4-factor Prothrombin Complex Concentrate Research Articles

Use of three procoagulants in improving bleeding outcomes in the warfarin patient with intracranial hemorrhage

: When patients on anticoagulation present with intracranial bleeding, stopping the bleeding is paramount. Despite the availability of multiple options to reverse anticoagulation, no study has directly compared the effectiveness of the procoagulants recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination, and 4-factor PCC on improving patient outcomes compared with a control. This study examined the medical records of 197 warfarin patients with intracranial hemorrhage, an initial international normalized ratio (INR) greater than 1.5, and who received rFVIIa (26), the combination (84), 4-PCC (50), or no procoagulant, the control group (37). Mortality, length of stay, location discharged, change in INR prior to and postdrug administration, plasma use, and number of thromboembolic complications were used to assess effectiveness. Although INR decreased in all groups (1.31 rFVIIa vs. 2.04 combination vs. 1.41 4-PCC vs. 1.20 control, P = 0.07), the combination group had the greatest percentage to reach an INR of less than 1.3 (46.2 vs. 73.8 vs. 58.0 vs. 43.2%, P = 0.004). The combination and control groups experienced a high, though nonsignificant, number of thromboembolic complications (5.6 vs. 19.0 vs. 7.7 vs. 12.9%, P = 0.533). The rFVIIa group used the most plasma and had the longest length of stay. Mortality did not differ significantly among groups. Although the combination improved INR compared with control, this had a high number of complications. Judicious use of procoagulants is recommended due to their expense and lack of significant improvement in outcomes compared with control.

Three- versus four-factor prothrombin complex concentrates for "factor-based" resuscitation in a porcine hemorrhagic shock model.

Bleeding is a leading cause of preventable death after severe injury. Prothrombin complex concentrates (PCC) treat inborn coagulation disorders and reverse oral anticoagulants, but are proposed for use in "factor-based" resuscitation strategies. Few studies exist for this indication in acidosis, or that compare 3-factor PCC (3PCC) versus 4-factor PCC (4PCC) products. We aimed to assess and compare their safety and efficacy in a porcine model of severe hemorrhagic shock and coagulopathy. Twenty-five adult Yorkshire swine underwent 35% volume hemorrhage, ischemia-reperfusion injury, and protocolized crystalloid resuscitation. Seventeen animals were randomized at 4 hours after model creation to receive a 45-IU/kg dose of either 3PCC or 4PCC. An additional eight animals received autologous plasma transfusion before 4PCC to better characterize response to PCC. Individual factor levels were drawn at 4 hours and 6 hours. The model created significant acidosis with mean pH of 7.21 and lactate of 9.6 mmol/L. After PCC, 66.7% of 3PCC animals and 25% of 4PCC animals (regardless of plasma administration) developed consumptive coagulopathy. The animals that developed consumptive coagulopathy had manifested the "lethal triad" with lower temperatures (36.3°C vs. 37.8°C), increased acidosis (pH, 7.14 vs. 7.27; base excess, -12.1 vs. -6.5 mEq/L), and worse coagulopathy (prothrombin time, 17.1 vs. 14.6 seconds; fibrinogen, 87.9 vs. 124.1 mg/dL) (all p < 0.05). In the absence of a consumptive coagulopathy, 3PCC and 4PCC improved individual clotting factors with transient improvement of prothrombin time, but there was significant depletion of fibrinogen and platelets with no lasting improvement of coagulopathy. PCC failed to correct coagulopathy and was associated with fibrinogen and platelet depletion. Of greater concern, PCC administration resulted in consumptive coagulopathy in the more severely ill animals. The incidence of consumptive coagulopathy was markedly increased with 3PCC versus 4PCC, and these products should be used with caution in this setting.

Outcomes Following Three-Factor Inactive Prothrombin Complex Concentrate Versus Recombinant Activated Factor VII Administration During Cardiac Surgery

To compare outcomes following inactive prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) administration during cardiac surgery. Retrospective propensity-matched analysis. Academic tertiary-care center. Patients undergoing cardiac surgery requiring cardiopulmonary bypass who received either rFVIIa or the inactive 3-factor PCC. Outcomes following intraoperative administration of rFVIIa (263) or factor IX complex (72) as rescue therapy to treat bleeding. In the 24 hours after surgery, propensity-matched patients receiving PCC versus rFVIIa had significantly less chest tube outputs (median difference -464 mL, 95% confidence interval [CI] -819 mL to -110 mL), fresh frozen plasma transfusion rates (17% v 38%, p = 0.028), and platelet transfusion rates (26% v 49%, p = 0.027). There were no significant differences between propensity-matched groups in postoperative stroke, deep venous thrombosis, pulmonary embolism, myocardial infarction, or intracardiac thrombus. Postoperative dialysis was significantly less likely in patients administered PCC versus rFVIIa following propensity matching (odds ratio = 0.3, 95% CI 0.1-0.7). No significant difference in 30-day mortality in patients receiving PCC versus rFVIIa was present following propensity matching. Use of rFVIIa versus inactive PCCs was significantly associated with renal failure requiring dialysis and increased postoperative bleeding and transfusions.

Low-dose Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage with INR Less Than 2.0.

Prothrombin complex concentrates (PCCs) have become the first-line therapy for warfarin reversal in the setting of central nervous system (CNS) hemorrhage. Randomized, controlled studies comparing agents for warfarin reversal excluded patients with international normalized ratio (INR) <2, yet INR values of 1.6-1.9 are also associated with poor outcomes. We retrospectively reviewed our use of a low-dose (15 units/kg) strategy of 4-factor PCC (4F-PCC) on warfarin reversal (INR 1.6-1.9) in the setting of both traumatic and spontaneous intracranial bleeding. A total of 21/134 (15.7%) patients with either spontaneous or traumatic intracranial hemorrhage presented with an INR value of 1.6-1.9. Nine patients (43%) presented with traumatic bleeding and 12 (57%) with spontaneous bleeding. The median (IQR) presenting INR was 1.8 (1.7, 1.9) which decreased to 1.3 (1.2, 1.3) following the administration of low-dose 4F-PCC (median dose=1062 units; 15.2 units/kg). A total of 19/20 (95%) patients achieved a goal INR value of ≤1.5 on the first check following dosing and 17/20 (85%) achieved an INR value ≤1.3. One patient did not have follow-up INR testing due to withdrawal of life support. No patient experienced hematoma expansion within 48h of 4F-PCC, and there were no thromboembolic events within 72h of administration. The administration of low dose (15 units/kg) of 4F-PCC for urgent warfarin reversal in the setting of CNS hemorrhage was effective in correcting the INR in patients presenting with INR values of 1.6-1.9. Further assessment of low-dose PCC for urgent reversal of modest INR elevation is warranted.

The Use of 3- and 4-Factor Prothrombin Complex Concentrate in Patients With Elevated INR

Background: PCC (Kcentra®) is an Food and Drug Administration (FDA)–approved 4-factor PCC used for the treatment of warfarin-related coagulopathy (WRC), but it has also been used off-label to treat non-WRC. Three-factor PCC in the form of coagulation factor IX human (Bebulin®) has also been used for WRC and off-label to treat non-WRC. It is unclear whether the use of 3- or 4-factor PCCs is effective for the treatment of non-WRC,. Objective: Our aim is to characterize the use of 3- and 4-factor PCCs for patients identified with a non-WRC. Methods: A retrospective analysis of patients who received PCCs for both WRC and non-WRC between January 2012 and July 2015 was conducted. Results: A total of 187 patients with elevated international normalized ratio (INR) who received PCCs were analyzed; 53.9% of patients in the WRC group and 27.7% in the non-WRC group corrected to an INR of 1.3 or less after 3- or 4-factor PCC administration. In those patients with non-WRC and who had underlying liver disease, 3- and 4-factor PCCs reduced mean INR by 0.98 and 1.43, respectively. Conclusion: Three and 4-factor PCCs can reduce INR in patients with WRC and in those with non-WRC secondary to liver disease.

Reversal Agents for Oral Antiplatelet and Anticoagulant Treatment During Bleeding Events: Current Strategies.

There is an increasing prevalence of cardiovascular diseases that warrant antithrombotic therapy. Antithrombotic therapy includes antiplatelet agents and anticoagulation therapy with vitamin K antagonists (VKAs) or non-Vitamin K oral anticoagulants (NOACs). Antithrombotic therapy is associated with increased rates of bleeding. In this review we summarize the evidence and provide strategies for the management of severe bleeding in the setting of antithrombotic therapy. There is limited data on the management of bleeding in the setting of antiplatelet therapy. We recommend discontinuation of the antiplatelet, as well as administration of platelet transfusions and desmopressin only in the setting of life-threatening bleeding. For patients presenting with severe bleeding in the setting of VKAs, we recommend discontinuation of VKA and prompt administration of 10 mg intravenous vitamin K plus 50 units/kg 4-factor prothrombin complex concentrate (PCC). If 4-factor PCC is not available 3-factor PCC or fresh frozen plasma (FFP) can be used, but these are inferior to 4-factor PCC. For patients presenting with severe bleeding while on dabigatran, we recommend discontinuation of dabigatran and intravenous administration of 5g idarucizumab. There is currently no available reversal agent for factor Xa inhibitors. Andexanet alpha is a factor Xa-specific inhibitor that is currently undergoing FDA review. Until andexanet alpha becomes available we recommend discontinuation of the factor Xa inhibitor and administration of 50 units/kg 4- factor PCC. The decision to discontinue and/or reverse antithrombotic therapy should be made on a case-by-case basis and the competing risk from discontinuation and/or reversal of antithrombotic therapy should be taken into consideration.

(140) - Four Factor Prothrombin Complex Concentrate and the Risk of Thrombosis in Continuous Flow LVAD

(140) - Four Factor Prothrombin Complex Concentrate and the Risk of Thrombosis in Continuous Flow LVAD

(1121) - Reduced Dose 4-Factor Prothrombin Complex Concentrate Prior to Heart Transplant in Patients with Ventricular Assist Devices

(1121) - Reduced Dose 4-Factor Prothrombin Complex Concentrate Prior to Heart Transplant in Patients with Ventricular Assist Devices

(1120) - Safety and Efficacy of Four Factor Prothrombin Complex Concentrate for the Reversal of Warfarin in LVAD Patients Prior to Heart Transplantation

(1120) - Safety and Efficacy of Four Factor Prothrombin Complex Concentrate for the Reversal of Warfarin in LVAD Patients Prior to Heart Transplantation

Abstract TP328: Ischemic Stroke Following Prothrombin Complex Concentrates Administration for Intracerebral Hemorrhage

Intro: There have been case reports of ischemic infarcts after treatment with prothrombotics for anticoagulation reversal following spontaneous intracerebral hemorrhage (ICH), though there have been no systematic studies evaluating MRI infarction following prothrombin complex concentrate (PCC) or factor eight inhibitor bypassing activity (FEIBA) administration. We evaluated the prevalence of ischemic infarcts on diffusion-weighted imaging (DWI) in ICH patients who received prothrombotics compared to those who did not. Methods: We performed a retrospective review of patients admitted with ICH between January 2013 and April 2016 in whom MRI brain with DWI imaging was performed within 2 weeks of admission and prior to digital subtraction angiography. PCC (4-factor Kcentra, weight, and INR based dosing) was administered to patients on warfarin at the time of ictus with a INR≥1.4 and FEIBA (50 u/kg) was given to patients exposed to an oral Factor Xa inhibitor or direct thrombin inhibitor if ICH occurred within 3-5 half lives of the last dose. Acute ischemia was defined as DWI hyperintensity with corresponding apparent diffusion coefficient hypointensity. Perihematoma lesions, and procedure-related infarctions were excluded from analysis. Groups were compared using chi-square and Wilcoxon Rank Sum tests. Results: A total of 254 patients were enrolled. Of these, 41 (16%) received either 4-factor PCC (n=33) or FEIBA (n=8). Comparing those who received prothrombotics to those who did not, there was no difference in age (median 68 with prothrombotics and without; p=0.724), sex (44% female in both groups; p=0.977), initial NIH Stroke Scale (median 6 versus 8, p=0.838), or hematoma volume (median 15ml versus 10ml; p=0.207). Patients who received prothrombotics were more likely to have lobar ICH than deep ICH (71% versus 47%; p=0.005). DWI infarctions were found in 16% of patients who receive PCC or FEIBA compared with 22% who did not (p=0.404). Conclusions: Our data suggests prothrombotics do not increase the risk of acute ischemic infarcts within two weeks of administration.

Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Vitamin K Antagonist Reversal in Acutely Bleeding Patients: A Retrospective Study

▪IntroductionVitamin K antagonist (VKA) drugs require immediate reversal in VKA-treated patients with major bleeding or requiring urgent surgery. 4-factor prothrombin complex concentrates (PCCs)are approved for urgent VKA reversalbecause they reverse the international normalized ratio (INR) more rapidly than fresh frozen plasma (FFP). Studies comparing the clinical benefits of PCC and FFP have focused on VKA reversal prior to urgent surgery. Few data comparing laboratory and clinical outcomes of patients receiving PCC or FFP for major hemorrhage have been published, and these pertain to intracranial hemorrhage (ICH) only. Given the complexity of performing randomized studies in this setting, observational studies are relevant to inform on this issue.AIMSTo compare the effects of PCC versus FFP on patient outcomes in VKA-associated major hemorrhage. The primary outcomes were the rate of INR reversal and blood product utilization. The secondary outcome was duration of intensive care and total hospital admission.MethodsWe performed a retrospective, single-center study of consecutive unselected patients receiving a 4-factor PCC for VKA reversal because of hemorrhage between January 2012 and April 2015 compared to consecutive unselected patients treated with FFP for the same indication from January 2010-December 2011, a period prior to introduction of PCC at the Meir Medical Center. Patients were identified by review of clinical and blood bank electronic medical records. We analyzed patient demographics, indication for VKA, underlying illnesses, aspirin use, site and severity of hemorrhage, INR pre- and post reversal, rate of INR reversal, transfusion requirements and duration of hospitalization, treatment.Results56 patients received PCC and were compared to 56 patients treated with FFP. In the PCC group 17 patients had ICH and 25 had gastrointestinal hemorrhage compared to 17 and 31 patients respectively in the FFP group. Patients were adjusted for age, sex, presence of renal failure, active cancer, aspirin use, site of hemorrhage, pre-treatment INR and hemoglobin concentration and hemorrhagic shock at presentation. Outcomes: Median time to INR of ≤1.3 was 0.5 (range 0.5-1.5) vs 15.5 (range 5-96) hours for PCC vs FFP respectively, P<0.001). Packed red cell transfusion did not differ between the groups: median =1(range 0-13) in the PCC group and median= 2(range=2-10) in the FFP group (P=0.3), but more FFP was transfused in the FFP vs PCC group median =0(range 0-8) in the PCC group and median= 4(range=2-8) in the FFP group (P<0.001). Duration of hospital admission was longer in the FFP (median=7 days, range 1-93) vs PCC patients (median =6 days, range=1-35) (P=0.04).ConclusionThis is the first observational study comparing PCC and FFP for VKA-related hemorrhage to our knowledge and the first study of PCC versus FFP for extracranial VKA-related hemorrhage. PCC was more effective than FFP in for reversal of the INR and was associated with less overall FFP use but not packed red cell transfusion. Similarly hospital admission duration was shorter among the PCC patients. Larger studies are required to determine whether PCC confers other clinical benefits over FFP for VKA reversal in acutely bleeding patients. DisclosuresEllis:Boehringer Ingelheim: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau.

Comparison of Long-term Functional Outcomes Following Treatment With and Without 4-Factor Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage

Comparison of Long-term Functional Outcomes Following Treatment With and Without 4-Factor Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage

Retrospective study of rFVIIa, 4-factor PCC, and a rFVIIa and 3-factor PCC combination in improving bleeding outcomes in the warfarin and non-warfarin patient.

In case of severe bleeding, the physician must rapidly and effectively halt bleeding without the risk of thromboembolic complications. Despite widespread use, no study has directly compared recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination ("combination"), and 4-factor PCC on their effectiveness in improving patient outcomes. This study examined the medical records of 299 patients, 65.2% on warfarin prior to admission, who received these hemostatic agents and were admitted to an ICU or through the emergency department at Oregon Health & Science University. Mortality, length of stay, change in international normalized ratio (INR), plasma use, and number of thromboembolic complications were used to assess effectiveness. In patients receiving warfarin, the combination group had the greatest decrease in INR as well as lowest overall INR, but experienced a higher number of clotting complications, while the rFVIIa group used the most plasma. Non-warfarin patients in the combination group had the shortest length of stay among survivors, but the rFVIIa group had the lowest mortality. Based on this data, it may be prudent to further study the use of rFVIIa in treating extreme bleeding in the non-warfarin patient, while this study supports other data that 4-factor PCC may be the most prudent for the warfarin patient. Am. J. Hematol. 91:705-708, 2016. © 2016 Wiley Periodicals, Inc.

Emergent reversal of vitamin K antagonists: addressing all the factors

BackgroundReversal 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. MethodsRetrospective 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). ResultsEighty-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). ConclusionsUse 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.

Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center

BackgroundThe U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal. The literature supporting its use over three-factor prothrombin complex concentrate (3-PCC) is limited. ObjectiveOur objective was to retrospectively compare the efficacy of 3-PCC to 4-PCC in reversing warfarin in patients who were actively bleeding. MethodsWe conducted a single-center, retrospective cohort analysis of adult patients who received 3-PCC or 4-PCC for international normalized ratio (INR) reversal. Our study excluded patients not actively bleeding and not on warfarin. The main outcome was the percentage of patients who achieved warfarin reversal defined as INR ≤ 1.3 at first INR check post factor administration. We recorded baseline data including PCC dose, location of bleed, pre- and posttreatment INR, and time to INR reversal. ResultsWe included a total of 53 patients. Intracranial hemorrhage was the most common site of bleeding (26 [74.3%] in 3-PCC vs. 12 [66.7%] in 4-PCC). The mean dose of 3-PCC was 25.5 units/kg, compared to 27.9 units/kg of 4-PCC. The mean baseline INR was 2.3 in the 3-PCC group and 3 in the 4-PCC group (p = 0.03), and the first posttreatment INRs were 1.4 and 1.2, respectively (p < 0.01). Warfarin reversal was achieved in 15 (42.9%) patients who received 3-PCC and 15 (83.3%) patients who received 4-PCC (p < 0.01). Faster time to INR reversal was noted in the 4-PCC group vs. the 3-PCC group (3.7 vs. 5 h, p = 0.48). ConclusionA higher percentage of patients achieved warfarin reversal with 4-PCC compared to 3-PCC treatment. A prospective randomized control trial is necessary to confirm our results.

Periprocedural warfarin reversal with prothrombin complex concentrate

IntroductionApproximately 10% of chronically anticoagulated patients require an invasive procedure annually. One in 10 procedures is emergent and requires prompt anticoagulation reversal. The study objective is to determine the safety and efficacy of a 3 factor prothrombin complex concentrate (PCC) for periprocedural anticoagulation reversal. Materials and MethodsConsecutive patients receiving 3 factor PCC for warfarin reversal for either urgent/emergent invasive procedures or major bleeding were analyzed. Primary endpoints included percent achieving INR <1.5, peri-operative major hemorrhage, thromboembolism and death during the 40day post-infusion period. ResultsBetween January 1, 2010–December 31, 2012, 52 patients were treated with PCC for pre-procedural warfarin reversal and 113 patients for major bleeding. Within the peri-procedure group, there were 24 intra-abdominal surgeries, 12 percutaneous interventions, 6 cardiothoracic surgeries, 5 orthopedic and 3 endoscopic procedures. INR values <1.5 were achieved in 51% at 2.5h post-infusion. Major bleeding (13%), thromboembolism (13%) and mortality rates (15%) were high. Within the major bleeding group, PCC therapy reversed INR values (<1.5) in 75% of patients within 4h. For this group, thromboembolism (21%) and mortality rates (16%) were likewise high. Post-PCC anticoagulation, reinitiated in 37%, had no impact on bleeding or thrombotic complications. Mortality rates were threefold higher for those patients not restarting warfarin therapy. ConclusionsAlthough PCC therapy promptly and effectively reverses INR values for patients requiring urgent/emergent invasive procedure both thromboembolic and fatal complications are soberingly high and call for judicious use of these agents in these high risk populations.

Administration of 4-Factor Prothrombin Complex Concentrate as an Antidote for Intracranial Bleeding in Patients Taking Direct Factor Xa Inhibitors

Direct factor Xa inhibitors rivaroxaban and apixaban are efficacious alternatives to warfarin and confer a lower risk of spontaneous intracranial hemorrhage (ICH); however, they lack a validated reversal strategy. We evaluated the efficacy and safety of 4-factor prothrombin complex concentrate (PCC) administration on rivaroxaban- and apixaban-mediated coagulopathy in patients with traumatic and spontaneous ICH. Retrospective review of patients presenting with traumatic and spontaneous ICH and concurrent use of rivaroxaban or apixaban. Demographic factors, reason for anticoagulation, hemorrhage type and location, Glasgow coma scale score, and when appropriate, ICH score, were included. Patient charts were reviewed for in-hospital mortality, thromboembolic events, pulmonary complications, worsening of hemorrhage, hemorrhagic complications after neurosurgical intervention, and 90-day modified Rankin scale score. Eighteen patients met inclusion criteria; 16 used rivaroxaban and 2 used apixaban. Eight patients presented with traumatic ICH, 8 with hemorrhagic stroke, 1 with subarachnoid hemorrhage, and 1 patient with tumoral hemorrhage. Mean Glasgow coma scale score was 12.6 (range, 6-15) and mean ICH score was 2.3 (range, 0-4). After reversal with PCC, 1 patient (5.6%) demonstrated worsening of ICH on follow-up head computed tomography. PCCs were administered before emergent placement of an external ventricular drain in 1 individual, with no hemorrhagic complications. Six patients (33.3%) experienced in-hospital mortality: family withdrew care in 4 and 2 died due to pneumonia. There was 1 (5.6%) thromboembolic complication. Favorable outcomes at 90 days were seen in 6 patients (33.3%). Despite no studies demonstrating the efficacy of 4-factor PCC administration for reversal of coagulopathy in patients on direct factor Xa inhibitors, our early experience demonstrates it to be safe, yet potentially reducing hemorrhagic complications and hematoma expansion in this critically ill population.

Different Heparin Contents in Prothrombin Complex Concentrates May Impair Blood Clotting in Outpatients With Ventricular Assist Devices Receiving Phenprocoumon.

Prothrombin complex concentrates (PCCs) are used to rapidly reverse anticoagulation by oral vitamin K antagonists. They differ in the content of clotting factors, endogenous anticoagulants, and heparin. The authors hypothesized that PCCs' specific heparin content may compromise the hemostatic effect. Prospective ex-vivo investigation. University hospital. Venous blood samples were obtained from 8 patients with implanted ventricular assist devices who also were receiving phenprocoumon. Four different 4-factor PCCs were added to patient blood to attain a calculated increase in prothrombin time by 20%, 40%, and 60% greater than baseline in paired experiments. Clotting was measured using thromboelastometry and endogenous thrombin potential. Two heparin-containing PCCs prolonged the clotting times in a concentration-dependent manner compared with baseline (p<0.01) and compared with PCCs containing significantly less or no heparin (p<0.01). The PCCs containing low or no heparin enhanced the area under the curve of thrombin generation and peak thrombin several fold relative to the heparin-containing PCCs (p<0.01). One of the PCCs containing heparin even decreased peak thrombin generation by ~90% compared with baseline (p<0.01). PCC with low or no heparin shortened the lag phase (p<0.01), whereas 1 heparin containing PCC prolonged the lag phase by 66% (p<0.01). Physicians should be aware of the differences in heparin contents. Extrapolation of results from one agent to other PCC preparations may be difficult. Patients with an implanted left ventricular assist device and anticoagulated with vitamin-K antagonists could benefit from the use of PCC with low heparin content when surgery or bleeding requires emergency reversal. Further clinical studies are warranted.

(123) - The Use of Three Factor Prothrombin Complex Concentrate to Reverse Warfarin Treated Mechanical Circulatory Device Patients Immediately Prior to Heart Transplant

To assess whether patients who are bridged to heart transplant by mechanical circulatory support (MCS) devices have lower incidences of bleeding and blood product transfusion when pre-treated with three factor prothrombin complex concentrate (PCC) immediately prior to heart transplant.

Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate.

The oral thrombin inhibitor dabigatran has the drawbacks that it does not have a validated antidote. Data from animal studies and plasma coagulation assays suggest that prothrombin complex concentrate (PCC) or recombinant factor VIIa (FVIIa) might reverse dabigatran anticoagulation. Cellular elements make a significant contribution to hemostasis. Our goals were to (1) test the hypothesis that both FVIIa and a 4-factor PCC improve parameters of thrombin generation in the presence of dabigatran in a cell-based model; and (2) determine whether results in a cell-based model correlate with hemostasis in vivo. PCC reversed dabigatran effects on the rate, peak, and total amount of thrombin but did not shorten the lag (n = 6 experiments in triplicate). By contrast, FVIIa shortened the lag, increased the rate and peak, but did not improve total thrombin (n = 6). Effects of PCC were seen at both therapeutic and markedly supratherapeutic dabigatran levels, whereas beneficial effects of FVIIa decreased as the dabigatran level increased. The PCC effect was reproduced by adding prothrombin, factor X, and factor IX. At therapeutic dabigatran levels, both PCC and FVIIa normalized hemostasis time in a mouse saphenous vein bleeding model. A cell-based model reflects the effects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. Enhancing the rate of thrombin generation and peak thrombin level appear to correlate best with hemostasis in vivo. The ineffectiveness of FVIIa at supratherapeutic dabigatran levels may explain conflicting reports of its efficacy in dabigatran reversal.