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Disorders of primary hemostasis have a vast differential diagnosis and may present in a variety of medical, obstetric, surgical, and critical care settings. When evaluating patients with thrombocytopenia or evidence of qualitative platelet dysfunction, clinicians must determine the significance of the platelet count as well as the risk for bleeding, thrombosis, and other potential complications. In one study, thrombocytopenia was observed in approximately 1% of adult inpatients in acute care hospitals.1 Surgical bleeding is of concern when platelet counts are <50,000/µL, or <100,000/µL in patients undergoing some high-risk cardiac, orthopedic, or neurosurgical procedures.2 In intensive care units (ICUs), thrombocytopenia develops in 13% to 44% of patients during their admission.2 Clinicians must be familiar with the conditions leading to disorders of primary hemostasis because swift, accurate identification of the underlying cause is crucial for appropriate management. This article reviews disorders of primary hemostasis that range in severity from benign to life-threatening, focusing on pathophysiology, distinguishing features, diagnostic assessment, and treatment.
Physiology of primary hemostasis
Megakaryocytes, which are derived from hematopoietic stem cell precursors in bone marrow, form and release platelets; these circulate in the blood for 8 to 10 days before they are removed by hepatic or splenic macrophages. The concentration of circulating platelets is normally 150,000 to 450,000/µL. A platelet count <150,000/µL traditionally defines thrombocytopenia; however, 2.5% of the population has a baseline concentration <150,000/µL.2 Clinicians should repeat the platelet count for trending; if the count is stable for 6 months, it is usually a normal variant.1 Normal vascular endothelium opposes thrombosis by resisting interactions with platelets and coagulation factors. Damage to vessels exposes collagen fibrils that trigger a series of adhesive reactions, allowing platelets to bind to the subendothelium and to other platelets to form a temporary hemostatic plug. A large protein, von Willebrand factor (vWF), is synthesized, stored in, and secreted by vascular endothelial cells following stimulation. Plasma vWF binds platelets to the subendothelial collagen via its platelet glycoprotein Ib complex. Platelets also have receptors that bind directly to collagen. Normal engagement of these receptors enhances platelet activation and signals extension of the plug. Activated platelets release pro-aggregatory granules containing adenosine 5′-diphosphate (ADP) and thromboxane A2 to amplify recruitment and aggregation. Fibrinogen and vWF also bind activated platelets together via the platelet glycoprotein IIb/IIIa complex. The hemostatic plug stops bleeding in a superficial wound. Initiation of the clotting cascade triggers secondary hemostasis, which culminates in the formation of a fibrin mesh that cross-links, reinforces, and further stabilizes the platelet plug. As a carrier protein for clotting factor VIII, vWF also functions in secondary hemostasis by protecting this factor from degradation.
Manifestations of disorders of primary and secondary hemostasis
Platelets play an essential role in preserving vessel wall integrity. Deficiency or dysfunction of platelets cause defects in primary hemostasis, characterized by superficial mucocutaneous bleeding and a prolonged bleeding time. Petechiae result from capillary bleeding and are likely to develop on dependent body regions. Confluence of petechiae results in the formation of purpura, which is “dry” when located on the skin and “wet” when located on mucous membranes. Wet purpura signifies potentially more serious hemorrhage.2 The common bleeding manifestations of primary hemostasis disorders (Table 1) occur frequently in many of the disorders discussed in this review. Because the normal values for platelets are >150,000/µL, the blood has a large protective reservoir. Mild thrombocytopenia is defined by platelet levels of 100,000 to 150,000/µL, moderate thrombocytopenia by levels of 50,000 to 100,000/µL, and severe thrombocytopenia by levels <50,000/µL. Significant spontaneous bleeding usually does not occur until platelet counts are <10,000 to 20,000/µL.1 Severe thrombocytopenia confers a greater risk for bleeding, but correlation between the platelet count and risk for bleeding varies with the underlying condition. Comparatively, clotting factor deficiency or dysfunction results in disorders of secondary hemostasis and may cause delayed, deep, or prolonged bleeding. Bleeding into the central nervous system (CNS), hemarthrosis (bleeding into the fingers, wrists, knees, feet, and spine), deep muscle hematomas, or retroperitoneal bleeding usually indicates a clotting factor disorder. Clinically, no specific type, location, or quantity of bleeding is certain to differentiate a primary from a secondary disorder of hemostasis, and both can be severe, even life-threatening. Laboratory testing will reveal a prolonged bleeding time with or without thrombocytopenia in a disorder of primary hemostasis; disorders of secondary hemostasis are characterized by prolongation of the partial thromboplastin time (PTT) with or without prolongation of the prothrombin time (PT), depending on the clotting factors affected. In disorders of secondary hemostasis, the bleeding time and platelet count will be normal. Disorders of secondary hemostasis are outside the scope of this article but may be discussed in the differential diagnoses as appropriate.