Emergency Reversal of Anticoagulation
The risk of bleeding varies with the type of anticoagulant agent used. The incidence of bleeding while on warfarin has been estimated at 15-20% per year
The risk of bleeding varies with the type of anticoagulant agent used. The incidence of bleeding while on warfarin has been estimated at 15-20% per year, with life-threatening bleeding occurring.
At a rate of 1-3% per year. Providers should remember that all patients with emergent or life-threatening bleeding require attention to basic interventions, including cessation of anticoagulation therapy, blood product transfusions, and assessment for airway protection.
Hemostasis occurs as part of a tightly regulated balance between clot formation and clot breakdown. Primary hemostasis depends on platelet count and platelet function. Medications such as aspirin, nonsteroidal anti inflammatory drugs, and others can inhibit platelet aggregation For varying durations. Secondary hemostasis is tested by measuring the prothrombin time (PT) and The partial thromboplastin time (PTT).
Despite the complexity of the coagulation cascade, a basic familiarity with five coagulation factors (ii, vii, viii, ix, x) can explain almost all of the clinically relevant aspects of coagulation, anticoagulation and its reversal.
The aPTT is a measure of the contact activation (intrinsic) coagulation pathway; aPTT becomes prolonged in patients on heparin. PT and INR represent the changes to the TF (extrinsic) and common pathways. INR is prolonged with the use of warfarin. PT can also be prolonged with the use of rivaroxaban (xarelto), An anti-Xa agent.
For these agents that primarily act on factor X, including the direct anti Xa agents, lmwh and fondaparinux, anti-Xa activity levels can be measured. Thrombin clotting time directly assesses factor II activity by reflecting the conversion of fibrinogen to fibrin, while ect assays test for factor ii generation and has a strong linear correlation with the plasma concentrations of dabigatran.
Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are functional tests of coagulation that measure the interaction of clotting factors, fibrinogen, and platelets. The test determines the viscoelasticity of the clot during formation and breakdown. The whole blood sample is placed in a cup in which a pin is suspended from a torsion wire. TEG/ROTEM, in addition to the INR and PTT, can augment the understanding of the patient’s overall coagulation Picture and help guide the need for transfusion of various blood products.
Warfarin inhibits hepatic synthesis of vitamin k-dependent coagulation factors ii, vii, ix, and x. This occurs through inhibition of vitamin K epoxide reductase and vitamin K1 reductase, which deplete vitamin HK2 (hydroquinone) and limit gamma-carboxylation of regulatory anticoagulant proteins c and s, as well as vitamin K-dependent coagulation. As reviewed by hirsh and raschke, unfractionated heparin binds to antithrombin through a high-affinity pentasaccharide. This complex then binds to factor ii, irreversibly inhibiting factor ii’s procoagulant activity, as well as coagulation factors xa, ixa, xia, and xiia. The halflife of heparin is approximately 60 minutes.
DOACs are so named because they work by binding directly to factor xa or factor ii without the need to first complex with antithrombin. Idarucizumab (praxbind) is a monoclonal antibody fragment that binds free and factor iia-bound dabigatran. Dabigatran binds to idarucizumab with 350 times greater affinity than for factor ii. A 5 g dose of idarucizumab was administered to patients who received dabigatran therapy. Group a included 301 patients with life-threatening bleeding (98 patients with ich and 137 with gastrointestinal |LS|gi|RS| bleeding). Group b included 202 non-bleeding patients requiring an urgent surgical procedure.46 the maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), as determined by diluted thrombin time (dtt) or ect. ECT and dtt were chosen because they correlate linearly with dabigatran concentrations measured by mass spectroscopy.
Apixaban (eliquis), rivaroxaban (xarelto), edoxaban (savaysa), and betrixaban (bevyxxa) reversibly and competitively inhibit free and clot-bound factor xa. The theory behind the use of these nonspecific reversal agents such as FEIBA, PCC, and RFVIIA is that they attempt to overwhelm the effect of a circulating factor xa inhibitor by supplementing either upstream factors (rviia) or factor x, along with both up and downstream factors. Andexanet alfa, now officially known by the new generic name “coagulation factor xa (recombinant), inactivated-zhzo,” And by the trade name andexxa, is a specific factor xa reversal agent.
Aspirin irreversibly inhibits cyclooxygenase (cox)-1 and cox-2 enzymes to cause downstream inhibition of thromboxane a2 , while thienopyridines such as clopidogrel (plavix), ticlopidine (ticlid), and prasugrel (effient) irreversibly inhibit the p2y12 receptor for adenosine diphosphate (adp) on platelets, preventing adp binding and platelet aggregation. The platelet transfusions for intracerebral hemorrhage (patch) trial reported that platelet transfusion for spontaneous ich in patients on antiplatelet therapy did not reduce bleeding and led to increased mortality And dependence at three months.
Reversal of anticoagulation requires basic knowledge of underlying physiology of hemostasis, as well as obtaining a thorough history. A key piece of information is the timing of the last dose of anticoagulant agent. This is particularly important for doac agents where testing for degree of anticoagulation is not easily obtained or timely. A morbidity or mortality benefit, however, has not yet been definitively demonstrated. It is critical to determine if expensive reversal agents that may promote thrombosis are actually beneficial.
Hemostasis is a complex, tightly regulated balance between bleeding and clotting. Through the use of anticoagulant agents, patients can be made to bleed, and with reversal agents (some of which are procoagulants by nature), patients can be forced to clot. In each of these situations, the harms and benefits should be weighed in the best interest of the patient and situation. Hopefully In the near future, safer anticoagulants and more-specific reversal agents will become available, along with easy access to specific testing that can guide our use of these powerful medications.
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