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1.  Four‐factor prothrombin complex concentrate reverses apixaban‐associated bleeding in a rabbit model of acute hemorrhage 
Journal of Thrombosis and Haemostasis  2015;13(12):2220-2226.
Summary
Background
Apixaban is a direct factor Xa inhibitor approved for the treatment and prevention of thromboembolic disease. There is a lack of data regarding its reversal in cases of acute bleeding or prior to emergency surgery that needs addressing.
Objectives
This study assessed whether a four‐factor prothrombin complex concentrate (4F‐PCC; Beriplex®/Kcentra®, CSL Behring) can effectively reverse apixaban‐associated bleeding in an in vivo rabbit model and evaluated the correlations between in vivo hemostasis and in vitro coagulation parameters.
Methods
For dose‐finding purposes, anesthetized rabbits were treated with a single intravenous dose of apixaban (800–1600 μg kg−1) and, following a standardized kidney incision, volume of blood loss and time to hemostasis were measured. In a subsequent study phase, anesthetized rabbits were treated with apixaban 1200 μg kg−1 followed by 4F‐PCC (6.25–100 IU kg−1), and the effects on the same bleeding parameters were assessed. In parallel, coagulation parameters were monitored.
Results
Dose‐dependent increases in time to hemostasis and total blood loss were observed post apixaban administration. Preincision treatment with 4F‐PCC resulted in a statistically significant reversal in bleeding time (all doses) and volume (doses ≥ 12.5 IU kg−1). Of the coagulation parameters measured, thrombin generation initiated using the RD reagent (phospholipids only) was the most sensitive to in vivo measures of 4F‐PCC's hemostatic efficacy, although some correlations were also observed for prothrombin time and whole blood clotting time.
Conclusions
In this rabbit model of acute hemorrhage, 4F‐PCC showed potential for reversing the bleeding effects of apixaban. Clinical data in apixaban‐treated patients are needed to confirm these results.
doi:10.1111/jth.13165
PMCID: PMC4738416  PMID: 26447393
anticoagulants; apixaban; hemorrhage; preclinical study; drug evaluation; prothrombin complex concentrates
5.  Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs 
Background
Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor IX (FIX) concentrates per week. A FIX molecule with a prolonged half-life has the potential to greatly improve convenience of, and adherence to, prophylaxis.
Objectives
The aim of our studies was to investigate the pharmacokinetic and pharmacodynamic profile of a recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP).
Methods
Cynomolgus monkeys and hemophilia B dogs received single intravenous doses of rIX-FP (50–500 IU kg−1). rIX-FP plasma levels were determined by an activity-based assay (dogs only) and anti-FIX enzyme-linked immunosorbent assay methods. Additionally, activated partial thromboplastin time (aPTT) was determined in hemophilia B dogs. Data were compared with a direct study comparator (recombinant FIX [rFIX]) or previously published data.
Results
Terminal half-life of rIX-FP was prolonged in both species compared with FIX reference data. In hemophilia B dogs, human FIX antigen levels remained above 0.05 IU mL−1 more than three times longer following rIX-FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed observed superior profile. Prolonged pharmacodynamics of rIX-FP was demonstrated with aPTT <60 seconds sustained around four times longer with rIX-FP (5.9 days) than rFIX (1.5 days).
Conclusions
These studies indicate that the recombinant albumin fusion technology successfully improves the pharmacokinetic profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half-life extension in patients with hemophilia B.
doi:10.1111/j.1538-7836.2012.04826.x
PMCID: PMC3928127  PMID: 22726310
factor IX; fusion protein; hemophilia B; rIX-FP; hemophilia B dog; cynomolgus monkey
6.  Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model 
BJA: British Journal of Anaesthesia  2010;105(5):576-582.
Background
Extracorporeal circuit priming and intravascular volume expansion during cardiopulmonary bypass (CPB) may lead to dilutional coagulopathy and excessive diffuse postoperative bleeding. Prothrombin complex concentrate (PCC) containing clotting factors II (FII), VII (FVII), IX (FIX), and X (FX) could be of potential value in correcting dilutional coagulopathy and reducing blood loss.
Methods
Anaesthetized pigs underwent CPB with hypothermia for 2 h at 25°C followed by 1 h of normothermia. Approximately 1 h after CPB, animals randomly received either isotonic saline 1 ml kg−1 or PCC 30 IU kg−1 in a volume of 1 ml kg−1. Diffuse coagulopathic bleeding was assessed as suture hole blood loss from a Gore-Tex patch placed over a full-thickness incision in the left carotid artery.
Results
After CPB, levels of FII, FVII, FIX, and FX declined from baseline by 32% to 48%, and PCC fully or partially reversed those deficits. Median suture hole blood loss after administration of saline placebo was 74 ml. PCC reduced suture hole bleeding by a median of 54 ml with a 95% confidence interval of 6–112 ml (P=0.026) compared with saline. PCC, but not saline, normalized skin bleeding time. Peak thrombin generation markedly decreased after CPB, but then returned in PCC-treated animals to a level higher than baseline by 28.7 nM (14.5–41.1 nM; P=0.031).
Conclusions
PCC was effective in correcting dilutional coagulopathy and reducing diffuse bleeding in an in vivo large-animal CPB model. Further research is warranted on PCC as a haemostatic agent in CPB.
doi:10.1093/bja/aeq216
PMCID: PMC2955534  PMID: 20716565
blood coagulation disorders; cardiopulmonary bypass; haemodilution; haemorrhage; prothrombin complex concentrates
9.  Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model 
BJA: British Journal of Anaesthesia  2009;102(3):345-354.
Background
Fluid resuscitation following traumatic injury causes haemodilution and can contribute to coagulopathy. Coagulation factor replacement may be necessary to prevent bleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) may potentially offer a more rapid and effective means of normalizing coagulation factor levels.
Methods
In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substituted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 ml kg−1 isotonic saline placebo, 25 IU kg−1 PCC, or 15 ml kg−1 FFP. Immediately thereafter, either a standardized femur or spleen injury was inflicted, and coagulation function, including thrombin generation, and bleeding were assessed. An additional group received high-dose FFP (40 ml kg−1) before femur injury.
Results
Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg−1 FFP, PCC shortened the time to haemostasis after either bone (P=0.001) or spleen (P=0.028) trauma and reduced the volume of blood lost (P<0.001 and P=0.015, respectively). Subsequent to bone injury, PCC also accelerated haemostasis (P=0.003) and diminished blood loss (P=0.006) vs 40 ml kg−1 FFP.
Conclusions
PCC was effective in correcting dilutional coagulopathy and controlling bleeding in an in vivo large-animal trauma model. In light of its suitability for more rapid administration than FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in trauma and surgery.
doi:10.1093/bja/aen391
PMCID: PMC2642652  PMID: 19168856
blood, haemodilution; complications, haemorrhagic disorder; complications, trauma; fresh frozen plasma; prothrombin complex concentrate
11.  Combined treatment with C1 esterase inhibitor and antithrombin III improves survival in severe acute experimental pancreatitis. 
Gut  1997;40(4):531-535.
BACKGROUND: Patients with severe acute pancreatitis die of complications closely related to the systemic activation of protease cascades. AIM: To examine the effects of human C1 esterase inhibitor (C1 INH) and antithrombin III (AT III) on two experimental models of acute pancreatitis. METHODS: Oedematous pancreatitis was induced by continuous intravenous infusion of caerulein and haemorrhagic pancreatitis by retrograde injection of sodium taurocholate into the biliopancreatic duct. C1 INH and AT III were given intravenously, either before or after the induction of pancreatitis. Treatment with C1 INH and AT III had no beneficial effect on oedematous pancreatitis. On the other hand, combined C1 INH and AT III therapy improved the survival in haemorrhagic pancreatitis compared with treatment with human serum albumin. This reduction in mortality was found regardless of whether the treatment was given prophylactically or therapeutically. CONCLUSIONS: Treatment with C1 INH and AT III represents a promising therapeutic concept for patients with severe haemorrhagic pancreatitis.
Images
PMCID: PMC1027131  PMID: 9176084
12.  Stimulation of cell-mediated immunity by bestatin correlates with reduction of bacterial persistence in experimental chronic Salmonella typhimurium infection. 
Infection and Immunity  1984;44(1):168-174.
The effect of bestatin, a low-molecular-weight immunomodulating drug isolated from Streptomyces olivoreticuli, on Salmonella typhimurium infection was elaborated. Bestatin enhanced the delayed-type hypersensitivity reaction against S. typhimurium in a dose- and time-dependent manner. Parallel to the activation of delayed-type hypersensitivity reaction, bestatin reduced the amount of persistent bacteria in livers and spleens as well as the amount of necrotic foci found in these organs. This was shown when bestatin was given either prophylactically or therapeutically. The therapeutic effect of bestatin was even seen when the drug was given in the chronic phase of the infection, i.e., 6 days after inoculation of the animals with the infectious agent. No influence of bestatin, however, could be observed on the initial multiplication rate of S. typhimurium and concomitantly on the initial mortality rate of the infected mice. As bestatin has no direct antibiotic effect on S. typhimurium, it must be concluded that the therapeutic effects of the drug on chronic infection must be solely contributed to elevation of the host's own defense mechanisms.
Images
PMCID: PMC263488  PMID: 6368392
13.  Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) 
Background
Recombinant factor VIIa (rFVIIa) is approved for use in controlling bleeding episodes in people with hemophilia who have developed inhibitors to replacement therapy. Due to its short half-life (t½), frequent injections are required, limiting its use as a prophylactic treatment. A novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) has been developed to extend the t½ of rFVIIa.
Objectives
The aim of our studies was to investigate the pharmacokinetic/pharmacodynamic characteristics of rVIIa-FP in preclinical animal species.
Methods
Pharmacokinetic (PK) parameters were derived after single intravenous dosing in hemophilia A mice, rats, rabbits and monkeys. PK analysis was based on human FVII plasma levels determined by measuring FVII antigen levels by ELISA in mice and rats, and FVIIa activity using STACLOT® VIIa-rTF in rabbits and monkeys. Induction of thrombin generation was investigated in mice, while hemostatic activity was assessed by thrombus formation in rabbits.
Results
Compared with rFVIIa, rVIIa-FP displayed a prolonged t½, enhanced in vivo recovery and reduced clearance in all species investigated. In mice, 16 h after treatment with rVIIa-FP, thrombin levels were quantifiable, indicating prolonged efficacy, whereas values had approached baseline at this time after treatment with rFVIIa. After 12 h, hemostatic efficacy was negligible in rFVIIa-treated rabbits, but sustained in animals receiving rVIIa-FP.
Conclusions
These studies indicate that the longer t½ of rVIIa-FP compared with rFVIIa translates into extended activity. These findings suggest that rVIIa-FP has the potential to be administered less frequently than rFVIIa-containing concentrates in clinical use.
doi:10.1111/jth.12477
PMCID: PMC4166693  PMID: 24641308
half-life; hemophilia; hemostasis; inhibitors; pharmacokinetics

Results 1-13 (13)