Fig. 8.1
Carolinas Medical Center warfarin reversal protocol
Newer direct oral anticoagulant agents including dabigatran (direct thrombin inhibitor), rivaroxaban (factor Xa inhibitor), apixaban (factor Xa inhibitor), and edoxaban (factor Xa inhibitor) are now being used in the older population. These drugs have advantages over warfarin in that they do not require laboratory monitoring, and they have significantly fewer drug interactions and no dietary interactions. All of these agents have been shown to be equal or superior to warfarin in stroke prevention, result in lower incidence of intracranial hemorrhage, and are all options for stroke prevention in atrial fibrillation [54]. In addition, all agents have been shown to be equal to warfarin in the therapy of venous thrombosis and the anti-Xa inhibitors to be safer than warfarin [55].
Reversal of these novel agents has been extremely difficult, but newer reversal agents show great promise. For example, 4-PCC does provide some reversal of factor Xa inhibitors. In a small study of healthy patients by Eerenberg of healthy subjects, 4-PCC completely reversed the effect of rivaroxaban on prothrombin time and endogenous thrombin potential [56]. Unfortunately, 4-PCC had no effect on the direct thrombin inhibitor dabigatran. Idarucizumab was recently approved by the FDA. This monoclonal antibody fragment binds to dabigatran with an affinity 350 times greater than thrombin. In an interim analysis of a larger randomized trial, idarucizumab normalized the dilute thrombin time and the ecarin clotting time (ECT) within minutes in 88–98 % of patients [57]. Frustratingly, the average time for cessation of bleeding was still 11.5 h. Andexanet alfa is a human factor Xa decoy protein that binds factor Xa inhibitors. A bolus of andexanet alfa effectively reduced anti-factor Xa activity in more than 90 % of volunteers treated with either apixaban or rivaroxaban [58]. An example of a rapid reversal protocol for non-vitamin K antagonists is shown in Table 8.1.
Table 8.1
OHSU anticoagulation reversal protocol
Definition of bleeding | |
Minor bleeding: any clinically overt sign of hemorrhage (including imaging) that is associated with a <5 g/dL decrease in the hemoglobin concentration or <15 % decrease in the hematocrit felt by the clinician to be related to anticoagulation | |
Major bleeding: intracranial hemorrhage or a ≥5 g/dL decrease in the hemoglobin concentration or ≥15 % absolute decrease in the hematocrit resulting in hemodynamic compromise or compression of a vital structure and felt by the clinician to be related to anticoagulation | |
Antiplatelet agents | |
Aspirin | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major – platelet transfusion | |
Clopidogrel (Plavix®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major – platelet transfusion, consider 2 units if life- or brain-threatening bleeding | |
Prasugrel (Effient®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major – platelet transfusion, consider 2 units if life- or brain-threatening bleeding | |
Ticagrelor (Brilinta®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major – platelet transfusion, consider 2 units if life- or brain-threatening bleeding | |
Sustained-release aspirin/dipyridamole (Aggrenox®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major – platelet transfusion | |
Abciximab (ReoPro®) | |
Major – platelet transfusion | |
Eptifibatide (Integrilin®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major bleeding reversal – platelet transfusions plus infusion of 10 units of cryoprecipitate | |
Tirofiban (Aggrastat®) | |
Minor – desmopressin 0.3 mcg/kg × 1 | |
Major bleeding reversal – platelet transfusions plus infusion of 10 units of cryoprecipitate | |
Heparin and heparin-like agents | |
Standard heparin | |
Time since the last heparin dose | Dose of protamine |
<30 min | 1 unit/100 units of heparin |
30–60 min | 0.5–0.75 units/100 units of heparin |
60–120 min | 0.375–0.5 units/100 units of heparin |
>120 min | 0.25–0.375 units/100 units of heparin |
Infusion rate should not exceed 5 mg/min. Maximum dose is 50 mg per dose | |
Low molecular weight heparin | |
Reversal of bleeding – protamine works just as well with LMWH as heparin. If within 4 h of dose, 1 mg of protamine for each 1 mg of enoxaparin or 100 units of dalteparin and tinzaparin. Repeat one-half dose of protamine in 4 h. If 4–8 h after dose, give 0.5 mg for each 1 mg of enoxaparin or 100 units of dalteparin and tinzaparin | |
Fondaparinux (Arixtra®) | |
Major bleeding reversal – protamine ineffective; rFVIIa (90 mcg/kg) may be of use | |
Dabigatran (Pradaxa®) | |
Reverse if patient shows signs of life-threatening bleeding and had an elevated aPTT | |
1. Idarucizumab 5 g; administer as two boluses of 2.5 g | |
Rivaroxaban (Xarelto®) | |
Reverse if patient shows signs of life-threatening bleeding and has an INR >1.5 | |
1. Profilnine (factor IX complex) 4000 units (50 units/kg for patients under 80 kg) plus 1 mg of rFVIIa | |
Apixaban (Eliquis®) | |
Reverse if patient shows signs of life-threatening bleeding | |
1. Profilnine (factor IX complex) 4000 units (50 units/kg for patients under 80 kg) plus 1 mg of rFVIIa | |
Edoxaban (Savaysa®) | |
Reverse if patient shows signs of life-threatening bleeding | |
1. Profilnine (factor IX complex) 4000 units (50 units/kg for patients under 80 kg) plus 1 mg of rFVIIa | |
Thrombolytic therapy | |
Reversal – immediate infusions of equivalent of 6–8 units of platelets (or one platelet pheresis product), 2 units of plasma, and 10 units of cryoprecipitate. No value in infusing antifibrinolytic agents | |
Conclusion
Considering the complexity of the hematologic system, its function is very well preserved during the aging process, but the trauma physician must be aware of the changes that impact older patients. An older patient will likely present with a lower baseline hemoglobin. It will be more difficult for the patient to recover from any hemorrhage secondary to the bone marrow and hematopoietic stem cell changes that are part of normal aging. After the initial injury, the older patient will return to a slightly hypercoagulable state, which is important to consider in the course of recovery. Finally, with the prescribing practices in the USA, the older patient may be taking certain medications that affect the hematologic system and may negatively impact post-injury recovery.
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