Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers

Ostermann, Helmut; Haertel, Sabine; Knaub, Sigurd; Kalina, Uwe; Jung, Kerstin; Pabinger, Ingrid

doi:10.1160/th07-05-0367

Cited by 83 publications

(76 citation statements)

References 48 publications

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“…The effects of one currently available PCC (Beriplex P/N; CSL Behring, Marburg, Germany) have been studied in healthy volunteers ( n = 15) [36]. Considerable increases in coagulation factor levels were observed, and these were accompanied by increases in plasma concentrations of proteins C and S. Importantly, there was no clinical evidence of thrombosis, and no increase in the thrombogenicity marker D-dimer [36].…”

Section: Differences Between Today's Pccs and Older Productsmentioning

confidence: 99%

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Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

et al. 2011

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Prothrombin complex concentrates (PCCs) are used mainly for emergency reversal of vitamin K antagonist therapy. Historically, the major drawback with PCCs has been the risk of thrombotic complications. The aims of the present review are to examine thrombotic complications reported with PCCs, and to compare the safety of PCCs with human fresh frozen plasma. The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents. The causes of PCC thrombogenicity remain uncertain but accumulating evidence indicates the importance of factor II (prothrombin). With the inclusion of coagulation inhibitors and other manufacturing improvements, today's PCCs may be considered safer than earlier products. PCCs may be considered preferable to fresh frozen plasma for emergency anticoagulant reversal, and this is reflected in the latest British and American guidelines. Care should be taken to avoid excessive substitution with prothrombin, however, and accurate monitoring of patients' coagulation status may allow thrombotic risk to be reduced. The risk of a thrombotic complication due to treatment with PCCs should be weighed against the need for rapid and effective correction of coagulopathy.

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Section: Differences Between Today's Pccs and Older Productsmentioning

confidence: 99%

“…Considerable increases in coagulation factor levels were observed, and these were accompanied by increases in plasma concentrations of proteins C and S. Importantly, there was no clinical evidence of thrombosis, and no increase in the thrombogenicity marker D-dimer [36]. …”

Section: Differences Between Today's Pccs and Older Productsmentioning

confidence: 99%

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

et al. 2011

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“…The doses of PCC were chosen according to the results of studies published previously. 5,8,32,33 The observation period ended 120 minutes after injury. Animals surviving for the whole of this period were euthanized with fentanyl, propofol, and potassium chloride.…”

Section: Liver Injury and Pcc Substitutionmentioning

confidence: 99%

Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury

Grottke¹,

Braunschweig

Spronk

et al. 2011

Blood

121

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Despite increasing use of prothrombin complex concentrate (PCC) to treat hemorrhage-associated coagulopathy, few studies have investigated PCC in trauma, and there is a particular lack of safety data. This study was performed to evaluate PCC therapy in a porcine model of coagulopathy with blunt liver injury. Coagulopathy was induced in 27 anesthetized pigs by replacing approximately 70% blood volume with hydroxyethyl starch 130/0.4 and Ringer's lactate solution; erythrocytes were collected and retransfused. Ten minutes after trauma, animals randomly received PCC (35 or 50 IU/kg) or saline. Coagulation parameters including thromboelastometry, thrombin generation, and blood loss were monitored for 2 hours. Internal organs were examined macroscopically and histologically to determine the presence of emboli and assess liver injury. Total blood loss was significantly lower and survival was higher in both PCC groups versus the control group (P < .05). These outcomes appeared to be dose-independent. Thromboembolism was found in all animals treated with 50 IU/kg PCC; 44% also showed signs of disseminated intravascular coagulation. Liver injury was similar in all animals. In conclusion, 35 IU/kg PCC safely improved coagulation and attenuated blood loss. However, the higher dose of PCC (50 IU/kg) appeared to increase the risk of thromboembolism and disseminated intravascular coagulation. (Blood. 2011;118(7): [1943][1944][1945][1946][1947][1948][1949][1950][1951]

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“…Rapid Beriplex P/N infusion (median 6 mL min −1 ) has additionally been described in patients with hemostatic defects due to severe liver disease [21]. Healthy volunteers participating in a pharmacokinetic study have also received Beriplex P/N rapidly (mean 7.9 mL min −1 ) [25].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the lower volumes of PCC can generally be administered within 10 to 60 min [16][17][18][19][20][21][22][23][24][25][26][27]. Consequently, international normalized ratio (INR) can be very rapidly decreased with PCC, and critical time can be saved under emergency circumstances [24].…”

Section: Introductionmentioning

confidence: 99%

Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate

et al. 2009

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Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex® P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a twophase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min −1 with a median of 7.5 mL min −1 . Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min −1 (95% confidence interval, 1.0-4.3 mL min −1 ) among patients receiving Beriplex P/N volumes ≥80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex® P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness.

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Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers

Cited by 83 publications

References 48 publications

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury

Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate

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