Anticoagulation Reversal


Reversing Warfarin EMERGENTLY

The American Heart Association among others now recommends using prothrombin complex concentrates — basically, powderized coagulation factors extracted from plasma — for emergent reversal of anti-coagulation in the setting of life-threatening bleeding.

The definition of life-threatening bleeding is obviously a clinical decision; it would include most intracranial hemorrhages and might include uncontrolled traumatic or GI bleeding in certain patients.

Dosing recommendations vary and are available in the package inserts, but in the cases of Kcentra, Profilnine and FEIBA, a reasonable starting dose is 25 units / kg.

Common PCCs include:

Kcentra. Marketed in Europe as Beriplex where it has a 20-year record of reasonably safe use. It is a 4-factor PCC and the only one FDA-approved for emergent anti-coagulation reversal. (Others, such as FEIBA and Profilnine, were developed for hemophilia management but also contain Warfarin-associated factors and so have been routinely given off-label for this indication.)

Profilnine SD (a.k.a. Factor IX Complex Profilnine SD).

FEIBA, or "Factor Eight Inhibitor Bypassing Activity". This is a suite of "activated" clotting factors, meaning: You aren't just repleting the missing factors, but you already have them turned on & primed to clot. Most other PCCs, including Profilnine and Beriplex / Kcentra, are not "activated." Beriplex / Kcentra, in fact, actually contains small amounts of heparin and Protein S, to help prevent over-clotting. (If you are protesting that Warfarin does not work on Factor 8, that is correct. But FEIBA also contains Factors 2, 7, 9 and 10 in addition to "Factor 8 Inhibitor Bypassing Activity" and "Factor 8 Coagulant Antigen.)

For comparison, here are the amounts of coagulation factors available:

Treatment II VII IX X
FFP (1 unit, or 250 mL) 250 250 250 250
Kcentra 1,000 units 760-1,600 400-1,000 800-1,240 1,000-2,040
Profilnine SD 1,000 units 1,500 350 1,000 1,000

(Each package insert reports the data differently; the Profilnine insert says "no more than" the amount given, Kcentra gives a range of amount, and the FEIBA package insert says nothing about it. But this gives a rough idea.)

A 70-kg patient receiving 25 units / kg of PCC would receive 1,750 units. A comparable amount of clotting factor from FFP would be about 6-8 units of FFP.

You generally should use Vitamin K in conjunction with PCCs just as you would if reversing Warfarin with FFP.

The main adverse effect to watch for would be undesirable clotting. (Presumably the patient was anti-coagulated for a reason.) Since these are also powderized blood products, there is a very small risk of passing on viral or prion infection.

According to 2010 guidelines from the American Heart / American Stroke Association for managing Warfarin-associated intracranial hemorrhages, “Although PCCs may theoretically increase the risk of thrombotic complications, this risk appears relatively low.”

Note that:
- An actively bleeding patient may also need FFP
- A patient with an elevated INR from liver disease may also need FFP as they will be short of all clotting (and anti-clotting) factors and not just the Warfarin / Vitamin K associated ones

Pregnancy category C.

Reversal of New Anti-Coagulants

There are no great options for reversal of many newer agents, including Rivaroxaban (Xarelto), Dabigatran (Pradaxa), Apixaban (Eliquis), and Fondaparinux.

PCCs have been given in attempts to reverse all of those agents, with some limited success.

There is some relatively weak data here and here suggesting FEIBA might be superior for reversing anticoagulation of Dabigatran in particular.

Reversal of Anti-Platelet Agents

Anti-platelet agents such as Clopidogrel (Plavix) or Aspirin can be safely and effectively reversed with DDAVP / Desmopressin. 0.3 mcg / kg IV

Reversal of Heparins

Recommendations: Ifseriousorlifethreateningbleeding
Protamine 1 mg IV for each 100 units of IV HePARin received in the past 2-3 hours (Max 50 mg)
 Hold HePARin, give Protamine mg IV in 50 mL NS over 30 minutes, repeat AXA in 4 hours

Recommendations: Ifseriousorlifethreateningbleeding For Enoxaparin (Lovenox) given in the past 8 hours:
Give 1 mg Protamine for each 1 mg Enoxaparin (Max 50 mg)
For Enoxaparin (Lovenox) given between 8 and 12 hours ago:
Give 0.5 mg Protamine for each 1 mg Enoxaparin (Max 50 mg)
For Enoxaparin (Lovenox) given greater than 12 hours ago:
Protamine is not recommended unless there is renal impairment
For persistent bleeding after first dose of Protamine:
May repeat with 0.5 mg Protamine for each 1 mg Enoxaparin (Max 50 mg)
 Hold Enoxaparin (Lovenox), give Protamine mg IV in 50 mL NS over 30 minutes, repeat AXA in 4 hours

Reversal of tPA

The most feared complication of IV thrombolysis for acute stroke is ICH, which occurs most commonly in older patients with severe deficits and large areas of ischemia at presentation (1,2). Most symptomatic ICHs after IV thrombolysis for stroke occur in the first 24 hours. Generally, small petechial hemorrhages do not require active intervention (1).

There is no universally accepted standardized guideline for reversal of thrombolysis-associated hemorrhage. Management algorithms are empirical rather than data based.

Administer cryoprecipitate (0.15 U/kg) if fibrinogen level <150 mg/dL
Antifibrinolytics (e.g. tranexamic acid 1000 mg) have not been well studied, but their use is backed by solid pathophysiologic rationale. Tranexamic acid competitively inhibits the activation of plasminogen and may stabilize hemorrhage expansion (1,3)
Consider platelet transfusion if platelet count < 100 x 109 or platelet dysfunction is suspected.

A suggested management algorithm may be found in the PDF Database.

(1) Fugate JE, et al. Mayo Clin Proc, epub, April 28 2014.
(2) Saver JL. Stroke 2007;38(8):2279-2283.
(3) French KF, et al. Neurocrit Care 2012;17(1):107-111.

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