DRUGS FOR TREATING BLEEDING DISORDERS

Hemostasis is the cessation of blood loss from a damaged vessel. Platelets first adhere to

macromolecules in the subendothelial regions of the injured blood vessel; they then aggregate to form the

primary hemostatic plug. Platelets stimulate local activation of plasma coagulation factors, leading to

generation of a fibrin clot that reinforces the platelet aggregate.

ANTI THROMBOLYTIC DRUGS• Antithrombin is a plasma protein that inhibits

coagulation factors of the intrinsic and common pathways (see below). Heparan sulfate proteoglycanssynthesized by endothelial cells stimulate the activity of antithrombin. Protein C is a plasma zymogen that is homologous to II, VII, IX, and X; its activity depends on the binding of Ca2+ to Gla residues within its amino-terminal domain.

• Activated protein C, in combination with its nonenzymatic Gla-containing cofactor (protein S), degrades cofactors Va and VIIIa and thereby greatly diminishes the rates of activation of prothrombin and factor X

• Conversion of Fibrinogen to Fibrin. Fibrinogen is a 330,000-dalton protein that consists of three pairs of polypeptide chains (designated Aa, Bb, and g) covalently linked by disulfide bonds. Thrombin converts fibrinogen to fibrin monomers by cleaving fibrinopeptides A (16 amino acid residues) and B (14 amino acid residues) from the amino-terminal ends of the Aa and Bb chains, respectively

• Initially, the fibrin monomers are bound to each other noncovalently. Subsequently, factor XIIIacatalyzes an interchain transglutamination reaction that cross-links adjacent fibrin monomers to enhance the strength of the clot.

•The fibrinolytic system dissolves intravascular clots as a result of the action of plasmin, an enzyme that digests fibrin. Plasminogen, an inactive precursor, is converted to plasmin by cleavage of a single peptide bond.

• Plasmin is a relatively nonspecific protease; it digests fibrin clots and other plasma proteins, including several coagulation factors. Therapy with thrombolytic drugs tends to dissolve both pathological thrombi and fibrin deposits at sites of vascular injury. Therefore, the drugs are toxic, producing hemorrhage as a major side effect.

• Two pathways of coagulation are recognized. An individual with a prolonged aPTT and a normal PT is considered to have a defect in the intrinsic coagulation pathway, because all of the components of the aPTT test (except kaolin) are intrinsic to the plasma.

• A patient with a prolonged PT and a normal aPTThas a defect in the extrinsic coagulation pathway,since thromboplastin is extrinsic to the plasma. Prolongation of both the aPTT and the PT suggests a defect in a common pathway.

• PARENTERAL ANTICOAGULANTS

Heparin

Biochemistry. Heparin is a glycosaminoglycan found in the secretory granules of mast cells. It is synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues

• Heparan Sulfate. Heparan sulfate is synthesized from the same repeating disaccharide precursor (D-glucuronic acid linked to N-acetyl-D-glucosamine) as is heparin. However, heparan sulfate undergoes less modification of the polymer than does heparin and therefore contains higher proportions of glucuronicacid and N-acetylglucosamine and fewer sulfate groups

• . Heparan sulfate on the surface of vascular endothelial cells or in the subendothelial extracellular matrix interacts with circulating antithrombin (see below) to provide a natural antithrombotic mechanism.

• Patients with malignancies may experience bleeding related to circulating heparan sulfate or related glycosaminoglycans that probably originate from lysisof the tumor cells.

• Source. Heparin is commonly extracted from porcine intestinal mucosa or bovine lung, and preparations may contain small amounts of other glycosaminoglycans.

• Low-molecular-weight heparins (1000 to 10,000 daltons; mean, 4500 daltons, or 15 monosaccharide units) are isolated from standard heparin by gel filtration chromatography, precipitation with ethanol, or partial depolymerization with nitrous acid and other chemical or enzymatic reagents

• . Low-molecular-weight heparins differ from standard heparin and from each other in their pharmacokinetic properties and mechanism of action.

• Mechanism of Action. Heparin catalyzes the inhibition of several coagulation proteases by antithrombin, a glycosylated, single-chain polypeptide composed of 432 amino acid residues

• Heparin increases the rate of the thrombin-antithrombin reaction at least a thousandfold by serving as a catalytic template to which both the inhibitor and the protease bind.

• Binding of heparin also induces a conformational change in antithrombin that makes the reactive site more accessible to the protease. Once thrombin has become bound to antithrombin, the heparin molecule is released from the complex.

• Low-molecular-weight heparin preparations produce an anticoagulant effect mainly through inhibition of Xaby antithrombin, because the majority of molecules are of insufficient length to catalyze inhibition of thrombin.

• Factor Xa bound to platelets in the prothrombinase complex and thrombin bound to fibrin are both protected from inhibition by antithrombin in the presence of heparin.

• Thus, heparin may promote inhibition of factor Xa and thrombin only after they have diffused away from these binding sites. Platelet factor 4, released from the a-granules during platelet aggregation, blocks binding of antithrombin to heparin or heparan sulfate and may promote local clot formation at the site of hemostasis.

• Miscellaneous Pharmacological Effects. High doses of heparin can interfere with platelet aggregation and thereby prolong bleeding time. It is unclear to what extent the antiplatelet effect of heparin contributes to the hemorrhagic complications of treatment with the drug.

• Clinical Use. Heparin is used to initiate treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action.

• An oral anticoagulant usually is started concurrently, and heparin is continued for at least 4 to 5 days to allow the oral anticoagulant to achieve its full therapeutic effect.

• Patients who experience recurrent thromboembolism despite adequate oral anticoagulation (e.g., patients with Trousseau's syndrome) may benefit from long-term heparin administration

• . Heparin is used in the initial management of patients with unstable angina or acute myocardial infarction, during and after coronary angioplasty or stent placement, and during surgery requiring cardiopulmonary bypass.

• Heparin also is used to treat selected patients with disseminated intravascular coagulation. Low-dose heparin regimens are effective in preventing venous thromboembolism in certain high-risk patients.

• Low-molecular-weight heparin preparations were first approved for prevention of venous thromboembolism. They are also effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina

• Low-molecular-weight heparin preparations were first approved for prevention of venous thromboembolism. They are also effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina.

• Low-molecular-weight heparin preparations were first approved for prevention of venous thromboembolism. They are also effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina.

• Absorption and Pharmacokinetics. Heparin is not absorbed through the gastrointestinal mucosa and therefore is given by continuous intravenous infusion or subcutaneous injection. Heparin has an immediate onset of action when given intravenously.

• In contrast, there is considerable variation in the bioavailability of heparin given subcutaneously, and the onset of action is delayed 1 to 2 hours; low-molecular-weight heparins are absorbed more uniformly

The half-life of heparin in plasma depends on the dose administered. When doses of 100, 400, or 800 units/kg of heparin are injected intravenously, the half-lives of the anticoagulant activities are approximately 1, 2.5, and 5 hours, respectively.

Administration and Monitoring. Full-dose heparin therapy usually is administered by continuous intravenous infusion. Treatment of venous thromboembolism is initiated with a bolus injection of 5000 units, followed by 1200 to 1600 units per hour delivered by an infusion pump. Therapy routinely is monitored by the aPTT.

• Subcutaneous administration of heparin can be used for the long-term management of patients in whom warfarin is contraindicated (e.g., during pregnancy). A total daily dose of about 35,000 units administered as divided doses every 8 to 12 hours usually is sufficient to achieve an aPTT of 1.5 times the control value (measured midway between doses). Monitoring generally is unnecessary once a steady dosage schedule is established.

Synthetic Heparin Derivatives. Fondaparinux (ARIXTRA) is a synthetic pentasaccharide based on the structure of the antithrombin binding region of heparin. It mediates inhibition of factor Xa by antithrombin but does not cause thrombin inhibition due to its short polymer length. Fondaparinux is administered by subcutaneous injection, reaches peak plasma levels in 2 hours, and is excreted in the urine with a half-life of 17 to 21 hours.

• Toxicities. Bleeding. Bleeding is the primary untoward effect of heparin. Major bleeding occurs in 1% to 5% of patients treated with intravenous heparin for venous thromboembolism. The incidence of bleeding is somewhat less in patients treated with low-molecular-weight heparin for this indication.

• Protamine is used routinely to reverse the anticoagulant effect of heparin following cardiac surgery and other vascular procedures. Anaphylactic reactions occur in about 1% of patients with diabetes mellitus who have received protamine-containing insulin (NPH insulin or protamine zinc insulin) but are not limited to this group. A less common reaction consisting of pulmonary vasoconstriction, right ventricular dysfunction, systemic hypotension, and transient neutropenia also may occur after protamineadministration.

• Other Toxicities. Abnormalities of hepatic function tests occur frequently in patients who are receiving heparin intravenously or subcutaneously. Mild elevations of the activities of hepatic transaminasesin plasma occur without an increase in bilirubinlevels or alkaline phosphatase activity.

• Osteoporosis resulting in spontaneous vertebral fractures can occur, albeit infrequently, in patients who have received full therapeutic doses of heparin (greater than 20,000 units per day) for extended periods of time (e.g., 3 to 6 months).

• Other Parenteral Anticoagulants

Lepirudin. Lepirudin (REFLUDAN) is a recombinant derivative (Leu1-Thr2-63-desulfohirudin) of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech. It is a 65-amino-acid polypeptide that binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin.

• The drug is excreted by the kidneys and has a half-life of about 1.3 hours. Lepirudin should be used cautiously in patients with renal failure, since it can accumulate and cause bleeding in these patients. Patients may develop antihirudin antibodies that occasionally cause a paradoxical increase in the aPTT; therefore, daily monitoring of the aPTT is recommended. There is no antidote for lepirudin.

•Bivalirudin. Bivalirudin (ANGIOMAX) is a synthetic, 20-amino-acid polypeptide that directly inhibits thrombin by a mechanism similar to that of lepirudin. Bivalirudincontains the sequence Phe1-Pro2-Arg3-Pro4, which occupies the catalytic site of thrombin, followed by a polyglycine linker and a hirudin-like sequence that binds to exosite I.

• Thrombin slowly cleaves the Arg3-Pro4 peptide bond and thus regains activity. Bivalirudin is administered intravenously and is used as an alternative to heparin in patients undergoing coronary angioplasty. The half-life of bivalirudin in patients with normal renal function is 25 minutes; dosage reductions are recommended for patients with moderate or severe renal impairment

• Argatroban. Argatroban, a synthetic compound based on the structure of L-arginine, binds reversibly to the catalytic site of thrombin. It is administered intravenously and has an immediate onset of action.

• Its half-life is 40 to 50 minutes. Argatroban is metabolized by cytochrome P450 enzymes in the liver and is excreted in the bile; therefore dosage reduction is required for patients with hepatic insufficiency. The dosage is adjusted to maintain an aPTT of 1.5 to 3 times the baseline value.

• Argatroban can be used as an alternative to lepirudinfor prophylaxis or treatment of patients with or at risk of developing heparin-induced thrombocytopenia.

• Drotrecogin Alfa. Drotrecogin alfa (XIGRIS) is a recombinant form of human activated protein C that inhibits coagulation by proteolytic inactivation of factors Va and VIIIa. It also has antiinflammatoryeffects.

• A 96-hour continuous infusion of drotrecogin alfadecreases mortality in adult patients who are at high risk for death from severe sepsis if given within 48 hours of the onset of organ dysfunction (e.g., shock, hypoxemia, oliguria). The major adverse effect is bleeding.

• ORAL ANTICOAGULANTSWarfarinHistory. Following the report of a hemorrhagic disorder in cattle that resulted from the ingestion of spoiled sweet clover silage, Campbell and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin (dicoumarol). In 1948, a more potent synthetic congener was introduced as an extremely effective rodenticide;

• Chemistry. Numerous anticoagulants have been synthesized as derivatives of 4-hydroxycoumarin and of the related compound, indan-1,3-dione . Only the coumarin derivatives are widely used; the 4-hydroxycoumarin residue, with a nonpolar carbon substituent at the 3 position, is the minimal structural requirement for activity.

• Mechanism of Action. The oral anticoagulants are antagonists of vitamin K.

Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9 to 13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding g-carboxyglutamate (Gla) residues.

• This reaction of the descarboxy precursor protein requires carbon dioxide, molecular oxygen, and reduced vitamin K, and is catalyzed by g-glutamylcarboxylase in the rough endoplasmic reticulum

• Reduced vitamin K must be regenerated from the epoxide for sustained carboxylation and synthesis of biologically competent proteins.

• The enzyme that catalyzes this, vitamin K epoxidereductase, is inhibited by therapeutic doses of warfarin. Vitamin K (but not vitamin K epoxide) also can be converted to the corresponding hydroquinone by a second reductase, DT-diaphorase.

• This enzyme requires high concentrations of vitamin K and is less sensitive to coumarin drugs, which may explain why administration of sufficient vitamin K can counteract even large doses of oral anticoagulants.

• Dosage. The usual adult dose of warfarin (COUMADIN) is 5 mg per day for 2 to 4 days, followed by 2 to 10 mg per day as indicated by measurements of the international normalized ratio (INR), a value derived from the patient's PT.

• A lower initial dose should be given to patients with an increased risk of bleeding, including the elderly. Warfarin usually is administered orally; age correlates with increased sensitivity to oral anticoagulants. Warfarin also can be given intravenously without modification of the dose. Intramuscular injection is not recommended because of the risk of hematoma formation.

• Absorption. The bioavailability of warfarin is nearly complete when the drug is administered orally, intravenously, or rectally. Bleeding has occurred from repeated skin contact with solutions of warfarin used as a rodenticide.

• Food in the gastrointestinal tract also can decrease the rate of absorption. Warfarin usually is detectable in plasma within 1 hour of its oral administration, and concentrations peak in 2 to 8 hours.

• Distribution. Warfarin is almost completely (99%) bound to plasma proteins, principally albumin, and the drug distributes rapidly into a volume equivalent to the albumin space (0.14 L/kg).

• Biotransformation and Elimination. Warfarin is a racemic mixture of R (weak) and S (potent) anticoagulant enantiomers. S-warfarin is transformed into inactive metabolites by CYP2C9 and R-warfarin is transformed by CYP1A2, CYP2C19 (minor pathway), and CYP3A4 (minor pathway).

• The inactive metabolites of warfarin are excreted in urine and stool. The average rate of clearance from plasma is 0.045 ml/min-1×kg-1. The half-life ranges from 25 to 60 hours, with a mean of about 40 hours; the duration of action of warfarin is 2 to 5 days.

• Drug and Other Interactions. The list of drugs and other factors that may affect the action of oral anticoagulants is prodigious and expanding .

• Any substance or condition is potentially dangerous if it alters (1) the uptake or metabolism of the oral anticoagulant or vitamin K; (2) the synthesis, function, or clearance of any factor or cell involved in hemostasis or fibrinolysis; or (3) the integrity of any epithelial surface.

• Patients must be educated to report the addition or deletion of any medication, including nonprescription drugs and food supplements.

• Frequently cited interactions that enhance the risk of hemorrhage in patients taking oral anticoagulants include decreased metabolism due to CYP2C9 inhibition by amiodarone, azole antifungals, cimetidine, clopidogrel, cotrimoxazole, disulfiram, fluoxetine, isoniazid, metronidazole, sulfinpyrazone, tolcapone, or zafirlukast, and displacement from protein binding sites caused by loop diuretics or valproate.

• Relative deficiency of vitamin K may result from inadequate diet (e.g., postoperative patients on parenteral fluids), especially when coupled with the elimination of intestinal flora by antimicrobial agents. Gut bacteria synthesize vitamin K and thus are an important source of this vitamin.

• Resistance to Warfarin. Some patients require more than 20 mg per day of warfarin to achieve a therapeutic INR. These patients often have excessive vitamin K intake from the diet or parenteral supplementation. Noncompliance and laboratory error are other causes of apparent warfarin resistance.

• Sensitivity to Warfarin. Approximately 10% of patients require less than 1.5 mg per day of warfarin to achieve an INR of 2 to 3. These patients are more likely to possess one or two variant alleles of CYP2C9, which is the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites

• Toxicities. Bleeding. Bleeding is the major toxicity of oral anticoagulant drugs. The risk of bleeding increases with the intensity and duration of anticoagulant therapy, the use of other medications that interfere with hemostasis, and the presence of a potential anatomical source of bleeding.

Birth Defects. Administration of warfarin during pregnancy causes birth defects and abortion. A syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that resemble chondrodysplasia punctata may result from maternal ingestion of warfarin during the first trimester.

Skin Necrosis. Warfarin-induced skin necrosis is a rare complication characterized by the appearance of skin lesions 3 to 10 days after treatment is initiated.

The lesions typically are on the extremities, but adipose tissue, the penis, and the female breast also may be involved.

Lesions are characterized by widespread thrombosis of the microvasculature and can spread rapidly, sometimes becoming necrotic and requiring disfiguring debridement or occasionally amputation.

• Other Toxicities. A reversible, sometimes painful, blue-tinged discoloration of the plantar surfaces and sides of the toes that blanches with pressure and fades with elevation of the legs (purple toe syndrome) may develop 3 to 8 weeks after initiation of therapy with warfarin; cholesterol emboli released from atheromatous plaques have been implicated as the cause.

• Other infrequent reactions include alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, and anorexia.

• Clinical Use

Oral anticoagulants are used to prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism following an initial course of heparin. They also are effective in preventing venous thromboembolism in patients undergoing orthopedic or gynecological surgery and in preventing systemic embolization in patients with acute myocardial infarction, prosthetic heart valves, or chronic atrialfibrillation.

• Monitoring Anticoagulant Therapy: The INR (International Normalized Ratio). To monitor therapy, a fasting blood sample is usually obtained 8 to 14 hours after the last dose of an oral anticoagulant, and the patient's PT is determined along with that of a sample of normal pooled plasma.

• Other Oral AnticoagulantsPhenprocoumon and Acenocoumarol. These agents are not generally available in the United States but are prescribed in Europe and elsewhere. Phenprocoumon(MARCUMAR) has a longer plasma half-life (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7 to 14 days). It is administered in daily maintenance doses of 0.75 to 6 mg.

•Rodenticides. Bromadiolone, brodifacoum, diphenadione, chlorophacinone, and pindone are long-acting agents (prolongation of the PT may persist for weeks). They are of interest because they sometimes are agents of accidental or intentional poisoning. In this setting, reversal of the coagulopathy can require very large doses of vitamin K (i.e., >100 mg/day) for weeks or months.

• Ximelagatran. Ximelagatran is a novel drug that is readily absorbed after oral administration and is rapidly metabolized to melagatran, a direct thrombin inhibitor. Therefore, its onset of action is much faster than that of warfarin.

• Ximelagatran is administered twice daily at a fixed dose and does not appear to require coagulation monitoring. Melagatran is excreted primarily by the kidney; therefore, dosage reduction may be necessary for patients with renal failure. Ximelagatran has been used successfully in clinical trials for prevention of venous thromboembolism

• FIBRINOLYTIC DRUGS

IntroductionThe action of fibrinolytic agents is best understood in conjunction with an understanding of the characteristics of the physiologic components.

Plasminogen. Plasminogen is a single-chain glycoprotein that contains 791 amino acid residues; it is converted to an active protease by cleavage at arginine560.

• High-affinity binding sites mediate the binding of plasminogen (or plasmin) to carboxyl-terminal lysine residues in partially degraded fibrin; this enhances fibrinolysis.

• Plasminogen concentrations in human plasma average 2 mM. A degraded form of plasminogen termed lys-plasminogen binds to fibrin much more rapidly than does intact plasminogen.

a2-Antiplasmin. a2 -Antiplasmin is a glycoprotein of 452 amino acid residues. It forms a stable complex with plasmin, thereby inactivating it. Plasma concentrations of a2-antiplasmin (1 mM) are sufficient to inhibit about 50% of potential plasmin.

• When massive activation of plasminogen occurs, the inhibitor is depleted, and free plasmin causes a "systemic lytic state," in which hemostasis is impaired. In this state, fibrinogen is destroyed and fibrinogen degradation products impair formation of fibrin and therefore increase bleeding from wounds.

• Streptokinase. Streptokinase (STREPTASE) is a 47,000-dalton protein produced by b-hemolytic streptococci. It has no intrinsic enzymatic activity, but it forms a stable, noncovalent 1:1 complex with plasminogen.

• This produces a conformational change that exposes the active site on plasminogen that cleaves arginine560 on free plasminogen to form free plasmin. Streptokinase is rarely used clinically for fibrinolysissince the advent of newer agents.

Tissue Plasminogen Activator (t-PA). t-PA is a serine protease that contains 527 amino acid residues. It is a poor plasminogen activator in the absence of fibrin.

• Hemorrhagic Toxicity of Thrombolytic Therapy. The major toxicity of all thrombolytic agents is hemorrhage, which results from two factors: (1) the lysis of fibrin in "physiological thrombi" at sites of vascular injury; and (2) a systemic lytic state that results from systemic formation of plasmin, which produces fibrinogenolysisand destruction of other coagulation factors (especially factors V and VIII). The actual toxicity of streptokinase and t-PA is difficult to assess.

• Inhibition of Fibrinolysis

Aminocaproic Acid. Aminocaproic acid (AMICAR) is a lysine analog that competes for lysine binding sites on plasminogen and plasmin, thus blocking the interaction of plasmin with fibrin. Aminocaproic acid is thereby a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

• The main problem with its use is that thrombi that form during treatment with the drug are not lysed. For example, in patients with hematuria, ureteralobstruction by clots may lead to renal failure after treatment with aminocaproic acid. Aminocaproic acid has been used to reduce bleeding after prostatic surgery or after tooth extractions in hemophiliacs

Aminocaproic acid is absorbed rapidly after oral administration, and 50% is excreted unchanged in the urine within 12 hours. For intravenous use, a loading dose of 4 to 5 g is given over 1 hour, followed by an infusion of 1 g per hour until bleeding is controlled. No more than 30 g should be given in a 24-hour period. Rarely, the drug causes myopathy and muscle necrosis.

• ANTIPLATELET DRUGS

Platelets provide the initial hemostatic plug at sites of vascular injury. They also participate in pathological thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses.

• Potent inhibitors of platelet function have been developed in recent years. These drugs act by discrete mechanisms, and thus in combination their effects are additive or even synergistic.

• Their availability has led to a revolution in cardiovascular medicine, whereby angioplasty and vascular stenting of lesions now is feasible with low rates of restenosis and thrombosis when effective platelet inhibition is employed.

• Aspirin. Processes including thrombosis, inflammation, wound healing, and allergy are modulated by oxygenated metabolites of arachidonate and related polyunsaturated fatty acids that are collectively termed eicosanoids.

• Interference with the synthesis of eicosanoids is the basis for the effects of many therapeutic agents, including analgesics, antiinflammatory drugs, and antithrombotic agents.

Aspirin blocks production of thromboxane A2 by acetylating a serine residue near the active site of platelet cyclooxygenase (COX-1), the enzyme that produces the cyclic endoperoxide precursor of thromboxane A2.

• Dipyridamole. Dipyridamole (PERSANTINE) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves. Dipyridamole has little or no benefit as an antithrombotic drug

• A formulation containing 200 mg of dipyridamole, in an extended-release form, and 25 mg of aspirin (AGGRENOX) is available. Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine 3¢,5¢-monophosphate(cyclic AMP).

• Ticlopidine. Purinergic receptors respond to extracellular nucleotides as agonists.

It is rapidly absorbed and highly bioavailable. It permanently inhibits the P2Y12 receptor by forming a disulfide bridge between the thiol on the drug and a free cysteine residue in the extracellular region of the receptor and thus has a prolonged effect.

Maximal inhibition of platelet aggregation is not seen until 8 to 11 days after starting therapy. Thus, "loading doses" of 500 mg sometimes are given to achieve a more rapid onset of action. The usual dose is 250 mg twice per day. Inhibition of platelet aggregation persists for a few days after the drug is stopped.

• Adverse Effects. The most common side effects are nausea, vomiting, and diarrhea. The most serious is severe neutropenia (absolute neutrophil count [ANC] <1500/mL), which occurred in 2.4% of stroke patients given the drug during premarketing clinical trials.

• Fatal agranulocytosis with thrombopenia has occurred within the first 3 months of therapy; therefore, frequent blood counts should be obtained during the first few months of therapy, with immediate discontinuation of therapy should cell counts decline.

• Therapeutic Uses. Ticlopidine has been shown to prevent cerebrovascular events in secondary prevention of stroke and is at least as good as aspirin in this regard

• Clopidogrel. The thienopyridine clopidogrel (PLAVIX) is closely related to ticlopidineand appears to have a slightly more favorable toxicity profile with less frequent thrombocytopenia and leukopenia, although thrombotic thrombocytopenic purpura has been reported .

• Clopidogrel is a prodrug with a slow onset of action. The usual dose is 75 mg per day with or without an initial loading dose of 300 mg. The drug is equivalent to aspirin in the secondary prevention of stroke, and in combination with aspirin it appears to be as effective as ticlopidine and aspirin. It is used with aspirin after angioplasty and should be continued for at least 1 year

• Abciximab. Abciximab (REOPRO) is the Fab fragment of a humanized monoclonal antibody directed against the aIIbb3 receptor. It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells.

• The antibody is used in conjunction with percutaneousangioplasty for coronary thromboses, and when used in conjunction with aspirin and heparin, has been shown to be quite effective in preventing restenosis, recurrent myocardial infarction, and death.

• It is given as a 0.25-mg/kg bolus followed by 0.125 mg/kg per minute for 12 hours or longer.

• Adverse Effects. The major side effect of abciximab is bleeding, and the contraindications to its use are similar to those for fibrinolytic agents listed in Table 54-1. The frequency of major hemorrhage in clinical trials varies from 1% to 10%, depending on the intensity of anticoagulation with heparin.

• Thrombocytopenia of less than 50,000 m/L is seen in about 2% of patients and may be due to development of neo-epitopes induced by bound antibody. Since the duration of action is long, if major bleeding or emergent surgery occurs, platelet transfusions can reverse the aggregation defect, because free antibody concentrations fall rapidly after cessation of infusion.

• Eptifibatide. Eptifibatide (INTEGRILIN) is a cyclic peptide inhibitor of the fibrinogen binding site on aIIbb3. It blocks platelet aggregation in vitro after intravenous infusion into patients.

• Eptifibatide is given as a bolus of 180 mg/kg followed by 2 mg/kg per minute for up to 96 hours. It is used to treat acute coronary syndrome and for angioplasticcoronary interventions. In the latter case, myocardial infarction and death have been reduced by about 20%.

• The duration of action of the drug is relatively short and platelet aggregation is restored within 6 to 12 hours after cessation of infusion. Eptifibatide generally is administered in conjunction with aspirin and heparin.

• Adverse Effects. The major side effect is bleeding, as is the case with abciximab. The frequency of major bleeding in trials was about 10%, compared with about 9% in a placebo group, which included heparin. Thrombocytopenia has been seen in 0.5% to 1% of patients.

• THE ROLE OF VITAMIN KVitamin K is essential in both mammals and in photosynthetic organisms. In certain photosynthetic bacteria, vitamin K is a cofactor in the photosynthetic electron-transport system; in green plants, vitamin K1 is a component of photosystem I, the membrane-bound macromolecular light-sensitive complex.

• Chemistry and Occurrence. Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K1 and vitamin K2. Vitamin K1, or phylloquinone (phytonadione), is 2-methyl-3-phytyl-1,4-naphthoquinone; it is found in plants and is the only natural vitamin K available for therapeutic use.

•Physiological Functions and Pharmacological Actions. In normal animals and humans, phylloquinone and menaquinones are virtually devoid of pharmacodynamic activity. However, in subjects deficient in vitamin K, the vitamin performs its normal physiological function

• Human Requirements. The human requirement for vitamin K has not been defined precisely. In patients made vitamin K-deficient by a starvation diet and antibiotic therapy for 3 to 4 weeks, the minimum daily requirement is estimated to be 0.03 mg/kg of body weight and possibly as high as 1 mg/kg, which is approximately the recommended intake for adults (70 mg/day).

•Symptoms of Deficiency. The chief clinical manifestation of vitamin K deficiency is an increased tendency to bleed. Ecchymoses, epistaxis, hematuria, gastrointestinal bleeding, and postoperative hemorrhage are common; intracranial hemorrhage may occur. Hemoptysis is uncommon.

• Toxicity. Phylloquinone and the menaquinones are nontoxic to animals, even when given at 500 times the RDA. However, menadione and its derivatives (synthetic forms of vitamin K) have been implicated in producing hemolytic anemia and kernicterus in neonates, especially in premature infants

• Absorption, Fate, and Excretion. The mechanism of intestinal absorption of compounds with vitamin K activity varies with their solubility. In the presence of bile salts, phylloquinone and the menaquinones are adequately absorbed from the intestine, almost entirely by way of the lymph.

Menaquinones, produced in the lower bowel, are less biologically active than phylloquinone due to their long side chain. Very little vitamin K accumulates in other tissues.

• Therapeutic Uses. Vitamin K is used therapeutically to correct the bleeding tendency or hemorrhage associated with its deficiency. Vitamin K deficiency can result from inadequate intake, absorption, or utilization of the vitamin, or as a consequence of the action of a vitamin K antagonist.

• AQUAMEPHYTON may be given by any parenteralroute; however, subcutaneous or intramuscular injection is preferred because severe reactions resembling anaphylaxis have followed its intravenous administration.

Inadequate Intake. After infancy, hypoprothrombinemia due to dietary deficiency of vitamin K is extremely rare: The vitamin is present in many foods and also is synthesized by intestinal bacteria.

• In the neonate with hemorrhagic disease of the newborn, the administration of vitamin K raises the concentration of these clotting factors to the level normal for the newborn infant and controls the bleeding tendency within about 6 hours.

• Inadequate Absorption. Vitamin K is poorly absorbed in the absence of bile. Thus, hypoprothrombinemiamay be associated with either intrahepatic or extrahepatic biliary obstruction or a severe defect in the intestinal absorption of fat from other causes.

Biliary Obstruction or Fistula Bleeding that accompanies obstructive jaundice or biliary fistula responds promptly to the administration of vitamin K.

• The treatment of a patient during hemorrhage requires transfusion of fresh blood or reconstituted fresh plasma. Vitamin K also should be given. If biliaryobstruction has caused hepatic injury, the response to vitamin K may be poor.

Malabsorption Syndromes Among the disorders that result in inadequate absorption of vitamin K from the intestinal tract are: cystic fibrosis, sprue, Crohn'sdisease and enterocolitis, ulcerative colitis, dysentery, and extensive resection of bowel.

• Inadequate Utilization. Hepatocellular disease may be accompanied or followed by hypoprothrombinemia. Hepatocellular damage also may be secondary to long-lasting biliary obstruction

• . In these conditions, the damaged parenchymalcells may not be able to produce the vitamin K-dependent clotting factors, even if excess vitamin is available.

• Drug-Induced Hypoprothrombinemia.Anticoagulant drugs such as warfarin and its congeners act as competitive antagonists of vitamin K and interfere with the hepatic biosynthesis of Gla-containing clotting factors.

• CLINICAL SUMMARYA variety of anticoagulant, thrombolytic, and antiplatelet agents are available and are among the most widely used drugs.

• Heparin and its low-molecular-weight derivatives are commonly used to treat venous thromboembolism, unstable angina, and acute myocardial infarction; these agents are also used to prevent thrombosis during and after coronary angioplasty, during surgery requiring cardiopulmonary bypass, and in certain other high-risk patients.

• The major toxicities of heparin are bleeding and the syndrome of heparin-induced thrombocytopenia, which often precipitates venous or arterial thrombosis.

• Direct thrombin inhibitors, such as lepirudin or argatroban, are indicated for patients with heparin-induced thrombocytopenia. Warfarin and other vitamin K antagonists are used to prevent the progression or recurrence of acute venous thromboembolism following an initial course of heparin.

• Warfarin causes major bleeding in a significant number of patients and produces fetal abnormalities when given during pregnancy.

• Fibrinolytic agents, such as t-PA or streptokinase, reduce the mortality of acute myocardial infarction and are used in situations in which angioplasty is not readily available.

• Antiplatelet agents, including aspirin, ticlopidine, clopidogrel, to prevent restenosis and thrombosis following coronary angioplasty and in the secondary prophylaxis of myocardial infarction and stroke.

• Bleeding is the major toxicity of the antiplatelet agents, but thrombocytopenia and neutropenia can also occur.