Introduction

Bleeding is a common side effect of anticoagulant use. However, the majority of bleeding events are not life threatening and can be managed conservatively.¹ To assess the severity of an anticoagulant-related bleeding event, clinicians should identify the source (if possible) and location of bleeding, evaluate laboratory studies (including blood counts and coagulation studies), and closely monitor vital signs. The first step in managing any significant bleeding event is to temporarily stop using the anticoagulant. Local measures, such as manual compression, can be useful in the case of skin-bleeds and epistaxis. Transfusion of blood products may be needed for more significant bleeding events. Ultimately, the decision to reverse an anticoagulant should be made based on the location of bleeding, time since last use of the anticoagulant, and patient's hemodynamic stability. The decision to reverse an anticoagulant is largely the same for patients with atrial fibrillation and venous thromboembolism. But the strategies for reversal differ based on the specific anticoagulant, as detailed in the next two paragraphs. The decision to restart the anticoagulant after bleeding has been controlled may differ based on indication, and is summarized in the final paragraph of this review.

Management of Vitamin K Antagonist-related Bleeding

In the setting of a life-threatening bleed related to vitamin K antagonist (VKA) use, rapid reversal of the VKA drug effects and replenishing clotting factors is a priority. To achieve that goal, administer vitamin K 10 mg intravenously along with prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) to achieve a sustained reduction of the international normalized ratio (INR).^1-5 Generally, a goal INR of ≤1.3-1.5, depending on the site of the bleed, is targeted. Several studies have demonstrated that PCC infusion results in more rapid and complete reversal of the INR as compared to use of FFP for VKA-related bleeding. However, there is inconsistency on whether this rapid resolution of the INR results in improved hemostatic efficacy or clinical outcomes.^6-10 In one of the few prospective, randomized controlled trials in acutely bleeding patients, 4F-PCC achieved a more rapid INR correction and significantly lower INR in the 12 hours after infusion compared to FFP, however hemostatic efficacy was similar in the two groups.¹⁰ In contrast, a second prospective randomized trial in patients with VKA-related intracranial hemorrhage (ICH) found a significant difference in INR correction and hematoma expansion at 3 hours favoring 4F-PCC.⁹ Other limitations of FFP use to reverse VKA-associated bleeding include: need for blood typing and thawing that results in administration delays;⁹ large volume requirement that leads to prolonged infusion times and potential for transfusion-associated circulatory overload (TACO);^9,10 and risk of transfusion-related acute lung injury (TRALI).

Historically, PCC has been dosed based on body weight and adjustment for initial INR in VKA-related bleeding events. There has been interest in fixed dose PCC (1000-1500 IU) for ease of ordering, reduced cost and potential reduction in thromboembolic complications. While some retrospective reports demonstrate acceptable reversal and no difference in clinical response,^11-15 others have shown less complete INR reversal and need for additional PCC administration with fixed dose strategies.^16,17 This may be particularly prominent in those with large body weight, INR >4.0, or intracranial bleeding (where target INR may be lower). However, it is important to note that clinical response to the two dosing strategies has not been different and larger trials would be helpful in determining the optimal dosing strategy.

Management of Direct Oral Anticoagulant-related Bleeding

Direct oral anticoagulants (DOACs) are now widely used in treatment of venous thromboembolism (VTE) and are recommended first-line over VKAs in non-cancer associated VTE.¹⁸ While routine assessment of anticoagulant effect is unnecessary, it can be helpful in determining the appropriate management strategy for an acutely bleeding patient. Unlike VKAs, standard coagulation tests such as activated partial thromboplastin time (aPTT) and prothrombin time (PT)/INR are unreliable markers of anticoagulant effect in DOAC-treated patients. Time since last dose and end-organ function affecting DOAC clearance should be used to guide the decision on need for reversal of the DOAC. Availability of drug specific assays or use of a low-molecular weight heparin calibrated anti-Xa level can be useful to determine activity but should not delay treatment in those known to have DOAC on board.

Until recently, supportive measures and infusion of clotting factors were the only available options for reversal of DOACs. Initial animal models evaluating activated PCC (aPCC) [FEIBA], 4-factor PCC, and recombinant factor VII demonstrated mixed and inconsistent effects on coagulation parameters, bleeding time, and hemostatic efficacy.^19-23 Additionally, high dose 4F-PCC (50 units/kg) in healthy subjects reversed abnormal coagulation tests from rivaroxaban but not dabigatran.²⁴ The use of aPCC in dabigatran-associated acute bleeding suggests good hemostatic efficacy as compared to historical controls²⁵ and specific antidote trials²⁶ (Table 2). In apixaban and rivaroxaban patients, two observational cohort reports describe 4F-PCC use with hemostasis rates of 70-80% and low rates of thromboembolism^27,28 (Table 2).

Within the last 4 years, approval of specific antidotes has led to hopes for improved outcomes in DOAC-related acute bleeding, however limitations remain including cost, availability (andexanet alfa), and "real-world" data. Relevant information regarding agent specific characteristics and study data can be found in Tables 1 and 2, respectively. A majority of patients in both trials demonstrated normalization of thrombin activity and reduction in unbound drug concentration. In REVERSE-AD, unbound dabigatran levels were suppressed for 12 hours at which point 23% of patients had re-elevation of levels.²⁹ In ANNEXA-4, unbound apixaban and rivaroxaban levels returned to that of the placebo group two hours after the end of the 2-hour infusion, however endogenous thrombin potential remained normalized.³⁰ Hemostasis was reported in a majority of patients in both trials. Use of agent specific antidotes is recommended over non-specific reversal agents for DOAC-associated life-threatening bleeding or bleeding at a critical site. If agent specific antidotes are not available, based on observational data, aPCC (25-50 units/kg) is recommended for reversal of dabigatran and 4F-PCC (25-50 units/kg) is recommended for reversal of oral anti-Xa inhibitors.^1,18,31,32

Resuming Anticoagulation

The acute management of anticoagulant-related bleeding in patients with VTE should also include an assessment for restarting anticoagulation once bleeding has been resolved. This is of particular importance for patients with VTE, who remain at elevated risk for recurrence. In fact, the majority of thromboembolic events and deaths occurring in the ANNEXA-4 study occurred after bleeding had been controlled but before anticoagulation had been resumed.³⁰ Among patients with atrial fibrillation who experienced an anticoagulant-related bleeding, data suggests lower rates of ischenmic stroke and death when the anticoagulant is restarted.³³ The same is likely to be true for patients with VTE. Recent guidelines recommend resuming anticoagulation within 90 days if the patient is at moderate-high risk for VTE recurrence and the risk of recurrent bleeding is adequately low.³⁴

Conclusion

Bleeding is a common complication of chronic anticoagulant therapy. Most bleeding events can be managed conservatively, usually by omitting a few doses of the anticoagulant. In severe and life-threatening bleeding events, use of non-specific (e.g. PCC) or specific (e.g. idarucizumab, andexanet alpha) reversal agents are recommended. However, further data is needed to compare outcomes between these two management strategies and identify the cost-effectiveness of these various strategies. Once bleeding has been controlled, clinicians and patients should discuss the appropriateness of resuming anticoagulant therapy to prevent potentially life-threatening future thrombotic events.

Table 1: Specific Reversal Agents for Direct Oral Anticoagulants

	Idarucizumab	Andexanet Alpha	Ciraparantag
Drug Reversed	Dabigatran	Rivaroxaban Apixaban Edoxaban (non-FDA) LMWH (non-FDA)	Dabigatran Xa Inhibitors LMWH UFH
Mechanism	Monoclonal Ab; binds dabigatran with high affinity	Recombinant human factor Xa protein; acts as a decoy	Noncovalent bonding and charge-charge interactions
Published Clinical Studies	Healthy volunteers; bleeding patients; emergent reversal	Healthy volunteers; bleeding patients	Healthy volunteers
FDA Approval	Approved	Approved	Not approved

Table 2: Studies of DOAC-reversal with Specific and Non-specific Agents

	Schulman et al. (n=14)		Dager et al. (n= 64)	Smith et al. (n=31)		Majeed et al. (n=84)		RE-VERSE AD (n=301)		ANNEXA-4 (n=352)
DOAC, n (%) Apixaban Rivaroxaban Dabigatran	-- -- 14		20 28 16	17 (55) 14 (45) --		39 (46) 45 (54) --		-- -- 301		194 (55) 128 (36) --
Bleeding Site, n (%) ICH Non-ICH	5 (35.7) 9 (64.3)		28 (29) 36 (37)	18 (58) 13 (42)		59 (70) 25 (30)		98 (33) 203 (67)		227 (64) 125 (36)
Reversal Agent	aPCC ~50 units/kg		aPCC ~10-25 units/kg	4F-PCC 25-50 units/kg		4F-PCC ~25 units/kg (1500-2000 units)		Idarucizumab		Andexanet alfa
Efficacy, n (%)	Good Moderate Poor	9 (64.3) 5 (35.7) 0	62/64 without active bleeding or hematoma expansion	Effective Ineffective	25 (81) 6 (19)	Effective Ineffective	58 (69) 26 (31)	Hemostasis Not determined	(n=203) 134 (67.7) 67 (33)	Excellent Good Poor/None	(n=249) 171 (69) 33 (13) 45 (18)
Thrombotic Events (30 day), n (%)	0		9 (14.1)	0*		3 (4)		14 (4.8)		34 (10)
Mortality (30 day), n (%)	1 (8)		5 (7.8)	5 (16)*		27 (32); 20 had ICH		41 (13.5)		49 (14)

References

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords: International Normalized Ratio, Anticoagulants, Vitamin K, Antidotes, Factor VII, Thrombin, Prothrombin Time, Partial Thromboplastin Time, Heparin, Low-Molecular-Weight, Bleeding Time, Venous Thromboembolism, Atrial Fibrillation, Retrospective Studies, Epistaxis, Cost-Benefit Analysis, Blood Grouping and Crossmatching, Healthy Volunteers, Prospective Studies, Blood Coagulation Factors, Factor Xa, Recombinant Proteins, Pyridones, Pyrazoles, Antibodies, Monoclonal, Humanized, Intracranial Hemorrhages, Hemostatics, Hemostasis, Stroke, Hematoma, Hemodynamics, Cohort Studies, Vascular Diseases, Aneurysm

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