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Primary Platelet Disorders
Introduction
Platelets are small anucleated discoid-shaped blood cells 2–3 μm in diameter, which are essential for regulating hemostasis. They are produced in the bone marrow by megakaryocytes, circulating in the blood stream for 5–10 days before being destroyed by phagocytosis in the spleen and liver. A normal platelet count is between 150,000 and 450,000/mm 3 of blood. Platelets provide hemostasis through adhesion, aggregation, and coagulation properties. In response to a vessel wall injury, platelets are instantly activated, adhering themselves to the exposed extracellular matrix . This adhesive effect depends on the interaction between platelet plasma membrane glycoproteins (GPIb) and subendothelial adhesion molecules such as laminin, von Willebrand factor (vWF), fibronectin, and other types of collagen . Platelet activation then leads to dense-granule secretion of calcium, thromboxane, and adenosine diphosphate, which help initiate platelet aggregation . This subsequently triggers the release of platelet granule contents, accelerating platelet aggregation, a process mediated by glycoprotein IIb-IIIa. Aggregation requires the binding of fibrinogen to its receptor on activated platelets. The release of other substances (i.e. platelet factor 4, beta-thromboglobulin, and platelet-derived growth factor) augments aggregation and facilitates thrombus formation. More platelets are then incorporated in the growing thrombus by binding to fibrin, thus leading to clot retraction .
Platelet disorders including thrombocytopenia and thrombocytosis are associated with higher risk of ischemic and hemorrhagic strokes through several mechanisms including increased platelet production, dysfunctional platelets, or autoimmune conditions.
Evaluation of platelet disorders includes objective clinical assessment of bleeding or clotting history, physical examination, and quantifiable and qualitative laboratory investigations. Diagnostic testing includes measurement of platelet count, size, and morphology, platelet granulation, tests for platelet hemostatic function, vWF screening tests, platelet function analyzer (PFA-100) closure time, platelet flow cytometry, and specific assays of platelet aggregation and glycoprotein analysis. Genetic studies and bone marrow examination are essential to differentiate between various types of myeloproliferative disorders (MPDs).
Thrombocytosis and Ischemic Stroke
Thrombocytosis is defined as a platelet count greater than 450,000/mm 3 . The three major pathophysiological causes of thrombocytosis are (1) clonal, including essential thrombocythemia and other MPDs; (2) familial, including rare cases of nonclonal myeloproliferation due to thrombopoietin mutations; and (3) reactive, in which thrombocytosis occurs secondary to a variety of acute and chronic clinical conditions.
Essential Thrombocythemia
Essential (primary) thrombocythemia (ET) or clonal thrombocytosis is a rare nonreactive chronic MPD of unknown etiology characterized by increased platelet count and short platelet survival . The disease affects adult patients of any age, with an incidence of 1.0 per 100,000 population . ET is associated with increased risk of arterial and venous thrombotic events, in particular in older patients with known vascular risk factors for atherosclerosis. Clinical manifestations include headache, visual disturbances, dizziness, lightheadedness, ocular ischemia, and venous and arterial thrombosis. Transient ischemic attack (TIA) and arterial cerebral ischemia (CI) occur in about 25% of patients, and often account for approximately two-thirds of all vascular events. Cerebral vein thrombosis can complicate ET and can be the first manifestation of the disease . Ischemic stroke is more likely to occur in patients with conventional vascular risk factors for atherosclerosis, in the absence of clear correlation between the platelet count and the stroke occurrence .
Diagnosis of ET is made when platelet count is sustained >450,000/mm 3 , with specific morphology on bone marrow biopsy showing proliferation in the megakaryocytic lineage with increased numbers of large mature cells in subjects not meeting the criteria for other MFDs or myeloid neoplasms, and in the presence of Janus kinase-2 ( JAK2 ) VF-mutation, less commonly CALR mutation or other clonal markers, when causes of reactive thrombocytosis have been excluded.
Cerebral ischemic changes usually occur predominantly in the periventricular or subcortical regions, although watershed ischemia in the absence of large-vessel arterial stenosis may occur ( Fig. 117.1 ) . Echocardiography may reveal aortic and mitral valvular lesions, including leaflet thickening and vegetations, similar to those described in nonbacterial thrombotic endocarditis .
Early management is necessary to reduce thrombotic complications. Strict control of vascular risk factors and smoking cessation may reduce the risk of thrombotic event . Although stroke risk does not directly correlate with the severity of thrombocytosis, treatment aims at reducing platelet count to a target of 400,000/mm 3 . Aspirin is typically the antiaggregant of choice, and is usually recommended in patients with ischemic events and those with vascular risk factors . Caution should be used in patients with platelet counts 1,000,000/mm 3 in patients with associated von Willebrand disease due to compromised hemolysis and potential increased bleeding risk . The prophylactic efficacy of antiplatelet agents in asymptomatic subjects with ET and low vascular risk has not been tested. Cytoreductive therapy is indicated in high-risk patients as first-line . Other agents such as interferon alpha, busulfan, and anagrelide may effectively induce hematological remission in ET and should be used as second-line drugs of choice .
Familial Thrombocytosis
Familial thrombocytosis (FT) is a rare genetically heterogeneous disorder caused by thrombopoietin gene mutation. FT has been associated with thrombotic episodes including myocardial infarction and ischemic stroke . Clinical manifestations and management are similar to ET.
Secondary Thrombocytosis
Secondary or reactive thrombocytosis (RT), defined as a platelet count greater than 400,000/mm 3 , is often a normal physiologic response. RT is by far the most common cause of thrombocytosis, observed in over 80% of people. RT may occur due to overproduction of thrombopoietin, interleukin-6, and other proinflammatory cytokines, in response to various stressors including infective state, chronic inflammatory conditions, bleeding disorders, surgical stress, trauma, hemolysis, iron deficiency anemia, post-splenectomy, and malignancy ( Table 117.1 ). RT is usually transient and benign. Arterial occlusive diseases and stroke have been reported in patients with iron deficiency anemia , secondary to cardiopulmonary bypass, and post-splenectomy . Management includes the treatment of the underlying predisposing condition. Antiplatelet therapy is not usually indicated.
Table 117.1
Causes of Reactive Thrombocytosis
| Chronic inflammatory disorders Connective tissues disorders Inflammatory bowel disease |
| Surgery Cardiopulmonary bypass Postsplenectomy |
| Trauma |
| Iron deficiency anemia |
| Hemolytic anemia |
| Infection |
| Malignancy |
| Drugs Vincristine Cytokines |
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