50 - SECTION 3 Disorders of Hemostasis

SECTION 3 Disorders of Hemostasis

Section 3 Disorders of Hemostasis Barbara A. Konkle

Disorders of Platelets

and Vessel Wall Hemostasis is a dynamic process in which the platelet and the blood vessel wall play key roles. Platelets are activated upon adhesion to von Willebrand factor (VWF) and collagen in the exposed subendothelium after injury. Platelet activation is also mediated through shear forces imposed by blood flow itself, particularly in areas where the vessel wall is diseased, and is also affected by the inflammatory state of the endo­ thelium. The activated platelet surface provides the major physiologic site for coagulation factor activation, which results in further platelet activation and fibrin formation. Genetic and acquired influences on the platelet and vessel wall, as well as on the coagulation and fibrino­ lytic systems, determine whether normal hemostasis or bleeding or clotting symptoms will result. THE PLATELET Platelets are released from the megakaryocyte, likely under the influ­ ence of flow in the capillary sinuses. The normal blood platelet count is 150,000–450,000/μL. The major regulator of platelet production is the hormone thrombopoietin (TPO), which is synthesized in the liver and other organs. Synthesis is increased with inflammation and specifically by interleukin 6. TPO binds to its receptor on platelets and megakaryo­ cytes, by which it is removed from the circulation. Thus, a reduction in platelet and megakaryocyte mass increases the level of TPO, which then stimulates platelet production. Platelets circulate with an average life span of 7–10 days. Approximately one-third of the platelets reside in the spleen, and this number increases in proportion to splenic size, although the platelet count rarely decreases to <40,000/μL as the spleen enlarges. Platelets are physiologically very active, but are anucleate, and thus have limited capacity to synthesize new proteins. Normal vascular endothelium contributes to preventing thrombosis by inhibiting platelet function (Chap. 69). When vascular endothelium is injured, these inhibitory effects are overcome, and platelets adhere to the exposed intimal surface primarily through VWF, a large multi­ meric protein present in both plasma and in the extracellular matrix of the subendothelial vessel wall. Platelet adhesion results in the genera­ tion of intracellular signals that lead to activation of the platelet glyco­ protein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation. Activated platelets undergo release of their granule contents, which include nucleotides, adhesive proteins, growth factors, and procoagu­ lants that serve to promote platelet aggregation and blood clot forma­ tion and influence the environment of the forming clot. During platelet aggregation, additional platelets are recruited to the site of injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is stabilized by the fibrin mesh that develops simultaneously as the product of the coagulation cascade. THE VESSEL WALL Endothelial cells line the surface of the entire circulatory tree, totaling 1–6 × 1013 cells, enough to cover a surface area equivalent to about six tennis courts. The endothelium is physiologically active, control­ ling vascular permeability, flow of biologically active molecules and nutrients, blood cell interactions with the vessel wall, the inflammatory response, and angiogenesis. The endothelium normally presents an antithrombotic surface (Chap. 69) but rapidly becomes prothrombotic when stimulated, which promotes coagulation, inhibits fibrinolysis, and activates plate­ lets. In many cases, endothelium-derived vasodilators are also platelet inhibitors (e.g., nitric oxide), and conversely, endothelium-derived

vasoconstrictors (e.g., endothelin) can also be platelet activators. The net effect of vasodilation and inhibition of platelet function is to promote blood fluidity, whereas the net effect of vasoconstriction and platelet activation is to promote thrombosis. Thus, blood fluidity and hemostasis are regulated by the balance of antithrombotic/prothrom­ botic and vasodilatory/vasoconstrictor properties of endothelial cells.

DISORDERS OF PLATELETS ■ ■THROMBOCYTOPENIA Thrombocytopenia results from one or more of three processes: (1) decreased bone marrow production; (2) sequestration, usually in an enlarged spleen; and/or (3) increased platelet destruction. Disorders of production may be either inherited or acquired. In evaluating a patient with thrombocytopenia, a key step is to review the peripheral blood smear and to first rule out “pseudothrombocytopenia,” particularly in a patient without an apparent cause for the thrombocytopenia. Pseu­ dothrombocytopenia (Fig. 120-1B) is an in vitro artifact resulting from platelet agglutination via antibodies (usually IgG, but also IgM and IgA) when the calcium content is decreased by blood collection in eth­ ylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes [purple top] used to collect blood for complete blood counts [CBCs]). If a low platelet count is obtained in EDTA-anticoagulated blood, a blood smear should be evaluated and a platelet count determined in blood collected into sodium citrate (blue top tube) or heparin (green top tube), or a smear of freshly obtained unanticoagulated blood, such as from a finger stick, can be examined. CHAPTER 120 Disorders of Platelets and Vessel Wall APPROACH TO THE PATIENT Thrombocytopenia The history and physical examination, results of the CBC, and review of the peripheral blood smear are all critical components in the initial evaluation of thrombocytopenic patients (Fig. 120-2). The overall health of the patient and whether they are receiving drug treatment will influence the differential diagnosis. A healthy young adult with thrombocytopenia will have a much more lim­ ited differential diagnosis than an ill hospitalized patient who is receiving multiple medications. Except in less common inherited disorders, decreased platelet production usually results from bone marrow disorders that also affect red blood cell (RBC) and/or white blood cell (WBC) production. Because myelodysplasia can present with isolated thrombocytopenia, the bone marrow should be exam­ ined in patients presenting with isolated thrombocytopenia who are older than 60 years of age or who do not respond to initial therapy. While inherited thrombocytopenia is uncommon, any prior platelet counts should be retrieved and a family history regarding thrombo­ cytopenia obtained. A careful history of drug ingestion should be obtained, including nonprescription and herbal remedies, because drugs are the most common cause of thrombocytopenia. The physical examination can document an enlarged spleen, evidence of chronic liver disease, and other underlying disorders. Mild to moderate splenomegaly may be difficult to appreciate in many individuals due to body habitus and/or obesity but can be eas­ ily assessed by abdominal ultrasound. A platelet count of approxi­ mately 5000–10,000 is required to maintain vascular integrity in the microcirculation. When the count is markedly decreased, petechiae first appear in areas of increased venous pressure, the ankles and feet in an ambulatory patient. Petechiae are pinpoint, nonblanching hemorrhages and are usually a sign of a decreased platelet num­ ber and not platelet dysfunction. Wet purpura, blood blisters that form on the oral mucosa, are thought to denote an increased risk of life-threatening hemorrhage in the thrombocytopenic patient. Excessive bruising is seen in disorders of both platelet number and function. Infection-Induced Thrombocytopenia  Many viral and bacte­ rial infections result in thrombocytopenia and are the most common