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1500 SECTION 18: Hematologic and Oncologic Disorders and chest pain. A severe febrile reaction may be difficult to initially dif ferentiate from the more serious hemolytic transfusion reaction or sepsis. For a febrile reaction during a patient’s first-time transfusion, or in any severe reaction, the transfusion should be stopped and the product returned to the blood bank for testing. Laboratory investigation similar to that done for possible hemolytic transfusion is done, and blood cul tures should be obtained. The febrile transfusion reaction is usually selflimited and will respond to antipyretics. A mild fever in a patient who has been transfused before is usually not serious. In most cases, the transfusion can be restarted after consultation with the blood bank physician. For patients with recurrent febrile reactions, the use of leukocyte-reduced blood products and pretreatment with antipyretics may be helpful.  ALLERGIC TRANSFUSION REACTIONS Allergic transfusion reactions typically manifest with urticaria and pruritus during the infusion. 8,10,46,47 A small percentage of patients will have more severe reactions, such as bronchospasm, wheezing, and anaphylaxis. These reactions are caused by an immune response to transfused plasma proteins. The incidence of allergic transfusion reactions varies widely. Antihistamine therapy usually will control urticaria and pruritus. The transfusion should be stopped, but can usually be restarted after evalu ation. For anaphylaxis with severe symptoms, the transfusion should be stopped and treatment with epinephrine, steroids, H 2 blockers, and bronchodilators begun. Patients with immunoglobulin A deficiency may experience severe anaphylactic reactions in response to exposure from immunoglobulin A in donor products. Washing the plasma from the red blood cells minimizes this type of reaction.  INFECTIOUS COMPLICATIONS Improved blood donor screening, serologic testing, safer handling of blood products, and viral inactivation of blood products have reduced the risk of infection from transfusion. 50-53 Despite screening donor blood for antibodies to the most concerning viral agents, there is still a small risk of viral transmission (Table 238-8). Most cases of transmission are thought to occur during the window period between infection and antibody production in the donor. This window can be reduced by antigen testing of donated blood for known viral antigens. In the United States, blood is tested for syphilis, hepatitis B and C, human immunodeficiency virus, human T-cell lymphotropic virus, West Nile virus, Chagas disease, and Zika virus. Prevalence for cytomegalovirus antibodies in the general population is between 50% and 80%; therefore, a transfusable unit is not tested routinely for cytomegalovirus unless the recipient is seronegative and either pregnant, a potential or present transplant candidate, immunocompro mised, or a premature infant. 8 Leukocyte-reduced blood components further decrease the risk of cytomegalovirus transmission to susceptible populations because most of the virus resides in the leukocytes. Other infections transmitted by blood transfusion include West Nile virus, variant Creutzfeldt-Jakob disease, babesiosis, and dengue. 49-51 Additionally, blood can become contaminated with bacteria during storage or processing. Transfusion-associated bacterial infection was more commonly reported with platelet concentrates than PRBC or FFP .

itted by blood transfusion include West Nile virus, variant Creutzfeldt-Jakob disease, babesiosis, and dengue. 49-51 Additionally, blood can become contaminated with bacteria during storage or processing. Transfusion-associated bacterial infection was more commonly reported with platelet concentrates than PRBC or FFP . Evaluation of a possible septic reaction involves obtaining blood cultures from the patient and examination of material from the blood container by Gram stain with cultures of specimens from the container and the administration set. 8,47 TABLE 238-8 Approximate Risk of Infection From Blood Product Transfusion Etiology Estimated Frequency: One Infection per Number of Units Transfused HIV-1 1 per 6 million Human T-cell lymphotropic virus types 1 and 2 1 per 640,000 Hepatitis B 1 per million Hepatitis C 1 per 100 million Parvovirus B19 1 per 10,000 Abbreviation: HIV = human immunodeficiency virus.  TRANSFUSION-RELATED ACUTE LUNG INJURY Transfusion-related acute lung injury is an uncommon but life-threatening complication of transfusion characterized by the development of acute respiratory distress associated with noncardiogenic pulmonary edema occurring within 6 to 72 hours after receiving a blood transfusion. Transfusion-related acute lung injury is due to antileukocyte antibodies in the donor product that produce polymorphonuclear leukocyte degranulation within the lung. 55 Transfusion-related acute lung injury is more common after plasma transfusion than red blood cell transfusion. Mitigation strategies with blood donor screening have been partially successful in reducing the risk of transfusion-related acute lung injury. 56 Transfusion-related acute lung injury is self-limiting and generally resolves spontaneously with only supportive care, although severe, fatal cases can occur. Because the pulmonary edema is noncardiogenic, use care to distinguish transfusionrelated acute lung injury from volume overload and avoid aggressive diuresis, which can cause rapid deterioration.  TRANSFUSION-ASSOCIATED CIRCULATORY OVERLOAD Transfusion of blood products can cause rapid volume expansion when compared to similar volumes of crystalloid fluids, leading to transfusionassociated cardiovascular overload. 57 Patients with limited cardiovascular reserve, such as those with severe chronic compensated anemia and the elderly, are at the highest risk. Clinical features include dyspnea, hypoxia, and pulmonary edema. Recognize the potential for volume overload so that blood can be transfused slowly, the patient can be monitored care fully, and treatment with diuretics can be initiated when necessary. The usual rate of PRBC or FFP transfusion is 2 to 4 mL/kg per h, but it can be slowed to 1 mL/kg per h in more delicate patients. Blood product units may also be split, as described earlier.  ELECTROLYTE IMBALANCE Large-volume transfusions may uncommonly cause hypocalcemia, hypokalemia, or hyperkalemia. The anticoagulant citrate is a component of many blood preservatives and chelates calcium, but the effect of infused citrate is clinically insignificant because patients with normal hepatic function metabolize the citrate to bicarbonate. Rarely with massive transfusions, hepatic metabolism is overwhelmed, and hypocalcemia can develop and/or the excess bicarbonate generated causes alkalemia, driving potassium into the cells and causing hypokalemia. 58 The potassium content in stored blood products increases during storage, and uncommonly, patients with renal insufficiency or neonates can develop hyperkalemia from transfusion. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Thrombotics and Antithrombotics David E. Slattery Charles V.

e potassium content in stored blood products increases during storage, and uncommonly, patients with renal insufficiency or neonates can develop hyperkalemia from transfusion. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Thrombotics and Antithrombotics David E. Slattery Charles V. Pollack, Jr INTRODUCTION Antithrombotic therapy (i.e., anticoagulants, antiplatelet agents, and fibrinolytics) is used to treat or reduce the risk of arterial and venous thromboembolic conditions, including acute coronary syndrome, deep venous thrombosis and pulmonary embolism (collectively, venous thromboembolic disease), transient ischemic attack, and ischemic stroke (Table 239-1). Moreover, antithrombotic agents help prevent occlusive CHAPTER Tintinalli_Sec18_p1461-1522.indd 1500 8/2/19 8:37 PM

ic conditions, including acute coronary syndrome, deep venous thrombosis and pulmonary embolism (collectively, venous thromboembolic disease), transient ischemic attack, and ischemic stroke (Table 239-1). Moreover, antithrombotic agents help prevent occlusive CHAPTER Tintinalli_Sec18_p1461-1522.indd 1500 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1501 TABLE 239-1 Indications for Antithrombotic Therapy Clinical Indication Comments Treatment of Deep Venous Thrombosis and Pulmonary Embolism Unfractionated heparin 80 units/kg IV bolus followed by 18 units/kg per h continuous IV infu sion, with the aPTT checked after 6 h and the infusion adjusted to maintain anti-FXa activity 0.3–0.7 IU/mL or aPTT 1.5–2.5 times reference range (e.g., 68–106 s) with concurrent institution of warfarin In most cases, heparin and warfarin started simultaneously, with an overlap of 3–5 d. Warfarin is monitored and dose adjusted to a target INR of 2.0–3.0 in most patients. Enoxaparin 1 milligram/kg SC every 12 h or 1.5 milligrams/kg SC once a day Laboratory monitoring not routinely required (see text) If CrCl <30 mL/min: 1 milligram/kg SC daily Dalteparin 200 units/kg SC once daily or 100 units/kg SC twice daily Not FDA approved for this indication Fondaparinux weight-tiered regimen <50 kg: 5 milligrams SC once a day 50–100 kg: 7.5 milligrams SC once a day >100 kg: 10 milligrams SC once a day Laboratory monitoring not routinely required Avoid in patients with CrCl <30 mL/min Dabigatran 150 milligrams PO twice daily Following 5–10 d of initial therapy with parenteral anticoagulant Avoid in patients with CrCl <30 mL/min or on hemodialysis Rivaroxaban 15 milligrams PO twice daily for 21 d with food, followed by 20 milligrams PO once daily with food Avoid use in patients with CrCl <30 mL/min Apixaban 10 milligrams PO twice daily for 7 d, followed by 5 milligrams twice daily Reduce dose by 50% if patient taking dual strong VYP3A4 and P-glycoprotein inhibitors. If Cr >1.5 milligrams/dL and either ≥80 years of age or body weight ≤60 kg: 2.5 milligrams twice daily Edoxaban 30 milligrams PO daily (if ≤60 kg) or 60 milligrams PO daily (if >60 mg) Following 5–10 d of initial therapy with parenteral anticoagulant If CrCl 15 to 50 mL/min: 30 milligrams PO daily If CrCl <15 mL/min: use not recommended Streptokinase 250,000 units IV bolus, followed by 100,000 units/h continuous IV infusion for 1–3 d Alteplase 100 milligrams IV infused over 2 h Tenecteplase weight-tiered single IV bolus <60 kg: 30 milligrams ≥60–<70 kg: 35 milligrams ≥70–<80 kg: 40 milligrams ≥80–<90 kg: 45 milligrams ≥90 kg: 50 milligrams Fibrinolytic treatment of deep venous thrombosis and pulmonary embolism is recommended only in carefully selected patients. Prophylaxis for Deep Venous Thrombosis and Pulmonary Embolism Unfractionated heparin 5000 units SC every 8–12 h Highest-risk patients for venous thromboembolism should receive every-8-h dosing. Recommend using in patients with renal dysfunction Dalteparin 2500 to 5000 IU SC once a day — Enoxaparin 40 milligrams SC once daily (normal renal function), 30 milligrams SC twice daily (trauma), or 40 milligrams SC twice daily (obese patients) — Fondaparinux 2.5 milligrams SC once a day — Rivaroxaban 10 milligrams PO once a day with or without food — Apixaban 2.5 milligrams PO twice daily For prophylaxis after hip and knee replacement surgery, initial dose taken 12–24 h after surgery Betrixaban 160 milligrams PO first dose, then 80 milligrams PO daily. If CrCl 15–30 mL/min, start 80 milligrams PO first dose, then 40 milligrams PO daily.

a day with or without food — Apixaban 2.5 milligrams PO twice daily For prophylaxis after hip and knee replacement surgery, initial dose taken 12–24 h after surgery Betrixaban 160 milligrams PO first dose, then 80 milligrams PO daily. If CrCl 15–30 mL/min, start 80 milligrams PO first dose, then 40 milligrams PO daily. Approved for VTE prophylaxis, not treatment ST-Segment Elevation Myocardial Infarction Aspirin (non–enteric coated) 162–325 milligrams PO once a day plus Clopidogrel 300 milligrams PO loading dose (consider 600 milligrams if PCI is planned) followed by 75 milligrams PO once a day Ticagrelor 180 milligrams PO loading dose, followed by 90 milligrams PO twice daily Prasugrel 60 milligrams PO loading dose followed by 10 milligrams PO once a day (in patients ≤60 kg, the recommended maintenance dose is 5 milligrams PO once a day) Dual therapy—aspirin plus another antiplatelet agent—is common. Prasugrel is contraindicated for patients with a previous stroke and not recommended in patients age ≥75 y. (Continued) Tintinalli_Sec18_p1461-1522.indd 1501 8/2/19 8:37 PM

in patients ≤60 kg, the recommended maintenance dose is 5 milligrams PO once a day) Dual therapy—aspirin plus another antiplatelet agent—is common. Prasugrel is contraindicated for patients with a previous stroke and not recommended in patients age ≥75 y. (Continued) Tintinalli_Sec18_p1461-1522.indd 1501 8/2/19 8:37 PM 1502 SECTION 18: Hematologic and Oncologic Disorders TABLE 239-1 Indications for Antithrombotic Therapy Clinical Indication Comments Unfractionated heparin 60 units/kg IV bolus (maximum, 4000 units according to the ACC/AHA guidelines or 5000 units according to the ESC guidelines) followed by 12 units/kg per h (maximum, 1000 units) continuous IV infusion adjusted to anti-FXa activity 0.3–0.6 IU/mL or aPTT 1.5–2.5 times reference range (e.g., 68–96 s) Enoxaparin 30 milligrams IV bolus, followed by 1 milligram/kg SC every 12 h (maximum, 100 milligrams for the first 2 doses only) for patients <75 y old or 0.75 milligram/kg SC every 12 h for patients >75 y old (no IV bolus is administered in this population) Bivalirudin 0.75 milligram/kg IV bolus followed by 1.75 milligrams/kg per h continuous IV infusion (FDA approved for use in cardiac catheterization laboratory only) Optimal anticoagulation strategies are not completely defined. Bivalirudin is recommended in patients with heparin-induced thrombocytopenia. Streptokinase 1.5 million units IV over 60 min Alteplase 15 milligrams IV bolus over 1–2 min followed by 0.75 milligram/kg IV over 30 min (maximum, 50 milligrams) and 0.50 milligram/kg IV over 60 min (maximum, 35 milligrams) Reteplase 10 units IV bolus, then a second 10-unit dose at 30 min Tenecteplase weight-tiered single IV bolus <60 kg: 30 milligrams ≥60–<70 kg: 35 milligrams ≥70–<80 kg: 40 milligrams ≥80–<90 kg: 45 milligrams ≥90 kg: 50 milligrams Early administration is more important than choice of specific fibrinolytic agent. Unstable Angina and Non–ST-Segment Myocardial Infarction Aspirin (non–enteric coated) 162–325 milligrams PO once a day Optimal antiplatelet strategies are not completely defined. Clopidogrel 300 milligrams PO loading dose (consider 600 milligrams if PCI is planned) followed by 75 milligrams PO once a day Prasugrel 60 milligrams loading dose followed by 10 milligrams PO once daily (in patients ≤60 kg, the recommended maintenance dose is 5 milligrams PO once a day) Ticagrelor 180 milligrams PO loading dose, followed by 90 milligrams PO twice daily Dual therapy—aspirin plus another antiplatelet agent—is common. Prasugrel is contraindicated for patients with a previous stroke and not recom mended in patients age ≥75 y. Unfractionated heparin 60 units/kg IV bolus (maximum, 4000 units according to the ACC/AHA guidelines or 5000 units according to the ESC guidelines) followed by 12 units/kg per h (maximum, 1000 units) continuous IV infusion adjusted to anti-FXa activity 0.3–0.6 IU/mL or aPTT 1.5–2.5 times reference range (e.g., 68–96 s) Enoxaparin 1 milligram/kg SC every 12 h Glycoprotein IIb/IIIa inhibitor, depending on risk and whether PCI is planned Bivalirudin 0.75 milligram/kg IV bolus followed by 1.75 milligrams/kg per hour continuous IV infu sion (FDA approved for use in cardiac catheterization laboratory only) Optimal anticoagulation strategies are not completely defined. Bivalirudin is recommended in patients with heparin-induced thrombocytopenia. Peripheral Arterial Disease Aspirin 162–325 milligrams PO once a day — Cilostazol 100 milligrams PO twice a day — Acute Ischemic Stroke Alteplase 0.9 milligram/kg (maximum, 90 milligrams) with 10% of total dose given as an IV bolus over 1 min followed by the remainder as an IV infusion over 60 min Use of fibrinolytics in acute ischemic stroke requires strict adherence to recommended guidelines and should be done with informed consent.

e Ischemic Stroke Alteplase 0.9 milligram/kg (maximum, 90 milligrams) with 10% of total dose given as an IV bolus over 1 min followed by the remainder as an IV infusion over 60 min Use of fibrinolytics in acute ischemic stroke requires strict adherence to recommended guidelines and should be done with informed consent. Adjunctive use of anticoagulants should be avoided for 48 h. Tenecteplace 0.25 milligrams/kg IV bolus Not FDA approved for this indication (see text). Recommend informed consent. Adjunctive use of anticoagulants should be avoided for 48 h. Postischemic Stroke Aspirin 81 milligrams PO once a day — Clopidogrel 75 milligrams PO once a day Use clopidogrel if aspirin allergic. Dipyridamole 200 milligrams extended-release PO twice a day Usually combined with aspirin 25–50 milligrams PO twice a day (Continued) ( Continued ) Tintinalli_Sec18_p1461-1522.indd 1502 8/2/19 8:37 PM

roke Aspirin 81 milligrams PO once a day — Clopidogrel 75 milligrams PO once a day Use clopidogrel if aspirin allergic. Dipyridamole 200 milligrams extended-release PO twice a day Usually combined with aspirin 25–50 milligrams PO twice a day (Continued) ( Continued ) Tintinalli_Sec18_p1461-1522.indd 1502 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1503 TABLE 239-1 Indications for Antithrombotic Therapy Clinical Indication Comments Transient Ischemic Attack Aspirin 81 milligrams PO once a day Use clopidogrel if “aspirin failure” or aspirin allergic. Clopidogrel 75 milligrams PO per day — Stroke Reduction in Nonvalvular Atrial Fibrillation Warfarin dose monitored and adjusted by INR Target INR is 2.0–3.0 in most patients. Dabigatran 150 milligrams PO twice daily (patients with CrCl >30 mL/min) or 75 milligrams PO twice daily (patients with CrCl 15–30 mL/min) Routine laboratory monitoring not necessary Rivaroxaban 20 milligrams PO once daily with evening meal (patients with CrCl >50 mL/min) or 15 milligrams once daily with evening meal (patients with CrCl 15–50 mL/min) Routine laboratory monitoring not necessary Apixaban 5 milligrams PO twice daily or 2.5 milligrams twice daily in patients with at least 2 of the following characteristics: age ≥80 y, body weight ≤60 kg, or serum Cr ≥1.5 milligrams/dL Routine laboratory monitoring not necessary Edoxaban 60 milligrams once daily (patients with CrCL between 50 and 95 mL/min) or 30 milligrams once daily (patients with CrCl 15–50 mL/min) Avoid use if CrCl >95 mL/min. Routine laboratory monitoring not necessary Abbreviations: ACC = American College of Cardiology; AHA = American Heart Association; aPTT = activated partial thromboplastin time; Cr = creatinine; CrCl = creatinine clearance; ESC = European Society of Cardiology; FDA = U.S. Food and Drug Administration; FXa = factor Xa; PCI = percutaneous coronary intervention; VTE = venous thromboembolism. (Continued ) vascular events in patients at risk for thrombosis due to atherosclerotic arterial disease, atrial fibrillation, medical illness with immobility, or surgical insult. These agents, however, can cause life-threatening com plications, primarily serious or life-threatening hemorrhage. Detailed management strategies for thromboembolic disorders are discussed in their respective chapters (see Chapter 49, “ Acute Coronary Syndromes”; Chapter 56, “Venous Thromboembolism Including Pulmonary Embolism”; and Chapter 167, “Stroke Syndromes”). Hemostasis—whether physiologic after accidental injury or pathologic after rupture of an atherosclerotic plaque—is initiated by platelet interaction with the vascular subendothelium and continues with a series of reactions among plasma coagulation proteins that generate the final product of cross-linked fibrin incorporated into the initial platelet plug (see Chapter 232, “Hemostasis”). Arterial thrombi, composed pri marily of platelets bound by thin fibrin strands, develop under high-flow conditions, especially at sites of ruptured plaques. Both anticoagulants and platelet-inhibiting drugs may effectively prevent and treat arte rial thrombosis. In contrast, venous thrombi tend to form in areas of sluggish blood flow and are composed mainly of red blood cells and large fibrin strands. Anticoagulant drugs are more effective than antiplatelet drugs in preventing venous thromboembolism. Antithrombotic agents are classified by their mechanism of action. Anticoagulants block the synthesis or activation of clotting fac tors, interfering with the coagulation cascade at one or more steps. Antiplatelet agents interfere with platelet activation or aggregation. Fibrinolytic agents (often but inaccurately referred to as throm bolytic agents) stimulate the enzymatic dissolution of the fibrin component.

ynthesis or activation of clotting fac tors, interfering with the coagulation cascade at one or more steps. Antiplatelet agents interfere with platelet activation or aggregation. Fibrinolytic agents (often but inaccurately referred to as throm bolytic agents) stimulate the enzymatic dissolution of the fibrin component. Thrombotics or hemostatic agents are used to diminish bleed ing due to either an antithrombotic agent or an acquired or genetic bleeding disorder (see Chapter 233, “ Acquired Bleeding Disorders, ” and Chapter 235, “Hemophilias and von Willebrand’s Disease, ” respectively).  ORAL ANTICOAGULANTS Oral anticoagulants are used to (1) stop further thrombosis when the condition already exists (e.g., venous thrombosis), (2) reduce the risk of embolism in patients with thrombotic disease (e.g., venous thrombosis or left ventricular mural thrombus), and (3) prevent thrombi from forming in patients with risk factors for their development (e.g., atrial fibrillation, prolonged immobilization, or prosthetic heart valve) (Table 239-1). Oral anticoagulants can be either indirect acting, such as the vitamin K antagonists (e.g., warfarin), or direct acting (termed direct-acting oral anticoagulants). WARFARIN  PHARMACOLOGY Warfarin, a hydroxy coumarin compound, is a widely used oral anticoagulant.1,2 Warfarin is readily absorbed after ingestion, reaching peak blood concentrations in 2 to 4 hours, and has a circulating half-life of 20 to 60 hours. Warfarin is bound to albumin, metabolized by the liver, and excreted in the urine. Warfarin blocks activation of vitamin K and thereby interferes with hepatic carboxylation of coagulation factors II, VII, IX, and X. The decrease in these vitamin K–dependent cofactors impairs the extrinsic and common coagulation pathway. Warfarin also blocks the synthesis of proteins C and S. Activated protein C (with protein S and phospholipid as cofactors) proteolyses factors Va and VIIIa, thereby inhibiting the coagulation cascade. Thus, warfarin has both an antithrombotic effect (by inhibiting the synthesis of factors II, VII, IX, and X) and a prothrombotic effect (through inhibition of proteins C and S production), but during maintenance therapy, the overwhelming effect is one of anticoagulation. Warfarin dosing is guided by measurement of the INR, a standardized measurement of prothrombin time, with a desired therapeutic range of 2.0 to 3.0 in most cases. 2 Drugs and food that interfere with warfarin absorption, bind to albumin, or alter hepatic metabolism can have a profound effect on warfarin activity (Table 239-2). Warfarin is generally TABLE 239-2 Warfarin Interactions Consideration Effect on PT or INR* Major Vitamin K malabsorption or dietary deficiency ↑ Excess vitamin K ↓ Reduced gut bacteria (antibiotics)† ↑ Decreased warfarin absorption ↓ Altered warfarin metabolism (cytochrome P450) Variable Drug effects† Variable Other Decreased clotting factor production (liver disease) ↑ Increased metabolism of clotting factors (fever) ↓ Confounding technical or laboratory factors (e.g., phlebotomy, handling in transport, thromboplastin reagents) Variable *↑ = prothrombin time (PT) or INR prolonged; ↓ = PT or INR decreased. †Consult drug-interaction reference for any new medications. Tintinalli_Sec18_p1461-1522.indd 1503 8/2/19 8:37 PM

actors (fever) ↓ Confounding technical or laboratory factors (e.g., phlebotomy, handling in transport, thromboplastin reagents) Variable *↑ = prothrombin time (PT) or INR prolonged; ↓ = PT or INR decreased. †Consult drug-interaction reference for any new medications. Tintinalli_Sec18_p1461-1522.indd 1503 8/2/19 8:37 PM 1504 SECTION 18: Hematologic and Oncologic Disorders • Administer Vitamin K1 5–10 milligrams SLOW IV bolus • For INR >6, give 4-factor PCC 50 units/kg (max 5000 units); For INR 4–6, give 4-factor PCC 35 units/kg (max 3500 units); for INR <4, 25 units/kg (max 2500 units) • Alte rnatively, may use 3-factor PCC 50 units/kg IV, FFP 10–15 mL/kg IV infusion, or rFVIIa 80 micrograms/kg slow IV bolus • Additional doses of PCC, FFP, or rFVIIa may be r equired depending on degree of coagulopathy Yes • Hold the next 1 or 2 doses • Administer oral vitamin K 2.0–2.5 milligrams PO • More frequent monitoring and administer more vitamin K as necessary † • Resume appropriately adjusted dose when INR is therapeutic Yes • Hold the next 1 or 2 doses • If high ri sk for bleeding* consider giving vitamin K 1–2 milligrams PO • More frequent monitoring • Resume appropriately adjusted dose when INR is therapeutic No significant bleeding and the INR is >10.0 No significant bleeding and the INR is between 4.5 and 10.0 Yes • Lower dose or omit one dose for patients at high ri sk of bleeding* • More frequent monitoring • Resume appropriately adjusted dose when INR is therapeutic No significant bleeding and the INR is between 3.0 and 4.5 YesElevated INR and life-threatening or serious bleeding present FIGURE 239-1. Management of prolonged INR (warfarin-induced coagulopathy). *High risk of bleeding: age >75 years, concurrent antiplatelet drug use, polypharmacy, liver or renal disease, alcoholism, recent surgery, or trauma. †There are no validated tools to predict risk of short-term major bleeding in patients with severe overanticoagulation. The decision to admit for observation relies on physician judgment. FFP = fresh frozen plasma; 4-factor PCC = prothrombin complex concentrate (human) containing coagulation factors 2, 7, 9, and 10; 3-factor PCC = coagulation factor IX complex containing coagulation factors 2, 9, and 10; rFVIIa = coagulation factor VIIa (recombinant). contraindicated in pregnancy because it is teratogenic (especially dur ing the 6th to 12th weeks of gestation) and can cause fetal hemorrhage. Protein C has a short half-life (8 hours), and plasma levels quickly fall after starting warfarin. The vitamin K–dependent coagulation factors have half-lives that range from approximately 7 hours for factor VII to approximately 60 hours for prothrombin (factor II). The phase delay between the fall in levels of protein C (an antithrombotic protein) and the fall in levels of the four affected coagulation factors (prothrombotic proteins) results in a transient state of increased thrombogenesis at the start of warfarin therapy that persists for 24 to 36 hours. This hypercoagulable state is mitigated by providing sufficient overlap with a parenteral anticoagulant (typically, a heparinoid) during the first 3 to 5 days of warfarin treatment 1,2 and during any interruption of warfarin therapy for surgery or an invasive procedure. 3-5 Because factors X and II have relatively long half-lives, the parenteral anticoagulant should not be discontinued until the INR is in the desired therapeutic range for 2 consecutive days. Thus, a noncompliant patient with the risk for catastrophic complications from sudden intravascular thrombosis—such as a patient with a mechanical prosthetic heart valve who has stopped oral anticoagulants—should be treated with a parenteral anticoagulant in addition to restarting warfarin.

ange for 2 consecutive days. Thus, a noncompliant patient with the risk for catastrophic complications from sudden intravascular thrombosis—such as a patient with a mechanical prosthetic heart valve who has stopped oral anticoagulants—should be treated with a parenteral anticoagulant in addition to restarting warfarin. There is also a prothrombotic rebound during the first 4 days after cessation of warfarin therapy. However, there is no increased incidence of clinical episodes of thrombosis with termination of warfarin therapy, and thromboembolic events that occur in patients after warfarin discontinuation are most likely related to the underlying condition. The two major complications of warfarin therapy are bleeding and, less commonly, skin necrosis. The most important factor influencing the risk of bleeding is the intensity of anticoagulant therapy. The risk of clinically significant bleeding is increased when the INR is >4.5 to 5.0. 1,2 Skin necrosis occurs primarily (but not exclusively) in patients with protein C deficiency. This complication usually develops 3 to 8 days after starting treatment and is caused by thrombosis of small cutaneous ves sels. Treatment includes discontinuation of warfarin, administration of a parenteral anticoagulant to maintain desired anticoagulation, vitamin K administration, and screening for protein C and S deficiencies. Patient-specific risk factors for increased risk of bleeding dur ing warfarin treatment include hypertension, anemia, prior cere brovascular disease, GI lesions, and renal disease. The relationship between advanced age and warfarin-associated bleeding is contro versial. Elderly individuals who are otherwise appropriate candidates for anticoagulant therapy should not have warfarin withheld solely because of their age, although elderly patients require more frequent and careful monitoring. Medications that increase warfarin activity and antiplatelet medications increase bleeding risk during warfarin therapy (Table 239-2). Potential drug–drug and drug–food interactions with warfarin are numerous and complex. Carefully review medications prescribed on ED discharge. In addition, it is recommended that drug–drug interaction references be used whenever adding a new medication to a patient on warfarin. Drugs frequently prescribed upon ED discharge that should generally be avoided in patients on warfarin because of the increased risk of bleeding, include NSAIDs, sulfa-containing drugs (e.g., sulfa methoxazole), macrolides, and fluoroquinolones. Drugs that induce hepatic cytochrome P450 activity may increase the metabolism and reduce the effect of warfarin. Because the effect may take several days to manifest, the following agents should only be prescribed upon ED discharge after careful review and with close follow-up: barbiturates, anticonvulsants (e.g., phenytoin, carbamazepine, primidone), antibiotics (e.g., dicloxacillin, nafcillin, rifampin), and antipsychotics or sedatives (e.g., haloperidol, trazodone).  WARFARIN COAGULOPATHY The two important principles when warfarin-treated patients bleed with a prolonged INR are as follows: (1) attempt to identify and attenuate the cause of bleeding, and (2) lower the intensity of the anticoagulant effect. In patients with a modestly elevated INR without clinically evident bleeding, cessation of warfarin, careful observation, and periodic monitoring compose the safest course ( Figure 239-1). 2,6,7 Conversely, reversal is recommended when the INR is markedly elevated or there Tintinalli_Sec18_p1461-1522.indd 1504 8/2/19 8:37 PM

ients with a modestly elevated INR without clinically evident bleeding, cessation of warfarin, careful observation, and periodic monitoring compose the safest course ( Figure 239-1). 2,6,7 Conversely, reversal is recommended when the INR is markedly elevated or there Tintinalli_Sec18_p1461-1522.indd 1504 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1505 is clinically significant bleeding. 2,7 The speed and extent of reversal should be balanced against the risk of recurrent thromboembolism in patients who require therapeutic anticoagulation. 8 For example, an overanticoagulated patient with a prosthetic mitral valve may develop fatal thrombosis if supratherapeutic anticoagulation is rapidly and fully reversed. Three approaches used to reverse warfarin-induced coagulopathy are as follows: (1) stop warfarin therapy; (2) administer vitamin K 1 (PO or IV); and (3) replace deficient coagulation factors using either fresh frozen plasma, prothrombin complex concentrate (human), coagulation factor IX complex (human), or coagulation factor VIIa (recombinant) (Figure 239-1).2,9-12 In asymptomatic patients with an elevated INR of 4.5 to 10 due to warfarin, oral vitamin K1 1.0 to 2.0 milligrams will produce a measurable reduction in INR by 16 hours, with a therapeutic level by the second day. 6,7 In asymptomatic patients with an INR >10, oral vitamin K1 2 milligrams is also effective, although the reduction in INR takes longer. Although low-dose oral vitamin K1 carries a small risk for patients who require therapeutic anticoagulation, it is reasonable to consult an appropriate specialist before using vitamin K 1 to reverse anticoagulation in stable patients. IV vitamin K1 carries a rare but serious, non–dose-dependent risk of anaphylaxis and should not be used for routine reversal of therapeutic overanticoagulation.13 For patients who require continued anticoagulation, IV administration also carries the risk of overcorrection not associated with oral use. IV vitamin K 1 should be restricted to patients with life-threatening bleeding2 and to symptomatic patients poisoned by an excessive ingestion of warfarin (e.g., suicidal overdose). Generally, overdose patients do not require long-term therapeutic anticoagulation, and reversal does not carry the risk of recurrent thrombosis. Administration of vitamin K to a warfarin-treated patient should not be considered reversal of anticoagulation. Vitamin K simply restores the patient’s ability to begin again to synthesize factors II, VII, IX and X, and reattaining physiologic levels and normal hemostasis may take hours to days to achieve. The fastest method of reversing therapeutic overanticoagulation is with coagulation factor repletion by IV infusion, using either fresh fro zen plasma, prothrombin complex concentrate (human) (PCC or fourfactor PCC), or coagulation factor IX complex (human) (or three-factor PCC) with or without coagulation factor VIIa (recombinant). 9-12 For patients with intense anticoagulation (INR >10) who require only par tial reversal, fresh frozen plasma 10 to 15 mL/kg would be expected to restore coagulation factors to about 30% of normal, corresponding to an INR of 1.7 to 1.8. Disadvantages of fresh frozen plasma include potential fluid overload, which can be difficult to reverse with furosemide. Some institutions provide “universal donor” fresh frozen plasma, which is derived from AB-Rh+ donors and thus contains no anti-A, anti-B, or anti-Rh antibodies. If available and indicated, it can be given without a type and cross-match of blood from the recipient and as soon as it is defrosted (20 to 30 minutes).

mide. Some institutions provide “universal donor” fresh frozen plasma, which is derived from AB-Rh+ donors and thus contains no anti-A, anti-B, or anti-Rh antibodies. If available and indicated, it can be given without a type and cross-match of blood from the recipient and as soon as it is defrosted (20 to 30 minutes). For patients with life-threatening hemorrhage who require rapid, complete reversal, such as those with warfarin-associated intracranial hemorrhage, give vitamin K 10 milligrams IV and PCC 25 to 50 milligrams/kg IV (Figure 239-1). 8,14,15 If factor IX complex (or threefactor PCC) is used, consider the addition of coagulation factor VIIa (recombinant) to make up for the minimal amount of factor VII in factor IX complex. Additional doses of these products may be required depending on the degree of coagulopathy. PCC reverses the INR within 30 minutes, with the degree of INR reduction depending on the initial INR. The half-life of PCC is about 4 to 6 hours. The onset of action of IV vitamin K is about 2 hours, with maximal effect at 6 to 12 hours, so PCC and IV vitamin K act synergistically in INR reduction. DIRECT THROMBIN INHIBITORS Dabigatran etexilate, an oral direct thrombin inhibitor, is used to reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, and the risk of recurrent deep venous thrombosis or pulmonary embolism after treatment of the acute episode. 1,16-19 After ingestion, dabigatran etexilate is converted to the active agent dabigatran by esterase, achieving peak serum concentrations in 2 hours with a terminal elimination half-life of 14 hours. Dabigatran is a reversible inhibitor of both circulating and clot-bound thrombin. Dabigatran has more predictable pharmacologic activity than warfarin, a broad therapeutic window, low interpatient variability, and no significant drug–drug (except for rifampin) or drug–diet interactions. Monitoring with standard coagulation tests during therapeutic use is not required. In routine use in patients with atrial fibrillation, dabigatran is generally safer than warfarin, with the notable exception of a higher risk of major GI bleeding. As with warfarin, the concomitant use of NSAIDs and other antiplatelet medications greatly increases the risk of bleeding for patients taking dabigatran. Prothrombin time and the activated PTT are insensitive to the activity of dabigatran, whereas the thrombin clotting time is typically overly sensitive.1,20 The ecarin clotting time has a linear dose response through the range of dabigatran concentrations seen during clinical use, but this test is not commonly available. For practical purposes, a normal thrombin time excludes a significant coagulopathy due to dabigatran. If avail able, a diluted thrombin time is even more specific. Only about 15% to 20% of absorbed dabigatran is metabolized, and the remainder is excreted unchanged in the urine. It is therefore important to maintain urinary output in patients with active bleeding while taking dabigatran to enhance drug elimination. Idarucizumab (Praxbind ® ), a monoclonal antibody fragment that binds dabigatran, is U.S. Food and Drug Administration approved when reversal of the anticoagulant effects of dabigatran is needed for life-threatening or uncontrolled bleeding or for emergency surgery or urgent procedures ( Table 239-3). 21,22 The recommended dose of idarucizumab is 5 grams, provided as two separate vials each contain ing 2.5 grams in 50 mL. 22 If bleeding continues, consider a repeat dose of 5 grams.

ects of dabigatran is needed for life-threatening or uncontrolled bleeding or for emergency surgery or urgent procedures ( Table 239-3). 21,22 The recommended dose of idarucizumab is 5 grams, provided as two separate vials each contain ing 2.5 grams in 50 mL. 22 If bleeding continues, consider a repeat dose of 5 grams. If idarucizumab is not available, observational experience suggests that either anti-inhibitor coagulant complex (FEIBA NF or activated PCC) or prothrombin complex concentrate (four-factor PCC) may reverse the anticoagulative effect of dabigatran, 23 whereas fresh frozen plasma does not. 1 If idarucizumab is not available, hemodialy sis can be effective with removal of 60% or more of the drug within 2 hours; however, hemodialysis should be performed only if idaruci zumab is not available. 1,12,21 TABLE 239-3 Reversal of Direct-Acting Oral Anticoagulants (DOACs) Oral Direct Thrombin Inhibitors Dabigatran Oral activated charcoal if recent or excessive ingestion Maintain urine output For severe bleeding or urgent reversal, idarucizumab 5 grams IV infusion or bolus (provided as two separate vials each containing 2.5 grams/50 mL) If idarucizumab not available and life-threatening bleeding is present, consider 50 units/kg IV (maximum dose 5000 units) of either aPCC or four-factor PCC Oral Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Coagulant factor Xa (recombinant), inactivated (aka, andexanet alfa): Approved for major bleeding secondary to rivaroxaban or apixaban Low dose: (1) Last dose of rivaroxaban or apixaban was ≥8 h or (2) last dose was <8 h and rivaroxaban dose ≤10 milligrams or apixaban dose ≤5 milligrams; 400-milligram bolus IV over 30 min, followed by a continuous infusion of 4 milligrams/min for 120 min (total dose, 880 milligrams) High dose: Otherwise, 800-milligram bolus IV over 30 min, followed by a continuous infusion of 8 milligrams/min for 120 min (total dose, 1760 milligrams) The infusion should be started within 2 min of the bolus. Andexanet alfa not approved for use in edoxaban- or betrixabanassociated bleeding If andexanet alfa not available, for major bleeding, consider four-factor PCC 50 units/kg IV (maximum dose 5000 units) Abbreviations: aPCC = anti-inhibitor coagulant complex, FEIBA, or activated prothrombin complex concentrate; four-factor PCC = prothrombin complex concentrate. Tintinalli_Sec18_p1461-1522.indd 1505 8/2/19 8:37 PM

t alfa not available, for major bleeding, consider four-factor PCC 50 units/kg IV (maximum dose 5000 units) Abbreviations: aPCC = anti-inhibitor coagulant complex, FEIBA, or activated prothrombin complex concentrate; four-factor PCC = prothrombin complex concentrate. Tintinalli_Sec18_p1461-1522.indd 1505 8/2/19 8:37 PM 1506 SECTION 18: Hematologic and Oncologic Disorders TABLE 239-4 Oral Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Typical dose 20 milligrams PO once a day 5 milligrams PO twice a day 60 milligrams PO once a day 80 milligrams PO once a day Oral bioavailability Dose dependent: 10-milligram tablets: 80%–100% not affected by food 15- and 20-milligram tablets: about 66% without food and increases to >90% with food Peak serum concentrations 2–4 h Approximately 50%, not affected by food Peak serum concentrations 3–4 h Approximately 62%, not affected by food Peak serum concentrations 1–2 h Approximately 34% Peak serum concentrations 3–4 h Serum protein binding 92%–95% 87% 55% 60% Metabolism Oxidative degradation by hepatic cytochrome P450 isoenzymes CYP3A4, CYP3A5, and CYP2J2 About 25% with O-methylation and hydroxylation by hepatic cytochrome P450, primarily isoenzyme CYP3A4 Minimal, <15% via hydrolysis, conjugation, or oxidation Hydrolysis extensively, minimal CYP450 metabolism Elimination About one third excreted unchanged in the urine, about one third excreted as inactive metabolites in the urine, and one third excreted as inactive metabolites in feces About 30% in urine and 70% in feces 50% in urine and 50% in feces Feces 85%, urine 11% Elimination half-life 5–9 h 12 h 10–14 h 19–27 h Drug concentration ranges with therapeutic doses (5th to 95th percentile), nanograms/mL Peak: 189–419 Trough: 66–87 Peak: 91–321 Trough: 41–230 Peak: 120–250 Trough: 10–40 No published data FACTOR X a INHIBITORS Rivaroxaban, apixaban, and edoxaban are oral direct factor Xa (FXa) inhibitors used for the treatment of venous thromboembolism and for the reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (Table 239-4). 1,24,25 Betrixaban is used for venous thromboembolism prophylaxis.26 These FXa inhibitors have predictable pharmacologic properties and do not require routine laboratory monitoring. The effect of the oral FXa inhibitors on standard coagulation tests is variable and not reliable for determining therapeutic effect or overanticoagulation. The preferred most clinically available test is drug level using the anti–FXa activity assay calibrated for the specific oral FXa inhibitor used. 27 Drug level (anti-FXa activity) can be measured at either peak (3 to 5 hours after ingestion) or trough (1 to 2 hours before next dose). Levels associated with therapeutic doses have been published, but clinical laboratories have not established reference ranges, nor is there a consensus as to which levels denote inadequate anticoagulation or overanticoagulation. The primary purpose of such assays is to determine drug presence prior to invasive procedures or thrombolytic therapy and assess compliance in cases of venous thromboembolism while on therapy. Discontinuation of the drug for at least 24 hours could be sufficient when there is no imminent need for reversal, as in elective or nonurgent procedures. However, in patients with renal impairment and the elderly, additional time for clearance would be required before any surgical procedures are undertaken. There is an increased risk of stroke or other thrombotic event when rivaroxaban is suddenly discontinued in patients with nonvalvular atrial fibrillation. 28 When possible, another anticoagulant should be substituted. Coagulant FXa (recombinant), inactivated (andexanet alfa), is a recombinant modified human FXa decoy protein that is U.S.

ed risk of stroke or other thrombotic event when rivaroxaban is suddenly discontinued in patients with nonvalvular atrial fibrillation. 28 When possible, another anticoagulant should be substituted. Coagulant FXa (recombinant), inactivated (andexanet alfa), is a recombinant modified human FXa decoy protein that is U.S. Food and Drug Administration approved for treatment of life-threatening or uncontrolled bleeding due to rivaroxaban and apixaban. 29 The dose of andexanet alfa is determined by (1) the timing of the last dose and (2) the dose (Table 239-3). The low-dose regimen is used if (1) the last dose was taken ≥8 hours previously or (2) if the last dose was taken within 8 hours and the dose of rivaroxaban was ≤10 milligrams or the dose of apixaban was ≤5 milligrams. Otherwise, the high-dose regimen should be used. Two important potential complications were observed after andexanet alfa administration: thromboembolic events (18% of patients within 30 days of treatment, mostly related to non-reinstitution of therapeutic anticoagulation) and infusion-related reactions (e.g. flush ing, feeling hot, cough, dyspnea, distorted taste, mild hives), which also occurred in 18% of patients. Due to high plasma protein binding, FXa inhibitors are not readily removed by dialysis. If andexanet alpha is not available, other options for the emergency reversal include activated anti-inhibitor coagulant complex (FEIBA NF or activated PCC) or PCC (four-factor PCC). 1,8,24,29 Administration of activated charcoal within 2 hours of taking an oral anticoagulant may adsorb the drug from the intestines before it reaches the plasma. It would be reasonable to administer activated charcoal to a patient who has deliberately or accidentally ingested an inappropriate amount of dabigatran or an FXa inhibitor, and also in a patient with significant bleeding who has recently ingested even a therapeutic dose.  HEPARINS UNFRACTIONATED HEPARIN Unfractionated heparin (UFH) is a heterogeneous mixture of polysaccharides ranging in molecular weight from 3 to 30 kD, with most commercial preparations possessing a mean molecular weight of about 15 kD, corresponding to about 45 saccharide units. 30 The anticoagulant effect of UFH requires binding to antithrombin (previously named antithrombin III), and heparins are therefore “indirect” anticoagulants. 30 Although the UFH– antithrombin complex interferes with several activated factors in both the extrinsic and common coagulation pathways (factors Xa, IXa, XIa, and XIIa, and thrombin), the primary anticoagulant effect of heparin is due to thrombin and FXa inhibition. The majority of heparin’s anticoagulant effect is dependent on a unique pentasaccharide sequence found in only about one third of heparin molecules. Variations in polysaccharide chain lengths found in UFH likely contribute to the unpredictable nature of heparin’s dose–response relationship. UFH is given parenterally with a half-life (30 to 150 minutes) that depends on the dose and route. Weight-based IV UFH dosing protocols are the most reliable approach for achieving a therapeutic effect and preventing further thrombosis during acute thromboembolic events. 29 Subcutaneous UFH is not recommended for the treatment of Tintinalli_Sec18_p1461-1522.indd 1506 8/2/19 8:37 PM

hat depends on the dose and route. Weight-based IV UFH dosing protocols are the most reliable approach for achieving a therapeutic effect and preventing further thrombosis during acute thromboembolic events. 29 Subcutaneous UFH is not recommended for the treatment of Tintinalli_Sec18_p1461-1522.indd 1506 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1507 TABLE 239-5 Advantages of Low-Molecular-Weight Heparin Over Unfractionated Heparin Pharmacologic Effects Clinical Benefit Quick and predictable SC absorption More reliable level of anticoagulation More stable dose response Eliminates need for monitoring Resistance to inhibition by platelet factor 4 Decreased incidence of thrombocytopenia Decreased antiheparin antibody production Greater antithrombotic effects Greater anti-FXa activity Potential for reduced bleeding Less antithrombin activity Absence of “rebound” Ease of administration Outpatient therapy acute thromboembolic disease because the bioavailability via this route of administration ranges from 10% to 90%, depending on the dose. However, subcutaneous UFH can be used to prevent thromboembo lism (Table 239-1). Because UFH interferes with most laboratory investigations for hypercoagulable states, these tests should ideally be ordered before the patient is anticoagulated. Neither UFH nor low-molecular-weight heparin crosses the placenta; consequently, both are safe to use in pregnancy. UFH has an unpredictable anticoagulation effect, requires frequent monitoring, binds nonproductively to vascular endothelium and ubiquitous plasma proteins, and actually activates platelets by interacting with platelet factor 4. The unpredictable inhibition of thrombin by heparin is attributable to a low bioavailability from extensive nonspecific bind ing to serum proteins, macrophages, and endothelial cells. Therapeutic IV UFH therapy is monitored using either anti-Xa activity or the PTT (Table 239-1). 30,31 The therapeutic range for anti-FXa activity is 0.3 to 0.7 IU/mL for venous thromboembolism treatment, 0.3 to 0.6 IU/mL for acute coronary syndrome treatment, and 0.3 to 0.45 IU/mL for anticoagulation in the management of atrial fibrillation. 31 The therapeutic range for an activated PTT is 1.5 to 2.5 times the reference range value, typically 68 to 100 seconds. UFH can increase the prothrombin time by a variable amount, typically 1 to 5 seconds depending on the heparin concentration and the thromboplastin reagent used in the assay. LOW-MOLECULAR-WEIGHT HEPARIN Low-molecular-weight heparins (LMWHs) are polysaccharide chains ranging in molecular weight from 2 to 9 kD, with commercial prepa rations (enoxaparin, dalteparin, and tinzaparin) possessing a mean molecular weight of approximately 4 to 5 kD, corresponding to about 15 saccharide units. LMWH possesses many clinical advantages compared to the parent compound (Table 239-5). 30 Both UFH and LMWH exert their anticoagulant effect by binding to and enhancing the activity of antithrombin. This interaction is mediated by a unique pentasaccharide sequence that induces a conformational change in antithrombin, enhancing binding to and inactivation of thrombin and factors Xa, IXa, XIa, and XIIa. Inhibition of thrombin is facilitated by an additional 13-saccharide group that brings the key binding regions of antithrombin and thrombin into contact. However, only the spe cific pentasaccharide sequence is necessary to bind to antithrombin for effective inhibition of FXa. UFH inhibits FXa and thrombin in roughly equal proportions (anti-FXa to antithrombin activity ratio of about 1) because chains of at least 18 saccharide units predominate.

nd thrombin into contact. However, only the spe cific pentasaccharide sequence is necessary to bind to antithrombin for effective inhibition of FXa. UFH inhibits FXa and thrombin in roughly equal proportions (anti-FXa to antithrombin activity ratio of about 1) because chains of at least 18 saccharide units predominate. In contrast, more than half of LMWH molecules are smaller than 18 saccharide units, resulting in a reduced ability to inactivate thrombin and an enhanced affinity for inactivating FXa (anti-FXa to antithrombin activity ratio between 2:1 and 4:1). LMWH is cleared by the kidneys, so bleeding complications due to accumulation of the agent can occur in patients with significant renal impairment. Appropriate dosing of LMWH in patients with severe renal insufficiency (creatinine clearance <30 mL/min) is unclear. In patients with severe renal insufficiency, it is suggested that either a reduced dose of enoxaparin (50% of the usual amount) be used or UFH be adminis tered instead. 29 Obese patients (body mass index >30) should receive weight-based LMWH dosing.30 The plasma half-life of LMWH is two to four times longer than UFH, allowing for once- or twice-daily dosing. LMWH has a decreased bind ing affinity for plasma proteins, endothelial cells, and macrophages, thus yielding a more predictable anticoagulant and dose–response relationship, allowing for SC administration at fixed dosages. There are greatly reduced interactions with the platelet factor 4 receptor, resulting in a much lower incidence of heparin-induced thrombocytopenia than that seen with UFH. Laboratory monitoring of the activity of LMWH is unnecessary in most patients, 32 but is suggested in high-risk patients (e.g., trauma, burns, critically ill) and those who experience recurrent thromboembolism while on therapy. 33 The gold standard for monitoring LMWH is the chromogenic anti-FXa assay, 33 drawn 3 to 4 hours after SC injection. The therapeutic level of LMWH for venous thromboem bolism prophylaxis is 0.2 to 0.5 IU/mL, 34 and the therapeutic level for venous thromboembolism treatment is 0.5 to 1.1 IU/mL. HEPARIN COMPLICATIONS The two major complications of heparin are bleeding and heparininduced thrombocytopenia. 35-37 Up to one third of patients receiving UFH develop some form of bleeding complication, with a 2% to 6% incidence of major bleeding. 30 An increased risk of up to 20% for major bleeding is associated with concomitant conditions, such as recent surgery or trauma, renal failure, alcoholism, malignancy, liver failure, and GI bleeding, as well as the concurrent use of warfarin, fibrinolytics, steroids, or antiplatelet drugs. Bleeding in patients being treated with UFH is managed according to the clinical severity and less by activated PTT level (Table 239-6). 2,30 Heparin-associated bleeding is not always reflected by a supratherapeutic activated PTT, so if bleeding develops during UFH therapy, heparin administration should be stopped immediately. Although UFH halflife is dose dependent (30 to 150 minutes), its anticoagulation effect can last up to 3 hours. Observation may be appropriate in less severe cases, with serial activated PTT used to determine when therapy may TABLE 239-6 Reversal of Parenteral Antithrombotic Therapy Agent Management Heparins Minor bleeding Immediate cessation of heparin administration Supratherapeutic aPTT not always present Anticoagulation effect lasts up to 3 h from last IV dose. Observation with serial aPTT may be sufficient. Major bleeding Protamine dose: 1 milligram IV per 100 units of total amount of IV UFH administered within the past 3 h, maximum single dose 50 milligrams Protamine administration: IV slowly, maximum rate 5 milligrams/min Protamine has an anaphylaxis risk. Protamine does not completely reverse LMWH.

T may be sufficient. Major bleeding Protamine dose: 1 milligram IV per 100 units of total amount of IV UFH administered within the past 3 h, maximum single dose 50 milligrams Protamine administration: IV slowly, maximum rate 5 milligrams/min Protamine has an anaphylaxis risk. Protamine does not completely reverse LMWH. Enoxaparin: Protamine 1 milligram IV (maximum dose, 50 milligrams) for every 1 milligram of enoxaparin given in the previous 8 h. If 8–12 h since last enoxaparin dose, give protamine 0.5 milligram IV for every 1 milligram of enoxaparin given. Dalteparin and tinzaparin: Protamine 1 milligram IV per every 100 units of dalteparin or tinzaparin given. If aPTT (measured 2–4 h after the protamine infusion) remains prolonged, give a second dose of protamine 0.5 milligram IV per 100 units of dalteparin or tinzaparin. Pentasaccharides Fondaparinux Antithrombotic effect of fondaparinux is 24–30 h. For life-threatening bleeding, anecdotal evidence suggests rFVIIa 90 micrograms/kg IV is effective. Abbreviations: aPTT = activate partial thromboplastin time; LMWH = low-molecular-weight heparin; rFVIIa = coagulation factor VIIa (recombinant); UFH = unfractionated heparin. Tintinalli_Sec18_p1461-1522.indd 1507 8/2/19 8:37 PM

e-threatening bleeding, anecdotal evidence suggests rFVIIa 90 micrograms/kg IV is effective. Abbreviations: aPTT = activate partial thromboplastin time; LMWH = low-molecular-weight heparin; rFVIIa = coagulation factor VIIa (recombinant); UFH = unfractionated heparin. Tintinalli_Sec18_p1461-1522.indd 1507 8/2/19 8:37 PM 1508 SECTION 18: Hematologic and Oncologic Disorders be resumed. Although protamine can reverse the anticoagulant effect of UFH, adverse effects are common and include hypotension, brady cardia, dyspnea, nausea, vomiting, and urticaria. Protamine should be given slowly IV at a maximum rate of 5 milligrams/min. Monitor aPTT starting at 5–15 min after the protamine infusion; the onset of reversal is seen within 5 minutes and the duration of reversal activity is about 2 h. Additional doses may be required if bleeding persists or the aPTT remains elevated. Reversal of subcutaneously administered heparin may require repeated or prolonged protamine administration. Allergic reactions are common, and approximately 0.2% of patients receiving protamine develop anaphylaxis. Thus, protamine should be reserved for major bleeding complications. Platelet count may fall in 10% to 20% of patients 2 to 3 days following initiation of UFH treatment due to nonimmunologic direct platelet aggregation. This process is sometimes termed “heparin-associated thrombocytopenia” and was previously termed “type I heparin-induced thrombocytopenia. ” The platelet nadir is typically no lower than 100,000/mm (100 × 10 9/L), there is no risk for associated thrombosis, and platelet count recovers within 4 days despite continued heparin treatment. Heparin-induced thrombocytopenia (HIT; previously termed “type II heparin-induced thrombocytopenia”) is a syndrome due to the for mation of immunoglobulin G or immunoglobulin M autoantibodies directed against both heparin and platelet factor 4 that activates platelets, producing both thrombocytopenia and a tendency for thrombosis. Thrombosis may involve the skin (similar to warfarin-induced cutane ous necrosis), major arteries (e.g., ischemic limbs), or the veins (e.g., recurrent venous thrombosis or pulmonary embolism). The onset of HIT is usually 5 to 10 days after heparin treatment is started, but may be sooner for patients who developed an antibody from a previous heparin exposure. Although rare, one of the earliest clues is an anaphylactoid reaction within 30 minutes of receiving an IV bolus of heparin, often while the patient is in the ED. Patients who exhibit acute systemic reac tions such as fevers, chills, hypertension, tachycardia, dyspnea, or chest pain should be evaluated for HIT by immediately obtaining a platelet count. Because a decrease in platelet count may be transient under these circumstances, the diagnosis can be missed if there is a delay in obtain ing the platelet count. The incidence of HIT is variable and influenced by the specific heparin preparation used, dose, duration, and patient characteristics. In general, between 1% and 3% of postoperative patients treated with UFH for 4 to 14 days will develop HIT, compared with only 0.1% to 1.0% of medical or obstetric patients who receive UFH for a similar duration. HIT is approximately 10 times less frequent in patients treated with LMWH products. With HIT, the platelet count nadir is variable, typically 20,000 to 150,000/mm 3 (20 to 150 × 10 9/L). Dur ing treatment with UFH, it is recommended that a baseline platelet count be obtained and the count be repeated at 24 hours and every 2 to 3 days thereafter during the duration of therapy. A drop of 50% or more from baseline is considered evidence of HIT, even if the platelet count is within a normal range.

10 9/L). Dur ing treatment with UFH, it is recommended that a baseline platelet count be obtained and the count be repeated at 24 hours and every 2 to 3 days thereafter during the duration of therapy. A drop of 50% or more from baseline is considered evidence of HIT, even if the platelet count is within a normal range. It is recommended to assess for recent use of UFH or LMWH before instituting heparin therapy for a new venous thrombosis that may, in fact, be a thrombotic com plication of HIT. A scoring system (4Ts score) has been developed to assist in the diagnosis of HIT, 38 scoring the severity of thrombocytopenia; the timing of platelet count fall; the presence of new thrombosis, skin necrosis, or systemic reaction after IV heparin bolus; and the lack of other causes for thrombocytopenia. With HIT, all heparin therapy (including “heparin lock” IVs and heparin-coated catheters) should be stopped. Protamine is not effective against the immune-mediated response. Platelet transfusion is not indicated because bleeding is not usually a manifestation of HIT and may precipitate thrombosis. The platelet count generally returns to normal in 4 to 6 days after heparin discontinuation. During the recovery phase, the risk of arterial or venous thrombosis is substantially elevated, and the potential complications include gangrene, stroke, and myocardial infarction. LMWH is not recommended to prevent thrombosis during this recovery period because of cross-reactivity between LMWH and the antiplatelet antibody. Additionally, warfarin should not be started until the platelet count has normalized and the patient is sufficiently anticoagulated by an alternative measure to avoid precipitating arterial or venous thrombosis or producing skin necrosis. Anticoagulation with a non-heparin anticoagulant, such as danaparoid, lepirudin, fondaparinux, or bivalirudin, is recommended for strongly suspected or confirmed cases of HIT, even in the absence of symptomatic thrombosis. 35,36,39 In general, LMWH preparations cause less bleeding than UFH. Other reported side effects of LMWH include local skin reaction, pruritus, and rarely skin necrosis. Protamine will neutralize the inhibitory effect of LMWH on thrombin but not the inhibitory effect on FXa. Thus, prot amine will not completely reverse the anticoagulant effect of LMWH (Table 239-6).  FONDAPARINUX AND HIRUDINS FONDAPARINUX Fondaparinux is a synthetic pentasaccharide that binds to antithrombin and enhances its affinity for FXa, but not thrombin. It is not considered a heparin product and does not cause HIT. It is used in venous thromboembolism prophylaxis and treatment, and is typically recommended as one alternative antithrombotic that can be used in patients with a history of HIT. 17,30,40 Fondaparinux is administered by SC injection using fixed doses stratified according to the indication and body weight (Table 239-1). The drug has a terminal half-life of about 17 hours, which allows for once-daily dosing. Laboratory monitoring of the activity of fondaparinux is unnecessary in most patients. If required, adequacy of anticoagulation is measured using anti–FXa activity assay obtained 4 hours after drug administration, with a therapeutic range for venous thromboembolism treatment of 0.8 to 1.2 IU/mL. For fondaparinux-associated bleeding, limited data suggest that coagulation factor VIIa (recombinant) and anti-inhibitor coagulant complex (activated PCC) can reverse the coagulopathy. 23,41,42 HIRUDINS Hirudins (hirudin and lepirudin) and hirudin analogs (bivalirudin and argatroban) are polypeptides and parenteral direct thrombin inhibitors, possessing several potential advantages over heparin.

ctor VIIa (recombinant) and anti-inhibitor coagulant complex (activated PCC) can reverse the coagulopathy. 23,41,42 HIRUDINS Hirudins (hirudin and lepirudin) and hirudin analogs (bivalirudin and argatroban) are polypeptides and parenteral direct thrombin inhibitors, possessing several potential advantages over heparin. 17,30 Unlike heparin, direct thrombin inhibitors are capable of inhibiting both circulating and clot-bound thrombin, do not inhibit other coagulation pathway or fibrinolytic enzymes, do not require antithrombin as a cofactor for activity, and do not interact with platelet factor 4 or plasma proteins. Therefore, direct thrombin inhibitors have a more predictable anticoagulant effect than UFH. Hirudin, lepirudin, and argatroban are used for anticoagulation in patients with heparin-induced thrombocytopenia. 35,36 Bivalirudin and argatroban are potential alternatives to UFH and LMWH for the treatment of acute coronary syndrome with percutaneous coronary intervention. 43,44 The primary adverse effect of direct thrombin inhibitors is bleeding, and the majority of bleeding events occur at invasive sites. Because the half-life of hirudin and its analogs is relatively short (<1 hour) and an antidote is not currently available, management of hemorrhage may require only stopping the IV infusion and waiting. Coagulation factor replacement with fresh frozen plasma or PCC can be used if bleeding persists.  ANTIPLATELET AGENTS ASPIRIN Aspirin irreversibly blocks cyclooxygenase, an enzyme that in platelets catalyzes the conversion of arachidonic acid to thromboxane A 2 and in the blood vessel wall promotes prostacyclin synthesis ( Table 239-7).45,46 The net effect of aspirin in ischemic arterial beds depends on the balance between reduction in thromboxane A 2 (a vasoconstrictor and plateletaggregation inducer) and reduction in prostacyclin (a vasodilator and platelet-aggregation inhibitor). Aspirin’s antithrombotic effect can be seen with doses as low as 30 milligrams, but for reliable antiplatelet effect, an initial dose of 162 to 325 milligrams is recommended (Table 239-1). Tintinalli_Sec18_p1461-1522.indd 1508 8/2/19 8:37 PM

reduction in prostacyclin (a vasodilator and platelet-aggregation inhibitor). Aspirin’s antithrombotic effect can be seen with doses as low as 30 milligrams, but for reliable antiplatelet effect, an initial dose of 162 to 325 milligrams is recommended (Table 239-1). Tintinalli_Sec18_p1461-1522.indd 1508 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1509 TABLE 239-8 Reversal of Oral Antiplatelet Agents Aspirin and NSAIDs Desmopressin 0.3–0.4 microgram/kg IV over 30 min Platelet transfusion to increase count by 50,000/mm 3 (typically requires one single donor apheresis-collected platelet concen trate or 6 units of random donor platelets) Aspirin-induced platelet inhibition may last for 7 d, so repeat platelet transfusions are sometimes required. Other antiplatelet agents: clopidogrel, prasugrel, ticagrelor Platelet transfusion to increase count by 50,000/mm 3 (typically requires one single donor apheresis-collected platelet concen trate or 6 units of random donor platelets) Desmopressin 0.3–0.4 microgram/kg IV over 30 min NSAID-induced platelet inhibition typically lasts <1 d. Clopidogrel-, prasugrel-, or ticagrelor-induced platelet inhibition may last up to 5–7 d. TABLE 239-7 Oral Antiplatelet Agents Class/Mechanism of Action Type of Inhibition Time to Peak Effect Elimination Half-Life Duration of Antiplatelet Effect Typical Dose Aspirin Nonselective cyclooxygenase inhibitor Irreversible 30 min 15–30 min Up to 7 d 325 milligrams PO initial dose for ACS Maintenance doses 81–162 milligrams PO once per day Clopidogrel ADP receptor inhibitor Prodrug; requires production of active metabolite Irreversible 3–7 d 8 h Up to 10 d 300 milligrams PO loading dose (consider 600 milligrams if PCI is planned) followed by 75 milligrams PO once per day Prasugrel ADP receptor inhibitor Prodrug; requires production of active metabolite Irreversible 30 min 7 h 5–7 d 60 milligrams PO loading dose, followed by 10 milligrams (5 milligrams if <60 kg) PO once per day Ticagrelor ADP receptor inhibitor Reversible 1.5 h 7 h 3–4 d 180 milligrams PO loading dose, followed by 90 milligrams PO twice per day Dipyridamole Multiple: reduces platelet aggregation, vasodilator, weak phosphodiesterase inhibitor Reversible N/A Biphasic: 40 min and 10 h 1–2 d 200 milligrams extended-release PO twice per day (usually combined with low-dose aspirin) Cilostazol Phosphodiesterase inhibitor: reduces platelet aggregation, vasodilator Reversible N/A 11–13 h 3–4 d 100 milligrams PO twice per day Abbreviations: ACS = acute coronary syndrome; ADP = adenosine diphosphate; N/A = not applicable; PCI = percutaneous coronary intervention. Aspirin is quickly absorbed in the upper GI tract (unless consumed in an enteric-coated formulation), reaches peak blood concentrations in 20 to 40 minutes, and circulates with a half-life of 3 to 4 hours. However, cyclooxygenase inactivation is irreversible and lasts for the life span of the platelet. Only non–enteric-coated aspirin should be administered when prompt onset of action is necessary, as in patients with acute coronary syndrome. 46-48 Side effects of aspirin use are mainly GI and are dose related. The side effects may be reduced in the maintenance therapy setting with con comitant use of antacids, enteric coating, and buffering agents. Aspirin should be avoided in patients with known hypersensitivity and used cautiously in those with bleeding disorders or severe hepatic disease. Active GI hemorrhage (e.g., bleeding peptic ulcer) is a contraindication to aspirin use. However, in acute coronary syndrome with occult GI bleeding (e.g., guaiac-positive stool), most experts favor aspirin use with careful monitoring. Daily aspirin therapy is advocated in the prevention of cardiovascular events in patients with known cardiovascular disease.

tic ulcer) is a contraindication to aspirin use. However, in acute coronary syndrome with occult GI bleeding (e.g., guaiac-positive stool), most experts favor aspirin use with careful monitoring. Daily aspirin therapy is advocated in the prevention of cardiovascular events in patients with known cardiovascular disease. The benefits in patients without cardiovascular disease (termed primary prevention) are modest and almost offset by the risk of hemorrhagic stroke and major bleeding. 48-50 In general, daily aspirin therapy does reduce recurrence of myocardial infarction, ischemic stroke, and sudden cardiovascular death (termed secondary prevention), with an increased risk of major bleeding events, primarily GI, and cerebral hemorrhage. The overall effect tends to be beneficial, although the magnitude of change with individual outcomes does vary with indication and between genders. NSAIDs reversibly inhibit platelet cyclooxygenase and have the potential to reduce the antiplatelet efficacy of aspirin. Myocardial infarction patients have an increased risk of mortality, reinfarction, heart failure, and shock if taking NSAIDs within 7 days of presentation 51 and up to 90 days after the acute event. 52 Current acute coronary syndrome guidelines contain cautions about the use of NSAIDs.52-55 Upper GI irritation is the most common side effect of aspirin therapy.46 Some patients are markedly sensitive to aspirin, such that even low doses lead to markedly prolonged bleeding times and risk of severe clinical hemorrhage, particularly related to surgery or trauma. Uremia and the combination of ethanol and aspirin are two circumstances where patients are especially sensitive to bleeding induced by aspirin. Management of acute aspirin-induced or NSAID-induced hemor rhage involves the transfusion of enough normal platelets to increase the platelet count by 50,000/mm 3 (50 × 10 9/L), a level that will halt most bleeding (Table 239-8). While desmopressin can reverse the effect of aspirin on platelet function, 23 it is not a safe option as it can lead to arterial vasospasm. Because of the irreversible effect of aspirin on platelets, the hemostatic compromise might last for up to 7 days after aspirin has been discontinued, and platelet transfusions may have to be repeated daily. ADENOSINE DIPHOSPHATE RECEPTOR AGENTS (CLOPIDOGREL, PRASUGREL, TICAGRELOR, TICLOPIDINE) Clopidogrel, prasugrel, ticagrelor, and ticlopidine inhibit platelet activation by blocking the adenosine diphosphate receptor. 45,56 These agents are also termed “membrane-deforming” agents because by inhibiting the adenosine diphosphate receptor, the adjacent region of the platelet membrane containing the fibrinogen receptor is deformed and the fibrinogen receptor is rendered ineffective. Clopidogrel is a prodrug that is metabolized into an irreversible adenosine diphosphate receptor inhibitor. Rapidly absorbed from the GI tract, oral doses of 600 milligrams result in a full antiplatelet effect by 2 hours that is sustained for up to 48 hours. Platelet function typically returns to normal 7 days after the last clopidogrel dose. Clopidogrel is used for the treatment of acute coronary syndrome 55,56 and established peripheral arterial disease,57 as well as for secondary prevention of myocardial infarction58 and ischemic stroke.59 Although clopidogrel is generally well tolerated, adverse effects include dyspepsia, rash, and diarrhea. Clopidogrel can also be used in patients who have a history of aspirin hypersensitivity or major GI intolerance. Tintinalli_Sec18_p1461-1522.indd 1509 8/2/19 8:37 PM

of myocardial infarction58 and ischemic stroke.59 Although clopidogrel is generally well tolerated, adverse effects include dyspepsia, rash, and diarrhea. Clopidogrel can also be used in patients who have a history of aspirin hypersensitivity or major GI intolerance. Tintinalli_Sec18_p1461-1522.indd 1509 8/2/19 8:37 PM 1510 SECTION 18: Hematologic and Oncologic Disorders TABLE 239-9 Glycoprotein IIb/IIIa IV Antagonists Type Mechanism of Action Half-Life Duration of Antiplatelet Effect Loading Dose Continuous Infusion Abciximab Monoclonal antibody fragment Noncompetitive inhibition 10 min 24–48 h 0.25 milligram/kg IV bolus 0.125 microgram/kg per min (maximum, 10 micrograms/min) IV Eptifibatide Cyclic heptapeptide Competitive inhibition 2.5 h 3–5 h 180 micrograms/kg IV bolus over 1–2 min (maximum, 22.6 milligrams) 2 micrograms/kg per min (maximum, 250 micrograms/min) IV CrCl <50 mL/min: 1 microgram/kg per min (maximum, 7.5 milligrams/h) Tirofiban Nonpeptide Competitive inhibition 2 h 3–5 h 25 micrograms/kg per min IV for 30 min 0.15 microgram/kg per min CrCl ≤60 mL/min: 0.075 microgram/kg per min for up to 18 h Abbreviation: CrCl = creatinine clearance. The active metabolite is produced by the cytochrome P450 system, principally isoenzyme 2C19 (CYP2C19). Patients with a diminished CYP2C19 metabolizer status have a lessened antiplatelet response to clopidogrel. The reported frequency for poor CYP2C19 metabolizer status varies by ethnic background: approximately 2% for whites, 4% for blacks, and 14% for Chinese. A patient’s CYP2C19 metabolizer status can be determined with genotype testing, and a higher dose regimen (600-milligram loading dose followed by 150 milligrams once daily) is suggested in poor metabolizers, although this dose regimen has not been validated in clinical outcome trials. 60 Omeprazole and esomeprazole are inhibitors of CYP2C19 and reduce the antiplatelet activity of clopidogrel if given within 12 hours of each other. While the effect on clinical outcome from this interaction is variable according to the patient’s risk for cardiovascular events, it is prudent instead to give pantoprazole in the ED to patients receiving clopidogrel for acute coronary syndrome. Prasugrel, like clopidogrel, is a prodrug that is converted to the active metabolite that is an irreversible inhibitor of the adenosine diphosphate receptor on platelets. 55 Prasugrel is used in the treatment of acute coro nary syndrome.57 Compared to clopidogrel, prasugrel has an increased risk of bleeding and is less effective in patients with a history of a stroke or transient ischemic attack, patients >75 years of age, and patients with a body weight of <60 kg. Ticagrelor is a reversible adenosine diphosphate receptor antagonist that does not need to be converted by the liver into an active metabolite. Ticagrelor is used in a broad range of acute coronary syndrome patients. 55,62 Compared with clopidogrel, ticagrelor reduces the subsequent deaths from all cardiovascular causes or myocardial infarction.63 There is a modest increase in the risk of major bleeding not related to coronary artery bypass graft surgery with ticagrelor and a trend toward more intracranial bleeding. Ticlopidine is associated with significant risk for hematologic prob lems, such as neutropenia and thrombotic thrombocytopenic purpura. Therefore, ticlopidine is now rarely used in the United States. Antiplatelet therapy is a risk factor for increased intracranial bleeding and worse outcome in closed head injury. 63 The observed risk is highest with clopidogrel.63 Uncontrolled bleeding in patients on adenosine diphosphate receptor antagonist therapy should be treated with supportive therapy, and possibly platelet transfusions or desmopressin. (Table 239-8).

ncreased intracranial bleeding and worse outcome in closed head injury. 63 The observed risk is highest with clopidogrel.63 Uncontrolled bleeding in patients on adenosine diphosphate receptor antagonist therapy should be treated with supportive therapy, and possibly platelet transfusions or desmopressin. (Table 239-8). PHOSPHODIESTERASE INHIBITORS (DIPYRIDAMOLE) Dipyridamole is both a vasodilator and antiplatelet agent. 46,64 The specific antiplatelet effects are multiple and include reversible phosphodiesterase inhibition. Clinical efficacy of dipyridamole appears to be enhanced by formation into an extended-release preparation. 65 Current recommendations highlight the use of dipyridamole when combined with aspirin for the secondary prevention of stroke or transient ischemic attacks. 59,64 A fixed combination of aspirin, 25 milligrams, and extendedrelease dipyridamole, 200 milligrams PO twice a day, is commonly used for this indication. Dipyridamole is occasionally used in the standard formulation (not extended release) for angina prophylaxis and the prevention of prosthetic cardiac valve thrombosis when combined with warfarin or aspirin where doses of 50 to 100 milligrams PO three or four times a day are typical. Common adverse side effects include headache, dizziness, flushing, and abdominal pain. Cilostazol is a strong reversible phosphodiesterase inhibitor in addi tion to having other effects on platelet metabolism. 65 Cilostazol is used to increase walking distance in patients with peripheral arterial disease66 and reduce the incidence of stroke in patients with cerebrovascular disease.59 GLYCOPROTEIN IIB/IIIA ANTAGONISTS (ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN) During platelet aggregation, fibrinogen binds to the glycoprotein platelet-surface IIb/IIIa receptor. Thus, fibrinogen attached to glycoprotein IIb/IIIa receptors connecting adjacent platelets represents the final common pathway for platelet aggregation. Three parenteral glycoprotein IIb/IIIa receptor inhibitors are currently available ( Table 239-9) for use in primary coronary angioplasty. 67 These agents are all administered as an initial IV loading dose (bolus for abciximab and eptifibatide and 30-minute infusion for tirofiban) followed by a continuous IV infusion. Abciximab is a noncompetitive glycoprotein IIb/IIIa inhibitor with a much longer platelet effect than its plasma half-life of 10 minutes; platelet function will take up to 48 hours to return to normal after discontinuing the infusion. Conversely, eptifibatide and tirofiban are competitive glycoprotein IIb/IIIa inhibitors, with a plasma half-life of approximately 2.5 and 2.0 hours, respectively, and functional platelet recovery is usually seen 3 to 5 hours after stopping either eptifibatide or tirofiban infusion. Glycoprotein IIb/IIIa inhibitors produce the greatest benefit in acute coronary syndrome patients undergoing percutaneous coronary inter vention. 68,69 Delaying initiation of eptifibatide to the time of percutane ous coronary intervention results in less bleeding with otherwise similar outcomes, suggesting that the preferred time for administration of glycoprotein IIb/IIIa inhibitors is in the cardiac catheterization laboratory, not in the ED. Patients receiving glycoprotein IIb/IIIa inhibitors have an increased risk for bleeding complications (often related to catheterization or coronary artery bypass surgery) but have no increased risk of intracranial hemorrhage. Treatment of major hemorrhage in patients on glycopro tein IIb/IIIa inhibitors requires red cell and platelet transfusions and replacement of coagulation factors as needed.  FIBRINOLYTICS Although mechanisms vary, each fibrinolytic agent enhances the con version of plasminogen to plasmin, which then enzymatically breaks apart the fibrin component of thrombi.

on glycopro tein IIb/IIIa inhibitors requires red cell and platelet transfusions and replacement of coagulation factors as needed.  FIBRINOLYTICS Although mechanisms vary, each fibrinolytic agent enhances the con version of plasminogen to plasmin, which then enzymatically breaks apart the fibrin component of thrombi. Currently approved fibrinolytic agents include streptokinase, anistreplase, alteplase, reteplase, and tenecteplase. 70-72 Tintinalli_Sec18_p1461-1522.indd 1510 8/2/19 8:37 PM

on glycopro tein IIb/IIIa inhibitors requires red cell and platelet transfusions and replacement of coagulation factors as needed.  FIBRINOLYTICS Although mechanisms vary, each fibrinolytic agent enhances the con version of plasminogen to plasmin, which then enzymatically breaks apart the fibrin component of thrombi. Currently approved fibrinolytic agents include streptokinase, anistreplase, alteplase, reteplase, and tenecteplase. 70-72 Tintinalli_Sec18_p1461-1522.indd 1510 8/2/19 8:37 PM CHAPTER 239: Thrombotics and Antithrombotics 1511 TABLE 239-10 General Contraindications to Fibrinolytic Therapy Absolute •   Active or recent (<14 d) internal bleeding •   Ischemic stroke within the past 2–6 mo •   Any prior hemorrhagic stroke •   Intracranial or intraspinal surgery or trauma within the past 2 mo •   Intracranial or intraspinal neoplasm, aneurysm, or arteriovenous malformation •   Known severe bleeding diathesis •   Current anticoagulant treatment (e.g., warfarin with INR >1.7 or heparin with increased activated PTT) •   Current use of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests •   Platelet count <100,000/mm3 (<100 × 109/L) •   Uncontrolled hypertension (i.e., blood pressure >185/110 mm Hg) •   Suspected aortic dissection or pericarditis •   Pregnancy Relative* •   Active peptic ulcer disease •   Cardiopulmonary resuscitation for longer than 10 min •   Hemorrhagic ophthalmic conditions •   Puncture of noncompressible vessel within the past 10 d •   Significant trauma or major surgery within the past 2 wk to 2 mo •   Advanced renal or hepatic disease *Concurrent menses is not a contraindication. STREPTOKINASE AND ANISTREPLASE (FIRST GENERATION) Streptokinase, derived from β-hemolytic streptococci, binds to and activates circulating plasminogen, converting it to plasmin, which in turn attacks fibrin. Circulating fibrinogen also undergoes plasmin-induced lysis, producing a state of “systemic fibrinolysis. ” Streptokinase is administered as a slow infusion (usually 1.0 to 1.5 million units IV over 60 minutes) and has a serum half-life of approximately 23 minutes, but in most patients, the fibrinolytic effect persists for up to 24 hours. Because of the prolonged systemic fibrinolytic state and increased risk of hemorrhage, anticoagulation with heparin is usually delayed following treatment with streptokinase. Anistreplase, a modified active plasminogen-streptokinase complex, has an effect similar to that of streptokinase, but its chief advantage is that it can be administered as a slow bolus (usually 30 units IV over 5 minutes) and has a serum half-life of approximately 90 minutes. Anistreplase has similar benefits and adverse effects compared to streptokinase. Both streptokinase and anistreplase are antigenic, with allergic reac tions occurring in approximately 6% of patients treated with streptoki nase. Antibodies to streptokinase develop approximately 5 days after treatment and persist for 6 months, so re-treatment with streptokinase or anistreplase is not advised during this interval. In addition, strepto kinase or anistreplase should not be administered within 12 months of a streptococcal infection. ALTEPLASE, OR TISSUE PLASMINOGEN ACTIVATOR (SECOND GENERATION) Alteplase, or tissue plasminogen activator, is a naturally occurring enzyme in vascular endothelial cells that directly cleaves a specific pep tide bond in plasminogen, converting it to active plasmin. Alteplase has binding sites for fibrin, which would suggest specificity for activity in the thrombus and less systemic fibrinolysis. 72 Despite the in vitro clot specificity of alteplase, its clinical side effect profile is comparable to that of other fibrinolytics. The serum half-life of alteplase is <5 minutes, and it produces a shorter fibrinolytic state than streptokinase. Heparin is commonly administered shortly after the completion of alteplase infusion.

the in vitro clot specificity of alteplase, its clinical side effect profile is comparable to that of other fibrinolytics. The serum half-life of alteplase is <5 minutes, and it produces a shorter fibrinolytic state than streptokinase. Heparin is commonly administered shortly after the completion of alteplase infusion. 54,72 Unlike streptokinase and anistreplase, alteplase is not antigenic; allergic reactions occur in <2% of patients treated with alteplase and IV heparin. Depending on the indication, alteplase is given as a weight-based dose via an IV infusion over 60 to 90 minutes. RETEPLASE AND TENECTEPLASE (THIRD GENERATION) Both reteplase and tenecteplase are derived from modifications of the parent alteplase molecule, with the intent of improving both efficacy and safety. 72 Reteplase is a deletion mutant in which the fibronectin finger (highaffinity fibrin binding), epidermal growth factor, and kringle-1 (receptor binding) regions of the wild-type alteplase molecule have been deleted. These modifications prolong the half-life of reteplase to 13-16 minutes, nearly fourfold longer than alteplase, allowing for bolus administration of reteplase as opposed to infusion administration of alteplase. 55,71,72 Tenecteplase is created using amino acid substitutions in four different regions of the alteplase molecule, with the intention of producing a product with a longer half-life, higher level of fibrin specificity, and extended duration. 72 The long half-life of tenecteplase (20-24 minutes) allows for weight-tiered bolus dosing. The specific amino acid substitutions produce a 14-fold greater fibrin specificity than alteplase and reduced systemic plasmin generation. Tenecteplase has a plasminogen activator inhibitor 1 resistance 80 times greater than alteplase, thus allowing for a longer association of tenecteplase with the fibrin-rich clot. In addition, tenecteplase does not stimulate an increase in thrombin-antithrombin complexes, in contrast to a fourfold increase following administration of streptokinase and a twofold increase after administration of alteplase, with the potential for reduced bleeding complications with tenecteplase. Despite theoretical advantages associated with genetic modification, neither reteplase nor tenecteplase demonstrates an absolute mortality or safety benefit in the treatment of ST-segment elevation myocardial infarction. Although bolus-dose fibrinolytics result in fewer medication errors, when compared with more complicated regimens, this has not translated into improved patient outcomes. 73,74 Tenecteplase is not FDA approved for acute ischemic stroke, but is used in other countries and the 2018 American Heart Association—American Stroke Association (AHA-ASA) Guidelines for the Early Management of Patients with Acute Ischemic Stroke contained a level IIb recom mendation that tenecteplase might be considered as an alternative to alteplase. 75 Meta-analysis of five randomized controlled trials comparing tenecteplase to alteplase found equivalent rates of functional outcomes, mortality, and symptomatic intracranial hemorrhage. 76 A tenecteplase dose of 0.25 milligrams/kg was recommended based on benefits without the increased risk for intracranial hemorrhage seen with higher doses. CONTRAINDICATIONS TO FIBRINOLYTIC THERAPY All available fibrinolytic agents have systemic antithrombotic effects and possess the potential for serious hemorrhage. Fibrinolytic-induced bleeding can be minor (such as oozing at IV sites), major (defined as hemodynamic compromise or significant drop in hemoglobin), or catastrophic (intra cranial hemorrhage). The prevalence with which bleeding occurs varies according to the condition being treated.

e potential for serious hemorrhage. Fibrinolytic-induced bleeding can be minor (such as oozing at IV sites), major (defined as hemodynamic compromise or significant drop in hemoglobin), or catastrophic (intra cranial hemorrhage). The prevalence with which bleeding occurs varies according to the condition being treated. For example, intracranial hemorrhage typically occurs in <1% of patients treated with fibrinolytics for acute myocardial infarction 54 but is seen in approximately 6% of patients treated with alteplase for acute ischemic stroke.77 Also, the risk of hemorrhage is increased according to patient characteristics and the use of concomitant drugs that also vary according to the condition under treatment. 77 General contraindications to fibrinolytic therapy are designed to reduce the risk of major and catastrophic bleeding (Table 239-10). COMPLICATIONS OF FIBRINOLYTIC THERAPY The most significant complications of fibrinolytic therapy are hemor rhagic, and the most catastrophic complication is intracranial hemor rhage. Allergic reactions such as urticaria and angioedema are seen in 1% to 5% of patients treated with alteplase. Treatment includes stopping the infusion, evaluating the airway to determine the need for intubation, and administering antihistamine (e.g., diphenhydr amine 50 milligrams IV) and corticosteroids (e.g., methylpredniso lone 125 milligrams IV). Hypotension occurs in up to 10% of patients Tintinalli_Sec18_p1461-1522.indd 1511 8/2/19 8:37 PM

stopping the infusion, evaluating the airway to determine the need for intubation, and administering antihistamine (e.g., diphenhydr amine 50 milligrams IV) and corticosteroids (e.g., methylpredniso lone 125 milligrams IV). Hypotension occurs in up to 10% of patients Tintinalli_Sec18_p1461-1522.indd 1511 8/2/19 8:37 PM 1512 SECTION 18: Hematologic and Oncologic Disorders treated with either streptokinase or alteplase and is treated by slowing the fibrinolytic infusion rate and administering IV crystalloid, paying close attention to the patient’s volume status. To minimize the bleeding risks associated with fibrinolytic therapy, the following precautions should be observed: (1) avoid all unnecessary needle sticks; (2) avoid any arterial punctures; (3) limit venous access to easily compressible sites (e.g., avoid central venous lines, especially the jugular or subclavian veins); and (4) avoid both nasogastric tubes and nasotracheal intubation. Careful monitoring of the patient is crucial. The hemoglobin level should be checked every 4 to 6 hours after fibrinolytic therapy is initiated. A fall in hemoglobin >1 to 2 grams/dL (0.6 to 1.2 mmol/L) should prompt a search for the source of blood loss. Most bleeding episodes (>70%) occur at vascular puncture sites, but intracranial, intrathoracic, retroperitoneal, GI, urologic, or soft tissue extremity hemorrhage may occur. External bleeding at any site should be controlled with prolonged manual pressure ( Table 239-11). Significant bleeding, especially from an internal site, mandates discontinuation of the fibrinolytic agent along with any antiplatelet agents and heparin. Volume replacement should be provided as necessary and supplemented with red blood cell transfusions if clinically indicated. The thrombin clotting time, activated PTT, platelet count, and fibrinogen level should be checked. Heparin administered within 4 hours of the onset of bleeding can be reversed with protamine. Massive bleeding with hemodynamic compromise necessitates empiric coagulation factor replacement with fibrinogen concentrate (human) and/or fresh frozen plasma. If bleeding persists after appropriate fibrinogen and fresh frozen plasma replacement, an antifibrinolytic agent (e.g., aminocaproic acid or tranexamic acid) with or without platelets should still be administered. Fibrinolytic-associated intracra nial hemorrhage requires an aggressive response with protamine (if the patient received heparin), fibrinogen concentrate (human), fresh frozen plasma, platelet transfusion, and an antifibrinolytic agent.  ANTIFIBRINOLYTIC AGENTS Two hemostatic agents are used clinically to inhibit the enzymatic deg radation of fibrin by plasmin: tranexamic acid and aminocaproic acid (Table 239-12). Both agents are derivatives of the amino acid lysine, have low molecular weight, can be administered both orally and IV , attach to several sites on plasminogen, prevent plasminogen from binding to fibrin, are minimally metabolized, and are primarily excreted by the kidney, but tranexamic acid has roughly eight times the antifibrinolytic activity of aminocaproic acid. INDICATIONS These agents are used in hemorrhagic states to stop excessive bleeding and reduce perioperative blood transfusion requirements (Table 239-13). 78-99 TABLE 239-12 Antifibrinolytic Agents Agent Suggested Initial Adult IV Dose for Emergent Indications * Excretion Elimination Half-Life Tranexamic acid (TXA) 10 milligrams/kg IV over 10 min (maximum, 1 gram); repeat doses every 6–8 h 95% by kidney 3 h Aminocaproic acid (ACA) 4–5 grams IV over 1 h, then 1 gram/h for 8 h or until bleeding stops (maximum, 30 grams/d) 65% by kidney 2 h *Doses vary between indications and route; consult prescribing information for specifics.

XA) 10 milligrams/kg IV over 10 min (maximum, 1 gram); repeat doses every 6–8 h 95% by kidney 3 h Aminocaproic acid (ACA) 4–5 grams IV over 1 h, then 1 gram/h for 8 h or until bleeding stops (maximum, 30 grams/d) 65% by kidney 2 h *Doses vary between indications and route; consult prescribing information for specifics. TABLE 239-11 Reversal of Fibrinolytic-Induced Bleeding Minor external bleeding Manual pressure Significant internal bleeding Immediate cessation of fibrinolytic agent, antiplatelet agent, and/or heparin Reversal of heparin with protamine, as discussed earlier Typed and cross-matched blood ordered with verification of activated PTT, CBC, thrombin clotting time, and fibrinogen level Volume replacement with crystalloid and packed red blood cells as needed Major bleeding or hemodynamic compromise All measures listed for significant internal bleeding Fibrinogen concentrate 70 milligrams/kg IV, and recheck fibrinogen level; if fibrinogen level <100 milligrams/dL, repeat fibrinogen concentrate dose. If bleeding persists after fibrinogen concentrate or despite fibrinogen level >100 milligrams/dL, administer FFP 2 units IV. If bleeding continues after FFP, administer an antifibrinolytic such as aminocaproic acid 5 grams IV over 60 min followed by 1 gram/h continuous IV infu sion for 8 h or until bleeding stops, or tranexamic acid 10 milligrams/kg IV every 6–8 h. Consider platelet transfusion. Intracranial hemorrhage All measures listed for significant internal and major bleeding with hemodynamic compromise Immediate neurosurgery consultation Abbreviation: FFP = fresh frozen plasma TABLE 239-13 Emergent Conditions Where Antifibrinolytic Agents Have Been Used Condition Comment* Adult trauma with significant hemorrhage (BP <90 mm Hg or HR >110 beats/min) or considered at risk for significant hemorrhage TXA IV reduces death from bleeding and all-cause mortality if administered prehospital or within 3 h. 81-85 Postpartum hemorrhage TXA IV may prevent and treat exces sive postpartum hemorrhage after vaginal and cesarean delivery. 87-89 Hemoptysis TXA IV or PO may reduce the duration and volume of bleeding. 90,91 Upper GI bleeding TXA IV may reduce mortality and rebleeding rate; there is no effect on transfusion requirement. Aneurysmal subarachnoid hemorrhage No proven benefit93 Traumatic intracranial hematoma TXA decreased hematoma growth rate and total hemorrhage, but there was no change in mortality or neurologic outcome. GI and nasal bleeding due to hereditary hemorrhagic telangiectasia ACA PO may reduce bleeding and transfusion requirements. 95,96 Dental bleeding in hemophilia FDA-approved indication for TXA PO Prevent bleeding in hemophilia patients during surgery TXA and ACA reduce bleeding and transfusion requirements. Traumatic hyphema FDA-approved indication for TXA PO; both TXA and ACA prevent secondary hemorrhage. Epistaxis Topical or PO TXA reduces rate of rebleeding. 98,99 Heavy menstrual bleeding FDA-approved indication for TXA PO; TXA available without prescription in Europe for menstrual bleeding. When fibrinolysis contributes to bleeding FDA-approved indication for ACA IV Abbreviation: ACA = aminocaproic acid; BP = blood pressure; FDA = U.S. Food and Drug Administration; HR = heart rate; TXA = tranexamic acid. *Not an FDA-approved indication unless otherwise noted. Tintinalli_Sec18_p1461-1522.indd 1512 8/2/19 8:37 PM