Emergent reversal of vitamin K antagonists: addressing all the factors.

BACKGROUND: Reversal of warfarin-induced coagulopathy after traumatic injury may be done exclusively with prothrombin complex concentrates (PCCs). No direct comparisons between different PCC regimens exist to guide clinical decision-making. Our institution has used 2 distinct PCC strategies for warfarin reversal; a 3-Factor PCC (Profilnine) combined with activated Factor VII (3F-PCC+rVIIa), and a 4-Factor PCC (Kcentra) given without additional factor supplementation. METHODS: Retrospective review of all PCC administrations to trauma patients with acute bleeding who were taking warfarin before injury. Primary endpoints were international normalized ratio (INR) reduction, in-hospital mortality, and diagnosis of deep venous thrombosis (DVT). RESULTS: Eighty-seven patients were identified from 2011 to 2015. Fifty-three were treated with 3F-PCC+rVIIa and 34 with 4F-PCC. Patient demographics, injury severity, and presenting laboratory data were similar. The 3F-PCC+rVIIa produced a lower median (IQR) INR postreversal compared with 4F-PCC (.75 (.69, 1.00) vs 1.28 (1.13, 1.36), P<.001). Both regimens were able to obtain an INR lower than 1.5 immediately after administration (3F+rVIIA 93.9% vs 4F 97.1%, P =.51). In the 4F-PCC group, there was a significant decrease in the incidence of DVT (2.9% vs 22.6%), P < .01), and a nonsignificant reduction in mortality (2.9% vs 17.0%, P = .08). CONCLUSIONS: Use of 4F-PCC for warfarin reversal after traumatic hemorrhage is associated with a less severe decrease in INR, a significant reduction in DVT rates and a trend toward reduced mortality when compared with similar patients treated with 3F-PCC+rVIIa.

Prothrombin complex concentrates as reversal agents for new oral anticoagulants: lessons from preclinical studies with Beriplex.

Although new oral anticoagulants (NOACs) represent an advance in anticoagulant therapy over vitamin K antagonists (VKAs), they nevertheless have a low, but significant risk for bleeding complications. Reversal agents for VKAs, such as prothrombin complex concentrates (PCCs), are currently being evaluated in preclinical studies for NOAC reversal. This article reviews the preclinical data for the most extensively studied PCC for NOAC reversal, Beriplex, a 4-factor PCC. The results from the Beriplex studies are also compared with those obtained with other reversal agents, including different nonactivated PCCs, activated PCCs, and recombinant activated factor VII.

Rapid Warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate.

OBJECTIVE: To compare the safety and effectiveness of three methods of reversing coagulopathic effects of warfarin in patients with potentially life-threatening intracranial hemorrhage. METHODS: A retrospective electronic medical record review of 63 patients with warfarin-related intracranial hemorrhage between 2007 and 2010 in an integrated health care delivery system was conducted. The three methods of rapid warfarin reversal were fresh-frozen plasma (FFP), activated factor VII (FVIIa; NovoSevenRT [Novo Nordisk, Bagsværd, Denmark]), and prothrombin complex concentrate (PCC; BebulinVH [Baxter, Westlake Village, California, USA], ProfilnineSD [Grifols, North Carolina, USA]), each used adjunctively with vitamin K (Vit K, phytonadione). We determined times from reversal agent order to laboratory evidence of warfarin reversal (international normalized ratio [INR]) in the first 48 hours and compared INR rebound rates and complications in the first 48 hours. RESULTS: Reversal with FFP took more than twice as long compared with FVIIa or PCC. To reach an INR of 1.3, mean (±SD) reversal times were 1933 ± 905 minutes for FFP, 784 ± 926 minutes for FVIIa, and 980 ± 1021 minutes for PCC (P < 0.001; P < 0.01 between FFP and FVIIa, P < 0.05 between FFP and PCC). INR rebound occurred in 0 of 31 patients for FFP, 4 of 8 for FVIIa, and 0 of 7 for PCC (P = 0.001). Complications were uncommon. FVIIa was 15 and 3.5 times as expensive as FFP and PCC, respectively. CONCLUSION: As an adjunct to Vit K for rapid warfarin reversal, FVIIa and PCC appear more effective than FFP. Either FVIIa or PCC are reasonable options for reversal, but FVIIa is considerably more expensive and may have greater risk of INR rebound.

Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose.

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.

Preclinical trauma studies of recombinant factor VIIa.

Preclinical studies in animals and ex vivo human blood have provided a solid rationale for conducting prospective randomized trials in trauma patients. Small animal models have been utilized to study the efficacy of recombinant activated factor VII (rFVIIa; NovoSeven) in treating thrombocytopenic rabbits and for the reversal of anticoagulation. Safety models in the rabbit also exist to test for systemic activation of clotting and pathologic thrombosis. Animal models simulating traumatic injuries in humans have primarily been performed in pigs because of species similarities in terms of coagulation characteristics and the larger internal organs. The pig studies, utilizing human rFVIIa, have shown increased strength of clot formation, decreased bleeding, and improved survival. However, these findings are not uniform and are dependant on the model chosen. All of the animal models described have provided good safety data and suggest that the use of rFVIIa is not associated with systemic activation of coagulation or microthrombosis of end organs.

Effect of recombinant FVIIa in hypothermic, coagulopathic pigs with liver injuries.

BACKGROUND: Previous experiments with diverse pig models to evaluate the ability of rFVIIa to reduce hemorrhage have provided divergent results. The current study was conducted to address concerns related to previous work by using larger sample sizes, and an extended observational period of 4 hours post-injury. The objectives were to evaluate further the hemostatic efficacy and safety of rFVIIa administration after traumatic, uncontrolled hemorrhage. METHODS: Anesthetized, splenectomized pigs (36.6 +/- 0.3 kg; n = 18/group) underwent an approximately 50% isovolemic blood exchange with 33 degrees C 6% hetastarch, and body temperature was adjusted to 32.5 +/- 0.5 degrees C. Subsequently, a Grade V liver injury was inflicted. After 30 seconds, either vehicle or treatment (180 microg/kg or 720 microg/kg rFVIIa) was administered intravenously as a bolus. Concomitantly, laparotomy pads were packed around the liver. Resuscitation with 33 degrees C lactated Ringer's solution (260 mL/min) was initiated and pigs were monitored for 4 hour post-injury or until death. Tissues were collected and examined histologically to assess the presence of disseminated intravascular coagulation (DIC). RESULTS: Liver injuries were comparable among all groups (p = 0.89). Measures associated with in vitro coagulation (prothrombin time, activated partial thromboplastin time, thromboelastographic split-point and R times) were enhanced by rFVIIa administration (p < 0.05). However, neither percent survival (p = 0.82), survival time (p = 0.56), nor blood loss (p = 0.63) were affected by treatment. DIC was not evident in lung or kidney tissue. CONCLUSIONS: These data indicate an inability of rFVIIa at these doses to reduce blood loss, or to increase survival time or percent survival in this pig model. Absence of DIC provides evidence for safe use of rFVIIa under conditions specific to this study.

Strategies for minimizing blood loss in orthopedic surgery.

Several major orthopedic surgical procedures including hip arthroplasty, femoral osteotomy, and spinal fusion may result in significant blood loss and the need for allogeneic blood transfusions. Due to the heightened awareness of the potential deleterious effects of allogeneic blood product administration, several techniques have been evaluated to determine their efficacy in limiting perioperative blood loss. The following article will discuss the options to limit the need for allogeneic blood product administration during orthopedic surgical procedures. These techniques include: general considerations, autologous transfusion therapy, intraoperative and postoperative blood salvage, pharmacologic manipulation of the coagulation cascade, and controlled hypotension. Undoubtedly, many of these techniques are effective alone; however, the goal of performing major orthopedic surgical procedures without the use of allogeneic blood products can only be accomplished by combining several of these techniques.

Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.

Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA). Suggested regimens for control of highly elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma (FFP) or a prothrombin complex concentrate (PCC). In contrast, this communication present the first report on the efficacious use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system (CNS) bleeding emergencies. Pre-treatment INRs ranged from 1.7 to 6.6, and 10 min after a single dose of rFVIIa (10-40 microg/kg) all INRs were

[Factor VII, a therapeutic alternative in the treatment of severe haemoghage disorders]. / Factor VII, alternativa terapéutica en el tratamiento de trastornos hemorrágicos graves.

Plasmatic coagulation has like purpose the formation of a stable clot of fibrina, this process is possible thanks to the intervention of the factors of the coagulation that are plasmatic proteins. Some of these factors are vitamin K dependent (factors II, VII, IX and X) and all except for the factors VIII, XII and XIII which are synthesized in the liver. Three clinical cases of patients are described who present serious hemorrhagic disorders, associated to different hepatic alterations, which do not respond to conventional treatments. As a measure of urgency and therapeutic alternative, the administration of recombinant factor VII is used with the aim of activating the extrinsic pathway of the coagulation and of obtaining a positive answer in the control of the hemorrhage.

Factor VII, alternativa terapeútica en el tratamiento de trastornos hemorrágicos graves / Factor VII, a therapeutic alternative in the treatment of severe haemoghage

La coagulación plasmática tiene como finalidad la formación de un coágulo estable de fibrina. Este proceso es posible gracias a la intervención de los factores de la coagulación que son proteínas plasmáticas. Algunos de estos factores son dependientes de vitamina K (factores II, VII, IX y X) y todos a excepción de los factores VIII, XII y XIII se sintetizan en el hígado. Se describen tres casos clínicos de pacientes que presentan trastornos hemorrágicos graves, asociados a distintas alteraciones hepáticas, que no responden a tratamientos convencionales. Como medida de urgencia y alternativa terapéutica se recurre a la administración de factor VII recombinante, con el objetivo de activar la vía extrínseca de la coagulación y obtener una respuesta positiva en el control de la hemorragia La coagulación plasmática tiene como finalidad la formación de un coágulo estable de fibrina. Este proceso es posible gracias a la intervención de los factores de la coagulación que son proteínas plasmáticas. Algunos de estos factores son dependientes de vitamina K (factores II, VII, IX y X) y todos a excepción de los factores VIII, XII y XIII se sintetizan en el hígado. Se describen tres casos clínicos de pacientes que presentan trastornos hemorrágicos graves, asociados a distintas alteraciones hepáticas, que no responden a tratamientos convencionales. Como medida de urgencia y alternativa terapéutica se recurre a la administración de factor VII recombinante, con el objetivo de activar la vía extrínseca de la coagulación y obtener una respuesta positiva en el control de la hemorragia (AU)

Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries.

BACKGROUND: Intravenous administration of recombinant activated human clotting factor VII (rFVIIa) has been used successfully to prevent bleeding in hemophilia patients undergoing elective surgery, but not in previously normal trauma patients. This study was conducted to determine whether rFVIIa was a useful adjunct to gauze packing for decreasing blood loss from grade V liver injuries in hypothermic and coagulopathic swine. METHODS: All animals (n = 10, 35 +/- 2 kg) underwent a 60% isovolemic exchange transfusion with 6% hydroxyethyl starch and were cooled to 33 degrees C core temperature. The swine then received a grade V liver injury and 30 seconds later, either 180 microg/kg rFVIIa, or saline control. All animals were gauze packed 30 seconds after injury and resuscitated 5.5 minutes after injury with lactated Ringer's solution to their preinjury mean arterial pressure. Posttreatment blood loss, mean arterial pressure, resuscitation volume, and clotting studies were monitored for 1 hour. Histology of lung, kidney, and small bowel were obtained to evaluate for the presence of microvascular thrombi. RESULTS: At the time of injury, core temperature was 33.3 degrees +/- 0.4 degrees C, hemoglobin was 6 +/- 0.7 g/dL, prothrombin time was 19.1 +/- 1.0 seconds, activated partial thromboplastin time was 29.0 +/- 4.8 seconds, fibrinogen was 91 +/- 20 mg/dL, and platelets were 221 +/- 57 x 105/mL, with no differences between groups (p > 0.05). Clotting factor levels confirmed a coagulopathy at the preinjury point. The posttreatment blood loss was less (p < 0.05) in group 1 (527 +/- 323 mL), than in group 2 (976 +/- 573 mL). The resuscitation volume was not different (p > 0.05). One-hour survival in both groups was 100%. Compared with the control group, rFVIIa increased the circulating levels of VIIa and, despite hypothermia, shortened the prothrombin time 5 minutes after injection (p < 0.05). Laboratory evaluation revealed no systemic activation of the clotting cascade. Postmortem evaluation revealed no evidence of large clots in the hepatic veins or inferior vena cava, or microscopic thrombi in lung, kidney, or small intestine. CONCLUSION: rFVIIa reduced blood loss and restored abnormal coagulation function when used in conjunction with liver packing in hypothermic and coagulopathic swine. No adverse effects were identified.

Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII.

Eight patients with inhibitors to factor VIII (4 hemophilia A and 4 nonhemophilic) were treated with recombinant activated factor VII (rFVIIa) to control severe abdominal bleeding. The recombinant factor was supplied under an open-label, emergency-use program to patients previously unresponsive to one or more alternative therapies. Therapy with rFVIIa was administered for nine separate bleeding events; one patient was treated for two separate bleeding episodes. Patients were treated for an average of 9 days and received a mean total dose of 5.2 mg of rFVIIa for control of bleeding. Treatment was considered successful and hemostasis adequate in 7 of the 9 episodes (78%). Treatment with rFVIIa was partially successful in one other episode. Four patients in this series experienced serious adverse events; all the adverse events were considered unrelated to rFVIIa therapy. The results of this limited series indicate that rFVIIa is an effective means of managing life-threatening abdominal bleeding in individuals with hemophilia or acquired antibodies to factor VIII.

Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit.

Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs, possibly due to the accumulation of 125I fibrin in the lungs, followed by a rapid decline of radioactivity, suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight), but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight, rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.