Disorders of Hemostasis

Anatomy and Physiology

Vascular integrity is maintained by a lining of overlapping endothelial cells supported by a basement membrane, connective tissue, and smooth muscle. These cells are important in maintaining a barrier to macromolecules, secreting clot-preventing substances and, when injured, in contributing to the metabolic response and local vasoconstriction. The endothelium regulates clot formation by secreting substances such as tissue factor pathway inhibitor (TFPI) and heparin sulfate, preventing propagation of the coagulation pathway, as well as prostacyclin and nitric oxide, which prevent platelet aggregation and act as vasodilators. The endothelium also expresses CD39 (cluster of differentiation 39), which degrades adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP), a potent antiplatelet and antithrombotic, and adenosine, a potent locally acting platelet inhibitor that prevents platelet plug formation ( Fig. 111.1A ). When the endothelium’s physical barrier has been compromised, exposed von Willebrand factor (vWF) links to platelet glycoprotein Ib (gpIb) receptors allowing platelet adhesion to the intravascular surface. Normal inhibitory mechanisms are disrupted through damage to the endothelial cells, allowing ATP and ADP to interact with receptors to amplify platelet activation ( Fig. 111.1B ).

Platelets have multiple roles in hemostasis. They are complex cytoplasmic fragments released from bone marrow megakaryocytes largely regulated by thrombopoietin. After initial exposure to damaged endothelium, platelets display glycoproteins to aid in adhesion and aggregation, such as gpIb and gpIIa/IIIb. Platelets also contain lysosomes, microtubules, and granules, among other components. Granules contain over 300 metabolically active substances, including platelet factor 4, additional adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors. Each participates in the process of coagulation and contributes to overall wound healing through the mediation of inflammation, immune response, and infection control. Platelet activity is summarized in Box 111.1 . Any step in the platelet pathway may be absent, altered, or inhibited by inherited or acquired disorders. The coagulation cascade forms fibrin, and cross-linked fibrin serves to reinforce the initial platelet plug.

The coagulation pathway is a complex system of checks and balances that results in controlled formation of a fibrin clot. Coagulation factors are summarized in Box 111.2 , and a simplified coagulation pathway is presented in Figure 111.2 . The clotting cascade is traditionally depicted as consisting of intrinsic and extrinsic pathways. A more modern approach is to view the extrinsic pathway as the initiation phase with exposed tissue factor at the site of vessel injury, and the intrinsic pathway as a parallel and amplification pathway. Both pathways converge to activate factor X, which then converts prothrombin to thrombin. Tissue factor is a critical cofactor that is required for activation of factor VII. Because of limited amounts of tissue factor and rapid inactivation by TFPI, the extrinsic pathway initiates the clot process, though sustained generation of thrombin and clot formation is dependent on the intrinsic pathway through activation of factor IX by activated factor VII. Once coagulation is initiated, controls are necessary to prevent overzealous local or generalized thrombosis ( Box 111.3 ).

Pathophysiology

Hemostasis is dependent on normal functioning and integration of the vasculature, platelets, and coagulation pathway. The most commonly encountered disorder of hemostasis is antithrombotic drug administration, including use of antiplatelet or anticoagulant medications. Disorders of hemostasis may also be congenital, or secondary to disease states that affect the various steps of the hemostatic pathway such as malignancy or hepatic dysfunction. Due to the interconnectedness between the endothelium and platelets, vascular disorders may share similar historical or examination features with platelet disorders. Despite some overlap, disorders of hemostasis are frequently grouped into vascular disorders (often with a component of platelet dysfunction), platelet disorders, and coagulation disorders.

Complete Blood Count and Blood Smear

The complete blood count can, in some cases, assess the degree of anemia associated with a bleeding episode. Reductions in hemoglobin and hematocrit often lag behind the actual loss of RBCs in acute hemorrhage owing to the time necessary for equilibration. The peripheral blood smear may demonstrate schistocytes or fragmented RBCs in microangiopathic hemolytic anemias, such as TTP or DIC. Teardrop-shaped or nucleated RBCs may reflect myelophthisic disease where hematopoietic bone marrow is infiltrated and replaced by fibrosis, tumors, or granulomas. Characteristic white blood cell morphologies are seen with thrombocytopenia associated with infectious mononucleosis (e.g., increased WBC cytoplasm and nucleoli in the nuclei), folate or vitamin B ₁₂ deficiency (e.g., hypersegmented neutrophils), or leukemia (e.g., immature WBCs, hairy cell lymphocytes, and myeloblasts with Auer rods).