الفهرس 
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Abstract
Most disorders of platelet function are acquired; heritable qualitative platelet disorders are rare. When critical pathways of platelet biochemistry are perturbed, bleeding typically occurs, but because of redundancy of biochemical and receptor pathways that mediate the function of platelets, other defects may be detectable only on laboratory testing and do not produce clinically significant bleeding. In most cases, transfusion of platelets or other therapies will (temporarily) augment hemostasis in a patient with a congenital or acquired qualitative platelet disorder who has bleeding or who is to undergo an invasive procedure.
Subendothelial molecules such as VWF, collagen, and fibronectin mediate adhesion of platelets to the exposed subendothelial matrix at sites of vessel wall compromise. In “high-shear” states such as arterioles, VWF is especially important, because it tethers the platelet to the endothelial surface via interaction with its receptor, platelet glycoprotein (GP) Ib (GPIb).
Subendothelial collagen activates platelets; thrombin, which has been generated locally in reactions following the interaction of factor VIIa and tissue factor (provided by the membranes of cells), also activates platelets by binding to receptors on the platelet surface and initiating a series of signal transduction events.
Agonists such as collagen, thrombin, adenosine triphosphate (ADP), and epinephrine bind to their receptors on the platelet membrane and induce a series of biochemical events that cause platelets to release the contents of their granules (Table 21.4), which act to promote further activation and aggregation.
Binding of agonists also promotes a conformational change in the platelet GP IIb/IIIa receptor, exposing its binding sites for fibrinogen and VWF; these molecules can then bridge between individual platelets at the site of vascular injury, promoting the formation and stability of the platelet plug.
Bernard-Soulier syndrome (BSS) comprises a triad including large platelets, moderate thrombocytopenia, and a prolonged bleeding time; individuals with this disorder have reduced or abnormal expression of platelet glycoprotein Ib/IX (the receptor for VWF) on the surface of their platelets. BSS is autosomal recessively inherited. Platelet aggregation studies are normal with all agonists except ristocetin. BSS is distinguished from VWD in that the reduced ristocetin-induced platelet aggregation in BSS is corrected by the addition of normal platelets, whereas in VWD, it is corrected by the addition of normal plasma (which contains adequate VWF). The diagnosis can be confirmed by platelet flow cytometry.
Glanzmann’s thrombasthenia is a recessively inherited qualitative or quantitative abnormality in GP IIb/IIIa expression on the platelet surface. Without adequate functional IIb/IIIa to bind fibrinogen and VWF (both of which cross-link platelets), platelet aggregation is markedly impaired. Patients may present with mucocutaneous bleeding in infancy. Interestingly, the severity of clinical bleeding does not correlate well with the degree of deficiency of IIb/IIIa. Allogeneic HSCT has been used in the management of severe cases.
The most common acquired qualitative platelet disorders are caused by the use of medications that directly or indirectly impair platelet function of these, aspirin and the nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently responsible. Patients who present with bruising or platelet-type bleeding and whose platelet function testing shows abnormal aggregation or secretion should be questioned regarding current medications, especially recently initiated drugs and including over-the-counter, naturopathic, and herbal agents. Treatment of clinically significant drug-induced platelet dysfunction first involves discontinuation of the offending agent and may require additional measures.
Aspirin irreversibly inhibits the platelet cyclooxygenase enzyme, which is responsible for the conversion of membrane-associated arachidonic acid to thromboxane A2 (TxA2); the inhibition is constant for the entire life span of the platelet (~7 days). Once liberated from the platelet, TxA2 binds to receptors on adjacent platelets, initiating secretion of platelet granule contents and further promoting aggregation. Platelet aggregation studies show decreased reactivity to most agonists, including low concentration of thrombin and collagen, but normal aggregation with high concentrations of thrombin and collagen. Using the PFA-100 system, aspirin-induced platelet dysfunction is evident in an increased time to aperture occlusion with the epinephrine/collagen reagent, while that of the ADP/collagen reagent is unaffected.
NSAIDs reversibly inhibit platelet cyclooxygenase; their inhibitory effect persists only as long as the drug is present in the circulation. Selective inhibitors of cyclooxygenase-2 (COX-2) do not bind or impair platelet cyclooxygenase (COX-1).
Platelet glycoprotein IIb/IIIa inhibitors are used in the management of patients with acute coronary syndromes or before or following percutaneous coronary intervention (PCI), frequently in conjunction with heparin.
Ticlopidine and clopidogrel irreversibly inhibit the binding of ADP to its receptor on the platelet membrane, impairing the ADP-dependent binding of fibrinogen to GPIIb/IIa, decreasing platelet aggregation. Neutropenia and aplastic anemia have been reported with increased frequency in patients taking ticlopidine (5); TTP has been described with use of ticlopidine and less frequently with clopidogrel.
Dipyridamole is used to prevent recurrent stroke or transient ischemic attack, usually in conjunction with aspirin. It inhibits ADP- and collagen-induced platelet aggregation via an effect on intracellular cyclic AMP.
The platelets that are produced in myelodysplasia (MDS) and the myeloproliferative disorders (chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis) may show abnormal receptor-ligand interactions, ineffective signal transduction, or decreased secretion of platelet granule contents; in a minority of patients these abnormalities lead to bleeding.
Platelets from individuals with impaired kidney function frequently show abnormalities upon aggregation testing. Although plasma urea itself may not be causative, other factors, such as increased levels of nitric oxide (9) or other products can cause decreased binding of fibrinogen to platelet GP IIb/IIIa or impaired release of platelet granules. Some of these patients experience clinically important bleeding, especially gastrointestinal (9). DDAVP (standard doses) (3), cryoprecipitate, and high-dose estrogens have been suggested to be of benefit in uremia-related bleeding. Because the presence of adequate numbers of intravascular red cells may facilitate interaction of platelets with the vessel wall, red cell transfusions are recommended in patients with anemia related to renal failure who are bleeding, to keep the hematocrit above 30% (11). Platelet transfusion may be beneficial temporarily if other measures fail and bleeding persists. If a dialyzable substance in the uremic plasma is responsible for the defect in platelet function, hemodialysis also may be beneficial.