Inherited platelet disorders: thrombocytopenias and thrombocytopathies.

Abstract

Platelets play an important role in normal haemostasis halting blood flow immediately after injuries through four fundamental different mechanisms: adhesion, aggregation, secretion, and expression of procoagulant activity. First, in the presence of vascular damage, platelets adhere to the connective tissue and, particularly when the damage occurs in vessels with a low shear rate, to subendothelial collagen, fibronectin and laminin. On the other hand, when damage occurs in regions with a high shear rate, platelet adhesion requires the presence of subendothelial von Willebrand factor (VWF) and specific platelet receptors, such as the glycoprotein Ib/IX/V (GPIb/IX/V) complex. In any case, following initial adhesion, platelets aggregate to complete the formation of a solid haemostatic plug. Platelet aggregation requires stimulation by agonists such as ADP, thrombin, collagen, or epinephrine, as well as the presence of calcium or magnesium ions and specific plasma proteins (fibrinogen, VWF and the glycoprotein IIb/IIIa (GPIIb/IIIa) complex). Platelet stimulation results in the generation of intracellular second messengers that convey the stimulus back to the platelet surface, exposing protein binding sites on GPIIb/IIIa. Fibrinogen (or VWF) then binds to GPIIb/IIIa and cross-links adjacent platelets to produce platelet aggregates, following platelet secretion and the elaboration of platelet procoagulant activity. In platelet disorders caused by a reduction in the number of platelets (thrombocytopenia) (Table I) or by platelet function defects (thrombocytopathies) (Table II), bleeding generally occurs immediately after injury, primarily in the skin, mucous membranes, nose, and gastrointestinal and urinary tracts and, generally, does not involve joints and muscles. Congenital disorders are uncommon and sometimes may be misdiagnosed with acquired disorders, which are much more frequently encountered in clinical practice. The differential diagnosis between congenital or acquired platelet disorders is often very complex and requires medical experience and a careful assessment of the patient’s personal and family history of bleeding episodes. A lifelong bleeding diathesis may suggest a congenital platelet disorder, which is often first recognised during childhood, but an onset in adulthood does not exclude a congenital defect. Because technological progress in laboratory practices and greater information about platelet functions have increased the specificity and accuracy of diagnosis of platelet disorders, a large number of cases has been identified recently. In this review, we describe current knowledge on congenital platelets disorders with regards to granule packaging, signalling and platelet coagulant function, and hereditary thrombocytopenias in order to improve information available for research and clinical practice. Table I Classification of thrombocytopathies