The Emergent Reversal of Coagulopathies Encountered in Neurosurgery and Neurology: A Technical Note

Results

The tables provided in this article review key information about the medical conditions and drugs used to cause various coagulopathies. Reversal agent options are specifically named and their half-lives are reported (for patients presumed to be without end-stage organ failure). The tables provide:

• Doses of reversal agents for adult patients

• The agents listed in order of preference

• Pediatric patient data was not compiled in these tables

• Associated laboratory tests that may be useful

• The levels of evidence offered are based on the University of Wisconsin Health Care (UWHC) Guidelines that follow criteria used by the American College of Cardiology and the American Heart Association (ACC/AHA).

Table 1 reviews those agents that indirectly affect thrombin (generally through antithrombin) and include drugs such as the heparinoids and their reversal agents.1,2 Heparin will potentiate the action of antithrombin III and thereby inactivates thrombin (as well as activated coagulation factors IX, X, XI, XII, and plasmin) and prevents the conversion of fibrinogen to fibrin. Therefore, thrombosis is blocked through the inactivation of activated Factor X and inhibition of prothrombin’s conversion to thrombin. Unfractionated heparin binds to antithrombin III (ATIII) at the site of the native pentasaccharide sequence, changing its conformation and converting it from a slow to a rapid inactivator of several coagulation factors, particularly factor Xa. However, in order to inactivate thrombin, heparin must bind to thrombin and AT simultaneously, an effect that occurs only when the molecule exceeds 18 monosaccharide units (greater than 6000 daltons). Low molecular weight heparins (LMWHs) have a similar mechanism of action of heparin and retain the ability to inactivate factor Xa. However, because they are smaller molecules, they cannot simultaneously bind to thrombin and AT and, therefore, have a lesser effect on thrombin. Fondaparinux causes an antithrombin III-mediated selective inhibition of only factor Xa, but cannot inactivate thrombin because of its extremely short length. It contains only a sulfated pentasaccharide unit with higher antithrombin affinity than the native pentasaccharide seen with unfractionated heparin.

The recommended laboratory tests to assess efficacy of each of these agents is as follows: activated partial thromboplastin time (aPTT) and/or activated clotting time (ACT) to measure heparin activity and anti-factor Xa +/− ACT to assess LMWH and fondaparinux activity. Protamine is the most commonly recommended reversal agent for heparin and LMWH. That said, protamine has not been shown to be successful in reversing fondaparinux. In severe cases, one could consider also giving Factor VIIa in an attempt to reverse severe bleeding after administration of fondaparinux.3

Table 2 lists the newest class of anticoagulants, the direct Factor Xa inhibitors.1,4 They differ from the agents in table 1 in that they do not require a cofactor (eg. ATIII) for activity and are considered direct Factor Xa inhibitors. While some practitioners will estimate drug activity with anti-factor Xa levels, it is important to emphasize that no therapeutic laboratory monitoring has been established. In mild to moderate cases of hemorrhage, it is advised to give 20–30 units/kg of prothrombin complex concentrate (PCC), while 40–50 units/kg should be given if bleeding is severe. While availability of PCCs varies among institutions, the authors advocate for the use of 4-factor PCCs over 3-factor PCC, if given the choice. There are ongoing efforts to develop reversal agents and effective treatment strategies for this class of anticoagulant.5

Table 3 reviews those agents that directly impact thrombin and includes some of the newer drugs such as dabigatran.1,4,6,7 There are no antidotes to these drugs at this time, but some are under development. There is also no reliable laboratory test to directly measure the extent of anticoagulation. Until such antidotes become available, 4-factor PCCs and 3-factor PCCs are recommended as an effective treatment strategy (although admittedly, the literature has some variation depending on the specific direct thrombin inhibitor used4,8). Some have advocated for the use of activated charcoal if the patient recently took a dose of the medication.9 Another agent, factor eight inhibitor bypassing activity (FEIBA), has been shown to be effective in human plasma ex vivo.10,11 Factor VII has been shown to be less effective as a management option.12,13 In addition, as the agents are partially protein bound, one could consider dialysis in patients with renal impairment.

Table 4 demonstrates those agents/clinical situations that impact clotting through thrombolysis.1,14 Both alteplase and desmoteplase can typically be effectively reversed with either aminocaproic acid or tranexamic acid (depending on which is available in a hospital formulary). Also included in this table are clinical conditions where plasminogen activation and fibrinolysis are hallmarks of the condition (as the tPA-like agents work through plasminogen activation). With acute disseminated intravascular coagulation (DIC) (such as with infection) there is an underlying hypercoagulable state that exists and results in a consumptive coagulopathy. This can then promote bleeding in other areas due to low amount of clotting factors. Primary treatment is reliant upon treating the underlying condition with concurrent supportive care and broad replacement of coagulation factors via fresh frozen plasma (FFP), cryoprecipitate, and platelets. Using fibrinolysis inhibitors in these situations can cause massive thrombosis, because the areas where clotting is occurring can propagate clot if fibrinolysis is not allowed to occur, resulting in ischemia to affected tissues/organs.4 For this reason, fibrinolysis inhibitors for reversal of acute DIC are not recommended.

Table 5 demonstrates those coagulopathies that are measured by international normalize ratio (INR).1,6,14 They typically relate to the vitamin K factors or to the synthetic function of the liver if it is substantially impaired. It is recommended to always give vitamin K for 3 to 5 days when reversing warfarin, as acute reversal strategies can be short lived. At this point in time, PCCs are effective and preferable acute reversal agents for warfarin-associated coagulopathy as opposed to Factor VII.3 As with other cases where PCCs are utilized, the dose can vary between 20 units/kg for minor bleeding to 50 units/kg for severe bleeding. Once the initial dose of PCC has been given, one can usually verify correction of INR and then administer FFP as needed to maintain correction.15

Table 6 shows those coagulopathies that are related to platelet dysfunction due to medications.1,16–18 Note that the laboratory tests listed may be of limited value due to the inherent differences in results between individual patients. Also note that fish oil is not listed, because the exact mechanism of action is not entirely known. It is generally thought to have weak anticoagulant properties. Fish oil affects cell membranes, and its effects are likely permanent with respect to the affected platelets. This means its duration of action could reside in the 5 to 10 day range until new platelets are made, but anticoagulation would also be based on the clearance of fish oil from the body, which is not known.14 A commonly employed and supported treatment strategy used with several antiplatelet agents is platelet transfusion.19 This is certainly the case for non-steroidal anti-inflammatory drugs, aspirin, and clopidogrel, prasugal, abciximab, cilostazol, and aggrenox. Admittedly, this is an area of active investigation for two reasons: (1) lab work to measure the extent of antiplatelet activity is notoriously inaccurate, and (2) the need for reversal for minor cases has not been validated (nor has the efficacy). However, it is typically agreed that in severe cases of bleeding it is prudent to administer platelet transfusion. In addition, many practitioners will give DDAVP (desmopressin acetate) in addition to platelet transfusion if a procedure is imminent. Antiplatelet agents that may respond to reversal strategies other than platelet transfusion include ticlopidine (can use methylprednisolone) and dipyridamole (where aminophylline may work).

Table 7 shows those coagulopathies that are related to platelet dysfunction from maldevelopment or acquired deficiencies on platelet function.1,14,20 The majority of these conditions respond to platelet transfusion with the exception of uremia/renal failure, which may require dialysis, cryoprecipitate, or desmopressin. It is also worth noting that there is no standardization when it comes to terminology surrounding platelet transfusion and dosage administered. In this paper, a “dose” is typically six random donor platelets (aka, a “six pack”).

Table 8 shows the occasional scenario where an immune-related factor inhibitor is present in the blood.1,14 This type of coagulopathy is often associated with an elevated aPTT. In such clinical cases, it is unlikely that a specific inhibitor will be identified in a timely matter. In addition, it is unlikely that a specific antidote will be available. Therefore, reversal strategies are broad in scope in hopes of controlling acute bleeding. At this point in time, PCCs are the favored agent. One could also consider Factor VII, aminocaproic acid, or tranexamic acid. Reversal strategies for inhibitor related coagulopathies can be augmented with steroids, intravenous immunoglobulin or plasmapheresis if severe. That said, if a particular factor specific inhibitor can be identified, it may be possible to give that specific factor when developing a reversal strategy.

Table 9 differs from table 8 in that the factor is inherently absent or inadequate in function rather than being blocked by an inhibitor.1,14,21 In Von Willebrand’s disease, the best treatment options include desmopressin (not in acute hemorrhage), PCC, or Factor VII. In pseudo-Von Willebrand’s, platelet transfusion is recommended. In cases of low fibrinogen or Factor XIII, cryoprecipitate is the recommended reversal agent. Lastly, Factor VII was specifically created for use in hemophilia A, while Factor IX concentrate can be given in hemophilia B (or PCC if not available).