Transfusion Management of Patients Receiving Antithrombotic Therapy


Hemostasis is the process by which blood components work in concert to halt bleeding as a consequence of injury. A blood clot forms in two general phases called primary and secondary hemostasis. Primary hemostasis involves the exposure of collagen in the subendothelium after a vascular injury. The collagen and blood flow shear forces stimulate von Willebrand factor to unfurl over the exposed collagen and provide a surface on which platelets can preferentially adhere. Adherent platelets undergo further activation and aggregate in response to physiologic agonists, which include collagen, adenosine diphosphate (ADP), arachidonic acid, thrombin, and epinephrine. Once an initial platelet plug is formed, it requires further stabilization in the form of a fibrin cap to continue to halt bleeding. It is on the surface of the aggregated platelets where the coagulation cascade occurs and results in the generation of cross-linked fibrin strands. While the prothrombotic processes are engaged to halt bleeding from the site of injury, simultaneously anticoagulant/fibrinolytic processes are also activated to keep the resultant thrombus from occluding the vessel. A brief overview of transfusion management of patients who are undergoing antithrombotic therapies will be discussed here.

Venous Thrombosis Prophylaxis

Patients with a prior history of spontaneous or provoked (prolonged periods of immobility, smoking, oral contraceptive use) venous thrombosis often undergo extensive laboratory workups to determine if a specific etiology can be found. These etiologies include activated protein C resistance (via the factor V Leiden mutation or others), prothrombin gene mutation, antiphospholipid syndrome, persistently elevated factor VIII, and homocysteinemia. Deficiencies in protein C, protein S, or antithrombin have also been implicated in pathological prothrombotic states. Prevention of further thromboses can be achieved with drug therapy, which includes warfarin, heparin (unfractionated or low molecular weight), fondaparinux (pentasaccharide), direct anti-Xa inhibitors, and direct thrombin inhibitors (DTIs) ( Table 54.1 ).

Table 54.1
Antithrombotic Therapies
Drug Class Agent Mechanism of Action Route of Admin T 1/2 Reversal
Vitamin K antagonists Warfarin Small molecule inhibitor of vitamin K epoxide reductase (VKOR), which prevents the in vivo regeneration of vitamin K PO 40 hours 4-factor PCC
Heparins Unfractionated heparin Increases antithrombin activity to primarily deactivate factors IIa and Xa IV, SC 1.5 hours 1 mg protamine sulfate (IV) per 100 U UFH administered over the last 4 hours.
Low-molecular-weight heparin Increases antithrombin activity to primarily deactivate factors Xa SC Variable, 4.5 hours for enoxaparin 1 mg protamine sulfate (IV) to 1 mg LMWH administered over the previous 4 hours (maximum dose 100 mg protamine sulfate over 2 hours).
Pentasaccharide Fondaparinux Increases antithrombin activity to primarily deactivate factors Xa SC 17–21 hours No antidote a
Direct Xa inhibitors Rivaroxaban Small molecule inhibitor of factor Xa PO 5–9 hours No antidote a
Low-dose aPCC (20–40 IU/kg) may have some efficacy in reversal but awaiting confirmation with clinical trials.
Apixaban PO 12 hours
Edoxaban PO 10–14 hours
Direct thrombin inhibitors (DTI) Dabigatran Small molecule inhibitor of factor IIa PO 12–17 hours Idarucizumab
Argatroban IV 50 minutes No antidote a
Bilvalrudin IV 25 minutes No antidote a
Lepirudin IV 1.3 hours No antidote a
Cyclooxygenase inhibitors Aspirin Irreversible inhibitor of cyclo-oxygenase-1 (COX-1) PO 2–5 hours No antidote a
Possible benefit from platelet administration 8–20 hours after last dose of aspirin.
ADP receptor inhibitors Clopidogrel Irreversible P2Y 12 inhibitors PO 7–8 hours No antidote a
Possible benefit from platelet administration 4 half-lives time after last dose of agent.
Prasugrel 7 [2–15] hours
Ticlodipine 12 hours
Ticagrelor Reversible P2Y 12 inhibitors 7–8.5 hours No antidote a
PAR-1 inhibitors Vorapaxar Reversible PAR-1 inhibitor (effectively irreversible) PO 8 days No antidote a Neither platelets nor dialysis are expected to be beneficial for bleeding episodes.
GPIIb/IIIa Inhibitors Abciximab Reversible inhibitor of GPIIb/IIIa IV 10–30 minutes No antidote a
Recovery of platelet function expected 4 half-lives time after last dose of agent.
Eptifibatide IV 2.5 hours
Tirofiban IV 2 hours

a The patient can be supported with appropriate component therapy to replete hemorrhaged blood until the antithrombotic effect of the drug is no longer present.

Warfarin

Warfarin (via PO) is a small molecule inhibitor of vitamin K epoxide reductase (VKOR), which prevents the in vivo regeneration of vitamin K and results in a vitamin K deficiency, which in turn reduces the amount of the properly carboxylated vitamin K–dependent coagulation factors (factors II, VII, IX, X and proteins C, S, and Z). The drug has a long half-life of 40 hours and variable activity in individuals secondary to genetic polymorphisms in VKOR or metabolic enzymes such as CYP2C9, all of which contribute to difficulty in proper dosing for individual patients. The therapeutic efficacy of the drug is monitored via a normalized prothrombin time (PT)–based ratio or international normalized ratio (INR) with a typical target range of 2–3. However, reversal of warfarin therapy is needed to recover clotting ability in patients who have any of the following: (1) overdosed (e.g., supratherapeutic INR), (2) active bleeding, or (3) a hemostatic challenge, such as surgery or other procedure. Depending on the rapidity and magnitude of correction of the warfarin effect needed, differing therapeutic options exist. First and foremost, vitamin K repletion via oral (PO), subcutaneous (SC), or intravenous (IV) routes is available. Alternatively, prothrombin complex concentrates (PCC: factors II, VII, IX, X and proteins C and S) has been recommended for rapid reversal in cases of severe hemorrhage or intracranial bleeding.

Of important note, as indicated in Table 41.1 , products in the PCC category vary markedly in composition such that they are likely not equally suitable for warfarin reversal (Kcentra [4 factor PCC] is FDA approved for warfarin reversal). When PCCs are not available, plasma can be used, often requiring higher transfusion volumes (10–20 mL/kg) to achieve similar corrections in clotting ability, typically with a goal of INR < 1.5 (see Chapter 34, Chapter 41 ).

Heparins

Unfractionated heparin (UFH) (via IV, SC) is a group of highly sulfated glycosaminoglycans, which bind to antithrombin and cause a 1000-fold kinetic increase in antithrombin’s activity, primarily deactivating factors IIa and Xa. UFH levels are usually monitored by either the activated partial thromboplastin time (PTT) or by an anti-Xa assay (see Chapter 156 ). UFH has a typical biological half-life of 1.5 hours, and it can be neutralized with protamine sulfate (via IV). Outside of the controlled, high-dose UFH therapy given during cardiopulmonary bypass, UFH therapeutic effect is infrequently actively reversed. Because UFH has a relatively short half-life, it is typically sufficient to stop therapy and monitoring. If deemed clinically necessary, protamine sulfate can be used to rapidly neutralize UFH; however, because protamine sulfate is an irreversible anticoagulant if given in excess, dosing should be carefully calculated. Reversal can be achieved with a 1-mg protamine sulfate per 100 U UFH administered over the last 4 hours. A general rule of thumb is to neutralize 80% of the estimated UFH dose (i.e., estimating residual dose since last administration taking into account a T 1/2 1.5 hours) as to ensure no overdose.

Low-molecular-weight heparin (LMWH) (via SC) and fondaparinux (via SC) are FDA approved without the need for routine monitoring, unlike UFH. Because of their smaller molecular size, when bound to antithrombin, the complex has preferential targeting to factor Xa and therefore the PTT is not a suitable test to monitor levels. LMWH (T 1/2 variable, 4.5 hours for enoxaparin) can be neutralized with protamine sulfate with 1-mg protamine sulfate to 1-mg LMWH administered over the previous 4 hours (maximum dose 100 mg protamine sulfate over 2 hours). Fondaparinux (T 1/2 17–21 hours), however, does not have an antidote and overdoses should be managed with clinical supportive measures, i.e., red cell transfusion if resultant hemorrhage is excessive. Administration of plasma products cannot reverse the effects of UFH/LMWH/fondaparinux. Similarly, because the targets of antithrombin are factors Xa and IIa, recombinant factor VIIa is not expected to reverse anticoagulation.

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