GENERAL PRINCIPLES
Hemostasis is a regulatory process with two functions: (1) maintain clot-free blood flow and (2) aggressively respond to localized vascular injury with formation of a hemostatic plug. Aberrancies in this system can cause either thrombus formation or uncontrolled bleeding. When hemostasis is inappropriately or overexuberantly activated, anticoagulants or thrombolytics are used to moderate this process, with a potential risk of bleeding. Procoagulantsare used to stop bleeding, reverse the effects of anticoagulation medications, or replenish factors required for clot formation and stabilization.
Normal Hemostasis
Endothelial cells line the inner surface of blood vessels. These cells produce vasodilators that prevent platelet aggregation and block the coagulation cascade, thrombus formation, and fibrin deposition. Disruption of endothelial cells bares the subendothelial extracellular matrix (ECM), which promotes platelet adherence and activation and exposes tissue factor, a membrane-bound procoagulant factor. Tissue factor, in conjunction with secreted platelet factors, induces platelet aggregation and activates the coagulation cascade. This converts prothrombin to thrombin (factor IIa), which forms the initial hemostatic plug. Thrombin converts fibrinogen to insoluble fibrin, which forms a permanent plug.
The coagulation cascade (Fig. 12-1) is a series of enzymatic reactions with feedback promotion and inhibition that regulate and restrict the process of hemostasis to the site of vascular injury. A deficiency of procoagulant factors or cofactors, such as vitamin K (necessary for the function of factors II, VII, IX, and X), can cause bleeding; whereas low levels or decreased function of factors involved in limiting coagulation can trigger thrombosis.
The adhesion of platelets (Fig. 12-2) to exposed collagen is mediated by von Willebrand factor (vWF), which links collagen fibrils to the surface of platelets. Activated platelets release factors such as thromboxane A2 (TXA2) and adenosine diphosphate (ADP), which bind to their respective receptors. This initiates a series of enzymatic reactions that decrease cyclic adenosine monophosphate (cAMP) levels and promote the release of the same factors to recruit additional platelets. Recruited platelets are connected by fibrin cross-linking of glycoprotein (GP) IIb/IIIa receptors.
ANTICOAGULANTS: AGENTS THAT PREVENT THROMBOSIS
Antiplatelet Drugs 1
Aspirin
Mechanism of action. Aspirin (acetylsalicylic acid) irreversibly inhibits cyclo-oxygen-ase-1 (COX-1) in platelets, blocking the conversion of arachidonic acid to TXA 2, which is involved in the recruitment and aggregation of platelets. A minimum dose of 160 mg of aspirin is required to maximally inhibit platelet function within 30 minutes. The effect of aspirin remains for the life span of the platelet (8 to 10 days). Normal hemostasis is regained when 20% of platelets have normal COX-1 activity.
Figure 12-1. The coagulation cascade. The coagulation cascade is divided into two pathways: extrinsic and intrinsic, which converge at factor X, the start of the common pathway leading to thrombin formation and fibrin cross-linking. The extrinsic pathway is activated by tissue factor. Contact with subendothelial surfaces or a negatively charged surface activates factor XII (Hageman factor) and starts the intrinsic coagulation cascade. (Diagram modified from Kumar V. Robbins & Cotran Pathologic Basis of Disease. Philadelphia: W. B. Saunders; 2004: Fig. 4-9.)
Figure 12.2 Mechanisms implicated in platelet adhesion, activation, and aggregation. Aspirin irreversibly inhibits thromboxane A 2 (TXA 2) synthesis, dipyridamole increases cAMP levels, clopidogrel irreversibly modifi es the ADP receptor, and abciximab antagonizes the glycoprotein IIb/IIIa receptor. (Hankey GJ and Eikelboom JW. Antiplatelet drugs. MJA 2003;178:568–574. © Copyright 2003 The Medical Journal of Australia—reproduced with permission.)
Preparation and dosage. Aspirin is absorbed through the mucous membranes of the gastrointestinal tract, achieving peak levels between 30 and 60 minutes, depending on dosage, formulation, and physiologic factors. Aspirin is hydrolyzed in the plasma, conjugated in the liver, and then primarily cleared by the kidneys. In the United States, aspirin is available as 81- or 325-mg doses.
Clinical indications 2,3
Ischemic stroke and transient ischemic attack (TIA). In patients with a history of stroke or ischemia due to fibrin platelet emboli, aspirin therapy (50 to 325 mg daily) reduces the combined end point of TIA, stroke, and death by 13% to 18%.
Suspected acute myocardial infarction (MI). Aspirin treatment in patients with acute coronary syndrome reduces vascular mortality by 23%. Patients are asked to chew the aspirin tablet(s) (160 to 325 mg) to enhance absorption due to formulation variability.
Prevention of recurrent MI and unstable angina. Aspirin therapy (75 to 325 mg daily) in patients with a history of MI is associated with a 20% reduction in death and reinfarction. A 5% to 10% decrease in event rate is observed in patients with unstable angina.
Chronic stable angina. Aspirin reduces the risk of nonfatal MI, fatal MI, and sudden death by 34%. The secondary end point for vascular events (first occur-rence of MI, stroke, or vascular death) is decreased by 32%.
Revascularization procedure. Lifelong aspirin is recommended for patients who undergo cardiac or peripheral revascularization, if there is a preexisting condition for which aspirin is already indicated.
Adverse effects. Common side effects of aspirin include stomach pain, nausea, vomiting, dyspepsia, and risk of gastrointestinal bleeding. Some of these effects can be moderated by enteric coating, which protects the gastric mucosa. Aspirin may cause urticaria, angioedema, and bronchospasm. It is contraindicated in patients with a known allergy to nonsteroidal anti-inflammatory drugs and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin should not be used in children with viral illness because of the risk of Reye syndrome.
Overdose. The earliest sign of salicylate toxicity is tinnitus (ringing in the ears). Respiratory alkalosis occurs early but is quickly followed by metabolic acidosis. Treatment is supportive.
Dipyridamole
Mechanism of action. Dipyridamole (Aggrenox, Persantine) reversibly inhibits the uptake of adenosine into platelets and endothelial cells, increasing cAMP levels and, therefore, inhibiting platelet response to recruitment factors. Dipyridamole also inhibits tissue phosphodiesterase, augments the antiplatelet adhesion effects of nitric oxide, and stimulates prostacyclin release, thereby inhibiting TXA 2 formation.
Preparation and dosage. Peak levels of dipyridamole are generally achieved 2 hours after ingestion (range, 1 to 6 hours). Metabolism occurs by liver conjugation and excretion through the gastrointestinal tract. Aggrenox is available as a capsule containing 25 mg of aspirin and 200 mg of extended-release dipyridamole. Persantine is available as 25-, 50-, and 75-mg tablets.
Clinical indications.4 In patients with a history of ischemic stroke or TIA, Aggrenox reduces the risk of subsequent stroke compared to therapy with aspirin alone.
Adverse effects. Aggrenox and Persantine have a gastrointestinal side-effect profile similar to that of aspirin, with twice the rate of headache and dizziness. Serious side effects include thrombocytopenia.
Clopidogrel
Mechanism of action. Clopidogrel (Plavix) irreversibly modifies the ADP receptor on platelets, inhibiting the binding of ADP to its receptor and the subsequent activation of the GPIIb/IIIa complex involved in platelet aggregation.
Preparation and dosage. Peak levels of clopidogrel occur 1 hour after tablet ingestion. Metabolism occurs by hydrolysis and renal excretion. Plavix is available as a 75-mg tablet
.
Clinical indications
Recent MI, recent stroke, or established peripheral vascular disease. The CAPRIE study compared a daily dose of 325 mg aspirin to 75 mg clopidogrel and demonstrated a relative risk reduction of 7% for fatal and nonfatal MI, stroke, and overall event rate in the clopidogrel-treated group.
Acute coronary syndrome. The CURE study demonstrated that patients presenting with a non-ST-elevation MI within 24 hours of the onset of symptoms had a 20% relative risk reduction in cardiovascular death, MI, or stroke when treated with an oral load of clopidogrel in addition to standard therapies (aspirin and heparin, no GPIIb/IIIa-receptor blocker 3 days prior to randomization) compared to patients receiving only standard therapies.
Adverse effects. Clopidogrel is associated with a higher rate of rash, diarrhea, and gastrointestinal bleeding compared to aspirin. The combination of clopidogrel and aspirin versus aspirin alone increases the risk of major bleeding (3.7% vs. 2.7%, respectively). There is a rare association with thrombotic thrombocytopenic purpura after short exposure (<2 weeks). Ticlopidine (Ticlid) is chemically similar to clopidogrel and is associated with a 0.8% risk of severe agranulocytosis. There was no difference in the incidence of agranulocytosis between the clopidogrel- and the aspirin-treated groups.
Glycoprotein IIb/IIIa Antagonists
Mechanism of action. Abciximab (ReoPro), tirofiban (Aggrastat), and eptifibatide (Integrilin) are GPIIb/IIIa antagonists. Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody, which binds to and causes a conformational change in the GPIIb/IIIa receptor, preventing the binding of platelet “glue”—fibrinogen or vWF. Abciximab also blocks other procoagulant properties of platelets and leukocytes. Tirofiban (a nonpeptide) and eptifibatide (a cyclic heptapeptide) are reversible antagonists of the GPIIb/IIIa receptor. GPIIb/IIIa inhibitors are intended for use with aspirin and heparin.
Preparation and dosage. Following IV bolus administration, plasma levels of abciximab decrease rapidly, with a half-life of <10 minutes. The second half-life is about 30 minutes, likely related to dose-dependent reversible binding of the GPIIb/ IIIa receptor. Platelet function recovers over 48 hours, although abciximab remains in the circulation for 15 days. Within 30 minutes of tirofiban infusion, >90% platelet inhibition is obtained. The half-life is ~ 2 hours, with clearance largely influenced by renal function; however, tirofiban can be dialyzed out of circulation, if needed. The pharmacokinetics of eptifibatide is essentially the same as that of tirofiban.
Clinical indications3
Abciximab. Following percutaneous coronary intervention (PCI) or atherectomy, an IV abciximab bolus (0.25 mg/kg) followed by an infusion (0.125 μg/kg/min × 12 hours) decreases the composite of death, MI, and urgent intervention for recurrent ischemia in the first 48 hours postprocedure, a benefit that extended to 3 years. The CAPTURE trial demonstrated a lower preintervention and 30-day postintervention MI rate with IV abciximab. However, there was no mortality benefit at 1 or 6 months and no difference in event rate between the abciximab-treated and the placebo groups.
Tirofiban. In a study of patients undergoing PCI or arthrectomy, tirofiban (with heparin therapy) decreased the composite end point (death, new MI, refractory ischemia, and repeat cardiac procedure) by 32%.
Eptifibatide. Eptifibatide infusion prior to PCI decreased the composite end point of death, MI, and urgent intervention by 1% at 30 days, and this benefit extended to 1 year.
Adverse effects. GPIIb/IIIa receptor blockers are associated with thrombocytopenia, which can be severe.
Anticoagulation Drugs
Anticoagulants interfere with the coagulation cascade, reducing the generation of thrombin and the buttressing effects of fibrin.
Warfarin
Mechanism of action. Warfarin (Coumadin) is an anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors (II, VII, IX, and X, proteins C and S). Since the half-lives of proteins C and S are about one-third the half-life of the other vitamin K-dependent procoagulation factors, patients are briefly hypercoagulable before anticoagulation effects take place. For this reason, patients are often bridged with heparin, as they become therapeutic on warfarin.
Preparation and dosage. The anticoagulation effects of warfarin occur within 24 hours of ingestion, peaking at 72 to 96 hours and lasting 2 to 5 days. Cytochrome P-450 is involved in the metabolism of warfarin. Drugs that affect P-450 expression will alter the metabolism of warfarin and affect International Normalized Ratio (INR) levels. Warfarin is available in multiple-dose tablets, and therapy requires periodic INR monitoring. For more detailed suggestions on dosage initiation for warfarin, visit www.WarfarinDosing.org.
Clinical indications
Deep venous thrombosis (DVT) and pulmonary embolism (PE). Current recommendation for anticoagulation in patients with an initial event and reversible risk factor for DVT or PE is 6 to 12 months. Recurrent thromboembolic disease warrants a hypercoagulable workup, and studies suggest a benefit of lifelong anticoagulation therapy (goal INR, 2 to 3).
Atrial fibrillation. Prospective trials of patients with atrial fibrillation show a risk reduction of 60% to 86% in systemic thromboembolism and less bleeding in the low INR range (1.4 to 3.0) compared to the high INR range (2.0 to 4.5).
MI. Warfarin can be used postinfarction to reduce the risk of recurrent MI and stroke. Some cardiologists would consider discontinuing anticoagulation 2 to 3 months postinfarction if wall motion abnormalities on echocardiography have resolved.
Mechanical and bioprosthetic valves. Anticoagulation with warfarin is generally not required in the management of bioprosthetic valves. A goal INR of 2.5 to 3.5 is generally recommended for mechanical aortic and mitral valve replacements, with the following exceptions: aortic St. Jude’s and other bileaflet aortic values can be maintained with an INR of 2 to 3. A subtherapeutic INR or need to change quickly the anticoagulation status is usually managed with IV heparin.
Adverse effects. Warfarin is associated with a significant risk of hemorrhage, which is associated with higher INR levels. The anticoagulation effects of warfarin can be reversed within 1 to 3 days with oral or IV vitamin K (Table 12-1). Immediate reversal of anticoagulation can be achieved with administration of fresh-frozen plasma (FFP). Warfarin is contraindicated in pregnancy due to teratogenic effects and the risk of fetal hemorrhage. Warfarin-induced skin necrosis (microthrombi due to earlier deficiency of proteins C and S compared to other vitamin K factors) is a rare complication of therapy; it occurs in areas of high-percentage adipose tissue and may become life threatening.
Unfractionated Heparin
Mechanism of action. Unfractionated heparin is a polysaccharide that binds to anti-thrombin III (ATIII) and increases the rate of ATIII inactivation of thrombin (II) and factor Xa.
Preparation and dosage. Heparin is administered IV or SC, based on patient lean body weight and clinical context (Table 12-2). IV heparin is monitored by measuring the partial thromboplastin time (PTT). Discontinuation of IV heparin results in normalization of anticoagulation within 2 to 3 hours.
Clinical indications
Anticoagulation bridge therapy. Heparin is used as bridge therapy to initiate and discontinue anticoagulation in patients with prosthetic heart valves (to prevent valve thrombosis) and thrombotic disease.
Prophylaxis. Hospitalized patients at significant risk for developing DVT and associated sequelae are given SC heparin (5000 U bid or tid) to decrease the incidence of thrombotic disease.
Acute coronary syndrome and vascular surgery. The advantage of heparin is immediate anticoagulation.
Invasive lines and catheters. Invasive pressure catheters and lines are flushed with heparin to prevent catheter clotting.
Adverse effects. Heparin is associated with a risk of bleeding. Rapid reversal of heparin can be achieved by infusion of protamine sulfate (1 mg protamine reverses 100 units of circulating heparin). Heparin-induced thrombocytopenia (HIT) is a complication that results in a rapid fall in platelet number (see Chap. 4). Suspicion of HIT should prompt discontinuation of heparin; platelet counts generally recover within 1 to 2 weeks. Warfarin should be avoided in acute HIT, unless combined with another anticoagulant while the INR is subtherapeutic.
Low-Molecular-Weight Heparin
Mechanism of action. Enoxaparin (Lovenox) is a low-molecular-weight heparin that inhibits thrombin (factor IIa) and factor Xa.
Preparation and dosage. Enoxaparin is administered SC. Maximum activity occurs 3 to 5 hours after SC injection, and it is administered every 12 hours, except in patients with renal impairment, in whom once-daily dosing is sufficient for anticoagulation.
Clinical indications
Prophylaxis of deep venous thrombosis. Enoxaparin is used to prevent thrombosis complications in patients with orthopedic, general surgical, or medical problems requiring prolonged immobilization (walking ≤10 m for ≤3 days). The prophylactic dose is 40 mg SC every 24 hours or 30 mg SC every 12 hours.
Prophylaxis of ischemic complications of unstable angina. Dose is 1 mg/kg lean body weight SC every 12 hours.
Treatment of deep venous thrombosis and pulmonary embolism. 1 mg/ kg lean body weight SC every 12 hours.
Adverse effects. Bleeding is a complication of enoxaparin, and no therapy to reverse anticoagulation is available. Thrombocytopenia occurs in about 1% of patients. A drop in platelet count to <100,000/mm3should prompt discontinuation of this medication. Patients with HIT from heparin therapy are at risk for enoxaparin-induced thrombocytopenia; thus other anticoagulation drugs are preferred in these situations. The use of enoxaparin for thromboprophylaxis in pregnant women and in patients with mechanical valves has not been thoroughly studied.
Fondaparinux
Mechanism of action. Fondaparinux (Arixtra) binds to ATIII and selectively inhibits factor Xa.
Preparation and dosage. A therapeutic level of fondaparinux is achieved within 2 hours of SC injection and is eliminated by renal excretion. Multiple prefilled syringe doses are available. Dosing is based on body weight: 5 mg (<50 kg), 7.5 mg (50 to 100 kg), and 10 mg (> 100 kg) SC daily.
Clinical indications
Prophylaxis. Fondaparinux is indicated for DVT prophylaxis in patients undergoing orthopedic and general surgery procedures.
DVT and PE. Fondaparinux is approved as bridge therapy for anticoagulation with warfarin.
Adverse effects. Fondaparinux carries a slightly higher risk of hemorrhage compared to enoxaparin (4% vs. 3%, respectively) and similar rates of thrombocytopenia. There is no antidote for fondaparinux.
Hirudin Derivatives
Mechanism of action. Lepirudin (Refludan) and bivalirudin (Angiomax) are recombinant hirudin polypeptides that directly inhibit thrombin. The hirudins were originally isolated from leech saliva but are now derived from recombinant DNA in yeast cells.
Preparation and dosage. The half-life of lepirudin is 10 minutes and that of bivalirudin is 25 minutes. Metabolism occurs by catabolic hydrolysis. The half-life is prolonged in patients with creatinine clearance ≤15 mL/min. Lepirudin and bivalirudin dosages are adjusted by PTT, checked 2 hours after the start or a change in infusion rate.
Clinical indications5
Lepirudin is indicated for anticoagulation in patients with HIT and associated thromboembolic disease, at a dose of 0.5 mg/kg bolus, then 0.15 mg/kg/min (up to 110 kg), to target PTT of 45 to 70 seconds.
Bivalirudin. In patients with HIT, dosing is 0.08 to 0.1 mg/kg/h for CrCl ≥30 mL/min or 0.04 to 0.06 mg/kg/h for CrCl <30 mL/min, to target PTT of 45 to 70 seconds. Bivalirudin can also be used in patients undergoing PCI (0.75 mg/kg bolus prior to intervention, then 1.75 mg/kg/h for the duration of the procedure, and up to 4 hours postprocedure); in acute coronary syndrome (0.1 mg/kg bolus, then 0.25 mg/kg/h); and as anticoagulation with streptokinase thrombolysis in ST-elevation MI and known HIT (0.25 mg/kg bolus 3 minutes before streptokinase, followed by 0.5 mg/kg/h × 12 hours, then 0.25 mg/kg/h × 36 hours).
Adverse effects. Antihirudin antibodies are observed in 40% of HIT patients treated with lepirudin. Back pain and nausea are common side effects of hirudin derivatives. There are reports of hypersensitivity and allergic reactions and liver function test abnormalities.
Argatroban
Mechanism of action. Argatroban is a synthetic derivative of L-arginine that directly inhibits thrombin by reversibly binding to the thrombin active site.
Preparation and dosage. Argatroban is 54% protein bound and is metabolized by the liver. Its half-life is 39 to 51 minutes. No dosage adjustment is necessary in renal dysfunction; however, the dosage should be adjusted in hepatic impairment (0.5 μg/kg/min). The INR may be falsely elevated with therapy.
Clinical indications.5 Argatroban is used for prophylaxis or treatment of thrombosis in patients with HIT (0.5 to 2 μg/kg/min until PTT is 1.5 to 3 × baseline) or as anticoagulation in patients with HIT undergoing PCI.
Adverse effects. Argatroban prolongs the INR with warfarin and should be discontinued when the INR is >4 on combined therapy. Fever and diarrhea are frequent side effects. Hypotension can occur with infusion.
Dabigatran
Mechanism of action. Dabigatran is an oral direct thrombin inhibitor.
Preparation and dosage. The approved dose is 150 mg PO bid. Dose reduction to 75 mg bid is indicated in patients with renal insufficiency (creatinine clearance 15 to 30 mL/min).
Clinical indications. Dabigatran is indicated to reduce the risk of stroke in patients with atrial fibrillation. In a randomized trial, dabigatran was as effective as warfarin in the treatment of acute DVT.6
Adverse effects. The primary risk is bleeding. Dabigatran should be discontinued 1 to 2 days before an invasive procedure or surgery (3 to 5 days in patients with renal insufficiency). No INR monitoring is required.
THROMBOLYTICS AND FIBRINOLYTICS: AGENTS THAT DISINTEGRAE CLOT
Thrombolytics and fibrinolytics convert plasminogen to the active enzyme plasmin, which digests fibrin clots (Table 12-3). Allergic reactions to these agents have been reported, particularly streptokinase and urokinase. The most commonly reported reactions to streptokinase are fever and shivering (1% to 4%). Anaphylactic shock is much rarer, occurring in <0.1% of patients. To anticipate allergic reaction to streptokinase, an intradermal test dose of 100 IU has been suggested. Hypersensitivity reactions should be treated with adrenergic, corticosteroid, and/or antihistamine agents as needed.
The major risk of thrombolytics and fibrinolytics is bleeding. Relative contraindications to their use include the following:
Recent surgery (within 10 days)
Gastrointestinal bleeding
Trauma, including intracranial or intraspinal trauma or surgery within the previous 3 months
Known intracranial neoplasm, arteriovenous malformation, or aneurysm
Known bleeding diathesis or INR 1.7
Platelet count <100,000/mm3
Systolic blood pressure >180 mm Hg or diastolic pressure >110 mm Hg
Subacute bacterial endocarditis
Pregnancy
Cerebrovascular disease
In these situations, the bleeding risk must be weighed against the benefits of thrombolysis.
COAGULANTS: AGENTS THAT TREAT BLEEDING
Desmopressin
Mechanism of action. Desmopressin (DDAVP) is a synthetic version of the naturally occurring pituitary hormone vasopressin (ADH). In patients with type 1 von Willebrand disease (vWD) and mild hemophilia A, desmopressin transiently increases plasma levels of vWF and factor VIII.
Preparation and dosage. Desmopressin can be administered intranasally, SC, IV, or orally. The dose and route of administration depend on the clinical context. The half-life of desmopressin given IV is 3 hours, and the drug is metabolized primarily by the kidney.
Clinical indications
Hemophilia A. Desmopressin is used in patients with hemophilia A prior to surgery or patients who have spontaneous bleeding.
vWD (type 1). Studies have demonstrated that patients with type 1 vWD have a qualitatively normal vWF and respond to desmopressin, unlike patients with type 2 vWD, who synthesize a qualitatively abnormal vWF.7
Adverse effects. Desmopressin has been associated with headaches, tachycardia, and facial flushing. Other side effects include rhinitis, stomach cramps, vulvar pain, and vomiting. In patients receiving repeated doses of the medication, tachyphylaxis can occur. Patients taking desmopressin should be educated to limit fluid intake to satisfaction of thirst only, as hyponatremia may occur via the ADH effect of the drug. Consequently, children taking this medication should have their body weight routinely monitored. Rarely, water intoxication and coma can occur.
Vitamin K
Mechanism of action. Phytonadione (vitamin K) is a fat-soluble vitamin required by the liver for synthesis of clotting factors II, VII, IX, and X. Vitamin K is derived from green, leafy vegetables and is also produced by bacteria in the digestive tract. It is given to reverse the effects of warfarin.
Preparation and dosage. Vitamin K can be taken orally from 2.5 mg to a maximum dose of 25 mg. Alternatively, the drug can be given SC, IM, or IV at doses ranging from 1 to 10 mg. Vitamin K is metabolized in the liver and excreted in the bile.
Clinical indications.8 Vitamin K can be administered to reverse the effects of warfarin. See section on warfarin (above) for more details.
Adverse effects. Reactions to vitamin K include taste changes, flushing, dizziness, and hypotension. Severe anaphylaxis reactions and death have been reported following parenteral administration of the drug. Hyperbilirubinemia can be seen in infants, following administration of the drug.
Aminocaproic Acid
Mechanism of action. Aminocaproic acid (Amicar) inhibits fibrinolysis by inhibiting plasminogen activators. It is often used to treat excessive postoperative bleeding, as well as gingival bleeding in hemophiliacs undergoing dental work.
Preparation and dosage. Aminocaproic acid can be administered orally or IV. The drug comes in 500- or 1000-mg tablets and 250-mg syrup or injectable vials. Aminocaproic acid is metabolized in the liver and is primarily excreted in urine. For treatment of acute bleeding, dosing is 5 g IV or PO over 1 hour, followed by 1 g/h IV or PO for 8 hours or until bleeding is controlled.
Clinical indications. Aminocaproic acid can improve hemostasis when hemorrhage is due in part or whole to fibrinolysis, including the following situations: after cardiac surgery, thrombocytopenic hematologic disorders, severe abruption placentae, hepatic cirrhosis, and various malignancies. Studies have shown aminocaproic acid to be safe and efficacious as an adjunctive therapy for hemophiliacs undergoing dental procedures.
Adverse effects. Side effects include abdominal pain, diarrhea, pruritus, headache, malaise, allergic reactions, thrombocytopenia, hypotension, convulsions, dyspnea, rash, and tinnitus. Rarely, rhabdomyolysis and acute renal failure can occur with this medication. Creatinine phosphokinase (CPK) monitoring should occur regularly in patients undergoing long-term therapy, and the drug should be discontinued if elevations of the enzyme are noted.
Protamine
Mechanism of action. Protamine sulfate is a parenterally administered medication used to treat heparin overdose. It binds heparin and forms a stable complex, which negates the anticoagulation effects of heparin. When given alone, protamine has a mild anticoagulant effect.
Preparation and dosage. Protamine has a rapid onset of action, and the reversal of heparin occurs within 5 minutes after administering the drug. One milligram of protamine neutralizes approximately 100 units of heparin. It is given at a rate of 5 mg/min IV over 10 minutes, and the dose should not exceed 50 mg at one time.
Clinical indications. Protamine is used to treat heparin overdose. It can also be used to treat bleeding complications in patients undergoing PCI.
Adverse effects. Following administration of protamine, patients may experience hypotension and bradycardia. Other effects include nausea, vomiting, dyspnea, flushing, and fatigue. Severe reactions to protamine include anaphylaxis and anaphylactoid reactions. Some penicillins and cephalosporins have been shown to be incompatible with protamine. Protamine overdoses may cause bleeding.
Humate-P
Mechanism of action. Humate-P (antihemophilic factor/vWF complex) is a product pooled from human plasma, which contains factor VIII and vWF. Administration of Humate-P promotes coagulation. It is approved for the treatment of (1) bleeding in hemophilia A patients, (2) bleeding in patients with severe vWD, and (3) patients with mild to moderate vWD in whom desmopressin is ineffective.
Preparation and dosage. Dosage of Humate-P depends on patient weight, severity of bleeding, and vWF:RCo (ristocetin cofactor) activity. Dosage is calculated as (patient’s weight [kg] × desired % increase in VFW activity) ÷ 1.5. The dose can be adjusted for the extent of bleeding.
Clinical indications. Humate-P has 95% efficacy when used to control bleeding in patients with vWD (types 1, 2A, 2B, and 3).9
Adverse effects. As Humate-P is derived from human plasma, it carries a risk of transmission of infectious agents. Common side effects include flushing, chills, fever, dizziness, and headache. Although allergic reactions have been reported, severe anaphylaxis is rare.
Recombinant Coagulation Factor VIIa
Mechanism of action. Coagulation factor VIIa (NovoSeven) is a recombinant human coagulation factor approved for bleeding in patients with hemophilia A or B with inhibitors or in patients with congenital factor VII deficiency. NovoSeven works by activating the extrinsic pathway of coagulation.
Preparation and dosage. NovoSeven is administered IV, and the dosage depends on the clinical context. For hemophiliacs with bleeding episodes, 90 μg/kg is given every 2 hours until bleeding stops. In patients with congenital factor VII deficiency, NovoSeven is given at 15 to 30 μg/kg every 4 to 6 hours until cessation of bleeding.
Clinical indications. NovoSeven has been shown to be at least partially effective in 85% of serious bleeding episodes.10
Adverse effects. As with any recombinant product, anaphylaxis is a potential side effect. NovoSeven is contraindicated in patients who have a known allergic reaction to mouse, hamster, or cow products. Common side effects include bleeding, fever, and hypertension. There is a slightly increased risk of thrombosis after administration of the medication.
References
1. Patrano C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):199S–233S.
2. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396–404.
3. Goodman SG, Menon V, Cannon CP, et al. Acute ST-segment elevation myocardial infarction: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest.2008;133(6 Suppl):199S–233S.
4. ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischemia of arterial origin (ESPRIT): randomized controlled trial. Lancet. 2006;367:1665–1673.
5. Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl);340S–380S.
6. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352.
7. Castaman G, Lethagen S, Federici AB, et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood.2008;111:3531–3539.
8. Dezee KJ, Shimeall WT, Douglas KM, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. 2006;166:391–397.
9. Auerswald G, Kreuz W. Haemate P/Humate-P for the treatment of von Willebrand disease: considerations for use and clinical experience. Haemophilia. 2008;14(Suppl 5):39–46.
10. Hardy JF, Bélisle S, van der Linden P. Efficacy and safety of recombinant activated factor VII to control bleeding in nonhemophiliac patients: a review of 17 randomized controlled trials. Ann Thorac Surg.2008;86:1038–1048.