Reversal therapy for anticoagulant and antiplatelet-associated life-threatening and major bleeding

1. Introduction
2. Warfarin
3. UFH and LMWH
4. Fondaparinux
5. Dabigatran
6. Rivaroxaban, Edoxaban and Apixaban
7. Antiplatelet drugs

1. INTRODUCTION

Bleeding is the most common complication of antiaggregants and anticoagulants. The rate of major bleeding among users of vitamin K antagonists (VKAs) is 1.5% to 5.2% per year; low-molecular-weight heparin (LMWH) and intravenous unfractionated heparin (UFH) are associated with about 2% and 5.5% respectively of major bleeding complications [1-2]. Bleeding complications range from about 2% to 3% with direct oral anticoagulants (DOACs) [3].

Major bleeding is defined as:

• bleeding causing haemodynamic instability
• symptomatic bleeding in a critical organ: intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular (if causing compartment syndrome)
• bleeding causing a fall in hemoglobin > 2 g/dL or more
• bleeding leading to transfusion of ≥ 2 UI of packed red blood cells
• resulting in death

according to the ISTH criteria [4].

DRUG	MONITORING	REVERSAL
Warfarin	PT/INR	Vitamin K PCC FFP
UFH	Aptt	Protamine
LMWH	anti-factor Xa level	Protamine
Fondaparinux	anti-factor Xa level	No specific antidote PCC rFVIIa Andexanet alfa Aripazine
Dabigatran (Pradaxa)	ECT, Hemoclot® thrombin inhibitor assay, PT, aPTT.	Idracizumab Ciraparantag/ aripazine/PER977*
Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoaxaban (Lixiana)	anti-factor Xa level	Andexanet alfa Ciraparantag/ aripazine/PER977* PCCFVIIa

In patients with hypofibrinogenemia, cryoprecipitate may be used to keep fibrinogen levels above 100 to 150 mg/dL depending on the severity of bleeding.

For all patients with major bleeding administration of an antifibrinolytic agent like tranexamic acid or epsilon-aminocaproic acid is suggested.

2. WARFARIN

Warfarin and other Coumarin derivatives act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X (FIG. 1), and the anticoagulant proteins C and S: The reverting agents act by restoring the synthesis of vitamin K dependent clotting factors or by providing vitamin K dependent clotting factors.

SETTING	ASH Guideline – 2018	ACCP Guideline – 2012
Life-threatening bleeding Any INR	4-factor PCC Vitamin K (intravenous) Hold warfarin	4-factor PCC Vitamin K (intravenous) Hold warfarin
No bleeding INR >10	(No recommendations given)	Vitamin K (oral) Hold warfarin
No bleeding INR 4.5 to 10	Hold warfarin No vitamin K	Hold warfarin Vitamin K (low dose, oral) is optional

Product	Time to Effect	Duration of Effect	Evidence of Efficacy for Warfarin Revesal	Risk of Thrombosis
Oral vitamin K	24 h	Days	++++	NS
Intravenous vitamin K	8–12 h	Days	++++	NS
Fresh frozen plasma	Immediate	12–24 h	++	NS
PCC	Immediate	12–24 h	+++	+ (Higher with activated PCC)
Recombinant factor VIIa	Immediate	2–6 h	+	++

Vitamin K is indicated for warfarin reversal if (TAB. 2):

• INR of >10 or 4.5 to 10 in the presence of other risk factors for bleeding. 
• INR is >10, NO active bleeding or minor bleeding (Vitamin K alone)
• In case of persistent INR elevation: Vitamin K administration can be repeated every 12 h

Fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) may be necessary in bleeding patients:

• In cases of major bleeding: PCC or FFP are given to reverse the immediate action of warfarin
• vitamin K is given to maintain the reversal effect against warfarin as the half-life for warfarin is 72 hours

Patients should repeat coagulation profile to ensure warfarin reversal. 3 – 5 units of FFP (10-15 mL/kg IV) are necessary to increase plasma coagulation factors by ∼15% to 25% [7].

PCC provides 3 (II,IX,X; does not contain factor VII) or 4 coagulation factors (Factors II, VII, IX, and X), depending on the preparation: 

• is preferred to FFP in cases of major bleeding [8]
• In a clinical trial that randomly assigned 216 patients with warfarin-associated bleeding to receive PCC or FFP with intravenous vitamin K, PCC was found to be at least as effective as FFP with similar hemostasis (72% vs 65%) and similar length of hospital stay (median 4.5 vs 4.2 days).
• The dose of PCC varies depending on INR, ranging from 25 to 50 units/kg. Higher dose: 5000 UI. If rFVIIa is used to supplement 3-factor PCC, a lower dose is preferred (20 mcg/kg). 
• Recombinant-activated factor VIIa (rFVIIa) is used off-label for warfarin reversal: it corrects INR but not fully restore hemostasis [9].

Two case series have reported thromboembolism rates ≥10% with rFVIIa [10,11]; a randomized trial compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo: thromboembolic events were similar in the three groups, but severe events were more common in those who received high-dose rFVIIa [12].

1. 4-factor PCC (4F PCC) is the preferred approach:

1. Give 4F PCC 1500 to 2000 Units IV over 10 min. Check INR 15 minutes after completion of the infusion. If INR is not ≤1.5, give additional 4F PCC.[Body weight-based and INR-based dosing: 25 UI/kg for INR 2 – 4; 35 UI/kg for INR 4 – 6; 50 UI/kg for INR >6 (maximum: 5000 UI)]

2. + vitamin K 10 mg IV (in 10 – 20 min).

2. If 4F PCC is not available: 3-factor PCC (3F PCC)

1. Give 3F PCC 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not ≤1.5, give additional 3F PCC.

2. + Factor VIIa 20 mcg/kg IV OR  FFP 2 units IV.

3. + vitamin K 10 mg IV (in 10 – 20 min).

3. If neither is available: FFP.

1. 2 units IV by rapid infusion Check INR 15 minutes after completion of infusion:- If INR ≥1.5:  2 additional units of FFP IV rapid infusion. Repeat process until INR ≤1.5.

2. + vitamin K 10 mg IV (in 10 – 20 min)

3. UFH AND LMWH

Heparin binds reversibly to ATIII and leads to instantaneous inactivation of factors IIa and Xa. The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin.  The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin. The antithrombotic effect of heparin is correlated to the inhibition of factor Xa (FIG. 2).

First: Discontinue heparin.  

Protamine sulfate is a reversal agent that completely reverses UFH:

• 1 mg of protamine sulfate neutralizes 100 units of heparin (eg 4000 UI : 40 mg of Protamine)
• The number of heparin units to be corrected depends on the heparin units administered and the time since the last administration (Heparin half-life: 1-2 h): if 4000 units was given 2 h ago, the number of units would be 2000 and the dose of protamine would be 20 mg).
• Alternatively a fixed dose of 50 mg or 25 mg may be given: someone give 50 mg while others give 25 mg followed by 25 mg if needed (eg, persistently prolonged aPTT).
• Protamine must be given by slow intravenous infusion (infusion rate < 20 mg/min or 50 mg/10-minute), because rapid infusion cause hypotension, particularly at high doses. Other related adverse effect are: cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension.
• In case of persistently high aPTT levels repeat doses may be given
• Protamine is derived from fish sperm and may elicit an allergic reaction, especially in previously exposed.

Protamine sulfate completely reverses the action of UFH but not of LMWH. A potential reversal agent for LMWH, aripazine is under development:

• Andexanet is preferred rather than protamine: efficacy was demonstrated in the ANNEXA-4 study where a small group of 16 people received LMWH [13].
• Protamine is less effective in reversing the effect of LMW heparin: Protamine only reverses ∼ 60 %  due to decreased binding to the shorter heparin chains. (is a reasonable treatment option if LMWH have been administrated within the previous 12 hours):
  • LMWH administered < 8 h: 1 mg protamine per 1 mg of enoxaparin.
  • LMWH administered ≥ 8 h, or if it has been deemed that a second dose of protamine is necessary: 0.5 mg protamine per 1 mg of enoxaparin.

4. FONDAPARINUX

Fondaparinux is a synthetic heparin pentasaccharide with a sequence identical to that found in heparin which acts by binding to antithrombin and inducing a conformational change that causes inhibition of factor Xa (half-life: 17-21 h).

• Protamine sulfate is ineffective for fondaparinux reversal.
• Andexanet is a reasonable option if it is available: It is a catalytically inactive form of factor Xa able to bind and sequester direct factor Xa inhibitors and is likely to be effective also for reversing indirect-acting factor Xa inhibitors like fondaparinux. [14,15].
• aPCC and rFVIIa may provide reversal against fondaparinux activity: clinical data are limited to in vitro studies rather than management of patients with bleeding [16,17]; aPCC better normalize thrombin generation time than rFVIIa. The high thrombotic risk of these agents should always be kept in mind and weighed against the bleeding risk.

5. DABIGATRAN

Dabigatran reversibly binds to the active site on the Factor II (Thrombin), preventing thrombin-mediated activation of coagulation factors. 

Dabigatran has an emergency reversal agent: Idarucizumab. It is an anti-dabigatran monoclonal antibody fragment. Other options, If Idarucizumab is not available, are PCC and FFP. 

If idarucizumab if available this is the drug of choice, rather than clotting factor products (aPCC, PCC, or plasma).

Unabsorbed dabigatran can be removed from the gastrointestinal tract using oral activated charcoal if the last dose was within 2 h. Dabigatran can also be removed by hemodialysis.

Idarucizumab:

• The dose is 5 g, administered either as two consecutive infusions (2.5 g + 2.5 g) or as a bolus. Repeat dosing may be appropriate in selected cases as overdose or persistently prologed aPTT.
• Use idarucizumab alone: Do not combine with PCC, aPCC, or rFVIIa.
• Thrombosis were more common with idarucizumab: These are associated with due to the patient’s underlying thrombotic risk factors.

Other:

• Activated PCC: dose of 50 to 80 units/kg. The aFVII activates the free factor X and may bypass dabigatran effect and promote clotting.
• Alternatively, 4-factor or 3-factor PCC at a dose of 50 units/kg would be reasonable. Three-factor PCC may be supplemented with rFVIIa or plasma. 
• Activated charcoal and dialysis

6. RIVAROXABAN, EDOXABAN and APIXABAN

Apixaban, Edoxaban and Rivaroxaban are direct inhibitor of free and clot-bound factor Xa.

For patients with major bleeding and anticoagulation with a factor Xa inhibitor, andexanet alfa or 4F  PCC are indicated. These agents have not been directly compared in a randomized trial. 

• Discontinue factor Xa inhibitor

ANDEXANET

In patients who received a lower dose of factor Xa inhibitor (rivaroxaban ≤10 mg, apixaban ≤5 mg, edoxaban ≤30 mg) or ≥ 8 h since the last dose of factor Xa inhibitor: bolus of 400 mg at 30 mg/min over 30 minutes, followed by an infusion of 480 mg given at 4 mg/min for up to 120 minutes. For those who receives a higher dose of factor Xa inhibitor, unknown dose or <8 h:  bolus of 800 mg at 30 mg/min over 30 minutes, followed by an infusion at 960 mg given at 8 mg/min for up to 120 minutes Do not combine andexanet with PCC, aPCC or rFVIIa.

4F PCC

50 units/kg, or a fixed-dose regimen (2000 – 2500 units)

Unabsorbed anticoagulant can be removed from the gastrointestinal tract using oral activated charcoal.

7. ANTIPLATELET  DRUGS

The AABB (American Association of Blood Banks) developed this guidelines on appropriate use of platelet transfusion in adult patients:

Recommendation 1	The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapyinduced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 × 10^9 cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective. (Grade: strong recommendation; moderate-quality evidence)
Recommendation 2	The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 × 10^9 cells/L. (Grade: weak recommendation; low-quality evidence)
Recommendation 3	The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 × 10^9 cells/L. (Grade: weak recommendation; very-low-quality evidence)
Recommendation 4	The AABB suggests prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than 50 × 10^9 cells/L. (Grade: weak recommendation; very-low-quality evidence)
Recommendation 5	The AABB recommends against routine prophylactic platelet transfusion for patients who are nonthrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. (Grade: weak recommendation; very-low-quality evidence)
Recommendation 6	The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous). (Grade: uncertain recommendation; very-low-quality evidence)

Due to the low level of evidence it was not possible to establish clear guidelines regarding the transfusion of platelets during therapy with antiplatelet agents.

DEVELOPMENT OF REVERSAL AGENTS FOR ANTIPLATELET THERAPY IS AN AREA OF UNMET NEED

Platelet transfusion:

• Platelets should be transfused in patients with a low platelet count (less than 50,000/microL) who are receiving antiplatelet agents (APT).
• In patients with intracerebral hemorrhage (ICH) who are receiving antiplatelet agents, the decision to transfuse platelets is based on:  size of the bleeding, patient’s level of consciousness and clinical factors. For neurosurgery, platelets are transfused prophylactically for a preprocedure platelet count less than 80 – 100 × 10^9 cells/L (low-quality data supporting this threshold) >>> Patients with ICH taking antiplatelet therapy should be transfused platelets only if planned for neurosurgical intervention but not if receiving medical management [20].
• Patients with upper gastrointestinal haemorrhage on APT do not benefit from platelet transfusions. They benefit from urgent endoscopic control of bleeding and proton pump inhibition only [20].
• The optimal dose of platelets and the timing of transfusion in patients on antiplatelet therapy are currently unknown; however, it must be borne in mind that:
  • Clopidogrel or prasugrel: wait at least 6 -8 hours after the last dose. 
  • Ticagrelor: consider transfusion especially if the last dose was >24 hours prior.
  • Aspirin half life: 20 min
• Platelets should not be transfused in patients with normal platelet counts who are on antiplatelet medications [21]. 
• Platelet and plasma transfusions should be considered in patients who receive massive RBC transfusions (>3 units of packed RBCs within one hour).
• Consider the use of pre-operative intravenous tranexamic acid which proved  to improve the platelet function of those exposed to APT, resulting in a reduction in bleeding and transfusion.
• rFVIIa may limit bleeding (Off -label): it acts by reversing the effects of APT on thrombin generation [22].  The increase the risk of arterial thromboembolic events is a major side effect:   rFVIIa should be considered only as a last source. 
• Desmopressin may be a useful agent to reduce bleeding and transfusion requirements for people with platelet dysfunction or with a history of recent antiplatelet drug administration (GRADE quality of evidence: very low to moderate) [23].

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AUTHORS

Dr. Lorenzo Pelagatti

Emergency Department – Nuovo Ospedale di Prato S. Stefano – Prato, Tuscany, Italy

High Dependency Unit – AOU Careggi – Florence, Tuscany, Italy

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Dr. Franco Lai

Emergency Department – Nuovo Ospedale di Prato S. Stefano – Prato, Tuscany, Italy

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