Agent Dose MoA/PK/Admin Adverse events Disadvantages Protamine Heparin: 1mg neutralizes ~ 100 units Heparin neutralization in ~ 5 min

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1 Nanik (Nayri) Hatsakorzian Pharm.D/MPH candidate 2014 Touro University College of Pharmacy CA Bleeding Reversal Agents Agent Dose MoA/PK/Admin Adverse events Disadvantages Protamine Heparin: 1mg neutralizes ~ 100 units Heparin neutralization in ~ 5 min - Strongly combines with heparin to form salt - If pt is on heparin infusion (1250 units/hr) only consider protamine for the past hours è ~30mg Lovenox: 1mg protamine for 1mg; if >8 hours elapsed then 0.5mg protamine for every 1 mg of lovenox - Slow IVP: 5mg/min; max= 50mg/10min - T 1/2= ~7 min - IV infusion can cause hypotension BBW Hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. Risk factors with high doses or overdose, repeated doses, previous protamine administration (including protamine- containing drugs), fish allergy, vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics. - Lovenox reversal with protamine is not predictable or complete as with heparin (~60-75%) - Excessive protamine (>100mg) might worsen bleeding by acting as anticoagulant NovoSeven (Factor rviia) ICH (d/t warfarin) unlabeled: mcg/kg concurrently with Vitamin K Hemophilia A or B: 90 mcg/kg Q 2 hours until hemostasis or judged ineffective Possible reversal agent for Apixaban, rivaroxaban (RPH letters) - Promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. It replaces deficient activated coagulation factor VII, which complexes with tissue factor and may activate coagulation factor X to Xa and factor IX to IXa. When complexed with other factors, coagulation factor Xa converts prothrombin to thrombin. - T 1/2= ~2 hours BBW serious thrombotic events - Hypertension, bradycardia, edema, hypotension - Thrombotic events more common in doses >80mcg/kg - High thromboembolic events with higher doses - Monitor INR, rebound increase in INR is quick - Duration of INR correction is dose dependent - Not recommended as sole agent for warfarin FEIBA (Anti- Inhibitor Coagulant Complex) Life threatening hemorrhage d/t dabigatran: 26 units/kg General dosing: units/kg Max 200 units/kg/day - IV only; bolus over 2-5 min - Vial concentration 1mg/ml - Activated Prothrombin Complex Concentrate - Peak onset min - Duration: 8-12 hours - T 1/2= 4-7 hours - Max infusion rate 2 units/kg/min BBW thromboembolic events - SE: arterial/venous thrombosis, embolic/thrombotic stroke, flushing, hypo/hypertension, HA, fever, angioedema - Caution with hepatic impairments - Monitor for Disseminated Intravascular Coagulation (DIC), and/or coronary ischemia when dose >100unit/kg per dose or >200 units/kg/day Possible reversal for rivaroxaban and apixaban also

2 Cyklokapron (Tranexamic Acid) Aminocaproic acid IV: 1000 mg over 10 min followed by 1000 mg over 8 hours Also used for hereditary angioedema Available in oral tablets as well IV: 5 grams over 1 hour followed by infusion of 1gram/hr - Max= 30 grams - Max = 24 grams if bleeding is d/t thrombocytopenia - Reversible complex that displaces plasminogen from fibrin è fibrinolysis inhibitor - Peak onset: - T 1/2= 2-11 hours - Max infusion rate is 100mg/min - Loading dose diluted in ml bag and infused over 5-30 min - Binds competitively to plasminogen; blocking the binding of plasminogen to fibrin è no plasmin conversion è fibrin degradation (fibrinolysis) - IVP is not recommended due to hypotension, bradycardia, arrhythmias - Infusion is 5g in 250ml (20mg/ml conc) - Seizures, hypersensitivity reaction, thrombotic events, visual changes - Monitor: ophthalmic screening at baseline and regular intervals esp in long term therapy patients - SE: seizures, stroke, HA, malaise, leukopenia, thrombocytopenia, fatigue, dizziness, hallucination, BUN and CPK increase, dyspnea, PE - Caution with renal impairment; dose reduction might be necessary - Close monitoring with psychotropics - May accumulate in renal impairment è reduce loading dose and use infusion rate 5mg/kg/hr Fresh Frozen Plasma - One unit contains ~ 200 units of factor VIII, and mg of fibrinogen. It contains factor IX as well as other stable and labile coagulation factors. One unit will raise patient's plasma level of fibrinogen about mg/dl; cryoprecipitate is a better source of fibrinogen. - Does not contain RBC, or platelets - Each unit ~ up to 500ml - Infuse FFP ~10 ml/minute, to a total dose of about 10 ml/kg - Anaphylaxis in IgA deficient patients - Contains antigens è fever, allergic rxn - May cause fluid overload - Severe deficiency of coagulation factors cannot be corrected with FFP - Not to be used as plasma expander - Possible transmission of infectious diseases Cryoprecipitate - Possible reversal agent for warfarin induced bleeding - Contains factor VIII, von Willebrand factor, fibrinogen, factor XIII, and fibronectin - 6 units = ~ ml - One bag provides at least 150 ml of fibrinogen - Possible SE: Febrile, allergic reactions - Once thawed cannot be refrozen - Poor source of factors II, V, IX, X, and XI - Only concentrated available source of fibrinogen for patients with clinical deficiencies

3 Kcentra (Prothrombin Complex Concentrate) - Administer with Vitamin K concurrently Pretreatment INR: 2 to <4: Administer 25 units/kg (maximum dose: 2500 units) Pretreatment INR: 4-6: Administer 35 units/kg (maximum dose: 3500 units) Pretreatment INR: >6: Administer 50 units/kg (maximum dose: 5000 units) - Kcentra 500 units Composition per vial: Factor II: units Factor VII: units Factor IX: units Factor X: units Protein C: units Protein S: units - Management of Intracerebral Hemorrhage (ICH) d/t Warfarin: The 2010 AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults state that prothrombin complex concentrates (PCC) may be considered as an alternative to FFP to replace vitamin K- dependent factors. PCCs are better tolerated due to the lower fluid volume compared to FFP. MoA: Prothrombin complex concentrate provides an increase in the levels of the vitamin K- dependent coagulation factors (II, VII, IX, and X) with the addition of protein C and protein S. Coagulation factors II, IX, and X are part of the intrinsic coagulation pathway, while factor VII is part of the extrinsic coagulation pathway. In the extrinsic pathway, damaged blood vessels release endothelial tissue factor (TF) which complexes with factor VII to form TF- factor VIIa. Within the intrinsic pathway, factor IX is converted to IXa. Factor IXa (as well as TF- factor VIIa) converts factor X to factor Xa in the final common pathway of coagulation. Factor Xa activates prothrombin (factor II) into thrombin (IIa) which converts fibrinogen into fibrin resulting in clot formation. Proteins C and S are vitamin K- dependent inhibiting enzymes involved in regulating the coagulation process. Protein S serves as a cofactor for protein C which is converted to activated protein C (APC). APC is a serine protease which inactivates factors Va and VIIIa, limiting thrombotic formation. - Administration rate: 0.12 ml/kg/min (~3 units/kg/minute) - Do not exceed: 8.4 ml/min (~210 units/minute) - Reconstituted product may be store and used within 4 hours of recon - INR decline within 10 min (vs. IV vitamin K 1-2hours, and peak 12-14hours) - Duration 6-8 hours BBW: Because patients being treated with vitamin K antagonist (VKA) therapy have an underlying risk of or a diagnosed thromboembolic disease state, administration of prothrombin complex concentrate (PCC) may predispose the patient to a thromboembolic complication. Benefits of reversing VKA therapy should be weighed against the potential risk of a thromboembolic event. Resumption of anticoagulation should occur once the risk of thromboembolism outweighs the risk of acute bleeding. SE: Hypersensitivity to any of the components (angioedema, bronchospasm, dyspnea, flushing, hypotension, nausea/vomiting, pulmonary edema, urticaria, tachycardia, tachypnea), DIC, hypovolemia, hypokalemia, HA, intracranial hemorrhage, mental status changes - Contains Heparin è HIT - Not to be confused with ProfilNine which contains non or low therapeutic levels of factor VII - Pregnancy cat: C due to possible infectious viruses in the product - Monitor INR - Not compatible with any other infusions

4 Profilnine SD Factor IX Complex (Human) [(Factors II, IX, X)] Warfarin reversal: INR <5: 30 units/kg INR >5: 50 units/kg MoA: Replaces deficient clotting factor including factor X - IV only, slow infusion - Rate: 10ml/min - Do not refrigerate after recon and use within 3 hours Antibody formation: development of factor IX antibodies has been reported with factor IX therapy (within exposure days) Hypersensitivity reactions: including anaphylaxis. Delayed reactions (up to 20 days after infusion) may also occur. - Caution with hepatic impairments - Contains heparin - Product packaging contains latex - Contains low or nontherapeutic levels of factor VII component - Monitor: levels of factor IX; PT, PTT; INR, signs and symptoms of hypersensitivity reactions, DIC, thrombosis Thrombotic events: Observe closely for signs or symptoms of DIC or thrombosis. - Slowing the rate of infusion, changing the lot of medication, or administering antihistamines may relieve some adverse reactions DIC Disseminated intravascular coagulation - Introduction: DIC is a systemic process producing both thrombosis and hemorrhage. DIC occurs in ~ 1 percent of hospital admissions. It is initiated by a number of defined disorders and consists of the following components: Exposure of blood to procoagulants such as tissue factor and cancer procoagulant Formation of fibrin within the circulation Fibrinolysis Depletion of clotting factors End- organ damage - Two types of DIC: Acute and chronic - Acute DIC: develops when blood is exposed to large amounts of tissue factor over a brief period of time, with massive generation of thrombin, resulting in the acute triggering of coagulation. The clinical consequence is a profound systemic bleeding and, due to widespread intravascular fibrin deposition, tissue ischemic injury, and hemolytic anemia. Along to bleeding, pt also presents with thromboembolism and dysfunction of the kidney, liver, lungs, and central nervous system. In one series of 118 patients with acute DIC, the main clinical manifestations included the following [3]: Bleeding (64 percent) Renal dysfunction (25 percent) Hepatic dysfunction (19 percent) Respiratory dysfunction (16 percent) Shock (14 percent) Thromboembolism (7 percent) Central nervous system involvement (2 percent) Acute DIC associated with a high mortality rate (40-80%) especially with severe sepsis or trauma.

5 Acute renal failure Acute renal failure occurs in 25 to 40 percent of patients. Two major mechanisms are involved: - - Microthrombosis of afferent arterioles may produce ischemia or necrosis, and hypotension and/or sepsis can lead to acute tubular necrosis. Endotoxin- induced endothelial injury may predispose to intrarenal thrombus formation by directly promoting platelet aggregation, by diminishing the release of nitric oxide Hepatic dysfunction Jaundice is common and may be due both to liver disease and increased bilirubin production secondary to hemolysis. In addition, hepatocellular injury may be produced by sepsis and hypotension Treatment: Platelet transfusion and fresh frozen plasma Patients with DIC bleed because of thrombocytopenia and coagulation factor deficiencies. Heparin there are no controlled trials indicating benefit and there is little evidence that the use of heparin improves organ dysfunction. Additional arguments against the routine use of heparin include potential aggravation of bleeding and the likelihood that it will have reduced effect due to the low levels of AT Reference: UpToDate. features- diagnosis- and- treatment- of- disseminated- intravascular- coagulation- in- adults?source=search_result&search=disseminated+intravascular+coagulation&selectedtitle=1~150#h26