Relationship between Factor VII Activity and Clinical Efficacy of Recombinant Factor VIIa Given by Continuous Infusion to Patients with Factor VIII Inhibitors

2001 ◽  
Vol 86 (10) ◽  
pp. 954-958 ◽  
Author(s):  
M. Morfini ◽  
A. Rocino ◽  
F. Baudo ◽  
F. A. Scaraggi ◽  
A. Gringeri ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Clinical Efficacy ◽  
Surgical Procedures ◽  
Factor Viia ◽  
Factor Vii ◽  
Major Surgery ◽  
Spontaneous Bleeding ◽  
Human Factor Viii ◽  
Minor Surgery

SummaryA multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out.Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 μg/kg (median: 100) were followed by CI given at median rates of 20 μg/kg/h for major surgery and of 17 and 16 μg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 μg/kg/h, respectively; median FVII:C: 14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.

The Fractionation Properties of Human Factor VIII (Antihaemophilic Factor)

1960 ◽  
Vol 04 (02) ◽  
pp. 253-260 ◽  
Author(s):  
Franco Gobbi
Keyword(s):  
Factor Viii ◽  
Human Factor ◽  
Maximum Yield ◽  
Factor Vii ◽  
Precipitation Method ◽  
Salting Out ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Two Factors ◽  
Thromboplastic Activity

SummaryThe fractionation properties of human Factor VIII (antihaemophilic factor, AHF, antihaemophilic globulin) have been studied using a plasma of congenital afibrinogenaemia as a starting material.From a fibrinogen-free plasma, Factor VIII does not precipitate with ethanol at a final concentration of 8%; on the contrary the maximum yield is reached at an ethanol concentration of 25%.With a precipitation method carried out by a one to ten dilution of plasma with distilled water and acidification by N/10 hydrochloric acid to a pFI 5.2, Factor VIII does not precipitate with the euglobulin fraction; when normal plasma is used, such a precipitation is almost complete.With the salting-out fractionation method by ammonium sulphate, Factor VIII precipitates at a concentration between 25 and 33% of saturation either from fibrinogen-free and from normal human plasma.A non-specific thromboplastic activity appears in the fractions prepared by every method. This activity, which is probably due to the activation of seric accelerators, is easily removed by Al(OH)s adsorption. Thus, in order to insure the specificity of Factor VIII assays, the preliminary adsorption of the fractions is indispensable before testing their antihaemophilic activity.Fibrinogen and Factor VIII have different and definite precipitation patterns. When these two factors are associated the fractionation properties of AHF appear quite modified, showing a close similarity to those of fibrinogen. This fact can explain the technical difficulties encountered in the attempt to purify the antihaemophilic factor, and the lack of reproducible procedures for removing fibrinogen without affecting Factor VII.

The Continuous Infusion of Recombinant Activated Factor VIIa (rFVIIa) in Patients with Factor VIII Inhibitors Activates the Coagulation and Fibrinolytic Systems without Clinical Complications

2000 ◽  
Vol 99 (1) ◽  
pp. 21-24 ◽  
Author(s):  
Francesco Baudo ◽  
Rosaria Redaelli ◽  
Teresa Maria Caimi ◽  
Giovanni Mostarda ◽  
Gabriella Somaini ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Factor Viia ◽  
Clinical Complications

scholarly journals Successful treatment of canine hemophilia by continuous expression of canine FVIIa

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3682-3689 ◽  
Author(s):  
Paris Margaritis ◽  
Elise Roy ◽  
Majed N. Aljamali ◽  
Harre D. Downey ◽  
Urs Giger ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Hemophilia A ◽  
Viral Vector ◽  
Canine Model ◽  
Factor Vii ◽  
Large Animal Model ◽  
Large Animal ◽  
Spontaneous Bleeding ◽  
Human Factor Viii

Abstract Continuous expression of activated factor VII (FVIIa) via gene transfer is a potential therapeutic approach for hemophilia patients with or without inhibitory antibodies to human factor VIII (FVIII) or IX (FIX). Here, we investigate whether gene transfer of an engineered canine FVIIa (cFVIIa) transgene can affect hemostasis in a canine model of hemophilia, a good predictor of efficacy of hemophilia treatments. Purified recombinant cFVIIa exhibited 12-fold higher tissue factor–dependent activity than purified recombinant zymogen cFVII. Subsequently, we generated a serotype 8 recombinant adeno-associated viral vector expressing cFVIIa from a liver-specific promoter. Vector delivery via the portal vein in hemophilia A and B dogs was well tolerated, and long-term expression of cFVIIa resulted in a shortening of the prothrombin time, partial correction of the whole blood clotting time and thromboelastography parameters, and a complete absence of spontaneous bleeding episodes. No evidence of hepatotoxicity, thrombotic complications, or inhibitory immune response was found. These data provide the first evidence for in vivo efficacy and safety of continuously expressed FVIIa as a FVIII/FIX-bypassing agent in a large animal model of hemophilia, avoiding the risk of inhibitor formation associated with bolus FVIII or FIX infusion.

Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII

2005 ◽  
Vol 94 (12) ◽  
pp. 1177-1180 ◽  
Author(s):  
Geir E. Tjønnfjord ◽  
Richard Wallensten ◽  
Uri Martinowitz ◽  
Gili Kenet ◽  
Sam Schulman
Keyword(s):  
Continuous Infusion ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Single Case ◽  
Thromboembolic Complication ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Different Types ◽  
Fvii Deficiency

SummaryThe administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factorVII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion, aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.

Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1330-1335 ◽  
Author(s):  
Cornelis van 't Veer ◽  
Neal J. Golden ◽  
Kenneth G. Mann
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Factor Vii ◽  
Lag Phase ◽  
Single Chain

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (∼10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect.

von Willebrand Factor/Factor VIII Concentrate (Humate-P®) Is Safe and Effective in the Prevention of Perioperative Bleeding in Patients with Very Low von Willebrand Factor: Ristocetin Cofactor (VWF:RCo).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4071-4071
Author(s):  
Joan Cox Gill ◽  
Cindy A. Leissinger ◽  
Jorge DiPaola ◽  
Jonathan Bernstein ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Adverse Events ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Treatment Duration ◽  
Major Surgery ◽  
Minor Surgery ◽  
Hemostatic Efficacy ◽  
Von Willebrand ◽  
Tooth Extractions ◽  
Willebrand Factor

Abstract Optimal dosing to prevent excessive surgical bleeding in von Willebrand Disease (VWD) was investigated in an open-label study of replacement therapy with a von Willebrand factor/factor VIII concentrate (VWF/FVIII, Humate-P®). This analysis focused on the subset of patients with very low VWF, defined as those with baseline VWF:RCo levels of <12 IU/dL. Of a total of 35 patients, 17 had very low levels of VWF:RCo; of these 17 “severe” VWD patients, 12 had type 3 VWD, one each had types 1, 2A or 2B, and 2 had type 2M VWD. Previous pharmacokinetic data in each patient was utilized to calculate pre-operative and immediate postoperative doses to raise plasma VWF:RCo and FVIII to 80–100 IU/dL for major surgery and 50–60 IU/dL for minor and oral surgery; subsequent doses were adjusted based on VWF:RCo levels. Eleven patients underwent major surgery including orthopedic, gynecologic and plastic surgery, and multiple tooth extractions; 4 had minor surgery and 2 had single tooth extractions. Hemostatic efficacy was assessed by investigators as excellent, good, moderate/poor, or none immediately after the surgery, 24 hours after the last VWF/FVIII infusion and 14 days post-op. Expected and actual estimated blood loss (EBL) was compared, transfusions recorded and adverse events (AEs) documented. The median loading dose was higher among subjects with severe VWD types (71 IU/kg, range 39 to 135) compared with non-severe VWD (44 IU/kg, range 17 to 121). Subjects with severe VWD types also used higher total doses (median: 280 IU/kg, range 63 to 859) and had longer treatment duration (6 days, range 1–26) than subjects with non-severe VWD types (median total dose: 208 IU/kg, range 79 to 1699; and treatment duration: 4.5 days, range 2–19). Hemostasis was rated as effective (good or excellent efficacy) in 15/17 (88.2%) patients immediately postoperatively, in 17/17 (100%) patients 24 hours after the last infusion (primary endpoint), and in 17/17 (100%) patients 14 days postoperatively. A bleeding related serious AE occurred in one patient; she had hemorrhage post-hysteroscopic resection of uterine fibroids followed by hysterectomy; actual EBL exceeded expected EBL and hemostatic efficacy was considered moderate/poor immediately post-op but good/excellent at the other time points. Three other surgery-related hemorrhagic events were mild in the severe VWD types; in the non-severe VWD patients, 1 severe, 1 moderate and 2 mild hemorrhagic adverse events were reported; none of these were considered to be related to poor efficacy of the drug. No thromboembolic complications or changes in viral titers were observed in the study. We conclude that patients with very low baseline VWF levels can safely undergo both major and minor surgery with VWF/FVIII concentrate when dosing is calculated to achieve and maintain hemostatic VWF levels based on VWF:RCo monitoring. It is important to base therapeutic decisions on the severity of disease as assessed by baseline plasma VWF and FVIII levels as well as VWD type.

The Use of Temporary Central Venous Catheters for Optimizing Continuous Infusion in Hemophilia Patients Undergoing Major Surgical Procedures

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2822-2822
Author(s):  
Ana Boban ◽  
Catherine M Lambert ◽  
Cedric R. Hermans
Keyword(s):  
Continuous Infusion ◽  
Surgical Procedures ◽  
Jugular Vein ◽  
Central Venous Catheters ◽  
Clotting Factor ◽  
Major Surgery ◽  
Peripheral Vein ◽  
Central Venous ◽  
Short Term ◽  
Factor Concentrate

Abstract Introduction: Continuous infusion (CI) of clotting factor concentrate has facilitated surgical procedures and intensive replacement therapy in hemophilia patients. The advantage of CI over bolus infusions is ability to maintain steady-state levels of coagulation factors and moreover, to reduce the total amount of factor concentrate spent. CI is commonly delivered through a peripheral vein. However, a significant number of hemophilia patients have distorted peripheral veins which can compromise continuous flow of factor concentrate needed for successful treatment. Also, thrombophlebitis at the site of venous access, an adverse effect of CI previously reported, can further impair the delivery of factor concentrate in CI and make the future use of the vein for concentrate administration impossible or difficult. Use of central venous catheter can ease the application of CI. By searching the literature, we found only a few case reports describing the use of temporary non-tunneled central venous catheters (CVC) for administrating CI in patients with hemophilia. The aim of this study was to evaluate the efficacy and safety of short-term used non-tunneled CVC for CI during surgical procedures in hemophilia patients. Methods: In this study we have retrospectively studied patients with hemophilia that had temporarily used non-tunneled CVC for CI of factor concentrate during and after major surgery in the Saint-Luc University Hospital in Brussels between August 2000 and April 2014. The indication for CVC usage was a major surgery with anticipated need for CI of factor concentrate longer than 5 days. CVC was inserted by an experienced anesthesiologist in the operating room after the induction of general anesthesia and normalization of APTT. Before the CVC insertion, the patient would have already received bolus of clotting factor concentrate and have the CI started through the peripheral vein. Upon placement, the CI was switched to the CVC. The CVC was kept in place until leaving hospital or cessation of the need for continuous infusion. Results: During the study period, 40 male patients with hemophilia A or B (37 and 3 patients, respectively) underwent 67 major surgical procedures covered by CI of factor concentrate delivered through CVC. Patients, age 21 -81, had severe, mild or moderate disease (33, 5 and 2 patients, respectively). Patients had altogether 65 CVC for 67 surgical procedures. The same catheter was used for 3 surgeries and 16 patients had CVC placed more than once; 14 patients twice, one patient three times and one ten times. Patients underwent orthopedic surgery (79%), gastrointestinal surgery (15%) and cardiovascular surgery (5%) while one patient (1%) had surgery of urinary tract. The CVC were placed in the right jugular vein (58%), the left jugular vein (18%), the left subclavian vein (8%) and right subclavian vein (3%), while the data were missing in 6 patients. Median duration of catheter was 12 days, with range from 5 to 107 days. No CVC was removed prematurely and no malfunctions of catheters were recorded. Moreover, no complications related to the CVC were noted whatsoever. We searched for bleeding at the site of puncture of the catheter, signs of local infection, pneumothorax following placement of CVC, catheter thrombosis, malfunction of the catheter and surgical site infection. Finally, most of the patients reported satisfaction related to the use of CVC for CI of factor concentrate. Conclusions: Based on results of this study, we can conclude that the use of short-term non-tunneled CVC should be considered in patients with hemophilia undergoing major surgery with the need for prolonged CI of factor concentrates. By placing CVC we can ensure undisturbed flow of factor concentrate during CI and preserve peripheral veins for the future concentrate administration. Disclosures No relevant conflicts of interest to declare.

scholarly journals The activation and inactivation of human factor VIII by thrombin: effect of inhibitors of thrombin

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 476-482
Author(s):  
MB Hultin ◽  
J Jesty
Keyword(s):  
Factor Viii ◽  
Protease Inhibitors ◽  
Human Factor ◽  
Initial Period ◽  
Model Systems ◽  
Thrombin Inhibitors ◽  
Factor Vii ◽  
Plateau Phase ◽  
First Order ◽  
Human Factor Viii

The activation and inactivation of human factor VIII by thrombin have been investigated by the use of thrombin inhibitors. The addition of inhibitors to nonactivated factor VIII blocks activation by thrombin. In contrast, their addition to factor VIII activated with thrombin does not block inactivation, but causes an initial period of decay that is more rapid than in the absence of inhibitor. This effect was seen only with protease inhibitors that inhibit thrombin. After the initial decay, low levels of factor VIII coagulant activity persist in the presence of inhibitors, but an assay specific for activated factor VIII showed this to be largely a result of the persistence of nonactivated factor VIII. Only in the case of reversible inhibition is activated factor VIII present in this plateau phase. Possible mechanisms that would account for these observations were studied by iterative computer simulation of model reactions. Two classes were considered: (formula: see text). The experimental results are inconsistent with the first mechanism, which predicts that thrombin indicators should stabilize activated factor VIII (VIIIt). Alternative mechanisms were studied where activation is thrombin-dependent, but inactivation is a first- order reaction (mechanism 2). This family of mechanisms includes those where VIIIt is an VIII. thrombin complex. Simulation of the addition of thrombin inhibitors to such model systems shows the initial rapid decay of activity characteristic of the experimental observations and predicts qualitatively the different effects of reversible and irreversible inhibitors that are observed in the plateau phase. These results argue strongly against a two-cleavage model for the activation and inactivation of factor VII by thrombin and support a one-cleavage model in which inactivation is due to first-order decay. In addition, they provide a plausible mechanistic explanation for the fact that serine protease inhibitors appear to inhibit thrombin-activated factor VIII.

scholarly journals Intravascular Clotting After Endotoxin in Rabbits With Impaired Intrinsic Clotting Produced by a Factor VIII Antibody

Blood ◽  
1973 ◽  
Vol 42 (4) ◽  
pp. 523-534 ◽  
Author(s):  
S. M-C. Shen ◽  
S. I. Rapaport ◽  
D. I. Feinstein
Keyword(s):  
Factor Viii ◽  
Rabbit Model ◽  
Saline Group ◽  
Factor Vii ◽  
Test Material ◽  
Control Group ◽  
Inert Material ◽  
Factor V ◽  
Mean Values ◽  
Human Factor Viii

Abstract A rabbit model in which intrinsic clotting was selectively impaired by injection of a human factor VIII antibody was used to evaluate the mechanism of endotoxin-induced intravascular clotting in cortisone-treated rabbits. Three groups of animals were studied: a control group given factor VIII antibody followed by saline; a second control group given an inert material followed by endotoxin; and an experimental group given factor VIII antibody followed by endotoxin. The following parameters were measured: 125I-fibrinogen kinetics, fibrinogen levels, factor VIII, factor VII, factor V, WBC, platelets, and hematocrit. The kidneys were examined for deposition of fibrin. Mean values for factor VIII at the time of injection of the second test material and mean values for fibrinogen consumed in the 6 hr after the second injection were as follows: antibody-saline group, 8.5% and 11.0 mg/kg; control material-endotoxin group, 90% and 29.6 mg/kg; and antibody endotoxin group, 7.0% and 32.7 mg/kg. Factor V, factor VII, granulocytes, and platelets fell in both groups of animals given endotoxin. One animal in each group given endotoxin developed gross renal cortical necrosis. These data establish that selective impairment of the intrinsic clotting reactions does not reduce the amount of clotting induced by a single injection of endotoxin in the cortisone-treated rabbit.

Sign in / Sign up

Export Citation Format

Share Document