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InternalMed_Harrison. Treatment with FFP is the most effective to correct hemostasis in patients with liver failure. Infusion of FFP (5–10 mL/kg; each bag contains ~200 mL) is sufficient to ensure 10–20% of normal levels of clotting factors but not correction of PT or aPTT. Even high doses of FFP (20 mL/kg) do not correct the clotting times in all patients. Monitoring for clinical symptoms and clotting times will determine if repeated doses are required 8–12 h after the first infusion. Platelet concentrates are indicated when platelet counts are <10,000–20,000/μL to control an ongoing bleed or immediately before an invasive procedure if counts are <50,000/μL. Cryoprecipitate is indicated only when fibrinogen levels are less than 100 mg/mL; dosing is six bags for a 70-kg patient daily. Prothrombin complex concentrate infusion in patients with liver failure should be avoided due to the high risk of thrombotic complications. The safety of the use of antifibrinolytic drugs to control bleeding in patients with


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InternalMed_Harrison. infusion in patients with liver failure should be avoided due to the high risk of thrombotic complications. The safety of the use of antifibrinolytic drugs to control bleeding in patients with liver failure is not yet well defined and should be avoided.


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InternalMed_Harrison. liver disease and tHromboembolism The clinical bleeding phenotype of hemostasis in patients with stable liver disease is often mild or even asymptomatic. However, as the disease progresses, the hemostatic bal ance is less stable and more easily disturbed than in healthy individuals. Furthermore, the hemostatic balance is compromised by comorbid complications such as infections and renal failure (Fig. 141-4). Based on the clinical bleeding complications in patients with cirrhosis and laboratory evidence of hypocoagulation such as a prolonged PT/aPTT, it has long been assumed that these patients are protected against thrombotic disease. Cumulative clinical experience, however, has demonstrated that these patients are at risk for thrombosis, especially those with advanced liver disease. Although hypercoagulability could explain the occurrence of venous thrombosis, according to Virchow’s with liver disease, and may be due to con-BLEEDING THROMBOSIS gestive splenomegaly (hypersplenism) or


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InternalMed_Harrison. hypercoagulability could explain the occurrence of venous thrombosis, according to Virchow’s with liver disease, and may be due to con-BLEEDING THROMBOSIS gestive splenomegaly (hypersplenism) or immune-mediated shortened platelet lifespan (primary biliary cirrhosis). In addition, several anatomic abnormalities secondary to underlying liver disease further promote the occurrence of hemorrhage (Table 141-3). Dysfibrinogenemia is a relatively common finding in patients with liver disease due to impaired fibrin polymerization. The development of DIC concomitant to chronic liver disease is not uncommon and may enhance the risk for bleeding. Laboratory evaluation is mandatory for an optimal therapeutic strategy, either to control ongoing bleeding or to prepare patients with liver disease for invasive procedures. Typically, these patients present with prolonged PT, aPTT, and TT depending on the degree of liver damage, thrombocytopenia, and normal or slight increase of FDP. Fibrinogen levels


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InternalMed_Harrison. procedures. Typically, these patients present with prolonged PT, aPTT, and TT depending on the degree of liver damage, thrombocytopenia, and normal or slight increase of FDP. Fibrinogen levels are diminished only in fulminant hepatitis, decompensated cirrhosis, or advanced liver disease, or in the presence of DIC. The presence of prolonged TT and normal fibrinogen and FDP levels suggest dysfibrinogenemia. FVIII levels are often normal or elevated in patients with liver failure, and decreased levels suggest superimposing DIC. Because FIGURE 141-4 Balance of hemostasis in liver disease. TAFI, thrombin-activated fibrinolytic FV is only synthesized in the hepatocyte and inhibitor; t-PA, tissue plasminogen activator; VWF, von Willebrand factor.


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InternalMed_Harrison. 740 triad, hemodynamic changes and damaged vasculature may also be a contributing factor, and both processes may potentially also occur in patients with liver disease. Liver-related thrombosis, in particular, thrombosis of the portal and mesenteric veins, is common in patients with advanced cirrhosis. Hemodynamic changes, such as decreased portal flow, and evidence that inherited thrombophilia may enhance the risk for portal vein thrombosis in patients with cirrhosis suggest that hypercoagulability may play a role as well. Patients with liver disease develop deep vein thrombosis and pulmonary embolism at appreciable rates (ranging from 0.5 to 1.9%). The implication of these findings is relevant to the erroneous exclusion of thrombosis in patients with advanced liver disease, even in the presence of prolongation of routine clotting times, and caution should be advised on overcorrection of these laboratory abnormalities.


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InternalMed_Harrison. ACQUIRED INHIBITORS OF COAGULATION FACTORS An acquired inhibitor is an immune-mediated disease characterized by the presence of an auto-antibody against a specific clotting factor. FVIII is the most common target of antibody formation, and is sometimes referred to as acquired hemophilia A, but inhibitors to prothrombin, FV, FIX, FX, and FXI are also reported. Acquired inhibitor to FVIII occurs predominantly in older adults (median age of 60 years), but occasionally in pregnant or postpartum women with no previous history of bleeding. In 50% of patients with inhibitors, no underlying disease is identified at the time of diagnosis. In the remaining patients, the causes are autoimmune diseases, malignancies (lymphomas, prostate cancer), dermatologic diseases, and pregnancy. Bleeding episodes occur commonly in soft tissues, the gastrointestinal or urinary tracts, and skin. In contrast to hemophilia, hemarthrosis is rare in these patients. Retroperitoneal hemorrhages and other


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InternalMed_Harrison. episodes occur commonly in soft tissues, the gastrointestinal or urinary tracts, and skin. In contrast to hemophilia, hemarthrosis is rare in these patients. Retroperitoneal hemorrhages and other life-threatening bleeding may appear suddenly. The overall mortality in untreated patients ranges from 8 to 22%, and most deaths occur within the first few weeks after presentation. The diagnosis is based on the prolonged aPTT with normal PT and TT. The aPTT remains prolonged after mixture of the test plasma with equal amounts of pooled normal plasma for 2 h at 37°C. The Bethesda assay using FVIII-deficient plasma as performed for inhibitor detection in hemophilia will confirm the diagnosis. Major bleeding is treated with bypass products such as PCC/aPCC or recombinant FVIIa. In contrast to hemophilia, inhibitors in nonhemophilic patients are typically responsive to immune suppression, and therapy should be initiated early for most cases. The first choice includes steroid or a combination of


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InternalMed_Harrison. inhibitors in nonhemophilic patients are typically responsive to immune suppression, and therapy should be initiated early for most cases. The first choice includes steroid or a combination of steroid with cytotoxic therapy (e.g., cyclophosphamide), with complete eradication of the inhibitors in more than 70% of patients. High-dose intravenous γ-globulin and anti-CD20 monoclonal antibody have been reported to be effective in patients with autoantibodies to FVIII; however, there is no firm evidence that these alternatives are superior to the first line of immunosuppressive drugs. Notably, relapse of the inhibitor to FVIII is relatively common (up to 20%) within the first 6 months following withdrawal of immunosuppression. Thus, after eradication, patients should be followed up regularly for early therapeutic intervention when indicated or prior to invasive procedure.


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InternalMed_Harrison. Topical plasma-derived bovine and human thrombin are commonly used in the United States and worldwide. These effective hemostatic sealants are used during major surgery such as for cardiovascular, thoracic, neurologic, pelvic, and trauma indications, as well as in the setting of extensive burns. The development of antibody formation to the xenoantigen or its contaminant (bovine clotting protein) has the potential to show cross-reactivity with human clotting factors that may hamper their function and induce bleeding. Clinical features of these antibodies include bleeding from a primary hemostatic defect or coagulopathy that sometimes can be life threatening. The clinical diagnosis of these acquired coagulopathies is often complicated by the fact that the bleeding episodes may be detectable during or immediately following major surgery and could be assumed to be due to the procedure itself.


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InternalMed_Harrison. Notably, the risk of this complication is further increased by repeated exposure to topical thrombin preparations. Thus, a careful medical history of previous surgical interventions that may have occurred even decades earlier is critical to assessing risk. The laboratory abnormalities are reflected by combined prolongation of the aPTT and PT that often fails to improve by transfusion of FFP and vitamin K. The abnormal laboratory tests cannot be corrected by mixing a test with equal parts of normal plasma that denotes the presence of inhibitory antibodies. The diagnosis of a specific antibody is obtained by the determination of the residual activity of human FV or other suspected human clotting factor. There are no commercially available assays specific for bovine thrombin coagulopathy.


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InternalMed_Harrison. There are no established treatment guidelines. Platelet transfusions have been used as a source of FV replacement for patients with FV inhibitors. Frequent injections of FFP and vitamin K supplementation may function as co-adjuvant rather than an effective treatment of the coagulopathy itself. Experience with recombinant FVIIa as a bypass agent is limited, and outcomes have been generally poor. Specific treatments to eradicate the antibodies based on immunosuppression with steroids, intravenous immunoglobulin, or serial plasmapheresis have been sporadically reported. Patients should be advised to avoid any topical thrombin sealant in the future. Novel plasma-derived and recombinant human thrombin preparations for topical hemostasis have been approved by the U.S. Food and Drug Administration. These preparations have demonstrated hemostatic efficacy with reduced immunogenicity compared to the first generation of bovine thrombin products.


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InternalMed_Harrison. The presence of lupus anticoagulant can be associated with venous or arterial thrombotic disease. However, bleeding has also been reported in lupus anticoagulant; it is due to the presence of antibodies to prothrombin, which results in hypoprothrombinemia. Both disorders show a prolonged PTT that does not correct on mixing. To distinguish acquired inhibitors from lupus anticoagulant, note that the dilute Russell’s viper venom test and the hexagonal-phase phospholipids test will be negative in patients with an acquired inhibitor and positive in patients with lupus anticoagulants. Moreover, lupus anticoagulant interferes with the clotting activity of many factors (FVIII, FIX, FXII, FXI), whereas acquired inhibitors are specific to a single factor. Jane E. Freedman, Joseph Loscalzo


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InternalMed_Harrison. Thrombosis, the obstruction of blood flow due to the formation of clot, may result in tissue anoxia and damage, and it is a major cause of morbidity and mortality in a wide range of arterial and venous diseases and patient populations. In 2009 in the United States, an estimated 785,000 people had a new coronary thrombotic event, and about 470,000 had a recurrent ischemic episode. Each year, approximately 795,000 people have a new or recurrent stroke. It is estimated that 300,000–600,000 people each year have a pulmonary embolism or deep venous thrombotic event. In the nondiseased state, physiologic hemostasis reflects a delicate interplay between factors that promote and inhibit blood clotting, favoring the former. This response is crucial as it prevents uncontrolled hemorrhage and exsanguination following injury. In specific settings, the same processes that regulate normal hemostasis can cause pathologic thrombosis, leading to arterial or venous occlusion. Importantly, many commonly


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InternalMed_Harrison. following injury. In specific settings, the same processes that regulate normal hemostasis can cause pathologic thrombosis, leading to arterial or venous occlusion. Importantly, many commonly used therapeutic interventions may also alter the thrombotic–hemostatic balance adversely.


InternalMed_Harrison

InternalMed_Harrison. Hemostasis and thrombosis primarily involve the interplay among three factors: the vessel wall, coagulation proteins, and platelets. Many prevalent acute vascular diseases are due to thrombus formation within a vessel, including myocardial infarction, thrombotic cerebrovascular events, and venous thrombosis. Although the end result is vessel occlusion and tissue ischemia, the pathophysiologic processes governing these pathologies have similarities as well as distinct differences. While many of the pathways regulating thrombus formation are similar to those that regulate hemostasis, the processes triggering thrombosis and, often, perpetuating the thrombus may be distinct and can vary in different clinical and genetic settings. In venous thrombosis, primary hypercoagulable states reflecting defects in the proteins governing coagulation and/or fibrinolysis or secondary hypercoagulable states involving abnormalities of blood vessels and blood flow or stasis lead to thrombosis. By


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InternalMed_Harrison. defects in the proteins governing coagulation and/or fibrinolysis or secondary hypercoagulable states involving abnormalities of blood vessels and blood flow or stasis lead to thrombosis. By contrast, arterial thrombosis is highly dependent on the state of the vessel wall, the platelet, and factors related to blood flow.


InternalMed_Harrison

InternalMed_Harrison. In arterial thrombosis, the platelets and abnormalities of the vessel wall typically play a key role in vessel occlusion. Arterial thrombus forms via a series of sequential steps in which platelets adhere to the vessel wall, additional platelets are recruited, and thrombin is activated (Fig. 142-1). The regulation of platelet adhesion, activation, aggregation, and recruitment will be described in detail below. In addition, while the primary function of platelets is regulation of hemostasis, our understanding of their role in other processes, such as immunity, wound healing, and inflammation, continues to grow.


InternalMed_Harrison

InternalMed_Harrison. Arterial thrombosis is a major cause of morbidity and mortality both in the United States and, increasingly, worldwide. Although the rates have declined in the United States, the overall burden remains high and accounts for approximately 33% of deaths. Overall, coronary heart disease is estimated to cause about 1 of every 5 deaths in the United States. In addition to the 785,000 Americans who will have a new coronary event, an additional 195,000 silent first myocardial infarctions are projected to occur annually. Although the rate of strokes has fallen by 741 a third, each year, about 795,000 people experience a new or recurrent stroke, although not all are caused by thrombotic occlusion of the vessel. Approximately 610,000 strokes are first events and 185,000 are recurrent events; it is estimated that 1 of every 18 deaths in the United States is due to stroke.


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InternalMed_Harrison. Many processes in platelets have parallels with other cell types, such as the presence of specific receptors and signaling pathways; however, unlike most cells, platelets lack a nucleus and are unable to adapt to changing biologic settings by altered gene transcription. Platelets sustain limited protein synthetic capacity from megakaryocyte-derived and intracellularly transported microRNA (miRNA) and messenger RNA (mRNA). Most of the molecules needed to respond to various stimuli, however, are maintained in storage granules and membrane compartments.


InternalMed_Harrison

InternalMed_Harrison. Platelets are disc-shaped, very small, anucleate cells (1–5 μm in diameter) that circulate in the blood at concentrations of 200–400,000/ μL, with an average lifespan of 7–10 days. Platelets are derived from megakaryocytes, polyploidal hematopoietic cells found in the bone marrow. The primary regulator of platelet formation is thrombopoietin (TPO). The precise mechanism by which megakaryocytes produce and release fully formed platelets is unclear, but the process likely involves formation of proplatelets, pseudopod-like structures generated by the evagination of the cytoplasm from which platelets bud. Platelet granules are synthesized in megakaryocytes before thrombo poiesis and contain an array of prothrombotic, proinflammatory, and antimicrobial mediators. The two major types of platelet granules, alpha and dense, are distinguished by their size, abundance, and con tent. Alpha-granules contain soluble coagulation proteins, adhesion molecules, growth factors, integrins, cytokines,


InternalMed_Harrison

InternalMed_Harrison. granules, alpha and dense, are distinguished by their size, abundance, and con tent. Alpha-granules contain soluble coagulation proteins, adhesion molecules, growth factors, integrins, cytokines, and inflammatory modulators. Platelet dense-granules are smaller than alpha-granules and less abundant. Whereas alpha-granules contain proteins that may be more important in the inflammatory response, dense-granules contain high concentrations of small molecules, including adenosine diphosphate (ADP) and serotonin, that influence platelet aggregation.


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InternalMed_Harrison. Platelet Adhesion (See Fig. 142-1) The formation of a thrombus is initiated by the adherence of platelets to the damaged vessel wall. Damage exposes sub-endothelial components responsible for triggering platelet reactivity, including collagen, von Willebrand factor, fibronectin, and other adhesive proteins, such as vitronectin and thrombospondin. The hemostatic response may vary, depending on the extent of damage, the specific proteins exposed, and flow conditions. Certain proteins are expressed on the platelet surface that subsequently regulate collagen-induced platelet adhesion, particularly under flow conditions, and include glycoprotein (GP) IV, GPVI, and the integrin α2β1. The platelet GPIb-IX-V complex adhesive receptor is central both to platelet adhesion and to the initiation of platelet activation. Damage to the


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InternalMed_Harrison. FIGURE 142-1 Platelet activation and thrombosis. Platelets circulate in an inactive form in the blood vessel wall exposes subendothelial vasculature. Damage to the endothelium and/or external stimuli activates platelets that adhere von Willebrand factor and collagen to the to the exposed subendothelial von Willebrand factor and collagen. This adhesion leads to activa-circulating blood. The GPIb-IX-V comtion of the platelet, shape change, and the synthesis and release of thromboxane (TxA2), serotonin plex binds to the exposed von Willebrand (5-HT), and adenosine diphosphate (ADP). Platelet stimuli cause conformational change in the factor, causing platelets to adhere (Fig. platelet integrin glycoprotein (GP) IIb/IIIa receptor, leading to the high-affinity binding of fibrino-142-1). In addition, the engagement of the gen and the formation of a stable platelet thrombus. GPIb-IX-V complex with ligand induces 742 signaling pathways that lead to platelet activation. von Willebrand


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InternalMed_Harrison. In addition, the engagement of the gen and the formation of a stable platelet thrombus. GPIb-IX-V complex with ligand induces 742 signaling pathways that lead to platelet activation. von Willebrand factor–bound GPIb-IX-V promotes a calcium-dependent conformational change in the GPIIb/IIIa receptor, transforming it from an inactive low-affinity state to an active high-affinity receptor for fibrinogen.


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InternalMed_Harrison. Platelet Activation The activation of platelets is controlled by a variety of surface receptors that regulate various functions in the activation process. Platelet receptors control many distinct processes and are stimulated by a wide variety of agonists and adhesive proteins that result in variable degrees of activation. In general terms, the stimulation of platelet receptors triggers two specific processes: (1) activation of internal signaling pathways that lead to further platelet activation and granule release and (2) the capacity of the platelet to bind to other adhesive proteins/platelets. Both of these processes contribute to the formation of a thrombus. Stimulation of nonthrombotic receptors results in platelet adhesion or interaction with other vascular cells including endothelial cells, neutrophils, and mononuclear cells.


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InternalMed_Harrison. Many families and subfamilies of receptors are found on platelets that regulate a variety of platelet functions. These include the seven transmembrane receptor family, which is the main agoniststimulated receptor family. Several seven transmembrane receptors are found on platelets, including the ADP receptors, prostaglandin receptors, lipid receptors, and chemokine receptors. Receptors for thrombin comprise the major seven transmembrane receptors found on platelets. Among this last group, the first identified was the protease activation receptor 1 (PAR1). The PAR class of receptors has a distinct mechanism of activation that involves specific cleavage of the N-terminus of thrombin, which, in turn, acts as a ligand for the receptor. Other PAR receptors are present on platelets, including PAR2 (not activated by thrombin) and PAR4. Adenosine receptors are responsible for transduction of ADP-induced signaling events, which are initiated by the binding of ADP to purinergic receptors on the


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InternalMed_Harrison. (not activated by thrombin) and PAR4. Adenosine receptors are responsible for transduction of ADP-induced signaling events, which are initiated by the binding of ADP to purinergic receptors on the platelet surface. There are several distinct ADP receptors, classified as P2X1, P2Y1, and P2Y12. The activation of both the P2Y12 and P2Y1 receptors is essential for ADP-induced platelet aggregation. The thienopyridine derivatives, clopidogrel and prasugrel, are clinically used inhibitors of ADP-induced platelet aggregation.


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InternalMed_Harrison. Platelet Aggregation Activation of platelets results in a rapid series of signal transduction events, including tyrosine kinase, serine/threonine kinase, and lipid kinase activation. In unstimulated platelets, the major platelet integrin GPIIb/IIIa is maintained in an inactive conformation and functions as a low-affinity adhesion receptor for fibrinogen. This integrin is unique as it is only expressed on platelets. After stimulation, the interaction between fibrinogen and GPIIb/IIIa forms intercellular connections between platelets, leading to the formation of a platelet aggregate (Fig. 142-1). A calcium-sensitive conformational change in the extracellular domain of GPIIb/IIIa enables the high-affinity binding of soluble plasma fibrinogen as a result of a complex network of inside-out signaling events. The GPIIb/IIIa receptor serves as a bidirectional conduit with GPIIb/IIIa-mediated signaling (outside-in) occurring immediately after the binding of fibrinogen. This leads to additional


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InternalMed_Harrison. events. The GPIIb/IIIa receptor serves as a bidirectional conduit with GPIIb/IIIa-mediated signaling (outside-in) occurring immediately after the binding of fibrinogen. This leads to additional intracellular signaling that further stabilizes the platelet aggregate and transforms platelet aggregation from a reversible to an irreversible process (inside-out).


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InternalMed_Harrison. Inflammation plays an important role during the acute thrombotic phase of acute coronary syndromes. In the setting of acute upper respiratory infections, people are at higher risk of myocardial infarction and thrombotic stroke. Patients with acute coronary syndromes have not only increased interactions between platelets (homotypic aggregates), but also increased interactions between platelets and leukocytes (heterotypic aggregates) detectable in circulating blood. These latter aggregates form when platelets are activated and adhere to circulating leukocytes. Platelets bind via P-selectin (CD62P) expressed on the surface of activated platelets to the leukocyte receptor, P-selectin glycoprotein ligand 1 (PSGL-1). This association leads to increased expression of CD11b/CD18 (Mac-1) on leukocytes, which itself supports interactions with platelets partially via bivalent fibrinogen linking this integrin with its platelet surface counterpart, GPIIb/IIIa. Platelet surface P-selectin also


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InternalMed_Harrison. which itself supports interactions with platelets partially via bivalent fibrinogen linking this integrin with its platelet surface counterpart, GPIIb/IIIa. Platelet surface P-selectin also induces the expression of tissue factor on monocytes, which promotes fibrin formation.


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InternalMed_Harrison. In addition to platelet–monocyte aggregates, the immunomodulator, soluble CD40 ligand (CD40L or CD154), also reflects a link between thrombosis and inflammation. The CD40 ligand is a trimeric transmembrane protein of the tumor necrosis factor family and, with its receptor CD40, is an important contributor to the inflammatory process leading both to thrombosis and atherosclerosis. While many immunologic and vascular cells have been found to express CD40 and/or CD40 ligand, in platelets, CD40 ligand is rapidly translocated to the surface after stimulation and is upregulated in the newly formed thrombus. The surface-expressed CD40 ligand is cleaved from the platelet to generate a soluble fragment (soluble CD40 ligand).


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InternalMed_Harrison. Links have also been established among platelets, infection, immunity, and inflammation. Bacterial and viral infections are associated with a transient increase in the risk of acute thrombotic events, such as acute myocardial infarction and stroke. In addition, platelets contribute significantly to the pathophysiology and high mortality rates of sepsis. The expression, functionality, and signaling pathways of toll-like receptors (TLRs) have been established in platelets. Stimulation of platelet TLR2, TLR3, and TLR4 directly and indirectly activates the platelet’s thrombotic and inflammatory responses, and live bacteria induce a proinflammatory response in platelets in a TLR2-dependent manner, suggesting a mechanism by which specific bacteria and bacterial components can directly activate platelet-dependent thrombosis.


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InternalMed_Harrison. Some studies have associated arterial thrombosis with genetic variants (Table 142-1 A); however, the associations have been weak and not confirmed in larger series. Platelet count and mean platelet volume have been studied by genome-wide association studies (GWAS), and this approach identified signals located to noncoding regions. Of 15 quantitative trait loci associated with mean platelet volume and platelet count, one located at 12q24 is also a risk locus for coronary artery disease. In the area of genetic variability and platelet function, studies have primarily dealt with pharmacogenetics, the field of pharmacology dealing with the interindividual variability in drug response based on genetic determinants (Table 142-2). This focus has been driven by the wide variability among individuals in terms of response to antithrombotic drugs and the lack of a common explanation for this variance. The best described is the issue of “aspirin resistance,” although heterogeneity for other


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InternalMed_Harrison. in terms of response to antithrombotic drugs and the lack of a common explanation for this variance. The best described is the issue of “aspirin resistance,” although heterogeneity for other antithrombotics (e.g., clopidogrel) has also been extensively examined. Primarily, platelet-dependent genetic determinants have been defined at the level of (1) drug effect, (2) drug compliance, and (3) drug metabolism. Many candidate platelet genes have been studied for their interaction with antiplatelet and antithrombotic agents.


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InternalMed_Harrison. Many patients have an inadequate response to the inhibitory effects of aspirin. Heritable factors contribute to the variability; however, ex vivo tests of residual platelet responsiveness after aspirin administration have not provided firm evidence for a pharmacogenetic interaction between aspirin and COX1 or other relevant platelet receptors. As such, currently, there is no clinical indication for genotyping to optimize aspirin’s antiplatelet efficiency. For the platelet P2Y12 receptor inhibitor clopidogrel, additional data suggest that genetics may affect the drug’s responsiveness and utility. The responsible genetic variant appears not to be the expected P2Y12 receptor but an enzyme responsible for drug metabolism. Clopidogrel is a prodrug, and liver metabolism by specific cytochrome P450 enzymes is required for activation. The genes encoding the CYP-dependent oxidative steps are polymorphic, and carriers of specific alleles of the CYP2C19 and CYP3A4 loci have increased platelet


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InternalMed_Harrison. P450 enzymes is required for activation. The genes encoding the CYP-dependent oxidative steps are polymorphic, and carriers of specific alleles of the CYP2C19 and CYP3A4 loci have increased platelet aggregability. Increased platelet activity has also been specifically associated with the CYP2C19*2 allele, which causes loss of platelet function in select patients. Because these are common genetic variants, this observation has been shown to be clinically relevant in large studies. In summary, although the loss-of-function polymorphisms in CYP2C19 is the strongest individual variable affecting pharmacokinetics and antiplatelet response to clopidogrel, it only


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InternalMed_Harrison. A. Arterial Thrombosis Plasma glutathione peroxidase H2 promoter haplotype Endothelial nitric oxide synthase −786T/C, −922A/G, −1468T/A Paraoxonase −107T allele, 192R allele Cystathionine β-synthase 833T → C 5,10-Methylene tetrahydrofolate reductase (MTHFR) 677C → T B. Venous Thrombosis Fibrinogen −455G/A, –854G/A Prothrombin (20210G → A) Factor V Leiden: 1691G → A (Arg506Gln) Thrombomodulin 1481C → T (Ala455Val) Fibrinolytic Proteins with Known Polymorphisms Tissue plasminogen activator (tPA) 7351C/T, 20 099T/C in exon 6, 27 445T/A in intron 10 Plasminogen activator inhibitor (PAI-1) 4G/5G insertion/deletion polymorphism at position –675 Cystathionine β-synthase 833T → C 5,10-MTHFR 677C → T accounts for 5–12% of the variability in ADP-induced platelet aggregation on clopidogrel. In addition, genetic variables do not appear to significantly contribute to the clinical outcomes of patients treated with the P2Y12 receptor antagonists prasugrel or ticagrelor.


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InternalMed_Harrison. Coagulation is the process by which thrombin is activated and soluble plasma fibrinogen is converted into insoluble fibrin. These steps account for both normal hemostasis and the pathophysiologic processes influencing the development of venous thrombosis. The primary forms of venous thrombosis are deep vein thrombosis (DVT) in the extremities and the subsequent embolization to the lungs (pulmonary embolism), referred to together as venous thromboembolic disease. Venous thrombosis occurs due to heritable causes (Table 142-1 B) and acquired causes (Table 142-3).


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InternalMed_Harrison. More than 200,000 new cases of venous thromboembolism occur each year. Of these cases, up to 30% of patients die within 30 days and one-fifth suffer sudden death due to pulmonary embolism; 30% go on to develop recurrent venous thromboembolism within 10 years. Data from the Atherosclerosis Risk in Communities (ARIC) study reported a 9% 28-day fatality rate from DVT and a 15% fatality rate from pulmonary embolism. Pulmonary embolism in the setting of cancer has a 25% fatality rate. The mean incidence of first DVT in the general population is 5 per 10,000 person-years; the incidence is similar in males and females when adjusting for factors related to reproduction and birth control and increases dramatically with age from 2 to 3 per 10,000 person-years at 30–49 years of age to 20 at 70–79 years of age.


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InternalMed_Harrison. Coagulation is defined as the formation of fibrin by a series of linked enzymatic reactions in which each reaction product converts the subsequent inactive zymogen into an active serine protease (Fig. 142-2). This coordinated sequence is called the coagulation cascade and is a key mechanism for regulating hemostasis. Central to the function of the coagulation cascade is the principle of amplification: due to a series of linked enzymatic reactions, a small stimulus can lead to much greater quantities of fibrin, the end product that prevents hemorrhage at the site of vascular injury. In addition to the known risk factors relevant to hypercoagulopathy, stasis, and vascular dysfunction, newer areas of research have identified contributions from procoagulant microparticles, inflammatory cells, microvesicles, and fibrin structure.


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InternalMed_Harrison. The coagulation cascade is primarily initiated by vascular injury exposing tissue factor to blood components (Fig. 142-2). Tissue factor may also be found in bloodborne cell-derived microparticles and, under pathophysiologic conditions, in leukocytes or platelets. Plasma factor VII (FVII) is the ligand for and is activated (FVIIa) by binding to tissue factor exposed at the site of vessel damage. The binding of FVII/ VIIa to tissue factor activates the downstream conversion of factor X (FX) to active FX (FXa). In an alternative reaction, the FVII/FVIIa–tissue factor complex initially converts FIX to FIXa, which then activates FX in conjunction with its cofactor factor VIII (FVIIIa). Factor Xa with its cofactor FVa converts prothrombin to thrombin, which then converts soluble plasma fibrinogen to insoluble fibrin, leading to clot or thrombus formation. Thrombin also activates FXIII to FXIIIa, a transglutaminase that covalently cross-links and stabilizes the fibrin clot. Formation of


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InternalMed_Harrison. to insoluble fibrin, leading to clot or thrombus formation. Thrombin also activates FXIII to FXIIIa, a transglutaminase that covalently cross-links and stabilizes the fibrin clot. Formation of thrombi is affected by mechanisms governing fibrin structure and stability including specific fibrinogen variants and how they alter fibrin formation, strength and structure.


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InternalMed_Harrison. 744 XII significantly increase the risk of venous thrombosis. While homozygous protein C or protein S deficiencies are rare and may lead to fatal purpura fulminans, heterozygous deficiencies are associated with a moderate risk of thrombosis. Activated protein C impairs coagulation by proteolytic degradation of FVa. Patients resistant to the activity of activated protein C may have a point mutation in the FV gene located on chromosome 1, a mutant denoted factor V Leiden. Mildly increased risk has been attributed to elevated levels of procoagulant factors, as well as low levels of tissue factor pathway inhibitor. Polymorphisms of methylene tetrahydrofolate reductase as well as hyperhomocysteinemia have been shown to be independent risk factors for venous thrombosis, as well as arterial vascular disease; however, many of the initial descriptions of genetic variants and their associations with thromboembolism are being questioned in larger, more current studies.


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InternalMed_Harrison. Specific abnormalities in the fibrinolytic system have been associated with enhanced thrombosis. Factors such as elevated levels of tissue plasminogen activator (tPA) and plasminogen activator FIGURE 142-2 Summary of the coagulation pathways. Specific coagulation factors (“a” inhibitor type 1 (PAI-1) have been associated with indicates activated form) are responsible for the conversion of soluble plasma fibrinogen decreased fibrinolytic activity and an increased into insoluble fibrin. This process occurs via a series of linked reactions in which the enzy-risk of arterial thrombotic disease. Specific genetic matically active product subsequently converts the downstream inactive protein into an variants have been associated with decreased fibriactive serine protease. In addition, the activation of thrombin leads to stimulation of plate-nolytic activity, including the 4G/5G insertion/ lets. HK, high-molecular-weight kininogen; PK, prekallikrein; TF, tissue factor. deletion polymorphism


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InternalMed_Harrison. of thrombin leads to stimulation of plate-nolytic activity, including the 4G/5G insertion/ lets. HK, high-molecular-weight kininogen; PK, prekallikrein; TF, tissue factor. deletion polymorphism in the (plasminogen activator type 1) PAI-1 gene. Additionally, the 311-bp Alu insertion/deletion in tPA’s intron 8 has been


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InternalMed_Harrison. Several antithrombotic factors also regulate coagulation; these associated with enhanced thrombosis; however, genetic abnormalities include antithrombin, tissue factor pathway inhibitor (TFPI), heparin have not been associated consistently with altered function or tPA levcofactor II, and protein C/protein S. Under normal conditions, these els, raising questions about the relevant pathophysiologic mechanism. factors limit the production of thrombin to prevent the perpetuation Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptiof coagulation and thrombus formation. Typically, after the clot has dase that regulates fibrinolysis; elevated plasma TAFI levels have been caused occlusion at the damaged site and begins to expand toward associated with an increased risk of both DVT and cardiovascular adjacent uninjured vessel segments, the anticoagulant reactions gov-disease. erned by the normal endothelium become pivotal in limiting the extent The metabolic syndrome also is


InternalMed_Harrison

InternalMed_Harrison. and cardiovascular adjacent uninjured vessel segments, the anticoagulant reactions gov-disease. erned by the normal endothelium become pivotal in limiting the extent The metabolic syndrome also is accompanied by altered fibrinoof this hemostatically protective clot. lytic activity. This syndrome, which comprises abdominal fat (cen tral obesity), altered glucose and insulin metabolism, dyslipidemia, and hypertension, has been associated with atherothrombosis. The mechanism for enhanced thrombosis appears to be due both to alteredThe risk factors for venous thrombosis are primarily related to hyper-platelet function and to a procoagulant and hypofibrinolytic state.


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InternalMed_Harrison. coagulability, which can be genetic (Table 142-1) or acquired, or due One of the most frequently documented prothrombotic abnormalitiesto immobilization and venous stasis. Independent predictors for recur-reported in this syndrome is an increase in plasma levels of PAI-1. rence include increasing age, obesity, malignant neoplasm, and acute In addition to contributing to platelet function, inflammation playsextremity paresis. It is estimated that 5–8% of the U.S. population has a role in both coagulation-dependent thrombus formation and throma genetic risk factor known to predispose to venous thrombosis. Often, bus resolution. Both polymorphonuclear neutrophils and monocytes/multiple risk factors are present in a single individual. Significant risk macrophages contribute to multiple overlapping thrombotic funcis incurred by major orthopedic, abdominal, or neurologic surgeries.


InternalMed_Harrison

InternalMed_Harrison. tions, including fibrinolysis, chemokine and cytokine production, and Moderate risk is promoted by prolonged bedrest; certain types of canphagocytosis. cer, pregnancy, hormone replacement therapy, or oral contraceptive use; and other sedentary conditions such as long-distance plane travel. It has been reported that the risk of developing a venous thromboem-THE DISTINCTION BETWEEN ARTERIAL AND VENOUS bolic event doubles after air travel lasting 4 h, although the absolute THROMBOSIS risk remains low (1 in 6000). The relative risk of venous thromboem- Although there is overlap, venous thrombosis and arterial thrombosis bolism among pregnant or postpartum women is 4.3, and the overall are initiated differently, and clot formation progresses by somewhatincidence (absolute risk) is 199.7 per 100,000 woman-years.


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InternalMed_Harrison. distinct pathways. In the setting of stasis or states of hypercoagulability, venous thrombosis is activated with the initiation of the coagulation GENETICS OF VENOUS THROMBOSIS cascade primarily due to exposure of tissue factor; this leads to the(See Table 142-2) Less common causes of venous thrombosis are formation of thrombin and the subsequent conversion of fibrinogen tothose due to genetic variants. These abnormalities include loss-of-fibrin. In the artery, thrombin formation also occurs, but thrombosisfunction mutations of endogenous anticoagulants as well as gain-is primarily promoted by the adhesion of platelets to an injured vesselof-function mutations of procoagulant proteins. Heterozygous anti-and stimulated by exposed extracellular matrix (Figs. 142-1 and 142-2).thrombin deficiency and homozygosity of the factor V Leiden mutation There is wide variation in individual responses to vascular injury, an important determinant of which is the predisposition an individual has to


InternalMed_Harrison

InternalMed_Harrison. and homozygosity of the factor V Leiden mutation There is wide variation in individual responses to vascular injury, an important determinant of which is the predisposition an individual has to arterial or venous thrombosis. This concept has been supported indirectly in prothrombotic animal models in which there is poor correlation between the propensity to develop venous versus arterial thrombosis.


InternalMed_Harrison

InternalMed_Harrison. Despite considerable progress in understanding the role of hyper-coagulable states in venous thromboembolic disease, the contribution of hypercoagulability to arterial vascular disease is much less well understood. Although specific thrombophilic conditions, such as factor V Leiden and the prothrombin G20210A mutation, are risk factors for DVT, pulmonary embolism, and other venous thromboembolic events, their contribution to arterial thrombosis is less well defined. In fact, to the contrary, many of these thrombophilic factors have not been found to be clinically important risk factors for arterial thrombotic events, such as acute coronary syndromes.


InternalMed_Harrison

InternalMed_Harrison. Clinically, although the pathophysiology is distinct, arterial and venous thrombosis do share common risk factors, including age, obesity, cigarette smoking, diabetes mellitus, arterial hypertension, hyperlipidemia, and metabolic syndrome. Select genetic variants, including those of the glutathione peroxidase gene, have also been associated with arterial and venous thrombo-occlusive disease. Importantly, arterial and venous thrombosis may both be triggered by pathophysiologic stimuli responsible for activating inflammatory and oxidative pathways. The diagnosis and treatment of ischemic heart disease are discussed in Chap. 293. Stroke diagnosis and management are discussed in Chap. 330. The diagnosis and management of DVT and pulmonary embolus are discussed in Chap. 300. Jeffrey I. Weitz 143 Antiplatelet, Anticoagulant, and fibrinolytic Drugs


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InternalMed_Harrison. Antiplatelet, Anticoagulant, and fibrinolytic Drugs Thromboembolic disorders are major causes of morbidity and mortal ity. Thrombosis can occur in arteries or veins. Arterial thrombosis is the most common cause of acute myocardial infarction (MI), ischemic stroke, and limb gangrene. Venous thromboembolism encompasses deep vein thrombosis (DVT), which can lead to postthrombotic syn drome, and pulmonary embolism (PE), which can be fatal or can result in chronic thromboembolic pulmonary hypertension.


InternalMed_Harrison

InternalMed_Harrison. Most arterial thrombi are superimposed on disrupted atherosclerotic plaque because plaque rupture exposes thrombogenic material in the plaque core to the blood. This material then triggers platelet aggregation and fibrin formation, which results in the generation of a platelet-rich thrombus that can temporarily or permanently occlude blood flow. In contrast, venous thrombi rarely form at sites of obvious vascular disruption. Although they can develop after surgical trauma to veins or secondary to indwelling venous catheters, venous thrombi usually originate in the valve cusps of the deep veins of the calf or in the muscular sinuses. Sluggish blood flow reduces the oxygen supply to the avascular valve cusps. Endothelial cells lining these valve cusps become activated and express adhesion molecules on their surface. Tissue factor–bearing leukocytes and microparticles adhere to these activated cells and induce coagulation. DNA extruded from neutrophils forms neutrophil extracelluar traps


InternalMed_Harrison

InternalMed_Harrison. on their surface. Tissue factor–bearing leukocytes and microparticles adhere to these activated cells and induce coagulation. DNA extruded from neutrophils forms neutrophil extracelluar traps (NETs) that provide a scaffold that traps red blood cells, promotes platelet adhesion and activation, and augments coagulation. Local thrombus formation is exacerbated by reduced clearance of activated clotting factors as a result of impaired blood flow. If the thrombi extend from the calf veins into the popliteal and more proximal veins of the leg, thrombus fragments can dislodge, travel to the lungs, and produce a PE.


InternalMed_Harrison

InternalMed_Harrison. Arterial and venous thrombi are composed of platelets, fibrin, and trapped red blood cells, but the proportions differ. Arterial thrombi FIGURE 143-1 Classification of antithrombotic drugs. are rich in platelets because of the high shear in the injured arteries. In contrast, venous thrombi, which form under low shear conditions, contain relatively few platelets and are predominantly composed of fibrin and trapped red cells. Because of the predominance of platelets, arterial thrombi appear white, whereas venous thrombi are red in color, reflecting the trapped red cells.


InternalMed_Harrison

InternalMed_Harrison. Antithrombotic drugs are used for prevention and treatment of thrombosis. Targeting the components of thrombi, these agents include (1) antiplatelet drugs, (2) anticoagulants, and (3) fibrinolytic agents (Fig. 143-1). With the predominance of platelets in arterial thrombi, strategies to attenuate arterial thrombosis focus mainly on antiplatelet agents, although, in the acute setting, often include anticoagulants and fibrinolytic agents. Anticoagulants are the mainstay of prevention and treatment of venous thromboembolism because fibrin is the predominant component of venous thrombi. Antiplatelet drugs are less effective than anticoagulants in this setting because of the limited platelet content of venous thrombi. Fibrinolytic therapy is used in selected patients with venous thromboembolism. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. Pharmaco-mechanical therapy also is used to restore blood flow in patients


InternalMed_Harrison

InternalMed_Harrison. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. Pharmaco-mechanical therapy also is used to restore blood flow in patients with extensive DVT involving the iliac and/or femoral veins.


InternalMed_Harrison

InternalMed_Harrison. In healthy vasculature, circulating platelets are maintained in an inactive state by nitric oxide (NO) and prostacyclin released by endothelial cells lining the blood vessels. In addition, endothelial cells also express CD39 on their surface, a membrane-associated ecto-adenosine diphosphatase (ADPase) that degrades ADP released from activated platelets. When the vessel wall is damaged, release of these substances is impaired and subendothelial matrix is exposed. Platelets adhere to exposed collagen via α2β1 and glycoprotein (Gp) V1 and to von Willebrand factor (VWF) via Gp Ibα and Gp IIb/IIIa (αIIbβ3)—receptors that are constitutively expressed on the platelet surface. Adherent platelets undergo a change in shape, secrete ADP from their dense granules, and synthesize and release thromboxane A2. Released ADP and thromboxane A2, which are platelet agonists, activate ambient platelets and recruit them to the site of vascular injury (Fig. 143-2).


InternalMed_Harrison

InternalMed_Harrison. Disruption of the vessel wall also exposes tissue factor–expressing cells to the blood. Tissue factor binds factor VIIa and initiates coagulation. Activated platelets potentiate coagulation by providing a surface that binds clotting factors and supports the assembly of activation complexes that enhance thrombin generation. In addition to converting fibrinogen to fibrin, thrombin serves as a potent platelet agonist and recruits more platelets to the site of vascular injury. Thrombin also amplifies its own generation by feedback activation of factors V, VIII, and XI and solidifies the fibrin network by activating factor XIII, which then cross-links the fibrin strands.


InternalMed_Harrison

InternalMed_Harrison. When platelets are activated, Gp IIb/IIIa, the most abundant receptor on the platelet surface, undergoes a conformational change that enables it to bind fibrinogen and, under high shear conditions, VWF. Divalent fibrinogen or multivalent VWF molecules bridge adjacent platelets together to form platelet aggregates. Fibrin strands, generated through the action of thrombin, then weave these aggregates together to form a platelet/fibrin mesh. Antiplatelet drugs target various steps in this process. The commonly used drugs include aspirin, ADP receptor inhibitors, which Antiplatelet, Anticoagulant, and Fibrinolytic Drugs


InternalMed_Harrison

InternalMed_Harrison. FIGURE 143-2 Coordinated role of platelets and the coagulation system in thrombogenesis. Vascular injury simultaneously triggers platelet activation and aggregation and activation of the coagulation system. Platelet activation is initiated by exposure of subendothelial collagen and von Willebrand factor (VWF), onto which platelets adhere. Adherent platelets become activated and release ADP and thromboxane A2, platelet agonists that activate ambient platelets and recruit them to the site of injury. When platelets are activated, glycoprotein IIb/IIIa on their surface undergoes a conformational change that enables it to ligate fibrinogen and/or VWF and mediate platelet aggregation. Coagulation is triggered by tissue factor exposed at the site of injury. Tissue factor triggers thrombin generation. As a potent platelet agonist, thrombin amplifies platelet recruitment to the site of injury. Thrombin also converts fibrinogen to fibrin, and the fibrin strands then weave the platelet


InternalMed_Harrison

InternalMed_Harrison. generation. As a potent platelet agonist, thrombin amplifies platelet recruitment to the site of injury. Thrombin also converts fibrinogen to fibrin, and the fibrin strands then weave the platelet aggregates together to form a platelet/fibrin thrombus.


InternalMed_Harrison

InternalMed_Harrison. include the thienopyridines (clopidogrel and prasugrel) and ticagrelor, dipyridamole, and Gp IIb/IIIa antagonists. The most widely used antiplatelet agent worldwide is aspirin. As a cheap and effective antiplatelet drug, aspirin serves as the foundation of most antiplatelet strategies. Mechanism of Action Aspirin produces its antithrombotic effect by irreversibly acetylating and inhibiting platelet cyclooxygenase (COX)-1 (Fig. 143-3), a critical enzyme in the biosynthesis of thromboxane A2. At high doses (~1 g/d), aspirin also inhibits COX-2, an inducible COX isoform found in endothelial cells and inflammatory cells. In endothelial cells, COX-2 initiates the synthesis of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation.


InternalMed_Harrison

InternalMed_Harrison. Indications Aspirin is widely used for secondary prevention of cardiovascular events in patients with coronary artery, cerebrovascular, or peripheral vascular disease. Compared with placebo, aspirin produces a 25% reduction in the risk of cardiovascular death, MI, or stroke. Aspirin is also used for primary prevention in patients whose estimated annual risk of MI is >1%, a point where its benefits are likely to outweigh harms. This includes patients older than age 40 years with two or more major risk factors for cardiovascular disease or men older than age 45 years and women over the age of 55 years with one or more such risk factors. Aspirin is equally effective in men and women. In men, aspirin mainly reduces the risk of MI, whereas in women, aspirin lowers the risk of stroke.


InternalMed_Harrison

InternalMed_Harrison. Dosages Aspirin is usually administered at doses of 75–325 mg once daily. Higher doses of aspirin are not more effective than lower aspirin doses, and some analyses suggest reduced efficacy with higher doses. Because the side effects of aspirin are dose-related, daily aspirin doses of 75–100 mg are recommended for most indications. When rapid


InternalMed_Harrison

InternalMed_Harrison. FIGURE 143-3 Site of action of antiplatelet drugs. Aspirin inhibits thromboxane A2 (TXA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activation and recruitment to the site of vascular injury. Clopidogrel and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor binding to activated glycoprotein (Gp) IIb/IIIa. Vorapaxar inhibits thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on human platelets. platelet inhibition is required, an initial aspirin dose of at least 160 mg should be given.


InternalMed_Harrison

InternalMed_Harrison. platelet inhibition is required, an initial aspirin dose of at least 160 mg should be given. Side Effects The most common side effects are gastrointestinal and range from dyspepsia to erosive gastritis or peptic ulcers with bleeding and perforation. These side effects are dose-related. Use of entericcoated or buffered aspirin in place of plain aspirin does not eliminate gastrointestinal side effects. The overall risk of major bleeding with aspirin is 1–3% per year. The risk of bleeding is increased twoto threefold when aspirin is given in conjunction with other antiplatelet drugs, such as clopidogrel, or with anticoagulants, such as warfarin. When dual or triple therapy is prescribed, low-dose aspirin should be given (75–100 mg daily). Eradication of Helicobacter pylori infection and administration of proton pump inhibitors may reduce the risk of aspirin-induced upper gastrointestinal bleeding in patients with peptic ulcer disease.


InternalMed_Harrison

InternalMed_Harrison. Aspirin should not be administered to patients with a history of aspirin allergy characterized by bronchospasm. This problem occurs in ~0.3% of the general population but is more common in those with chronic urticaria or asthma, particularly in individuals with nasal polyps or chronic rhinitis. Hepatic and renal toxicity are observed with aspirin overdose. Aspirin Resistance Clinical aspirin resistance is defined as the failure of aspirin to protect patients from ischemic vascular events. This is not a helpful definition because it is made after the event occurs. Furthermore, it is not realistic to expect aspirin, which only blocks thromboxane A2–induced platelet activation, to prevent all vascular events.


InternalMed_Harrison

InternalMed_Harrison. Aspirin resistance has also been described biochemically as failure of the drug to produce its expected inhibitory effects on tests of platelet function, such as thromboxane A2 synthesis or arachidonic acid-induced platelet aggregation. Potential causes of aspirin resistance include poor compliance, reduced absorption, drug-drug interaction with ibuprofen, and overexpression of COX-2. Unfortunately, the tests for aspirin resistance have not been well standardized, and there is little evidence that they identify patients at increased risk of recurrent vascular events, or that resistance can be reversed by giving higher doses of aspirin or by adding other antiplatelet drugs. Until such information is available, testing for aspirin resistance remains a research tool. The ADP receptor antagonists include the thienopyridines (clopidogrel and prasugrel) and ticagrelor. All of these drugs target P2Y12, the key ADP receptor on platelets.


InternalMed_Harrison

InternalMed_Harrison. The ADP receptor antagonists include the thienopyridines (clopidogrel and prasugrel) and ticagrelor. All of these drugs target P2Y12, the key ADP receptor on platelets. Thienopyridines • mecHanism of action The thienopyridines are structurally related drugs that selectively inhibit ADP-induced platelet aggregation by irreversibly blocking P2Y12 (Fig. 143-3). Clopidogrel and prasugrel are prodrugs that require metabolic activation by the hepatic cytochrome P450 (CYP) enzyme system. Prasugrel is about 10-fold more potent than clopidogrel and has a more rapid onset of action because of better absorption and more streamlined metabolic activation.


InternalMed_Harrison

InternalMed_Harrison. indications When compared with aspirin in patients with recent ischemic stroke, recent MI, or a history of peripheral arterial disease, clopidogrel reduced the risk of cardiovascular death, MI, and stroke by 8.7%. Therefore, clopidogrel is more effective than aspirin but is also more expensive. In some patients, clopidogrel and aspirin are combined to capitalize on their capacity to block complementary pathways of platelet activation. For example, the combination of aspirin plus clopidogrel is recommended for at least 4 weeks after implantation of a bare metal stent in a coronary artery and for at least a year in those with a drug-eluting stent. Concerns about late in-stent thrombosis with drug-eluting stents have led some experts to recommend longterm use of clopidogrel plus aspirin for the latter indication. However, these recommendations are likely to change because the risk of late stent thrombosis is decreasing with the newer generation of drug-eluting coronary stents.


InternalMed_Harrison

InternalMed_Harrison. The combination of clopidogrel and aspirin is also effective in patients with unstable angina. Thus, in 12,562 such patients, the risk of cardiovascular death, MI, or stroke was 9.3% in those randomized to the combination of clopidogrel and aspirin and 11.4% in those given aspirin alone. This 20% relative risk reduction with combination therapy was highly statistically significant. However, combining clopidogrel with aspirin increases the risk of major bleeding to about 2% per year. This bleeding risk persists even if the daily dose of aspirin is ≤100 mg. Therefore, the combination of clopidogrel and aspirin should only be used when there is a clear benefit. For example, this combination has not proven to be superior to clopidogrel alone in patients with acute ischemic stroke or to aspirin alone for primary prevention in those at risk for cardiovascular events.


InternalMed_Harrison

InternalMed_Harrison. Prasugrel was compared with clopidogrel in 13,608 patients with acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention. The incidence of the primary efficacy endpoint, a composite of cardiovascular death, MI, or stroke, was significantly lower with prasugrel than with clopidogrel (9.9% and 12.1%, respectively), mainly reflecting a reduction in the incidence of nonfatal MI. The incidence of stent thrombosis also was significantly lower with prasugrel (1.1% and 2.4%, respectively). However, these advantages were at the expense of significantly higher rates of fatal bleeding (0.4% and 0.1%, respectively) and life-threatening bleeding (1.4% and 0.9%, respectively) with prasugrel. Because patients older than age 75 years and those with a history of prior stroke or transient ischemic attack have a particularly high risk of bleeding, prasugrel should generally be avoided in older patients, and the drug is contraindicated in those with a history of


InternalMed_Harrison

InternalMed_Harrison. stroke or transient ischemic attack have a particularly high risk of bleeding, prasugrel should generally be avoided in older patients, and the drug is contraindicated in those with a history of cerebrovascular disease. Caution is required if prasugrel is used in patients weighing less than 60 kg or in those with renal impairment.


InternalMed_Harrison

InternalMed_Harrison. When prasugrel was compared with clopidogrel in 7243 patients with unstable angina or MI without ST-segment elevation, prasugrel failed to reduce the rate of the primary efficacy endpoint, which was a composite of cardiovascular death, MI, and stroke. Because of the negative results of this study, prasugrel is reserved for patients undergoing percutaneous coronary intervention. In this setting, prasugrel is usually given in conjunction with aspirin. To reduce the risk of bleeding, the daily aspirin dose should be ≤100 mg.


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InternalMed_Harrison. dosing Clopidogrel is given once daily at a dose of 75 mg. Loading 747 doses of clopidogrel are given when rapid ADP receptor blockade is desired. For example, patients undergoing coronary stenting are often given a loading dose of 300 mg, which produces inhibition of ADP-induced platelet aggregation in about 6 h; loading doses of 600 or 900 mg produce an even more rapid effect. After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg. Patients older than age 75 years or weighing less than 60 kg should receive a lower daily prasugrel dose of 5 mg. side effects The most common side effect of clopidogrel and prasugrel is bleeding. Because of its greater potency, bleeding is more common with prasugrel than clopidogrel. To reduce the risk of bleeding, clopidogrel and prasugrel should be stopped 5–7 days before major surgery. In patients taking clopidogrel or prasugrel who present with serious bleeding, platelet transfusion may be helpful.


InternalMed_Harrison

InternalMed_Harrison. Hematologic side effects, including neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura, are rare.


InternalMed_Harrison

InternalMed_Harrison. tHienopyridine resistance The capacity of clopidogrel to inhibit ADP-induced platelet aggregation varies among subjects. This variability reflects, at least in part, genetic polymorphisms in the CYP isoenzymes involved in the metabolic activation of clopidogrel. Most important of these is CYP2C19. Clopidogrel-treated patients with the loss-offunction CYP2C19*2 allele exhibit reduced platelet inhibition compared with those with the wild-type CYP2C19*1 allele and experience a higher rate of cardiovascular events. This is important because estimates suggest that up to 25% of whites, 30% of African Americans, and 50% of Asians carry the loss-of-function allele, which would render them resistant to clopidogrel. Even patients with the reduced function CYP2C19*3, *4, or *5 alleles may derive less benefit from clopidogrel than those with the full-function CYP2C19*1 allele. Concomitant administration of clopidogrel with proton pump inhibitors, which are inhibitors of CYP2C19, produces a small


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InternalMed_Harrison. benefit from clopidogrel than those with the full-function CYP2C19*1 allele. Concomitant administration of clopidogrel with proton pump inhibitors, which are inhibitors of CYP2C19, produces a small reduction in the inhibitory effects of clopidogrel on ADP-induced platelet aggregation. The extent to which this interaction increases the risk of cardiovascular events remains controversial.


InternalMed_Harrison

InternalMed_Harrison. In contrast to their effect on the metabolic activation of clopidogrel, CYP2C19 polymorphisms appear to be less important determinants of the activation of prasugrel. Thus, no association was detected between the loss-of-function allele and decreased platelet inhibition or increased rate of cardiovascular events with prasugrel. The observation that genetic polymorphisms affecting clopidogrel absorption or metabolism influence clinical outcomes raises the possibilities that pharmacogenetic profiling may be useful to identify clopidogrelresistant patients and that point-of-care assessment of the extent of clopidogrel-induced platelet inhibition may help detect patients at higher risk for subsequent cardiovascular events. Clinical trials designed to evaluate these possibilities have thus far been negative. Although administration of higher doses of clopidogrel can overcome a reduced response to clopidogrel, the clinical benefit of this approach is uncertain. Instead, prasugrel or


InternalMed_Harrison

InternalMed_Harrison. far been negative. Although administration of higher doses of clopidogrel can overcome a reduced response to clopidogrel, the clinical benefit of this approach is uncertain. Instead, prasugrel or ticagrelor may be better choices for these patients.


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InternalMed_Harrison. Ticagrelor As an orally active inhibitor of P2Y12, ticagrelor differs from the thienopyridines in that ticagrelor does not require metabolic activation and it produces reversible inhibition of the ADP receptor. mecHanism of action Like the thienopyridines, ticagrelor inhibits P2Y12. Because it does not require metabolic activation, ticagrelor has a more rapid onset and offset of action than clopidogrel, and it produces greater and more predictable inhibition of ADP-induced platelet aggregation than clopidogrel. indications When compared with clopidogrel in patients with acute coronary syndromes, ticagrelor produced a greater reduction in the primary efficacy endpoint—a composite of cardiovascular death, MI, and stroke at 1 year—than clopidogrel (9.8% and 11.7%, respectively; p = .001). This difference reflected a significant reduction in both cardiovascular death (4.0% and 5.1%, respectively; p = .001) and MI (5.8% and 6.9%, respectively; p = .005) with ticagrelor compared with


InternalMed_Harrison

InternalMed_Harrison. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs 748 clopidogrel. Rates of stroke were similar with ticagrelor and clopido-Indications Dipyridamole plus aspirin was compared with aspirin grel (1.5% and 1.3%, respectively), and no difference in rates of major or dipyridamole alone, or with placebo, in patients with an ischemic bleeding was noted. When minor bleeding was added to the major stroke or transient ischemic attack. The combination reduced the risk bleeding results, however, ticagrelor showed an increase relative to of stroke by 22.1% compared with aspirin and by 24.4% compared clopidogrel (16.1% and 14.6%, respectively; p = .008). Ticagrelor also with dipyridamole. A second trial compared dipyridamole plus aspirin was superior to clopidogrel in patients with acute coronary syndrome with aspirin alone for secondary prevention in patients with ischemic who underwent percutaneous coronary intervention or cardiac sur-stroke. Vascular death, stroke, or MI occurred in 13% of


InternalMed_Harrison

InternalMed_Harrison. syndrome with aspirin alone for secondary prevention in patients with ischemic who underwent percutaneous coronary intervention or cardiac sur-stroke. Vascular death, stroke, or MI occurred in 13% of patients gery. Based on these observations, some guidelines give ticagrelor given combination therapy and in 16% of those treated with aspirin preference over clopidogrel, particularly in higher risk patients. alone. Another trial randomized 20,332 patients with noncardioembolic ischemic stroke to either Aggrenox or clopidogrel. The primarydosing Ticagrelor is initiated with an oral loading dose of 180 mg efficacy endpoint of recurrent stroke occurred in 9.0% of those given followed by 90 mg twice daily. The dose does not require adjustment Aggrenox and in 8.8% of patients treated with clopidogrel. Althoughin patients with renal impairment, but the drug should be used with this difference was not statistically significant, the study failed to meet caution in patients with hepatic disease


InternalMed_Harrison

InternalMed_Harrison. Althoughin patients with renal impairment, but the drug should be used with this difference was not statistically significant, the study failed to meet caution in patients with hepatic disease and in those receiving potent the prespecified margin to claim noninferiority of Aggrenox relativeinhibitors or inducers of CYP3A4 because ticagrelor is metabolized in to clopidogrel. These results have dampened enthusiasm for the usethe liver via CYP3A4. Ticagrelor is usually administered in conjunc-of Aggrenox.tion with aspirin; the daily aspirin dose should not exceed 100 mg. Because of its vasodilatory effects and the paucity of data supporting the use of dipyridamole in patients with symptomatic coronary artery side effects In addition to bleeding, the most common side effects of disease, Aggrenox should not be used for stroke prevention in such ticagrelor are dyspnea, which can occur in up to 15% of patients, and patients. Clopidogrel is a better choice in this setting.


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InternalMed_Harrison. asymptomatic ventricular pauses. The dyspnea, which tends to occur soon after initiating ticagrelor, is usually self-limiting and mild in Dosing Aggrenox is given twice daily. Each capsule contains 200 mg intensity. The mechanism responsible for this side effect is unknown. of extended-release dipyridamole and 25 mg of aspirin. To reduce the risk of bleeding, ticagrelor should be stopped 5–7 Side Effects Because dipyridamole has vasodilatory effects, it must days prior to major surgery. Platelet transfusions are unlikely to be of be used with caution in patients with coronary artery disease. benefit in patients with ticagrelor-related bleeding because the drug Gastrointestinal complaints, headache, facial flushing, dizziness, and will bind to P2Y12 on the transfused platelets. hypotension can also occur. These symptoms often subside with continued use of the drug.


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InternalMed_Harrison. hypotension can also occur. These symptoms often subside with continued use of the drug. Dipyridamole is a relatively weak antiplatelet agent on its own, but an extended-release formulation of dipyridamole combined with low- As a class, parenteral Gp IIb/IIIa receptor antagonists have an estab dose aspirin, a preparation known as Aggrenox, is used for prevention lished niche in patients with acute coronary syndromes. The three of stroke in patients with transient ischemic attacks. agents in this class are abciximab, eptifibatide, and tirofiban.


InternalMed_Harrison

InternalMed_Harrison. Mechanism of Action By inhibiting phosphodiesterase, dipyridamole Mechanism of Action A member of the integrin family of adhesion blocks the breakdown of cyclic adenosine monophosphate (AMP). receptors, Gp IIb/IIIa is found on the surface of platelets and mega-Increased levels of cyclic AMP reduce intracellular calcium and inhibit karyocytes. With about 80,000 copies per platelet, Gp IIb/IIIa is the platelet activation. Dipyridamole also blocks the uptake of adenosine most abundant receptor. Consisting of a noncovalently linked hetby platelets and other cells. This produces a further increase in local erodimer, Gp IIb/IIIa is inactive on resting platelets. When platelets cyclic AMP levels because the platelet adenosine A2 receptor is coupled are activated, inside-outside signal transduction pathways trigger a to adenylate cyclase (Fig. 143-4). conformational activation of the receptor. Once activated, Gp IIb/ IIIa binds adhesive molecules, such as fibrinogen and, under high shear


InternalMed_Harrison

InternalMed_Harrison. pathways trigger a to adenylate cyclase (Fig. 143-4). conformational activation of the receptor. Once activated, Gp IIb/ IIIa binds adhesive molecules, such as fibrinogen and, under high shear conditions, VWF. Binding is mediated by the Arg-Gly-Asp (RGD) sequence found on the α chains of fibrinogen and on VWF, and by the Lys-Gly-Asp (KGD) sequence located within a unique dodecapeptide domain on the γ chains of fibrinogen. Once bound, fibrinogen and/or VWF bridge adjacent platelets together to induce platelet aggregation. Although abciximab, eptifibatide, and tirofiban all target the Gp IIb/ IIIa receptor, they are structurally and pharmacologically distinct (Table 143-1). Abciximab is a Fab fragment of a humanized murine monoclonal antibody directed against the activated form of Gp IIb/IIIa. Abciximab binds to the activated receptor with high affinity and blocks the binding of adhesive molecules. In contrast, eptifibatide and tirofiban are synthetic small molecules. Eptifibatide is a


InternalMed_Harrison

InternalMed_Harrison. Abciximab binds to the activated receptor with high affinity and blocks the binding of adhesive molecules. In contrast, eptifibatide and tirofiban are synthetic small molecules. Eptifibatide is a cyclic heptapeptide that


InternalMed_Harrison

InternalMed_Harrison. FIGURE 143-4 Mechanism of action of dipyridamole. Dipyridamole increases levels of cyclic AMP binds Gp IIb/IIIa because it incorpo(cAMP) in platelets by (1) blocking the reuptake of adenosine and (2) inhibiting phosphodiesterase-rates the KGD motif, whereas tirofiban mediated cyclic AMP degradation. By promoting calcium uptake, cyclic AMP reduces intracellular is a nonpeptidic tyrosine derivative that levels of calcium. This, in turn, inhibits platelet activation and aggregation. acts as an RGD mimetic. Abciximab has clopidogrel (3.8% and 4.7%, respec a long half-life and can be detected on the surface of platelets for up to 2 weeks; eptifibatide and tirofiban have short half-lives.


InternalMed_Harrison

InternalMed_Harrison. Whereas eptifibatide and tirofiban are specific for Gp IIb/IIIa, abciximab also inhibits the closely related αvβ3 receptor, which binds vitronectin, and α β , a leukocyte integrin. Inhibition of α β and α β may endow abciximab with anti-inflammatory and/or antiproliferative properties that extend beyond platelet inhibition. Indications Abciximab and eptifibatide are used in patients undergoing percutaneous coronary interventions, particularly those who have not been pretreated with an ADP receptor antagonist. Tirofiban is used in high-risk patients with unstable angina. Eptifibatide also can be used for this indication.


InternalMed_Harrison

InternalMed_Harrison. Dosing All of the Gp IIb/IIIa antagonists are given as an IV bolus followed by an infusion. The recommended dose of abciximab is a bolus of 0.25 mg/kg followed by an infusion of 0.125 μg/kg per minute to a maximum of 10 μg/kg for 12 h. Eptifibatide is given as two 180 μg/kg boluses given 10 min apart, followed by an infusion of 2.0 μg/kg per minute for 18–24 h. Tirofiban is started at a rate of 0.4 μg/kg per minute for 30 min; the drug is then continued at a rate of 0.1 μg/kg per minute for up to 18 h. Because these agents are cleared by the kidneys, the doses of eptifibatide and tirofiban must be reduced in patients with renal insufficiency. Thus, the eptifibatide infusion is reduced to 1 μg/kg per minute in patients with a creatinine clearance below 50 mL/min, whereas the dose of tirofiban is cut in half for patients with a creatinine clearance below 30 mL/min.


InternalMed_Harrison

InternalMed_Harrison. Side Effects In addition to bleeding, thrombocytopenia is the most serious complication. Thrombocytopenia is immune-mediated and is caused by antibodies directed against neoantigens on Gp IIb/IIIa that are exposed upon antagonist binding. With abciximab, thrombocytopenia occurs in up to 5% of patients. Thrombocytopenia is severe in ~1% of these individuals. Thrombocytopenia is less common with the other two agents, occurring in ~1% of patients. New agents in advanced stages of development include cangrelor, a parenteral, rapidly acting, reversible inhibitor of P2Y12, and vorapaxar, an orally active inhibitor of protease-activated receptor 1 (PAR-1), the major thrombin receptor on platelets (Fig. 143-3).


InternalMed_Harrison

InternalMed_Harrison. Cangrelor An adenosine analogue, cangrelor binds reversibly to P2Y12 and inhibits its activity. The drug has a half-life of 3–6 min and is given IV as a bolus followed by an infusion. When stopped, platelet function recovers within 60 min. A trial comparing cangrelor with placebo during percutaneous coronary interventions and a study comparing cangrelor with clopidogrel after such procedures revealed little or no advantage of cangrelor. A third trial compared cangrelor (given as an IV bolus of 30 μg/kg followed by an infusion of 4 μg/kg per minute for at least 2 h, or for the duration of the procedure, whichever was longer) with a loading dose of clopidogrel (300 or 600 mg) in 11,145 patients undergoing urgent or elective percutaneous coronary intervention. The rate of the primary efficacy endpoint, a composite of death, MI, ischemia-driven revascularization, and stent thrombosis, was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (p = .005). The rates of severe


InternalMed_Harrison

InternalMed_Harrison. efficacy endpoint, a composite of death, MI, ischemia-driven revascularization, and stent thrombosis, was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (p = .005). The rates of severe bleeding, the primary safety endpoint, were 0.16% and 0.11% in the cangrelor and clopidogrel groups, respectively. Using the same efficacy endpoint, a prespecified meta-analysis of the three trials thrombosis (0.5% and 0.8%, respec-


InternalMed_Harrison

InternalMed_Harrison. Yes tively) with no significant increase in Long (2.0 h) serious bleeding. Based on these data, Short (s) cangrelor is currently under regula- Yes tory review. antagonist, vorapaxar is slowly eliminated with a half-life of about 200 h. When compared with placebo in 12,944 patients with acute coronary syndrome without ST-segment elevation, vorapaxar failed to significantly reduce the primary efficacy endpoint, a composite of cardiovascular death, MI, stroke, recurrent ischemia requiring rehospitalization, and urgent coronary revascularization. Moreover, vorapaxar was associated with increased rates of bleeding, including intracranial bleeding.


InternalMed_Harrison

InternalMed_Harrison. In a second trial, vorapaxar was compared with placebo for secondary prevention in 26,449 patients with prior MI, ischemic stroke, or peripheral arterial disease. Overall, vorapaxar reduced the risk for cardiovascular death, MI, or stroke by 13%, but doubled the risk of intracranial bleeding. In the prespecified subgroup of 17,779 patients with prior MI, however, vorapaxar reduced the risk for cardiovascular death, MI, or stroke by 20% compared with placebo (from 9.7% to 8.1%, respectively). The rate of intracranial hemorrhage was higher with vorapaxar than with placebo (0.6% and 0.4%, respectively; p = .076) as was the rate of moderate or severe bleeding (3.4% and 2.1%, respectively; P <0.0001). Based on these data, the drug is under consideration for regulatory approval in MI patients under the age of 75 years who have no history of stroke or transient ischemic attack and have a weight over 60 kg.


InternalMed_Harrison

InternalMed_Harrison. There are both parenteral and oral anticoagulants. The parenteral anticoagulants include heparin, low-molecular-weight heparin (LMWH), fondaparinux (a synthetic pentasaccharide), lepirudin, desirudin, bivalirudin, and argatroban. Currently available oral anticoagulants include warfarin; dabigatran etexilate, an oral thrombin inhibitor; and rivaroxaban and apixaban, oral factor Xa inhibitors. Edoxaban, a third oral factor Xa inhibitor, is undergoing regulatory review. PARENTERAL ANTICOAGULANTS Heparin A sulfated polysaccharide, heparin is isolated from mammalian tissues rich in mast cells. Most commercial heparin is derived from porcine intestinal mucosa and is a polymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine residues.


InternalMed_Harrison

InternalMed_Harrison. mecHanism of action Heparin acts as an anticoagulant by activating antithrombin (previously known as antithrombin III) and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa. Antithrombin, the obligatory plasma cofactor for heparin, is a member of the serine protease inhibitor (serpin) superfamily. Synthesized in the liver and circulating in plasma at a concentration of 2.6 ± 0.4 μM, antithrombin acts as a suicide substrate for its target enzymes.


InternalMed_Harrison

InternalMed_Harrison. To activate antithrombin, heparin binds to the serpin via a unique pentasaccharide sequence that is found on one-third of the chains of commercial heparin (Fig. 143-5). Heparin chains without this pentasaccharide sequence have little or no anticoagulant activity. Once bound to antithrombin, heparin induces a conformational change in the reactive center loop of antithrombin that renders it more readily accessible to its target proteases. This conformational change enhances the rate at which antithrombin inhibits factor Xa by at least two orders of magnitude but has little effect on the rate of thrombin inhibition. To catalyze thrombin inhibition, heparin serves as a template that binds antithrombin and thrombin simultaneously. Formation of this ternary complex brings the enzyme in close apposition to the inhibitor, thereby


InternalMed_Harrison

InternalMed_Harrison. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs promoting the formation of a stable covalent thrombin-antithrombin may render patients at risk for recurrent thrombosis, whereas excescomplex. sive anticoagulation increases the risk of bleeding.


InternalMed_Harrison

InternalMed_Harrison. Only pentasaccharide-containing heparin chains composed of at least 18 saccharide units (which correspond to a molecular weight monitoring tHe anticoagulant effect Heparin therapy can be moniof 5400) are of sufficient length to bridge thrombin and antithrom-tored using the activated partial thromboplastin time (aPTT) or bin together. With a mean molecular weight of 15,000, and a range anti-factor Xa level. Although the aPTT is the test most often used for of 5000–30,000, almost all of the chains of unfractionated heparin this purpose, there are problems with this assay. aPTT reagents vary are long enough to do so. Consequently, by definition, heparin has in their sensitivity to heparin, and the type of coagulometer used for equal capacity to promote the inhibition of thrombin and factor Xa testing can influence the results. Consequently, laboratories must by antithrombin and is assigned an anti-factor Xa to anti-factor IIa establish a therapeutic aPTT range with each


InternalMed_Harrison

InternalMed_Harrison. and factor Xa testing can influence the results. Consequently, laboratories must by antithrombin and is assigned an anti-factor Xa to anti-factor IIa establish a therapeutic aPTT range with each reagent-coagulometer (thrombin) ratio of 1:1. combination by measuring the aPTT and anti-factor Xa level in plasma


InternalMed_Harrison

InternalMed_Harrison. Heparin causes the release of tissue factor pathway inhibitor (TFPI) samples collected from heparin-treated patients. For most of the aPTT from the endothelium. A factor Xa–dependent inhibitor of tissue reagents and coagulometers in current use, therapeutic heparin levels factor–bound factor VIIa, TFPI may contribute to the antithrombotic are achieved with a twoto threefold prolongation of the aPTT. activity of heparin. Longer heparin chains induce the release of more Anti-factor Xa levels also can be used to monitor heparin therapy. TFPI than shorter ones. With this test, therapeutic heparin levels range from 0.3 to 0.7 units/ mL. Although this test is gaining in popularity, anti-factor Xa assays pHarmacology Heparin must be given parenterally. It is usually have yet to be standardized, and results can vary widely between administered SC or by continuous IV infusion. When used for thera-laboratories. peutic purposes, the IV route is most often employed. If heparin is Up to 25% of


InternalMed_Harrison

InternalMed_Harrison. and results can vary widely between administered SC or by continuous IV infusion. When used for thera-laboratories. peutic purposes, the IV route is most often employed. If heparin is Up to 25% of heparin-treated patients with venous thromboemgiven SC for treatment of thrombosis, the dose of heparin must be bolism require >35,000 units/d to achieve a therapeutic aPTT. These patients are considered heparin resistant. It is useful to measure anti-factor Xa levels in heparin-resistant patients because many will have a therapeutic anti-factor Xa level despite a subtherapeutic aPTT. This dissociation in test results occurs because elevated plasma levels of fibrinogen and factor VIII, both of which are acute-phase proteins, shorten the aPTT but have no effect on anti-factor Xa levels. Heparin therapy in patients who exhibit this phenomenon is best monitored using anti-factor Xa levels instead of the aPTT. Patients with congenital or acquired antithrombin deficiency and those with elevated


InternalMed_Harrison

InternalMed_Harrison. therapy in patients who exhibit this phenomenon is best monitored using anti-factor Xa levels instead of the aPTT. Patients with congenital or acquired antithrombin deficiency and those with elevated levels of heparin-binding proteins may also need high doses of heparin to achieve a therapeutic aPTT or anti-factor Xa level. If there is good correlation between the aPTT and the anti-factor Xa levels, either test can be used to monitor heparin therapy.


InternalMed_Harrison

InternalMed_Harrison. dosing For prophylaxis, heparin is usually given in fixed doses of 5000 units SC two or three times daily. With these low doses, coagulation monitoring is unnecessary. In contrast, monitoring is essential when the drug is given in therapeutic doses. Fixed-dose or weight-based heparin nomograms are used to standardize heparin dosing and to shorten the time required to achieve a therapeutic anticoagulant response. At least two heparin nomograms have been validated in patients with venous thromboembolism and reduce the time required to achieve a therapeutic aPTT. Weight-adjusted heparin nomograms have also been evaluated in patients with acute coronary syndromes. After an IV heparin bolus of 5000 units or 70 units/kg, a heparin infusion rate of 12–15 units/kg per hour is usually administered. In contrast, weight-adjusted heparin nomograms for patients with venous thromboembolism use an initial bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/kg per h. Thus,


InternalMed_Harrison

InternalMed_Harrison. In contrast, weight-adjusted heparin nomograms for patients with venous thromboembolism use an initial bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/kg per h. Thus, patients with venous thromboembolism appear to require higher doses of heparin to achieve a therapeutic aPTT than do patients with acute coronary syndromes. This may reflect differences in the thrombus burden. Heparin binds to fibrin, and the amount of fibrin in patients with extensive DVT is greater than that in those with coronary thrombosis.


InternalMed_Harrison

InternalMed_Harrison. Heparin manufacturers in North America have traditionally measured heparin potency in USP units, with a unit defined as the concentration of heparin that prevents 1 mL of citrated sheep plasma from clotting for 1 h after calcium addition. In contrast, manufacturers in Europe measure heparin potency with anti-Xa assays using an international heparin standard for comparison. Because of problems with heparin contamination with oversulfated chondroitin sulfate, which the USP assay system does not detect, North American heparin manufacturers now use the anti-Xa assay to assess heparin potency. The use of international units in place of USP units results in a 10% reduction in heparin doses, which is a difference unlikely to affect patient care because monitoring will help to ensure that a therapeutic anticoagulant response has been achieved.


InternalMed_Harrison

InternalMed_Harrison. limitations Heparin has pharmacokinetic and biophysical limitations (Table 143-2). The pharmacokinetic limitations reflect heparin’s propensity to bind in a pentasaccharide-independent fashion to cells and plasma proteins. Heparin binding to endothelial cells explains its dose-dependent clearance, whereas binding to plasma proteins results in a variable anticoagulant response and can lead to heparin resistance. Poor bioavailability at low doses Binds to endothelial cells and macrophages Dose-dependent clearance Binds to macrophages Variable anticoagulant response Binds to plasma proteins whose levels vary from patient to patient Reduced activity in the vicinity of Neutralized by platelet factor 4 platelet-rich thrombi released from activated platelets


InternalMed_Harrison

InternalMed_Harrison. Reduced activity in the vicinity of Neutralized by platelet factor 4 platelet-rich thrombi released from activated platelets Limited activity against factor Xa Reduced capacity of heparin-incorporated in the prothrombinase antithrombin complex to inhibit complex and thrombin bound to factor Xa bound to activated platelets fibrin and thrombin bound to fibrin


InternalMed_Harrison

InternalMed_Harrison. The biophysical limitations of heparin reflect the inability of the 751 heparin-antithrombin complex to inhibit factor Xa when it is incorporated into the prothrombinase complex, the complex that converts prothrombin to thrombin, and to inhibit thrombin bound to fibrin. Consequently, factor Xa bound to activated platelets within platelet-rich thrombi has the potential to generate thrombin, even in the face of heparin. Once this thrombin binds to fibrin, it too is protected from inhibition by the heparin-antithrombin complex. Clot-associated thrombin can then trigger thrombus growth by locally activating platelets and amplifying its own generation through feedback activation of factors V, VIII, and XI. Further compounding the problem is the potential for heparin neutralization by the high concentrations of PF4 released from activated platelets within the platelet-rich thrombus.


InternalMed_Harrison

InternalMed_Harrison. side effects The most common side effect of heparin is bleeding. Other complications include thrombocytopenia, osteoporosis, and elevated levels of transaminases. bleeding The risk of bleeding rises as the dose of heparin is increased. Concomitant administration of drugs that affect hemostasis, such as antiplatelet or fibrinolytic agents, increases the risk of bleeding, as does recent surgery or trauma. Heparin-treated patients with serious bleeding can be given protamine sulfate to neutralize the heparin. Protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm, binds heparin with high affinity, and the resultant protamine-heparin complexes are then cleared. Typically, 1 mg of protamine sulfate neutralizes 100 units of heparin. Protamine sulfate is given IV. Anaphylactoid reactions to protamine sulfate can occur, and drug administration by slow IV infusion is recommended to reduce the risk.


InternalMed_Harrison

InternalMed_Harrison. tHrombocytopenia Heparin can cause thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is an antibody-mediated process that is triggered by antibodies directed against neoantigens on PF4 that are exposed when heparin binds to this protein. These antibodies, which are usually of the IgG isotype, bind simultaneously to the heparin-PF4 complex and to platelet Fc receptors. Such binding activates the platelets and generates platelet microparticles. Circulating microparticles are prothrombotic because they express anionic phospholipids on their surface and can bind clotting factors and promote thrombin generation.


InternalMed_Harrison

InternalMed_Harrison. The clinical features of HIT are illustrated in Table 143-3. Typically, HIT occurs 5–14 days after initiation of heparin therapy, but it can manifest earlier if the patient has received heparin within the past 3 months. A platelet count below 100,000/μL or a 50% decrease in the platelet count from the pretreatment value should raise the suspicion of HIT in those receiving heparin. HIT is more common in surgical patients than in medical patients and, like many autoimmune disorders, occurs more frequently in females than in males. HIT can be associated with thrombosis, either arterial or venous. Venous thrombosis, which manifests as DVT and/or PE, is more common than arterial thrombosis. Arterial thrombosis can manifest as ischemic stroke or acute MI. Rarely, platelet-rich thrombi in the distal aorta or iliac arteries can cause critical limb ischemia. Thrombocytopenia Platelet count of ≤100,000/μL or a decrease in platelet count of ≥50%


InternalMed_Harrison

InternalMed_Harrison. Thrombocytopenia Platelet count of ≤100,000/μL or a decrease in platelet count of ≥50% Type of heparin More common with unfractionated heparin than low-molecular-weight heparin Type of patient More common in surgical patients and patients with cancer than general medical patients; more common in women than in men Antiplatelet, Anticoagulant, and Fibrinolytic Drugs Stop all heparin. Give an alternative anticoagulant, such as lepirudin, argatroban, bivalirudin, or fondaparinux. Do not give platelet transfusions. Do not give warfarin until the platelet count returns to its baseline level. If warfarin was administered, give vitamin K to restore the INR to normal. Evaluate for thrombosis, particularly deep vein thrombosis. Abbreviation: INR, international normalized ratio.


InternalMed_Harrison

InternalMed_Harrison. Evaluate for thrombosis, particularly deep vein thrombosis. Abbreviation: INR, international normalized ratio. The diagnosis of HIT is established using enzyme-linked assays to detect antibodies against heparin-PF4 complexes or with platelet activation assays. Enzyme-linked assays are sensitive but can be positive in the absence of any clinical evidence of HIT. The most specific diagnostic test is the serotonin release assay. This test is performed by quantifying serotonin release when washed platelets loaded with labeled serotonin are exposed to patient serum in the absence or presence of varying concentrations of heparin. If the patient serum contains the HIT antibody, heparin addition induces platelet activation and serotonin release.


InternalMed_Harrison

InternalMed_Harrison. Management of HIT is outlined in Table 143-4. Heparin should be stopped in patients with suspected or documented HIT, and an alternative anticoagulant should be administered to prevent or treat thrombosis. The agents most often used for this indication are parenteral direct thrombin inhibitors, such as lepirudin, argatroban, or bivalirudin, or factor Xa inhibitors, such as fondaparinux.


InternalMed_Harrison

InternalMed_Harrison. Patients with HIT, particularly those with associated thrombosis, often have evidence of increased thrombin generation that can lead to consumption of protein C. If these patients are given warfarin without a concomitant parenteral anticoagulant to inhibit thrombin or thrombin generation, the further decrease in protein C levels induced by the vitamin K antagonist can trigger skin necrosis. To avoid this problem, patients with HIT should be treated with a direct thrombin inhibitor or fondaparinux until the platelet count returns to normal levels. At this point, low-dose warfarin therapy can be introduced, and the thrombin inhibitor can be discontinued when the anticoagulant response to warfarin has been therapeutic for at least 2 days.


InternalMed_Harrison

InternalMed_Harrison. osteoporosis Treatment with therapeutic doses of heparin for >1 month can cause a reduction in bone density. This complication has been reported in up to 30% of patients given long-term heparin therapy, and symptomatic vertebral fractures occur in 2–3% of these individuals. Heparin causes bone loss both by decreasing bone formation and by enhancing bone resorption. Thus, heparin affects the activity of both osteoblasts and osteoclasts. elevated levels of transaminases Therapeutic doses of heparin are frequently associated with modest elevations in the serum levels of hepatic transaminases without a concomitant increase in the level of bilirubin. The levels of transaminases rapidly return to normal when the drug is stopped. The mechanism responsible for this phenomenon is unknown.