Reversal of Warfarin-Induced Hemorrhage in the Emergency Department

Abstract

Warfarin, an oral vitamin K antagonist, is used to prevent arterial and venous thromboembolism in patients suffering from a multitude of diseases. In 2004, 31 million warfarin prescriptions were dispensed in the United States. Warfarin inhibits the activation of the vitamin K–dependent clotting factors (Factors II, VII, IX, and X) and regulatory proteins (proteins C, S, and Z). It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Annually the frequency of bleeding complications associated with overanticoagulation is 15% to 20%, with fatal bleeds measuring as high as 1% to 3%. The most effective method of warfarin reversal involves the use of Four Factor Prothrombin Complex Concentrate (PCC), which is widely used throughout Europe but is unavailable in the United States. The current therapies available to emergency room physicians in the United States are fresh frozen plasma, recombinant Factor VIIa (rFVIIa), Factor Eight Inhibitory Bypassing Activity, or Three Factor PCC concomitantly administered with vitamin K. We review the advantages and disadvantages of these therapies and recommend Three Factor PCC with small doses of rFVIIa and with vitamin K in life-threatening situations if Four Factor PCC is unavailable.

Spontaneous subcutaneous tissue haematoma associated with warfarin

“…It is estimated that in 1 year, up to 6.5% of patients on anticoagulant therapy will experience a major bleeding event affecting their soft tissue, gastrointestinal tract or urinary tract 3. Approximately 1% of patients will develop a fatal bleed, often an intracranial haemorrhage 3.…”

Reversal of Oral Anticoagulation

“…Although FFP has a relatively quick onset of action and is widely available and inexpensive, it involves administration of a large volume with a corresponding longer infusion time and slower reversal than what is typically achieved with other factor replacement methods. The usual dose for warfarin‐induced bleeding is 15 ml/kg with most patients receiving ~3 units of FFP (range: 1–6 units; each unit averaging 217 ml) . Normalization of coagulation often requires a large volume (2–4 L) of fluid to be administered over a period of 3–6 hours, which can induce volume overload and adversely affect cardiac function, especially in patients with marginal cardiac function.…”

“…Another option for anticoagulation reversal is to administer rFVIIa, thereby replenishing factor VII and increasing coagulant activity through interaction with tissue factor . rFVIIa doses of 10–90 μg/kg produce rapid reversal of warfarin‐associated supratherapeutic INRs . However, administration of rFVIIa has not demonstrated an improvement in clinical outcomes compared with FFP or PCCs.…”

Untitled

“…Bleeding frequency due to warfarin has been estimated to occur (15%-20%) per year, and the life threatening or fatal bleeding, the rates was estimated to be (1%-3%) per year 29 .…”