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Drugs Used in Disorders of Coagulation MECHANISMS OF BLOOD COAGULATION Hemostasis: spontaneous arrest of bleeding from damaged blood vessel. Immediate hemostatic response of damaged vessel is vasospasm. Within seconds, platelets stick to exposed collagen of damaged endothelium (platelet adhesion) & to each other (platelet aggregation). Fibrin reinforcement results from local stimuli to blood coagulation: exposed collagen of damaged vessels & membranes & released contents of platelets. Thrombus formation at the site of the damaged vascular wall White Thrombus Versus Red Thrombus White thrombus forms initially in high-pressure arteries by adherence of circulating platelets to areas of abnormal endothelium →↓ arterial flow → fibrin formation → red thrombus. Red thrombus can form around white thrombus in low-pressure veins, initially by adherence of platelets → formation of long tail consisting of fibrin network in which red cells are enmeshed. These tails become detached easily & travel as emboli to pulmonary arteries PE Arterial Thrombus Versus Venous Thrombus Although all thrombi are mixed, platelet nidus dominates arterial thrombus & fibrin tail venous thrombus. Arterial thrombi cause serious disease by producing local occlusive ischemia amputation; venous thrombi, by giving rise to distant embolization PE sudden death Blood Clotting Factors & Drugs That Affect Them A model of blood coagulation. Role of thrombin Has central role in hemostasis & many functions: 1. 2. 3. 4. 5. In clotting, thrombin proteolytically: fibrinogen → fibrin activates many upstream clotting factors, leading to more thrombin generation, Activates factor XIII, a transaminase that cross-links the fibrin polymer & stabilizes the clot. Thrombin is a potent platelet activator & mitogen. Thrombin also exerts anticoagulant effects by activating the protein C pathway, which attenuates the clotting response → Under normal circumstances, repair of vascular injury occurs without thrombosis & downstream ischemia;. Eventually vascular remodeling and repair occur with reversion to the resting anticoagulant endothelial cell phenotype Antithrombin (AT) III Is an endogenous anticoagulant Inactivates the serine proteases IIa, IXa, Xa, XIa, & XIIa. The endogenous anticoagulants protein C & protein S attenuate the blood clotting cascade by proteolysis of the two cofactors Va & VIIIa. Defects in natural anticoagulants result in an increased risk of venous thrombosis. The most common defect in the natural anticoagulant system is a mutation in factor V (factor V Leiden), which results in resistance to inactivation by the protein C, protein S mechanism. clinically useful activators useful in some bleeding disorders Basic Pharmacology of Antithrombotic Agents _______________ 1. Anticoagulants (Heparin & Warfarin) HEPARIN: UFH Chemistry & Source Heparin: heterogeneous mixture of sulfated mucopolysaccharides. Prevents further thrombus growth, allowing the body’s own thrombolytic system to dissolve clot. Regular (UFH) is standardized as units of activity by bioassay. Commercial heparin is extracted from porcine intestinal mucosa & bovine lung. UFH is eliminated by lungs, RES (macrophages of liver), & kidney. Mechanism of UFH action UFH activates plasma antithrombin III (AT III). Heparin molecules have unique pentasaccharide sequence, allowing it to bind & catalyze ATIII. This complex inactivates factors, IXa, Xa, & IIa (thrombin) Special requirement for inactivation of thrombin: heparin acts as bridge to which both thrombin & ATIII bind. UFH vs LMWH High-molecular-weight fractions of heparin with high affinity for antithrombin markedly inhibit blood coagulation by inhibiting all 3 clotting factors involved, especially thrombin and factor Xa. the shorter-chain low-molecular-weight (LMWH) inhibit activated factor X but have less effect on thrombin than UFH. Unfractionated heparin (UFH) has a molecular weight range of 5000-30,000. LMWHs such as enoxaparin, dalteparin, & tinzaparin are effective in several thromboembolic conditions. LMWHs in comparison with UFH have equal efficacy, increased bioavailability from the SQ injection, & less frequent dosing (1-2 times daily). Laboratory Monitoring for UFH Close monitoring of the activated partial thromboplastin time (aPTT) is necessary in patients receiving UFH. Levels of UFH may also be determined by protamine titration (therapeutic levels 0.2-0.4 unit/mL) or anti-Xa units (therapeutic levels 0.3-0.7 unit/mL). Weight-based dosing of the LMW heparins results in predictable pharmacokinetics & plasma levels in patients with normal renal function→ Thus, levels are not generally measured except in the setting of renal insufficiency, obesity, & pregnancy by anti-Xa units. UFH Toxicity 1. The major adverse effect is bleeding (elderly women & pts. w renal insufficiency are at the highest risk) 2. Heparin is of animal origin & should be used cautiously in patients with allergy. 3. Increased loss of hair (reversible alopecia) 4. Long-term heparin therapy: osteoporosis 5. Hyperkalemia (decreases aldosterone) 6. Heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia (HIT) a systemic hypercoagulable state that occurs in 1-4% of individuals treated with UFH for a minimum of 7 days. Surgical patients are at greatest risk. The risk is higher in individuals treated with UFH of bovine origin HIT is lower in those treated exclusively with LMWH. HIT is related to thrombotic events: venous thrombosis, occlusion of peripheral or central arteries The following points should be considered in all patients receiving heparin : platelet counts should be performed frequently. thrombocytopenia should be considered to be HIT. any new thrombus can be result of heparin. HIT treated by discontinuance of heparin & administration of direct thrombin inhibitor or fondaparinux Administration & Dosage (cont’d) The synthetic pentasaccharide molecule fondaparinux avidly binds antithrombin with high specific activity, resulting in efficient inactivation of factor Xa. Fondaparinux long half-life of 15 hours, once-daily dosing by SC It is used once-daily SQ for prevention & treatment of venous thromboembolism, The use of fondaparinux as an alternative anticoagulant in HIT is currently being tested in clinical trials. Reversal of Heparin Action Protamine: highly basic peptide that combines with heparin as ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in patient, 1 mg of protamine sulfate is used IV; the rate of infusion should not exceed 50 mg in any 10-min. period. Excess protamine must be avoided; it also has an anticoagulant effect. Blood or FFP (fresh frozen plasma) are sometimes necessary Protamine will not reverse the activity of fondaparinux ORAL ANTICOAGULANTS : WARFARIN & THE COUMARIN ANTICOAGULANTS Introduction “warfarin” from the Wisconsin Alumni Research Foundation. is also widely used as a rodenticide. is generally used as sodium salt & has 100% bioavailability. > 99% is bound to plasma albumin → small Vd, long t1/2 (36 hr) & lack of urinary excretion of unchanged drug. Levorotatory S-warfarin is 4 times > potent than the R-warfarin. Structural formulas of several oral anticoagulant drugs and of vitamin K. The carbon atom of warfarin shown at the asterisk is an asymmetric center Warfarin Mechanism of Action Blocks γ-carboxylation of several glutamate residues in prothrombin & factors VII, IX, & X, as well as the proteins C and S. The blockade results in incomplete molecules that are biologically inactive in coagulation. This carboxylation is physiologically coupled with the oxidative deactivation of vitamin K. Warfarin prevents reductive metabolism of inactive vitamin K epoxide back to its active hydroquinone form. Warfarin Mechanism of Action There is an 8- to 12-hour delay in the action of warfarin. Its anticoagulant effect results from a balance between partially inhibited synthesis & unaltered degradation of the 4 vitamin K-dependent clotting factors. The resulting inhibition of coagulation is dependent on their degradation half-lives in the circulation: 6, 24, 40, & 60 hours for factors VII, IX, X, & II, respectively. Larger initial doses of warfarin (up to 0.75 mg/kg) hasten the onset of the anticoagulant effect. Warfarin Administration & Dosage Initiation is recommended at dose of 5-10 mg daily. The therapeutic range for oral anticoagulant therapy is defined in terms of an international normalized ratio (INR). The INR is the prothrombin time (PT) ratio (patient prothrombin time/mean of normal prothrombin time for lab)ISI, The ISI serves to relate measured prothrombin times to WHO reference standard thromboplastin The recommended INR for prophylaxis & treatment of thrombotic disease is 2-3. Patients with some types of artificial heart valves (eg, tilting disk) or other medical conditions increasing thrombotic risk have a recommended range of 2.5-3.5 Warfarin Toxicity 1. Bleeding – the most dangerous. 2. Warfarin crosses the placenta readily & can cause hemorrhagic disorder in the fetus. 3. birth defect: abnormal bone formation (fetal proteins with γ-carboxyglutamate residues found in bone and blood may be affected).Thus, warfarin should never be administered during pregnancy. 4. Cutaneous necrosis, infarction of breast, fatty tissues, intestine, & extremities due to venous thrombosis (↓activity of protein C). Warfarin Drug Interactions 1. Pharmacokinetic mechanisms enzyme induction, enzyme inhibition, ↓plasma protein binding. 2. Pharmacodynamic mechanisms synergism (impaired hemostasis, ↓ clotting factor synthesis as in hepatic disease), competitive antagonism (vitamin K). and an altered physiologic control loop for vitamin K (hereditary resistance to oral anticoagulants) Warfarin Drug Interactions The most serious interactions are those that ↑ anticoagulant effect & risk of bleeding. The most dangerous are pharmacokinetic interactions with phenylbutazone and sulfinpyrazone: not only augment hypoprothrombinemia but also ↓platelet function & may induce peptic ulcer disease. The use of drug that interacts with warfarin is not absolute contraindication to addition of warfarin. Pharmacokinetic & pharmacodynamic drug & body interactions with oral anticoagulants. Increased Prothrombin Time Pharmacokinetic Pharmacodynamic Decreased Prothrombin Time Pharmacokinetic Pharmacodynamic Amiodarone Drugs Barbiturates Drugs Cimetidine Aspirin (high doses) Cholestyramine Diuretics Disulfiram Cephalosporins, third-generation Rifampin Vitamin K Metronidazole1 Heparin Body factors Fluconazole1 Body factors Hereditary resistance Phenylbutazone1 Hepatic disease Hypothyroidism Sulfinpyrazone1 Hyperthyroidism Trimethoprimsulfamethoxazole1 1Stereoselectively inhibits oxidative metabolism of (S)-warfarin enantiomorph of racemic warfarin. Warfarin -Disease Interactions augment warfarin pharmacodynamically by : 1. ↑ turnover rate of clotting factors: - hepatic disease, - fever, hyperthyroidism 2. by reducing vitamin K absorption - diarrhea reduce warfarin effect pharmacodynamically: - hereditary resistance (mutation of vitamin K reactivation cycle molecules) - hypothyroidism (↓turnover rate of clotting factors). Reversal of warfarin action: stopping the drug oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates such as Bebulin & Proplex T, recombinant factor VIIa (rFVIIa). FIBRINOLYTIC DRUGS Pharmacology Fibrinolytic drugs rapidly lyse thrombi by catalyzing formation of serine protease plasmin from its precursor, plasminogen. Streptokinase: protein (but not enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen to catalyze conversion of inactive plasminogen to active plasmin. Pharmacology Urokinase: human enzyme synthesized by kidney that directly converts plasminogen to active plasmin. Plasmin formed inside thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse thrombus from within. Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC) consists of a complex of purified human plasminogen & bacterial streptokinase that has been acylated to protect the enzyme's active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase-proactivator complex. This product has been recently discontinued in the USA Pharmacology (cont’d) Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PA): preferentially activate plasminogen that is bound to fibrin, which confines fibrinolysis to formed thrombus. Human t-PA is manufactured as alteplase by means of recombinant DNA technology. Reteplase is another recombinant human t-PA from which several amino acid sequences have been deleted. It is less expensive than t-PA. Because it lacks the major fibrinbinding domain, reteplase is less fibrin-specific than t-PA. Tenecteplase is a mutant form of t-PA that has a longer half-life, & it can be given as an IV bolus. Tenecteplase is slightly more fibrin-specific than t-PA. Fibrinolytics in AMI: thrombolytic therapy is still very important where PCI is not readily available. The proper selection of patients for thrombolytic therapy is critical: Patients with ST-segment elevation & bundle branch block on ECG have the best outcomes. The greatest benefit for thrombolytic therapy: when given early, within 6 hours after onset Thrombolytic drugs ↓ mortality of AMI. Adjunctive drugs such as aspirin, heparin, ß blockers, & ACEIs ↓ mortality even further. Indications & Dosage of Fibrinolytics - - - Administration of fibrinolytic drugs by IV route is indicated in cases of pulmonary embolism (PE) with hemodynamic instability, severe deep venous thrombosis (DVT) such as the superior vena caval syndrome, ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema. intra-arterially for peripheral vascular disease. Indications & Dosage of Fibrinolytics (cont’d) In AMI: Streptokinase - IV infusion of a loading dose of 250,000 units → 100,000 units/h for 24-72 hours. Patients with antistreptococcal antibodies can develop fever, allergic reactions, & therapeutic resistance. Alteplase (t-PA) is given by IV infusion of 60 mg over the first hour → 40 mg at a rate of 20 mg/h. A single course of fibrinolytic drugs is expensive: hundreds of dollars for streptokinase & thousands for urokinase & t-PA. Recombinant t-PA has also been approved for use in acute ischmic (non-hemorrhagic) stroke within 3 hours of symptom onset. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus & the remainder during a 1 hour infusion. ANTIPLATELET AGENTS 1. Platelet function is regulated by three categories of substances. Agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines, collagen, thrombin, and prostacyclin. 2. Agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D2, prostaglandin E2, and serotonin. 3. Agents generated within the platelet that act within the platelet, eg, prostaglandin endoperoxides and thromboxane A2, the cyclic nucleotides cAMP and cGMP, and calcium ion. Thrombus formation at the site of the damaged vascular wall Targets for platelet inhibitory drugs: inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-induced platelet aggregation (clopidogrel, ticlopidine), blockade of GP IIb/IIIa receptors on platelets (abciximab, tirofiban, & eptifibatide). dipyridamole & cilostazol are additional antiplatelet drugs ASPIRIN The prostaglandin thromboxane A2 (TxA2) causes platelets to aggregate Aspirin inhibits synthesis of TxA2 by irreversible acetylation of COX enzyme. Other salicylates & NSAIDs also inhibit COX but have a shorter duration of inhibitory action because they cannot acetylate COX; that is, their action is reversible. Aspirin (cont’d) The FDA has approved the use of 325 mg/d for primary prophylaxis of MI but urges caution in this use of aspirin by the general population except when prescribed as an adjunct to risk factor management by smoking cessation & lowering of blood cholesterol & BP. Meta-analysis of many published trials of aspirin & other antiplatelet agents confirms the value of this intervention in the secondary prevention of vascular events among patients with a history of vascular events. CLOPIDOGREL & TICLOPIDINE (Thienopyridine derivatives) - Irreversibly inhibit ADP binding to its receptor on platelets. used to prevent vascular events in patients with: transient ischemic attacks (TIA) & strokes, unstable angina pectoris. now considered standard practice in patients undergoing placement of a coronary stent. CLOPIDOGREL & TICLOPIDINE Adverse Effects Ticlopidine nausea, dyspepsia, diarrhea (20%), hemorrhage (5%) Most seriously: Leukopenia (1%) regular monitoring of WBCs during the first 3 months is necessary thrombotic thrombocytopenic purpura (TTP) Clopidogrel – fewer SE than with ticlopidine Rarely: neutropenia. TTP thrombotic thrombocytopenic purpura A rapidly fatal or occasionally protracted disease with varied symptoms in addition to purpura, including signs of central nervous system involvement, due to formation of fibrin or platelet thrombi in arterioles and capillaries in many organs. Synonym: Moschcowitz' disease. CLOPIDOGREL & TICLOPIDINE Dosage Because of its superior side effect profile and dosing requirements, clopidogrel is preferred over ticlopidine. The antithrombotic effects of clopidogrel are dosedependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7-10 days BLOCKADE OF PLATELET GP IIB/IIIA RECEPTORS A new class of antiplatelet agents for use in patients with acute coronary syndromes (ACCs). The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin & von Willebrand factor. Activation of this receptor complex is the "final common pathway" for platelet aggregation. BLOCKADE OF PLATELET GP IIB/IIIA RECEPTORS Abciximab, a chimeric monoclonal antibody directed against the IIb/IIIa complex including the vibronectin receptor, was the first agent approved in this class of drugs- approved for use in PCI & ACCs. Eptifibatide is an analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen, which mediates the binding of fibrinogen to the receptor. Tirofiban is a smaller molecule with similar properties. Eptifibatide & tirofiban inhibit ligand binding to the IIb/IIIa receptor by their occupancy of the receptor but do not block the vibronectin receptor. All three agents are administered parenterally ADDITIONAL ANTIPLATELETDIRECTED DRUGS Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake & cyclic GMP phosphodiesterase activity. Primarily used in combination with aspirin to prevent cerebrovascular ischemia. may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. Cilostazol is a newer PDE inhibitor that promotes vasodilation & inhibition of platelet aggregation. Cilostazol is used primarily to treat intermittent claudication. Figure 2. Mechanism of action of dipyridamole on platelet activation CLINICAL PHARMACOLOGY OF DRUGS USED TO PREVENT CLOTTING VENOUS THROMBOSIS Risk Factors A. INHERITED DISORDERS Tendency to form thrombi (thrombophilia) Deficiencies (loss of function mutations) in the natural anticoagulants antithrombin, protein C, & protein S account for thrombosis. Gain of function mutations such as the factor V Leiden mutation & the prothrombin 20210 mutation, Elevated clotting factor & cofactor levels, & hyperhomocysteinemia VENOUS THROMBOSIS (cont’d) B. ACQUIRED DISEASE ↑ risk of thromboembolism: atrial fibrillation, placement of mechanical heart valves prolonged bed rest, high-risk surgical procedures, presence of cancer antiphospholipic antibody syndrome drugs may function as synergistic risk factors in concert with inherited risk factors (e.g., women who have the factor V Leiden mutation and take oral contraceptives) Antithrombotic Management PREVENTION Primary prevention of venous thrombosis ↓ incidence of & mortality rate from pulmonary emboli. Heparin & warfarin may be used to prevent venous thrombosis. SQ low-dose UFH, LMWH, or fondaparinux provides effective prophylaxis. Warfarin is also effective but requires laboratory monitoring of the prothrombin time. Antithrombotic Management B. TREATMENT OF ESTABLISHED venous thrombosis initiated with UFH or LMWH for the first 5-7 days, with an overlap with warfarin. Once therapeutic effects of warfarin have been established, therapy with warfarin is continued for a minimum of 3-6 months. Warfarin readily crosses the placenta. It can cause hemorrhage at any time during pregnancy as well as developmental defects when administered during the first trimester → venous thromboembolic disease in pregnant women is generally treated with heparin SQ ARTERIAL THROMBOSIS Activation of platelets is considered an essential process for arterial thrombosis Thus, treatment with platelet-inhibiting drugs such as aspirin, ticlopidine & clopidogrel is indicated in patients with transient ischemic attacks & strokes or unstable angina ´ myocardial infarction. In angina & infarction, these drugs are often used in conjunction with ß-blockers, calcium channel blockers, & fibrinolytic drugs. DRUGS USED IN BLEEDING DISORDERS VITAMIN K: Mechanism of action confers biologic activity upon prothrombin & factors VII, IX, & X by participating in their postribosomal modification. fat-soluble substance found primarily in leafy green vegetables. dietary requirement is low, because it is additionally synthesized by intestinal bacteria. Vitamin K1 (phytonadione) is found in food. Vitamin K2 (menaquinone) is synthesized by intestinal bacteria. VITAMIN K: Administration & Clinical Uses Vitamins K1 & K2 require bile salts for GIT absorption. Vitamin K1 is available in 5 mg tablets & 50 mg ampules. The effect is delayed for 6 hours. Complete in 24 hrs. IV administration of vitamin K1 should be slow (rapid infusion can produce dyspnea, chest & back pain & death). in all newborns to prevent the hemorrhagic disease of vitamin K deficiency esp. if premature. in reversal of warfarin effect. Vitamin K deficiency frequently occurs in hospitalized patients in intensive care units because of: poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy, and uremia. Severe hepatic failure results in diminished protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K. PLASMA FRACTIONS Spontaneous bleeding occurs when factor activity is <than 5-10% of normal. Factor VIII deficiency (classic hemophilia, or hemophilia A) & factor IX deficiency (Christmas disease, or hemophilia B) account for most of the heritable coagulation defects. Concentrated plasma fractions are available for the treatment of these deficiencies. PLASMA FRACTIONS (cont’d) Transmission of viral diseases such as hepatitis B, C &HIV is ↓ or eliminated by pasteurization & by extraction of plasma with solvents & detergents. However, this treatment does not remove other potential causes of transmissable diseases such as prions → recombinant clotting factor preparations Intermediate purity factor VIII concentrates (as opposed to recombinant or high purity concentrates) contain significant amounts of von Willebrand factor. Humate-P is a factor VIII concentrate that is approved by the FDA for the treatment of bleeding associated with von Willebrand disease. PLASMA FRACTIONS (cont’d) Desmopressin acetate (arginine vasopressin) ↑ factor VIII activity of patients with mild hemophilia A or von Willebrand's disease. Intranasal formulations are available PLASMA FRACTIONS (cont’d) Freeze-dried concentrates of plasma containing prothrombin, factors IX & X, & varied amounts of factor VII (Proplex, etc) are commercially available for treating deficiencies of these factors. Some preparations of factor IX concentrate contain activated clotting factors, which has led to their use in treating patients with inhibitors or antibodies to factor VIII or factor IX (to arrest hemorrhage) Recombinant activated factor VII (NovoSeven) is used to treat coagulopathy associated with liver disease & major blood loss in trauma & surgery. These recombinant & plasma-derived factor concentrates are very expensive PLASMA FRACTIONS (cont’d) Cryoprecipitate is a plasma protein fraction obtainable from whole blood. It is used to treat deficiencies or qualitative abnormalities of fibrinogen, such as that which occurs with DIC & liver disease. A single unit of cryoprecipitate contains 300 mg of fibrinogen. Cryoprecipitate may also be used for patients with factor VIII deficiency & von Willebrand disease The concentration of factor VIII & von Willebrand factor in cryoprecipitate is less than in concentrated plasma fractions. Cryoprecipitate is not treated to ↓ risk of viral exposure. Rh-negative women with potential for childbearing should receive only Rh-negative cryoprecipitate because of possible contamination of the product with Rh-positive blood cells. Therapeutic products for the treatment of coagulation disorders Factor Deficiency State I Hypofibrinogenemia II Prothrombin deficiency V Factor V def. VII VIII Factor VII deficiency Hemophilia A Hemostatic Levels t1/2 Replacement Source 4 days Cryoprecipitate FFP 30-40% 3 days Prothrombin complex concentrates (intermediate purity factor IX concentrates) 20% 1 day FFP 4-6 hours FFP Prothrombin complex concentrates (intermediate purity factor IX concentrates) Recombinant fr VIIa 12 hours Recombinant factor VIII products Plasma-derived high purity concentrates Cryoprecipitate1 Some patients with mild deficiency will respond to DDAVP 1 g/dL 30% 30-50% 100% for major bleeding or trauma 30-50% 100% for major 24 hours bleeding or trauma Recombinant factor IX products Plasma-derived high purity concentrates IX Hemophilia B Christmas disease X Stuart-Prower defect 25% 36 hours FFP Prothrombin complex concentrates XI Hemophilia C 30-50% 3 days FFP XII Hageman defect Not required Von Von Willebrand Willebra 30% disease nd XIII Factor XIII deficiency 5% Treatment not necessary Intermediate purity factor VIII concentrates that Approxim contain von Willebrand ately 10 factor hours Some patients respond to DDAVP Cryoprecipitate1 6 days FFP Cryoprecipitate FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Aminocaproic acid (EACA), chemically similar to amino acid lysine, is synthetic inhibitor of fibrinolysis: competitively inhibits plasminogen activation. Used orally or by IV infusion. Clinical uses: as adjunctive therapy in hemophilia, & for bleeding from other causes. Tranexamic acid is an oral analog of aminocaproic acid and has the same properties SERINE PROTEASE INHIBITORS: APROTININ Aprotinin: serine protease inhibitor ("serpin") - inhibits fibrinolysis by free plasmin and also plasmin-streptokinase complex. is currently approved for use in patients undergoing coronary artery bypass grafting (CABG) who are at high risk of excessive blood loss. ADRs: ↑ risk of MI, stroke, & renal damage, possible association with anaphylaxis → a small test dose is recommended before the full therapeutic dose is given