Thrombosis

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Chapter 10 Thrombosis

Overview of Thrombosis

Abnormal hemostasis leads to thrombus formation. Thrombosis in either the arterial or venous system is a leading cause of significant morbidity and mortality. When thrombosis occurs in the arterial system, myocardial infarction (MI) and stroke may result, whereas thrombosis in the venous system leads to venous thromboembolic disease. Thrombosis and thrombotic-related events are among the most common causes of mortality in the Western World. It is estimated that 785,000 people in the United States had new thrombotic events within the coronary circulation in 2009, and that over 450,000 had recurrent events. Stroke also accounts for significant morbidity, with 795,000 people per year suffering from a thrombotic event within the cerebral circulation. There are 200,000 new cases of venous thromboembolism each year, 30% of which result in death in the first 30 days after diagnosis, the majority of deaths being sudden in the setting of a pulmonary embolism (PE).

The pathogenesis of thrombosis was elucidated as early as 1856 when Virchow first described its major determinants, including abnormalities in the vessel wall, platelets, and coagulation proteins as essential for establishing a thrombus. The composition of arterial thrombi is distinct from that of thrombi that form in the venous circulation. Arterial thrombi are composed mainly of platelets and occur in areas of vascular wall injury; venous thrombi, by contrast, are rich in fibrin and dependent on a hypercoagulable response associated with individual coagulation factor abnormalities or mechanical issues related to blood flow limitation. Under normal circumstances, the endothelial lining is not a thrombotic surface, with endothelial cells (ECs) constantly interacting with other cell types, including platelets, to directly inhibit thrombus formation through release of antithrombotic factors such as thrombomodulin, tissue factor pathway inhibitor (TFPI), plasmin, and antithrombin systems. At the same time, platelet aggregation is inhibited through prostacyclins and nitric oxide (NO) released directly from platelets.

When the endothelial surface becomes damaged, however, release of many procoagulant proteins (especially tissue factor) and activation of platelets result in uncontrolled hemostasis at the site of vascular injury.1 As the thrombus begins to form, it recruits additional platelets to the area, leading to further platelet activation. Initially, tethering of platelets is dependent upon exposure of glycoprotein (Gp)Ib-V-IX in damaged collagen, which binds to von Willebrand factor (vWF), resulting in adhesion of platelets to the area of injury. Further recruitment of platelets is mediated through activation of the GPIIb-IIa platelet receptor, which undergoes a conformational change leading to increased affinity for fibrinogen. These events culminate with further platelet activation that results in release of many essential components for thrombus formation, including adenosine diphosphate (ADP), serotonin, and thromboxane A 2 (TxA2).

Exposure of vascular collagen also leads to activation of the normal mechanisms of hemostasis—including the coagulation cascade—through exposure of tissue factor, leading to “hemostasis in the wrong place.” The coagulation regulatory system is outlined in Figure 10-1 and discussed in detail in Chapter 5. Briefly, both the tissue factor–mediated pathway (extrinsic) and the contact-mediated pathway (instrinsic pathway) rely on activation of inactive enzyme precursors of serine proteases, which then reflexively lead to activation of another protein within the cascade. The ultimate step results in cross-linking of fibrin to stabilize a platelet plug, leading to thrombus formation. The tissue factor–initiated pathway is essential for thrombus formation. When tissue factor is released during cellular injury, factor VII is activated and complexes. This complex next activates factors X and XI. Activation of factor X is essential for conversion of prothrombin (factor II) to thrombin through the prothrombinase complex on activated platelets. This cascade of coagulation proteins is essential for hemostasis but also can have deleterious affects when it occurs unregulated, leading to unwanted thrombotic complications.

Platelets, Thrombosis, and Vascular Disease

Venous Thrombosis

It is estimated that between 100,000 and 180,000 deaths due to a venous thromboembolic event occur annually. These events occur mainly in the vasculature at the area of the vessel sinus where stasis can lead to a hypercoagulable microenvironment. The hemostatic process is activated when tissue factor is exposed at the site of vascular injury; initiation of the coagulation cascade follows, with subsequent formation of thrombin and conversion of fibrinogen to fibrin. This process evolves at the same time platelets are actively being recruited to the area of injury through collagen exposure, leading to platelet and fibrin thrombus formation. A number of physiological anticoagulants are also present and modulate this response: antithrombin, TFPI, and activated protein C (APC) and its cofactor protein S. Defects in these hemostatic proteins can lead to disorders that elevate the risk of thrombus formation.

Risk factors for venous thromboembolism are associated with venous stasis or acquired and congenital hypercoagulable states and include obesity, smoking, malignancy, pregnancy, hormone therapy, and recent trauma or surgery. Immobilization due to prolonged hospitalization following surgical intervention, and during long-distance air travel also contribute to the risk of VTE.

Genetic risk factors associated with increased risk of VTE include mutations in factor V (Leiden) and prothrombin 20210, as well as mutations leading to deficiencies in antithrombin, protein C, and protein S. Approximately 5% of the Caucasian population has at least one mutation for factor V Leiden, and 15% to 20% of patients who present with a VTE carry the mutation.25 Approximately 2% of the population carry the prothrombin gene mutation, but it may be present in approximately 5% to 15% of persons with VTE.6 The population frequencies of mutations in other genes responsible for other coagulation factors (e.g., protein C) are estimated to be 1 in 500 individuals. Antithrombin III deficiency is associated with a frequency of 1 in 300 in the general population, and in 3% to 5% of those with thrombotic events. Previously it was thought that genetic mutations in genes important for methylene tetrahydrofolate reductase and hyperhomocysteinemia increased the risk of VTEs; however, recently this association has been shown to be less likely.7

One of the acquired risk factors known to be important in both venous and arterial thrombosis is acquisition of antiphospholipid antibodies, which represent a family of antibodies against phospholipids (e.g., cardiolipins) and phospholipid binding proteins (e.g., GpI β2). Mechanisms responsible for thrombosis are still speculative but may include inhibition of protein C, antithrombin, and annexin A5 expression; binding and activation of platelets; enhanced EC tissue factor expression; and activation of the complement cascade.8 Criteria for diagnosis of the associated disorder, antiphospholipid syndrome, includes the presence of both clinical events and laboratory evidence for the presence of antiphospholipid antibodies.9

Arterial Thrombosis

Arterial thrombosis, which accounts for MI and thrombotic cerebrovascular events, initiates from damage to the vessel wall, leading to a cascade of platelet-mediated cellular interactions. Endothelial injury resulting from plaque rupture with exposure of subendothelial collagen and vWF is the core event that leads to arterial thrombosis. Platelet activation through direct interaction with exposed collagen or thrombin generated by tissue factor leads to thrombus formation. Important in this process are platelet factors that are released with activation, including ADP, serotonin, and TxA. Recruitment of additional platelets leads to thrombus growth as platelets aggregate through bridges formed from the binding of fibrinogen to the platelet receptor GpIIb-IIIa. Recruitment and activation of platelets is modulated by a tightly regulated process that involves factors released from the platelet as well as the endothelium, including prostacyclin, NO, and ecto-AD (T)Pase. Prostacyclin, which is generated from arachidonic acid by the endothelium works through cyclic adenosine monophosphate (cAMP) to inhibit platelet function. Nitric oxide, through stimulation of the soluble guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), directly inhibits platelet activation and prevents thrombosis; cGMP signaling cascades lead to a decrease in fibrinogen binding to GpIIb-IIIa and inhibits the phospholipase A2 and C pathways.

A primary mechanism of arterial thrombosis is rupture of atherosclerotic plaques, precipitating platelet-rich aggregates. Arterial thrombosis can have catastrophic consequences when it occurs in the coronary or carotid artery circulation. Factors that can exacerbate these types of thrombotic events include smoking, diabetes, hypertension, and hyperlipidemia. Thrombosis generally occurs when there is disruption in the hemostatic balance that results when pro- and anticoagulant molecules are at disequilibrium. Endothelial damage shifts this balance towards a more procoagulant force, leading to exposure of collagen and tissue factor. Collagen that is now exposed can activate platelets in the blood flowing through the vessel, and concomitantly thrombin is generated as the coagulation cascade is initiated in the presence of tissue factor. Genetic modifications of proteins important in coagulation can alter this process, creating a propensity to form thrombi in the arterial system (Box 10-1). These mutations affect platelet function, leading to increased propensity to aggregation.