9.pdf

Anticoagulation 6. 7. 8. 9. Prothrombin complex concentrate (PCC) a. Clotting factor proteins are taken from a plasma sample. b. About 25-fold more concentrated in clotting factors than FFP c. Types (what each contains) i. 3-factor: Clotting factors II, IX, and X ii. 4-factor: Clotting factors...

Anticoagulation 6. 7. 8. 9. Prothrombin complex concentrate (PCC) a. Clotting factor proteins are taken from a plasma sample. b. About 25-fold more concentrated in clotting factors than FFP c. Types (what each contains) i. 3-factor: Clotting factors II, IX, and X ii. 4-factor: Clotting factors II, IX, X, and VII (4PCC) iii. aPCC: II, IX, X, and VIIa iv. All contain varying concentrations of protein C, protein S, and UFH. d. Undergoes viral inactivation, reduces adverse effects, and does not require type-and-crossing Cryoprecipitate a. Derived by thawing 1 unit of FFP in the cold (cryoprecipitate) (4°C) and then collecting the precipitated globulins, which are then resuspended in 20–40 mL of plasma b. Contains concentrations of factor VIII, XIII, von Willebrand factor, fibronectin, and fibrinogen c. May be used for bleeding from fibrinolytics to provide more fibrinogen to the patient. May be part of a massive transfusion protocol d. Dosing of cryoprecipitate can be calculated using the following formula: To increase serum fibrinogen 1 g/dL, administer cryoprecipitate 0.2 units × weight (in kg). e. Takes 10–20 minutes to thaw f. Fibrinogen concentrate (human) is also available (RiaSTAP). Recombinant activated factor VII a. Not technically a blood product because made through recombinant technology b. Has been used to treat bleeding in patients receiving UFH, LMWH, and DOACs. Most trials are small and observational. c. Risk of thrombosis by administering an activated clotting factor d. Standard dose is 90 mcg/kg, but lower doses (e.g., 18–30 mcg/kg) have been documented to be effective and are significantly less expensive. Massive transfusion protocols a. Indications – When to activate the protocol: i. 30%–40% blood volume loss with hypotension ii. 10 units of PRBCs in 24 hours iii. Transfuse entire blood volume in 24 hours iv. 50% blood volume replacement in 3 hours v. 3 or more units of PRBCs in 1 hour or 4 units of PRBCs in 4 hours, knowing the need to administer more b. Components – Typically, 1:1:1 of PRBCs, platelets, and FFP by volume i. Provides an Hct of 29% ii. Provides a Plt of 88,000/mm3 iii. Provides clotting factor activity of 62% of normal iv. May need to provide periodic units of cryoprecipitate c. Issues to monitor i. Dilution-induced thrombocytopenia ii. Citrate-induced hypocalcemia iii. Hyperkalemia iv. Acidosis ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-173 Anticoagulation B. UFH (inhibits thrombin and some factor Xa) 1. Protamine is an effective and rapid antidote for reversal of UFH. a. Basic protein derived from fish sperm that binds to heparin to form a stable salt b. Used to manage significant bleeding, reversal before surgery, or reversal of UFH administered during surgery (e.g., coronary artery bypass graft surgery) c. Dosing: 1 mg of protamine neutralizes approximately 100 units of heparin received in the past 2–2½ hours (maximum dose 50 mg), depending on the half-life of intravenous heparin of 60–90 minutes d. aPTT can be used to assess the effectiveness of UFH neutralization and need to redose protamine. e. Adverse effects i. Hypotension, bradycardia ii. Minimized by administering over slow intravenous infusion instead of intravenous push iii. Patients previously receiving protamine sulfate–containing insulin (i.e., NPH [neutral protein Hagedorn]) having undergone a vasectomy or having a known sensitivity to fish are at increased risk of having protamine antibodies and more likely to have allergic reactions. iv. If risk of allergic reaction is of concern, corticosteroids and/or antihistamines can be administered before protamine. 2. Blood products may be needed in patients with significant bleeding. C. LMWH (inhibits factor Xa and thrombin) 1. No specific antidote is available for LMWH. 2. Protamine a. Reverses about 50%–60% of the anticoagulant activity of LMWH b. Dosing i. 1 mg of protamine neutralizes about 100 anti-Xa units of LMWH (dalteparin). ii. 1 mg of protamine neutralizes about 1 mg of enoxaparin (1 mg enoxaparin = 100 anti-Xa units). iii. If the LMWH dose was administered less than 8 hours before need for reversal, the following dose should be administered: 1 mg of protamine per 100 anti-Xa units (maximum dose 50 mg). May administer additional 0.5 mg of protamine per 100 anti-Xa units, if needed. One-half the initial dose can be repeated, if needed. iv. If the LMWH dose was administered more than 8 hours before need for reversal, administer 0.5 mg of protamine for every 100 anti-Xa units. 3. Recombinant factor VIIa as evaluated in small observational studies has been found effective and may be considered for significant bleeding when protamine fails. D. Warfarin (VKA) 1. Vitamin K (phytonadione or vitamin K1) – Reverses the anticoagulant effect of warfarin. Because the anticoagulant effect of warfarin is mainly because of the inhibition of vitamin K epoxide reductase, exogenous vitamin K can continue to be reduced and produce functional carboxylated clotting factors II, VII, IX, and X. a. Vitamin K reversal onset is delayed because several new clotting factors must be created to neutralize the effect of warfarin therapy. i. Oral vitamin K can take 24–48 hours to normalize the INR. This is the preferred route for managing INRs above the therapeutic range that are not associated with bleeding (Figure 1) or when reversal is needed before a planned surgical procedure. ii. Intravenous vitamin K can take 8–12 hours to normalize the INR, with full effects not seen until 24 hours. Should be administered as slow infusion over 20 minutes instead of intravenous “push” because of the risk of anaphylactoid allergic reactions ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-174 Anticoagulation 2. iii. S  ubcutaneous or intramuscular injection of vitamin K should be avoided because of delayed and erratic absorption in administering a fat-soluble vitamin into subcutaneous fat tissue and because of the risk of the patient developing a hematoma from intramuscular injection. b. Vitamin K helps reverse high INRs (see Figure 1) or helps when reversal is needed before planned surgical procedures. c. Of importance, vitamin K should not be overdosed because this can lead to overaggressive reversal and difficulty in reinitiating warfarin therapy (warfarin resistance). FFP vs. 4PCC – Historically, FFP has commonly been used for reversal of warfarin therapy in patients needing urgent surgery or when bleeding. However, more recent clinical data have shown that 4PCC provides much faster INR reversal than FFP. a. Similar concepts are described in the overview of 4PCCs as a reversal agent earlier in this section. b. A study of patients with acute major bleeding receiving warfarin (n=202) compared FFP (INR 3.6) with 4PCC (INR 3.9). i. Patients receiving 4PCC had their INR reversed to baseline within 30 minutes; FFP took about 8 hours to achieve the same INR. ii. Patients receiving FFP had more fluid overload because of the volume administered than did patients receiving 4PCC (5.8% vs. 12.8%). The treatment volume was more than 8 times greater with FFP than with 4PCC (813.5 vs. 99.4 mL). iii. More posttreatment thrombotic events occurred with 4PCC than with FFP (8.7% vs. 5.5%). c. Dosing (using actual body weight) – Only one 4PCC is available in the United States. i. INR 2 to less than 4: 25 units/kg with maximum dose of 2500 units ii. INR 4–6: 35 units/kg with maximum dose of 3500 units iii. INR greater than 6: 50 units/kg with maximum dose of 5000 units iv. Patients with an INR greater than 1.4 but less than 2.0 with cerebral bleeding may still receive 4PCC at a lower dose of 12.5–25 units/kg, but this approach was not part of the prospective study. v. Fixed doses of 4PCC (1000–1500 units) have also been investigated for major non-intracranial and intracranial hemorrhage, but data are limited to retrospective and observational studies. d. American College of Chest Physicians guidelines recommend a 4PCC over FFP for the rapid reversal of warfarin therapy. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-175 Anticoagulation Evidence of major or life-threatening bleeding during warfarin treatment?a YES NO Administer vitamin K 5–10 mg by slow IV infusion, together with 4PCC as needed. Check INR in 12 hr, and repeat vitamin K infusion as needed until INR is normalized or within therapeutic range Above therapeutic range but < 4.5 4.5–10.0 What is the INR value? > 10.0 Hold warfarin. May consider low-dose oral vitamin K (2.5–5 mg) Check INR daily. Reinitiate warfarin at reduced maintenance dose Hold doses of warfarin AND Administer vitamin K 2.5–5 mg orally. Check INR in 12–24 hr. If INR still > 9, repeat administration of vitamin K. Check INR daily. Restart warfarin at reduced maintenance dose once therapeutic INR achieved Hold dose(s) of warfarin. Recheck INR in 3–7 days. Consider reinitiating warfarin at reduced maintenance dose Figure 1. Management of bleeding and/or elevated INRs with warfarin therapy. Bleeding at a critical site (e.g., intracranial hemorrhage, CNS hemorrhage, pericardial tamponade, intra-abdominal bleeding, retroperitoneal hemorrhage), hemodynamic instability, and/or clinically overt bleeding with an Hgb decrease of ≥ 2 g/dL or administration of ≥ 2 units of RBCs. 4PCC = 4-factor prothrombin complex concentrate; IV = intravenous(ly). a E. Other Oral Anticoagulants 1. For direct thrombin and Xa inhibitors, reversal before most procedures is not necessary as long as the drug is held for the appropriate number of days (Table 27 shows preoperative DOAC management). 2. Vitamin K and protamine are not effective. FFP cannot provide enough clotting factor replacement. 3. aPCC at doses of 50 units/kg (maximum dose 4000 units) can normalize the aPTT, ecarin clotting time, and diluted thrombin time within 30 minutes. 4. Activated charcoal may be used for a known recent (within 2–4 hours) ingestion. urgent surgery ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-176 Anticoagulation Table 27. Preoperative DOAC Management Drug Preprocedural Holding Time Dabigatran: Low/moderatea bleed risk procedures: CrCl ≥ 50 mL/min CrCl < 50 mL/min Highb bleed risk procedures: CrCl ≥ 50 mL/min CrCl < 50 mL/min Apixaban, rivaroxaban, and edoxaban: Low/moderatea bleed risk procedures Highb bleed risk procedures 1 day 2 days 2 days 4 days 1 day 2 days Low/moderate bleed risk procedures include arthroscopy, foot/hand surgery, coronary angiography, GI endoscopy/colonoscopy, and abdominal hernia repair. b High-bleed risk procedures include cancer surgery, major orthopedic surgery, genitourinary surgery, and cardiac intracranial or spinal surgery. DOAC = direct oral anticoagulant. a 5. Direct Thrombin Inhibitor (dabigatran) a. Although recombinant factor VIIa and aPCC may be used for reversal of dabigatran, these agents have shown mixed results. Guidelines recommend administration of PCC or aPCC if idarucizumab is not available. b. Idarucizumab – A specific antidote for direct thrombin inhibitor (e.g., dabigatran) i. Fully humanized antibody Fab portion with a 350-fold affinity for dabigatran compared with thrombin. Can take dabigatran out of circulation and the patient off thrombin to render it inactive ii. Administered at a total dose of 5 g intravenously iii. R E-VERSE-AD trial (n=503) evaluated patients receiving dabigatran with uncontrolled bleeding (group A; n=301) or requiring urgent surgery (group B; n=202) receiving 5 g of idarucizumab. (a) Primary outcome of the trial was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of administering idarucizumab. Reversal was 100% in both groups for both assays. Full reversal occurred within 15 minutes and remained for 12–24 hours. (b) Group A most common sites of bleeding were GI (46%), intracranial hemorrhage (33%), and trauma (26%). Cessation of bleeding in patients without intracranial hemorrhage was a median of 2½ hours, with 68% having cessation within 24 hours. (c) Group B most common types of surgery were abdominal or infection (24%), fracture or septic arthritis (20%), and cardiovascular (18%). Periprocedural hemostasis was assessed by the investigators as normal in 93% of patients, mildly abnormal in 5%, and moderately abnormal in 2%, with no reports of severely abnormal hemostasis. (d) Thrombotic events occurred in 4.8% of patients within 30 days and 6.8% of patients within 90 days, most likely because patients were not reinitiated on anticoagulant therapy in a timely fashion. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-177 Anticoagulation 6.  actor Xa Inhibitors (apixaban, rivaroxaban, edoxaban) F a. Vitamin K and protamine are not effective. FFP cannot provide enough clotting factor replacement. b. aPCC at doses of 25–50 units/kg can normalize the PT within 30 minutes. Data are limited to animal models and spiked blood samples. c. PCC: Has been used for reversal of a direct Xa inhibitor. Doses are typically 50 units/kg. Another option, with limited data, is to use a fixed dose of 2000 units as evaluated for warfarin reversal. i. One prospective study (n=66) showed a 24-hour hemostatic efficacy of 85%. These patients were, on average, 18 hours from their last dose of factor Xa inhibitor. Anti-Xa function was not assessed in these patients. ii. A nother prospective study (n=77) showed a 24-hour hemostatic efficacy of 69%. Although the average time from the last dose was 12 hours, anti-Xa function was not assessed. iii. Small trials and limited participants have been evaluated, providing limited data to determine the thrombotic potential with this reversal strategy. Administration of supratherapeutic concentrations of clotting factors in patients who already require anticoagulant therapy suggests a risk exists. d. Andexanet alfa – Specific antidote for factor Xa inhibitors i. Decoy factor Xa protein with high affinity for Xa inhibitors (also LMWH and fondaparinux) (a) Change in serine to alanine prevents catalytic activity and prevents the ability to convert prothrombin to thrombin. (b) GLA (carboxylation/γ-carboxyglutamic) domain is also removed. This prevents the ability to bind to a phospholipid membrane (platelets) and incorporation of the decoy protein into the prothrombinase complex. ii. Within minutes of the bolus, Xa concentrations return to baseline, where they remain throughout the rest of the infusion. Although anti-Xa activity returns to placebo concentrations within 2 hours once the infusion is discontinued, thrombin generation is maintained. iii. ANNEXA-4 (n=352) evaluated patients receiving a factor Xa inhibitor with an acute major bleed who received a bolus, followed by a 2-hour infusion of andexanet. Andexanet reversed the anti-Xa activity of apixaban and rivaroxaban by 92% and provided hemostatic efficacy of 82% within 12 hours. (a) The thrombotic event rate at the end of the ANNEXA-4 trial was 10% at 30 days. (b) Only 2% of patients receiving any anticoagulant developed a thrombotic event, and no patient receiving oral anticoagulation developed a thrombotic event. iv. Low-dose andexanet is a 400-mg intravenous bolus, followed by 4 mg/minute for 2 hours. This dose is indicated for patients with (1) the last dose of apixaban of 5 mg or less or 10 mg or less of rivaroxaban dose administered less than 8 hours earlier or timing unknown or (2) the last dose of apixaban or rivaroxaban administered 8 hours or more earlier. v. High-dose andexanet is an 800-mg intravenous bolus, followed by 8 mg/minute for 2 hours. This dose is indicated for patients with (1) the last dose of apixaban greater than 5 mg or rivaroxaban greater than 10 mg taken less than 8 hours earlier or timing unknown or (2) an unknown dose of apixaban or rivaroxaban taken less than 8 hours earlier. e. Not currently indicated for reversal of edoxaban, enoxaparin, or fondaparinux. In addition, only indicated for life-threatening bleeding and not for patients requiring urgent surgery ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-178