Setting

• For ambulatory patients:
  • With isolated thrombocytopenia consider
    • immune thrombocytopenia (ITP) in patients with
      • platelet count ≤ 100 × 10⁹/L and no alternative explanation for the thrombocytopenia, including familial thrombocytopenia, chronic liver disease, and alcohol use disorder
      • conditions associated with secondary ITP including systemic lupus erythematosus (SLE), infections (especially HIV and hepatitis C virus [HCV]), and lymphoproliferative disorders
    • drug-induced thrombocytopenia (DITP) in patients:
      • with severe isolated thrombocytopenia
      • who have started a new medication within the past 5-10 days
    • familial thrombocytopenia in patients with:
      • family history of isolated thrombocytopenia
      • clinical findings associated with syndromic forms of familial thrombocytopenia
      • peripheral smear showing giant, normal-sized, or small platelets
    • gestational thrombocytopenia
  • With other cytopenias (anemia and/or leukopenia), consider myelodysplastic syndrome, bone marrow failure, chronic liver disease, primary myelofibrosis, chronic lymphocytic leukemia, Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia), chronic liver disease with hypersplenism, drugs, and vitamin B12 deficiency
  • With mild-to-moderate thrombocytopenia who are bleeding, consider concurrent platelet function defect or coagulopathy
• For patients in an urgent care setting:
  • With isolated thrombocytopenia consider
    • immune thrombocytopenia (ITP) in patients with
      • platelet count ≤ 100 × 10⁹/L and no alternative explanation for the thrombocytopenia, including familial thrombocytopenia, chronic liver disease, and alcohol use disorder
      • conditions associated with secondary ITP including systemic lupus erythematosus (SLE), infections (especially HIV and HCV) and lymphoproliferative disorders
    • drug-induced thrombocytopenia (DITP) in patients:
      • with severe isolated thrombocytopenia
      • who have started a new medication within the past 5-10 days
    • alcohol-induced thrombocytopenia in patients with heavy alcohol intake
  • With thrombocytopenia and microangiopathic hemolytic anemia (schistocytes on peripheral smear and laboratory evidence of hemolysis including elevated lactate dehydrogenase and indirect bilirubin, and reduced haptoglobin), consider thrombotic microangiopathy
    • Patients with thrombotic thrombocytopenic purpura may also present with fever or neurological findings.
    • Patients with complement-mediated thrombotic microangiopathy (for example, atypical hemolytic-uremic syndrome (aHUS) typically have serum creatinine at or above the upper limit of normal range.
    • Patients with Shiga toxin-mediated HUS may have renal failure, abdominal pain, vomiting, or diarrhea.
• For hospitalized patients:
  • Consider infection, especially sepsis, which may or may not be associated with disseminated intravascular coagulation (DIC).
  • Consider heparin-induced thrombocytopenia in patients with recent exposure to heparin (unfractionated heparin or, less commonly, low-molecular-weight heparin).
  • Consider DITP in patients who have started a new medication within the past 5-10 days.
  • Consider DIC in patients with infection, solid and hematological malignancies, obstetric diseases, trauma, aneurysms, or liver disease.
  • Consider posttransfusion purpura in patients who have recently received a blood transfusion.
  • Additional considerations for patients in the cardiac or surgical intensive care unit:
    • Consider hemodilution in patients who have received massive transfusion.
    • Transient thrombocytopenia is common in patients:
      • undergoing major surgery, including hip, vascular, abdominal, and cardiac surgery)
      • with extracorporeal circuits (intra-aortic balloon pump, ventricular assist devices)
    • Consider DITP in patients exposed to GPIIb/IIIa inhibitors, such as abciximab or tirofiban.
• For pregnant women, work up should be tailored to the more likely causes of thrombocytopenia.

Management

• Treatment depends on the underlying cause of thrombocytopenia.
• Goals of treatment are to:
  • Control bleeding if present:
    • For patients with severe bleeding, transfuse platelets to maintain platelet count > 50 × 10⁹/L (Strong recommendation).
    • Consider platelet transfusion for patients with:
      • less than severe bleeding to maintain platelet count if < 30 × 10⁹/L (Weak recommendation)
      • intracerebral hemorrhage, multiple trauma, or traumatic brain injury, to maintain platelet count at > 100 × 10⁹/L (Weak recommendation)
      • DIC who are actively bleeding with platelet count < 50 × 10⁹/L (Weak recommendation)
  • Minimize risk of bleeding:
    • Clinically significant spontaneous bleeding does not typically occur until the platelet count is < 10-20 × 10⁹.
    • For patients with therapy-induced hypoproliferative thrombocytopenia, transfuse platelets when platelet count is ≤ 10 × 10⁹/L (Strong recommendation).
    • Consider platelet transfusion for patients with DIC with a high risk of bleeding and a platelet count < 20 × 10⁹/L.
    • Consider platelet transfusion for patients with thrombocytopenia undergoing an invasive procedure such as:
      • elective central venous catheter placement when platelet count is < 20 × 10⁹/L (Weak recommendation)
      • elective diagnostic lumbar puncture or major elective nonneuraxial surgery when platelet count < 50 × 10⁹/L (Weak recommendation)
      • cardiac surgery with cardiopulmonary bypass, who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction (Weak recommendation)
  • Minimize risk of thrombosis in cases where thrombocytopenia is associated with an underlying hypercoagulable state (heparin-induced immune thrombocytopenia [HIT] and TTP):
    • In patients with suspected HIT, discontinue heparin immediately and start alternative nonheparin anticoagulants (Strong recommendation).
    • Do not administer platelet transfusions in patients with TTP unless there is a life-threatening hemorrhage (Strong recommendation).
    • Platelet transfusions are not recommended in patients with HIT unless they are bleeding or during an invasive procedure with high risk of bleeding (Weak recommendation).
  • Treat the underlying condition:
    • In patients with immune thrombocytopenia (ITP):
      • First-line therapy includes corticosteroids, IV immunoglobulin (IVIG), or anti-D immune globulin (anti-D).
      • Platelet transfusion may be considered for emergency management of patients with ITP, with or without concurrent IVIG.
    • For cases of suspected drug-induced thrombocytopenia:
      • Stop the implicated drug immediately.
      • Consider platelet transfusion for patients with severe thrombocytopenia.
      • If bleeding develops, consider IVIG (1 g/kg body weight) on 2 consecutive days or platelet transfusion.
      • Corticosteroids have not been shown to be effective in this setting.
    • In patients with suspected TTP:
      • Treat as a medical emergency (Strong recommendation).
      • Initiate plasma exchange (Strong recommendation).
      • Give methylprednisolone (1 g/day IV for 3 days in adults) or high-dose oral prednisolone (1 mg/kg/day) (Strong recommendation).
    • In patients with suspected complement-mediated thrombotic microangiopathy, treat with C5 inhibitor eculizumab.
    • In patients with moderate-high suspicion for heparin-induced thrombocytopenia (HIT) or confirmed HIT:
      • Discontinue heparin immediately and start alternative nonheparin anticoagulants (Strong recommendation).
      • Consider platelet transfusion for patients with HIT and severe thrombocytopenia only if bleeding or during an invasive procedure with high risk of bleeding (Weak recommendation).
    • In patients with disseminated intravascular coagulation (DIC):
      • Vigorously treat the underlying condition when possible (Strong recommendation).
      • Supportive treatment may be required in order to correct coagulation abnormalities in patients who are bleeding or who are at high risk of bleeding (replacement therapies), or to modulate thrombin generation in certain patients with a thrombotic phenotype (heparin and anticoagulant factor concentrates).