Platelets are cell fragments that function in the clotting system. Thrombopoietin, primarily produced in the liver in response to decreased numbers of bone marrow megakaryocytes and circulating platelets, stimulates the bone marrow to synthesize platelets from megakaryocytes. Platelets circulate for 7 to 10 days. About one third are always transiently sequestered in the spleen. The platelet count is normally 140,000 to 440,000/μL. However, the count can vary slightly according to menstrual cycle phase, decrease during near-term pregnancy (gestational thrombocytopenia), and increase in response to inflammatory cytokines (secondary, or reactive, thrombocytosis). Platelets are eventually destroyed by apoptosis, a process independent of the spleen.

Platelet disorders include

• An abnormal increase in platelets (thrombocythemia and reactive thrombocytosis )
• A decrease in platelets (thrombocytopenia)
• Platelet dysfunction

Any of these conditions, even those in which platelets are increased, may cause defective formation of hemostatic plugs and bleeding.

The risk of bleeding is inversely proportional to the platelet count and platelet function (see Table 1: Thrombocytopenia and Platelet Dysfunction: Platelet Count and Bleeding Risk). When platelet function is reduced (eg, as a result of uremia or aspirin use), the risk of bleeding increases.

Table 1
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Platelet Count and Bleeding Risk Platelet Count Risk of Bleeding* ≥ 50,000/μL Minimal 20,000–50,000/μL Minor bleeding after trauma < 20,000/μL Spontaneous bleeding < 5000/μL Severe, possibly life-threatening spontaneous bleeding *Reduced platelet function (eg, due to uremia or aspirin use) adds to risk of bleeding in each platelet count range.

Etiology

Thrombocythemia and thrombocytosis

Essential thrombocythemia is a myeloproliferative disorder (see Myeloproliferative Disorders: Essential Thrombocythemia) involving overproduction of platelets because of a clonal abnormality of a hematopoietic stem cell. A markedly elevated platelet count typically leads to thrombosis, but some patients develop bleeding.

Reactive thrombocytosis (see Myeloproliferative Disorders: Thrombocytosis) is platelet overproduction in response to another disorder. There are many causes, including acute infection, chronic inflammatory disorders (eg, RA, inflammatory bowel disease, TB, sarcoidosis), iron deficiency, and certain cancers.

Thrombocytopenia

Causes of thrombocytopenia can be classified by mechanism (see Table 2: Thrombocytopenia and Platelet Dysfunction: Classification of Thrombocytopenia) and include failed platelet production, increased splenic sequestration of platelets with normal platelet survival, increased platelet destruction or consumption (both immunologic and nonimmunologic causes), dilution of platelets, and a combination of these mechanisms.

Increased splenic sequestration is suggested by splenomegaly.

A large number of drugs may cause thrombocytopenia (see Thrombocytopenia and Platelet Dysfunction: Drug-induced immunologic destruction), typically by triggering immunologic destruction.

Overall, the most common specific causes of thrombocytopenia include

• Gestational thrombocytopenia
• Drug-induced thrombocytopenia due to immune-mediated platelet destruction (commonly quinine, trimethoprim/sulfamethoxazole)
• Drug-induced thrombocytopenia due to dose-dependent bone marrow suppression (by chemotherapeutic agents)
• Thrombocytopenia accompanying systemic infection
• Immune thrombocytopenia (ITP, formerly called immune thrombocytopenic purpura)

Platelet dysfunction

Platelet dysfunction may stem from an intrinsic platelet defect or from an extrinsic factor that alters the function of normal platelets. Dysfunction may be hereditary or acquired. Hereditary disorders of platelet function consist of von Willebrand disease, the most common hereditary hemorrhagic disease, and hereditary intrinsic platelet disorders (see Thrombocytopenia and Platelet Dysfunction: Hereditary Intrinsic Platelet Disorders), which are much less common. Acquired disorders of platelet function (see Thrombocytopenia and Platelet Dysfunction: Acquired Platelet Dysfunction) are commonly due to diseases as well as to aspirin and other drugs.

Table 2
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Classification of Thrombocytopenia Cause Conditions Diminished or absent megakaryocytes in bone marrow Aplastic anemia Leukemia Myelosuppressive drugs (eg, hydroxyurea, interferon alfa-2b, chemotherapy drugs) Paroxysmal nocturnal hemoglobinuria (some patients) Diminished platelet production despite the presence of megakaryocytes in bone marrow Alcohol-induced thrombocytopenia HIV-associated thrombocytopenia Myelodysplastic syndromes (some) Vitamin B12 or folate (folic acid) deficiency Platelet sequestration in enlarged spleen Cirrhosis with congestive splenomegaly Gaucher disease Myelofibrosis with myeloid metaplasia Immunologic destruction Connective tissue disorders Drug-induced thrombocytopenia HIV-associated thrombocytopenia Immune thrombocytopenia Lymphoproliferative disorders Neonatal alloimmune thrombocytopenia Posttransfusion purpura Pregnancy (gestational thrombocytopenia) Nonimmunologic destruction Disseminated intravascular coagulation Sepsis Certain systemic infections (eg, hepatitis, Epstein-Barr virus, cytomegalovirus, or dengue virus infection) Thrombocytopenia in acute respiratory distress syndrome Thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome Dilution Massive red blood cell replacement or exchange transfusion (loss of platelet viability in stored blood)

Symptoms and Signs

Petechiae in Immune Thrombocytopenia (ITP)

Ecchymoses in Immune Thrombocytopenia

Platelet disorders result in a typical pattern of bleeding:

• Multiple petechiae in the skin (typically most evident on the lower legs)
• Scattered small ecchymoses at sites of minor trauma
• Mucosal bleeding (oropharyngeal, nasal, GI, GU)
• Excessive bleeding after surgery

Heavy GI bleeding and bleeding into the CNS may be life threatening. However, bleeding into tissues (eg, deep visceral hematomas or hemarthroses) does not occur with thrombocytopenia, which causes immediate, superficial bleeding. Bleeding into the tissues (often delayed for up to a day after trauma) suggests a coagulation disorder (eg, hemophilia).

Diagnosis

• Clinical presentation of petechiae and mucosal bleeding
• CBC with platelets, coagulation studies, peripheral blood smear
• Sometimes bone marrow aspiration
• Sometimes von Willebrand antigen and factor activity studies

Platelet disorders are suspected in patients with petechiae and mucosal bleeding. A CBC with platelet count, coagulation studies, and a peripheral blood smear are obtained. Excessive platelets and thrombocytopenia are diagnosed based on the platelet count; coagulation studies are normal unless there is a simultaneous coagulopathy. In patients with a normal CBC, platelet count, and INR and normal or only slightly prolonged PTT, platelet dysfunction is suspected.

Pearls & Pitfalls Suspect platelet dysfunction in patients with petechiae and/or hemorrhage but with normal platelet count and coagulation tests.

Thrombocytopenia

In patients with thrombocytopenia, the peripheral smear may suggest the cause (see Table 3: Thrombocytopenia and Platelet Dysfunction: Peripheral Blood Findings in Thrombocytopenic Disorders). If the smear shows abnormalities other than thrombocytopenia, such as nucleated RBCs or abnormal or immature WBCs, bone marrow aspiration is indicated. Bone marrow aspiration reveals the number and appearance of megakaryocytes and is the definitive test for many disorders causing bone marrow failure. However, normal number and appearance of megakaryocytes does not always indicate normal platelet production. For example, in patients with immune thrombocytopenia, platelet production may be decreased despite the normal appearance and increased number of megakaryocytes. If the bone marrow is normal but the spleen is enlarged, increased splenic sequestration is the likely cause of thrombocytopenia; if the bone marrow is normal and the spleen is not enlarged, excess platelet destruction is the likely cause. Measurement of antiplatelet antibodies is not clinically useful. HIV testing is done in patients at risk of HIV infection.

Table 3
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Peripheral Blood Findings in Thrombocytopenic Disorders Findings Conditions Normal RBCs and WBCs Drug-induced thrombocytopenia Gestational thrombocytopenia HIV-related thrombocytopenia Immune thrombocytopenia Posttransfusion purpura RBC fragmentation (schistocytes) Metastatic cancer DIC Preeclampsia with DIC Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome WBC abnormalities Hypersegmented polymorphonuclear leukocytes in megaloblastic anemias Immature cells or increased mature lymphocytes in leukemia Markedly diminished granulocytes in aplastic anemia Frequent giant platelets (approaching the size of RBCs) Bernard-Soulier syndrome Disorders related to the myosin, heavy chain 9, non-muscle gene (MYH9) Other congenital thrombocytopenias RBC abnormalities, nucleated RBCs, and immature granulocytes Myelodysplasia DIC = disseminated intravascular coagulation.

Schistocytes

Suspected platelet dysfunction

In patients with platelet dysfunction, a drug cause is suspected if symptoms began only after patients started taking a potentially causative drug. A hereditary cause is suspected if there is a lifelong history of easy bruising, bleeding after tooth extractions or surgery, or heavy menstruation. In the case of a suspected hereditary cause, von Willebrand antigen and factor activity studies are done. Platelet dysfunction caused by systemic disorders is typically mild and of minor clinical importance. In these patients, the causative systemic disorder is the clinical concern, and hematologic tests are unnecessary.

Treatment

• Avoidance of drugs that impair platelet function
• Rarely platelet transfusions

In patients with thrombocytopenia or platelet dysfunction, drugs that further impair platelet function, particularly aspirin and other NSAIDs, should not be given. Patients who are already taking such drugs should consider alternative drugs, such as acetaminophen, or simply stop using them.

Patients may require platelet transfusion, but transfusions are given only in limited situations (see Transfusion Medicine: Platelets). Prophylactic transfusions are used sparingly because they may lose their effectiveness with repeated use due to the development of platelet alloantibodies. In platelet dysfunction or thrombocytopenia caused by decreased production, transfusions are reserved for patients with active bleeding, severe thrombocytopenia (eg, platelet count < 10,000/μL), or in need of invasive procedures. In thrombocytopenia caused by platelet destruction, transfusions are reserved for life-threatening or CNS bleeding.

Last full review/revision October 2012 by David J. Kuter