Platelet Underproduction

The hallmark of platelet underproduction is decreased marrow megakaryocytes or, when available, a decreased peripheral blood reticulated platelet count.² Common causes include infections (including HIV), drugs (usually chemotherapeutic agents or alcohol, but other medications in rare cases), radiotherapy, vitamin deficiency (e.g., folate, vitamin B₁₂), or marrow infiltration by tumor, storage diseases, or marrow failure syndromes (e.g., aplastic anemia). In addition, the myelodysplastic syndromes are a commonly overlooked group of disorders associated with thrombocytopenia in older adults.

Management involves treatment of the underlying condition and supportive platelet transfusions if needed. Two first-generation recombinant thrombopoietin (TPO) agents have been evaluated in clinical trials (recombinant human thrombopoietin [rhuTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhuMGDF]).³ Both rhuTPO and PEG-rhuMGDF have shown the ability to increase platelet count, reduce the duration of thrombocytopenia, and result in a decrease in platelet transfusion for patients receiving dose-intense chemotherapy for ovarian cancer.³ However, when PEG-rhuMGDF was administered to platelet donors, it resulted in the development of antibodies that cross-reacted with endogenous TPO and caused severe thrombocytopenia. This led to the discontinuation of investigations using these two products.

Second-generation TPO mimetics (AMG531 [Romiplostin] and SB497115 [eltrombopag]) have undergone evaluation in patients with immune thrombocytopenic purpura, and romiplostin has been approved by the U.S. Food and Drug Administration (FDA) for treating immune thrombocytopenic purpura (ITP). Romiplostin is a recombinant peptibody that is given subcutaneously once weekly. Eltrombopag is an oral daily hydrazone organic compound. Both agents activate the TPO receptor without structural homology to native TPO. These agents are discussed in more detail in the ITP section (later).

Platelet Sequestration

Hypersplenism from a variety of causes, including liver disease or malignancy, can result in platelet sequestration (Box 1). Mild to moderate thrombocytopenia is caused by platelet sequestration when there is an associated mild reduction in neutrophil count and hemoglobin and with minimal impairment of hematopoiesis on bone marrow examination. If physical examination fails to detect splenomegaly, evaluation with ultrasonography or radionuclide imaging is recommended to document splenomegaly.

Management includes treating the underlying condition and transfusing platelets as needed. Cytopenias secondary to hypersplenism are often not sufficiently severe to warrant treatment in the form of total or partial splenectomy, partial splenic embolization, or transjugular intrahepatic portosystemic shunting for congestive splenomegaly.⁴

Increased Platelet Destruction

The hallmark of increased platelet destruction is increased marrow megakaryocytes or, when available, high reticulated platelet count. Platelet destruction results from various immune and nonimmune conditions, including immune thrombocytopenic purpura (ITP), thrombotic microangiopathies, post-transfusion purpura (PTP), heparin-induced thrombocytopenia (HIT), and disseminated intravascular coagulation (DIC).

Prevalence

The incidence of ITP in a Danish study was 100 cases per 1 million person-years, with 50% of cases occurring in the pediatric age group. It can be of adult or childhood onset. Adult onset is more likely to be chronic and insidious. Adult-onset ITP is more common in women than men (female-to-male ratio of 1.7 : 1), whereas childhood onset has equal sex distribution.⁵

ITP is subdivided into chronic or acute; acute ITP is 6 months or less in duration.⁵

Etiology

ITP can be primary or secondary. Causes of secondary ITP include systemic lupus erythematosus, antiphospholipid antibody syndrome, immunoglobulin A (IgA) deficiency, common variable hypogammaglobulinemia, lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, lymphomas), viral (e.g., HIV, hepatitis C), or drug-induced.

Many drugs have been linked to thrombocytopenia, but those known to be associated with immune thrombocytopenia are heparin and quinidine. Patients with drug-induced ITP usually present within 1 to 2 weeks from the initiation of the offending drug with petechiae and a platelet count of less than 20,000/mm³. Recovery usually occurs 5 to 7 days after discontinuation of the offending agent, but it is occasionally more prolonged.

Here we focus on primary ITP. The guidelines are derived from recommendations of the consensus guideline of the American Society of Hematology.⁶

Pathophysiology

The pathophysiology of primary ITP involves the formation of antiplatelet antibodies, often directed at platelet glycoproteins IIb/IIIA, IIb/IX, Ia/IIa, and V, or multiple platelet antigens. A relative impaired platelet production in response to platelet destruction is thought to contribute to the pathophysiology of ITP as evidenced by the clinical success of TPO-mimetic agents.

Clinical Features

On history and physical examination, the absence of systemic symptoms is helpful in ruling out secondary causes. Evidence of platelet-type (mucosal) bleeding should be noted, and the absence of splenomegaly supports the diagnosis. Bleeding is often less pronounced than in cases of decreased production with similar platelet counts.

Diagnosis

The complete blood cell (CBC) count should be unremarkable except for thrombocytopenia or easy-to-account-for anemia. The peripheral smear must confirm thrombocytopenia, and large immature platelets are often noted. A bone marrow biopsy or aspirate is required in patients older than 60 years, with presence of atypical features (e.g., fatigue, fever, joint pain, macrocytosis, neutropenia), or before splenectomy in the patient whose diagnosis is not definitive. Testing for antiplatelet antibodies is generally not recommended. A negative test result does not rule out the diagnosis.

Treatment

Diagnosis

A pentad of signs is classically described to establish a diagnosis of TTP: thrombocytopenia (platelet counts usually <20,000/mm³), microangiopathic hemolytic anemia, fever, renal dysfunction, and neurologic signs. A clinical triad of thrombocytopenia, red blood cell fragments (schistocytosis), and an increased lactate dehydrogenase (LDH) level is enough to suggest the diagnosis.⁷ Examination of the peripheral blood smear in patients with thrombocytopenia of unclear cause is imperative to exclude this diagnosis (Fig. 1). If severe renal failure is a prominent feature of the syndrome, the hemolytic-uremic syndrome may be a more likely diagnosis. Although ADAMTS13 (a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor [vWF]) levels can be measured, the diagnosis of TTP is a clinical one and results are often not available at the time of diagnosis.

Figure 1 Peripheral blood smear of a patient with microangiopathic hemolytic anemia.

Schistocytes (arrows) are also noted in patients with severe burns, dysfunctional prosthetic valves, and disseminated intravascular coagulation.

Pathophysiology

Thrombotic microangiopathies are characterized by destructive thrombocytopenia, erythrocyte fragmentation, and tissue ischemia and necrosis, as evidenced by increased LDH levels. In nonacquired TTP, systemic clumping of platelets is caused by unusually large amounts of vWF, often caused by a deficiency of the metalloproteinase ADAMTS13 that cleaves vWF into smaller, less-thrombogenic multimers.⁷