Antiplatelet and anticoagulant drugs (antithrombotics) predispose to acute and chronic subdural hematomas. Patients on these drugs are at higher likelihood of presenting with larger hematomas and more severe neurologic deficits. Standard neurosurgical and neurocritical care of subdural hematomas involves reversal of antithrombosis preoperatively, whereas reversing antiplatelet drugs is less clear. This article highlights the spectrum of antithrombotic agents in common use, their mechanisms of action, and strategies for reversal.
Key points
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Antithrombotic drugs should be reversed emergently in all patients with chronic subdural hematomas (SDHs) who require urgent surgery; if surgery can be delayed, it is less certain whether to do this or to wait for spontaneous recovery from anticoagulation.
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There are no data to guide practitioners on whether or not to reverse antiplatelet drugs.
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Appropriate laboratory monitoring should guide the adequacy of reversal for all agents.
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Postoperative resumption of anticoagulant and antiplatelet drugs should be guided by a thorough and individualized assessment of hemorrhagic and thromboembolic risk.
Introduction
The use of antithrombotic agents, either antiplatelet or anticoagulant drugs, is expanding with a progressive rise in prevalence of patients with atherosclerotic risk factors as well as thrombogenic cardiac arrhythmias typically seen in the elderly. There is strong evidence for short-term dual-antiplatelet therapy as the standard of care for patients with acute coronary syndromes and oral anticoagulation in patients with atrial fibrillation at high risk of thromboembolism.
Antiplatelet and anticoagulant drugs are known to predispose to the development of both acute and chronic SDHs. These may occur in a dose-dependent manner; 1 series of patients on warfarin found an increase in subdural hemorrhage risk by more than 7-fold, with an increase in prothrombin ratio from 2.0 to 2.5, whereas another demonstrated a 2.4-fold increase in risk of SDH formation with increasing doses of dabigatran. The impact of preoperative antithrombosis on hematoma recurrence postoperatively remains controversial.
Patients on antithrombosis presenting with acute or chronic SDHs are thought to be at higher likelihood of presenting with larger hematomas or more severe neurologic deficits. Although the literature specific to SDH is limited on the impact of antithrombosis on hematoma size or propensity for expansion, there is strong evidence for increased expansion of intracerebral hematomas (ICHs) with warfarin anticoagulation. Standard neurosurgical and neurocritical care of subdural hematomas, therefore, involves reversal of antithrombosis preoperatively, where possible, and a thorough individualized risk-benefit assessment of antithrombosis resumption.
This article highlights the spectrum of antithrombotic agents in common use, their mechanisms of action, and strategies for reversal. The current evidence for antithrombosis resumption, with available metrics for stratifying hemorrhagic and thromboembolic risk, is also reviewed.
Introduction
The use of antithrombotic agents, either antiplatelet or anticoagulant drugs, is expanding with a progressive rise in prevalence of patients with atherosclerotic risk factors as well as thrombogenic cardiac arrhythmias typically seen in the elderly. There is strong evidence for short-term dual-antiplatelet therapy as the standard of care for patients with acute coronary syndromes and oral anticoagulation in patients with atrial fibrillation at high risk of thromboembolism.
Antiplatelet and anticoagulant drugs are known to predispose to the development of both acute and chronic SDHs. These may occur in a dose-dependent manner; 1 series of patients on warfarin found an increase in subdural hemorrhage risk by more than 7-fold, with an increase in prothrombin ratio from 2.0 to 2.5, whereas another demonstrated a 2.4-fold increase in risk of SDH formation with increasing doses of dabigatran. The impact of preoperative antithrombosis on hematoma recurrence postoperatively remains controversial.
Patients on antithrombosis presenting with acute or chronic SDHs are thought to be at higher likelihood of presenting with larger hematomas or more severe neurologic deficits. Although the literature specific to SDH is limited on the impact of antithrombosis on hematoma size or propensity for expansion, there is strong evidence for increased expansion of intracerebral hematomas (ICHs) with warfarin anticoagulation. Standard neurosurgical and neurocritical care of subdural hematomas, therefore, involves reversal of antithrombosis preoperatively, where possible, and a thorough individualized risk-benefit assessment of antithrombosis resumption.
This article highlights the spectrum of antithrombotic agents in common use, their mechanisms of action, and strategies for reversal. The current evidence for antithrombosis resumption, with available metrics for stratifying hemorrhagic and thromboembolic risk, is also reviewed.
Platelet activation
The initial response to endothelial injury begins with platelet adhesion to exposed extracellular matrix ( Fig. 1 ). This interaction is mediated by the glycoprotein (GP) Ib/V/IX receptor complex on the platelet surface and von Willebrand factor bound to exposed collagen at the site of vessel injury. Adhesion leads to platelet activation by several pathways, initiated by collagen, ADP, thromboxane A 2 , serotonin, and thrombin (factor II). Collectively, these pathways alter the morphology as well as secretory and receptor phenotypes of platelets into an active form. The primary effector of activated platelets is the GPIIb/IIIa surface receptor, activation of which is responsible for mediating platelet aggregation and thrombus propagation, stabilized by fibrin deposition from concurrent activation of coagulation cascades.
Coagulation cascade
Classically, the coagulation cascade comprises an extrinsic pathway, initiated by tissue injury, and a contact-initiated intrinsic pathway, both leading to a common final pathway ( Fig. 2 ). This system is useful for understanding tests of coagulation activity but is likely simplified from current understanding of coagulation as a cell-based and surface-based process. Prolonged activated partial thromboplastin time (aPTT) may be secondary to heparin; lupus anticoagulant; deficiencies of factors 8, 9, and 11; and von Willebrand disease. An increased prothrombin time may be due to warfarin, vitamin K deficiency, liver dysfunction, or congenital factor 7 deficiency. Thrombin time depends on the conversion of fibrinogen to fibrin; hence, this test is sensitive to the detection of fibrinogen abnormalities and inhibitors acting at this level, such as heparin and dabigatran.
Fibrinolysis is initiated as a normal physiologic response for remodeling of a completed fibrin clot. It involves activation of plasminogens to plasmin by tissue and urokinase activators. Fibrinolysis is inhibited endogenously by plasminogen activator inhibitor and thrombin-activatable fibrinolysis inhibitor, mainly α 2 -antiplasmin. Exogenous inhibitors of fibrinolysis in current clinical use include aprotinin and the lysine derivatives tranexamic acid (TXA) and aminocaproic acid.
Common antiplatelet agents
A list of oral antiplatelet agents in common use, along with their relevant pharmacologic properties and reversal strategies, is shown in Table 1 .
| Generic Name | Mechanism of Action | Elimination Half-Life | Reversal Strategy | Laboratory Monitoring |
|---|---|---|---|---|
| ASA | Irreversible COX inhibition | 20 min | Platelet transfusion (4–5 U); desmopressin (0.3 μg/kg IV) | Arachidonic acid–based testing (VerifyNow ASA) |
| Dipyridamole | Phosphodiesterase inhibitor | 10–12 h | None | None |
| Ticlopidine | Thienopyridine — irreversible P2Y 12 receptor inhibition | 4–5 d | None | Bleeding time |
| Clopidogrel | Thienopyridine — irreversible P2Y 12 receptor inhibition | 6 h | Platelet transfusion (10 U q12 h × 48 h); desmopressin (0.3 μg/kg IV) | P2Y 12 receptor cascade test (VerifyNow P2Y 12 ) |
| Prasugrel | Thienopyridine — irreversible P2Y 12 receptor inhibition | 2–15 h | Platelet transfusion (10 U q12 h × 48 h); desmopressin (0.3 μg/kg IV) | P2Y 12 receptor cascade test (VerifyNow P2Y 12 ) |
| Ticagrelor | Cyclopentyl-triazolo-pyrimidine — reversible P2Y 12 receptor inhibition | 7 h | None | None |
Current antiplatelet agents target predominantly 1 of 3 pathways. Acetylsalicylic acid (ASA) irreversibly inhibits cyclooxygenase (COX)-1 selectively (at low doses) or both COX-1 and COX-2 (at high doses), leading to anti-inflammatory and analgesic effects. COX-1 inhibition attenuates the thromboxane A 2 –mediated pathway of platelet activation (see Fig. 1 ).
Antagonists of the P2Y 12 receptor represent the second-most common class of antiplatelet drugs, including ticlopidine, clopidogrel, prasugrel, and ticagrelor, in order of their clinical development (see Fig. 1 ). Ticlopidine has largely been replaced by the latter agents because of its hematological side effects. Clopidogrel and prasugrel, both thienopyridines, are active only in their metabolite form and irreversibly bind the ADP binding site on the P2Y 12 receptor. Ticagrelor, a cyclopentyl-triazolo-pyrimidine, instead binds reversibly to a different site on the P2Y 12 receptor, thereby inhibiting G protein–coupled signaling, in both prodrug and metabolite forms (see Fig. 1 ).
The GPIIb/IIIa inhibitors are commonly given intravenously (IV) in endovascular revascularization procedures. These are given intravascularly; there are no enteral formulations available. Agents in this class include abciximab, eptifibatide, and tirofiban.
Reversal strategies for commonly prescribed antiplatelet drugs relate directly to their mechanism of action. Because both ASA and the thienopyridines (clopidogrel and prasugrel) bind irreversibly to their targets, transfusion of exogenous platelets beyond the circulating half-life of both drugs somewhat attenuates their effect, although full reversal requires turnover of the endogenous platelet pool, typically over 2 to 3 days. A higher platelet transfusion mass seems to be required for thienopyridines than ASA. By contrast, because ticagrelor binding is reversible, circulating ticagrelor and its metabolite likely inhibit exogenously introduced platelets as well, limiting the effectiveness of platelet transfusions.
Common anticoagulant agents
A list of anticoagulant agents in common use, along with their relevant pharmacologic properties and reversal strategies, is shown in Table 2 .
| Generic Name | Mechanism of Action | Elimination Half-Life | Reversal Strategy | Laboratory Monitoring |
|---|---|---|---|---|
| Warfarin | Inhibition of hepatic production of vitamin K–dependent factors | T1/2: 25–60 h | Vitamin K 5–10 mg IV plus PCC at weight-based dosing (25–100 U/kg IV); FFP (15 mL/kg IV) | INR |
| Dabigatran | Direct thrombin (IIa) inhibition | T1/2: 12–14 h | Idarucizumab 5 g IV + 2.5 g IV (1 h apart); PCC (25–100 U/kg IV); FFP (15 mL/kg IV); rVIIa (10–90 μg/kg IV); hemodialysis | aPTT |
| Rivaroxaban | Factor Xa inhibition | T1/2: 7–11 h | PCC (25–100 U/kg IV); FFP (15 mL/kg IV); rVIIa (10–90 μg/kg IV) | Anti–factor Xa assay |
| Apixaban | Factor Xa inhibition | T1/2: 8–15 h | PCC (25–100 U/kg IV); FFP (15 mL/kg IV); rVIIa (10–90 μg/kg IV) | Anti–factor Xa assay |
Commonly prescribed anticoagulant drugs fall into 3 classes: heparin based, vitamin K antagonists (VKAs), and novel oral anticoagulants (NOACs). Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs), including enoxaparin, dalteparin, and tinzaparin, potentiate antithrombin III–mediated inhibition of factor Xa (see Fig. 2 ). UFH inhibits thrombin as well as factor Xa so its effect is detected in the aPTT whereas LMWHs inhibit factor Xa and generally do not affect the aPTT. UFH is administered either IV or subcutaneously, whereas LMWHs are typically given only subcutaneously.
Warfarin was the first drug of the VKA class. Warfarin interferes with the conversion of vitamin K to its 2,3 epoxide, inhibiting the activity of vitamin K–dependent procoagulant factors (factors II, VII, IX, and X) as well as reducing the anticoagulant activity of proteins C and S.
NOACs are targeted inhibitors of either factor Xa or thrombin directly. Oral Xa inhibitors include rivaroxaban and apixaban, whereas fondaparinux is a subcutaneously administered Xa inhibitor. Rivaroxaban and apixaban reversibly bind the active site of free and bound Xa molecules, whereas fondaparinux achieves indirect Xa inhibition through interaction with antithrombin III. Direct thrombin inhibitors include argatroban and bivalirudin (parenteral) as well as dabigatran (oral). All function via direct, competitive inhibition of the thrombin active site, without requirement for cofactors; hence, their efficacy is reported to be less variable although monitoring of and reversal of their activities is more problematic (see Fig. 2 ).
Reversal of heparin-based drugs is accomplished by direct ionic interaction and binding of heparin to protamine, a cationic protein. Reversal of VKA is accomplished, in the acute phase, by direct replacement of vitamin K–dependent procoagulant factors and, in the subacute phase, with vitamin K replenishment. Due to their reversible binding, reversal of NOACs is considerably more variable, with only 1 specific agent receiving accelerated approval: idarucizumab, a humanized monoclonal antibody fragment that binds dabigatran. Replacement of factors from various sources, including fresh frozen plasma (FFP), cryoprecipitate, prothrombin complex concentrate (PCC), recombinant activated factor VII (rVIIa), and factor VIII inhibitor bypassing activity, has been attempted with varying efficacy.
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