Postoperative Bleeding in a Sufficiently Substituted Patient with Severe Hemophilia A: Successful Therapy with Administration of Recombinant Factor VIIa

2001 ◽  
pp. 336-341
Author(s):  
H. J. Siemens ◽  
S. Brückner ◽  
J. Gille ◽  
A. Martinez-Schramm ◽  
M. Ruslies ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Postoperative Bleeding ◽  
Severe Hemophilia ◽  
Successful Therapy

Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 175-179 ◽  
Author(s):  
Ton Lisman ◽  
Laurent O. Mosnier ◽  
Thierry Lambert ◽  
Evelien P. Mauser-Bunschoten ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
In Vitro Study ◽  
Clot Lysis ◽  
Severe Hemophilia ◽  
Large Variability ◽  
Lysis Time ◽  
Clot Lysis Time

Recombinant factor VIIa (rFVIIa) is a novel prohemostatic drug for patients with hemophilia who have developed inhibitory antibodies. The postulation has been made that hemophilia is not only a disorder of coagulation, but that hyperfibrinolysis due to a defective activation of thrombin activatable fibrinolysis inhibitor (TAFI) might also play a role. In this in vitro study, the potential of rFVIIa to down-regulate fibrinolysis via activation of TAFI was investigated. rFVIIa was able to prolong clot lysis time in plasmas from 17 patients with severe hemophilia A. The prolongation of clot lysis time by rFVIIa was completely abolished by addition of an inhibitor of activated TAFI. The concentration of rFVIIa required for half maximal prolongation of clot lysis time (Clys½-VIIa) varied widely between patients (median, 73.0 U/mL; range, 10.8-250 U/mL). The concentration of rFVIIa required for half maximal reduction of clotting time (Cclot½-VIIa) was approximately 10-fold lower than the Clys½-VIIa value (median, 8.4 U/mL; range, 1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody significantly decreased Clys½-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas Cclot½-VIIa values did not change (median, 7.2 U/mL; range, 2.2-22.5 U/mL). On addition of 100 ng/mL recombinant full-length TFPI, a nonsignificant increase of Clys½-VIIa values was observed (median, 119.2 U/mL; range, 12.3-375.0 U/mL), whereas Cclot½-VIIa values did not change (median, 8.8 U/mL; range, 2.6-34.6 U/mL). In conclusion, this study shows that rFVIIa both accelerates clot formation and inhibits fibrinolysis by activation of TAFI in factor VIII-deficient plasma. However, a large variability in antifibrinolytic potential of rFVIIa exists between patients.

Recombinant Factor VIIa Combined with Plasma Factor XIII Stabilize Clot Formation and Increase Clot Stability in Whole Blood from Patients with Severe Hemophilia A.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1039-1039 ◽  
Author(s):  
Benny Sorensen ◽  
Rasmus Rojkjaer ◽  
Jorgen Ingerslev
Keyword(s):  
Whole Blood ◽  
Factor Xiii ◽  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Ex Vivo ◽  
Clot Formation ◽  
Severe Hemophilia ◽  
Clot Strength ◽  
Clot Stability

Abstract Patients with severe hemophlia A and inhibitors suffer from significantly compromised clot formation as well as reduced clot stability. Recombinant factor VIIa (rFVIIa - NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) has proven safe and efficacious for securing haemostasis in hemophilia patients with inhibitors. Recently, it was proposed that the reduced thrombin generation in severe haemophilia hinders sufficient activation of factor XIII and thereby result in insufficient covalent lateralization of fibrin (Blood2005; 106: 11, Abstract 321). The present study aimed at exploring the effect of rFVIIa and rFVIIa + plasma-derived FXIII (Haematological Technologies Inc) on whole blood clot (WB) formation and WB clot stability in severe hemophilia A. In total, 14 patients with a verified FVIII:C < 0.01 IU/ml were enrolled. Ex vivo studies were performed with rFVIIa (2 μg/ml), rFVIIa+FXIII (2+10 μg/ml), and a buffer control. Dynamic WB coagulation profiles describing initiation (clotting time=CT[sec]), propagation (maximum velocity=MaxVel [mm*100/sec]) and clot strength (maximum clot firmness=MCF[mm*100]) were recorded using thrombelastography and activation with a minute amount of tissue factor (TF, Innovin, final dilution 1:50000). WB clot stability was evaluated using a reaction mixture containing TF and tPA (1nM), followed by evaluation of the MCF and the total area under the elasticity curve after 120 min analysis time (AUEC[mm*100*sec]). Data are presented as mean and Wilcoxon statistical results. In the absence of tPA, Both rFVIIa+FXIII and rFVIIa significantly shortened the CT (Buffer=1424, rFVIIa+FXIII=739 (p=0.010), rFVIIa=881, (p=0.0005)) and accelerated WB MaxVel (Buffer=3.8, rFVIIa+FXIII=10.5 (p=0.0001), rFVIIa=9.2, (p=0.0002)). The standard deviation (SD) of the CT was significant lower in WB spiked with rFVIIa+FXIII than rFVIIa (Buffer SD=697, rFVIIa+FXIII SD=289 vs rFVIIa SD=655, p=0.007). In the absence of tPA, rFVIIa+FXIII increased the MCF significantly more than rFVIIa (Buffer=4441, rFVIIa+FXIII=6414 vs rFVIIa=5943, p=0.04) and the SD of the MCF was significant lower in WB spiked with rFVIIa+FXIII than rFVIIa (Buffer SD=2174, rFVIIa+FXIII SD=331 vs rFVIIa SD=948, p=0.0006). In the presence of tPA, rFVIIa+FXIII induced higher clot strength and stability than rFVIIa alone (MCF: Buffer=1313, rFVIIa+FXIII=3295 vs rFVIIa=3023, p=0.10 (N.S.); AUEC: Buffer=3.8*106, rFVIIa+FXIII=12.8*106 vs rFVIIa=10.2*106, p=0.0269). In conclusion, both rFVIIa (2μg/mL) and FXIII (10 μg/ml) added to rFVIIa (2 μg/ml), significantly increased WB clot formation and stability in this ex vivo evaluation of the clotting potential of WB from patients with severe hemophilia A.

Risk of Bleeding and Inhibitor Development After Circumcision in Minimally Treated Severe Hemophilia A Patients: A One Year Prospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4653-4653
Author(s):  
Mohsen Saleh Elalfy ◽  
Nancy Samir Elbarbary ◽  
Mohamed Soliman Eldebeiky
Keyword(s):  
Single Dose ◽  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
High Titer ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Factor Concentrate

Abstract Abstract 4653 Background Circumcision is a cultural practice for males in the Middle-East during first weeks of life. All parents of hemophilics are eager to do circumcision to their sibs, however, it may carry a risk for development of factor VIII inhibitors as well as risk of excessive bleeding. Objective To evaluate post-circumcision bleeding and assess incidence and time of inhibitor development over 12 months follow-up period of minimally treated severe hemophilia A patients. Patients and methods This prospective analysis has been conducted on eighteen minimally treated patients with severe hemophilia A (age range 8–36 months) with a median age of 18 months, who underwent circumcision during 2009 and twenty four age matched non circumcised patients minimally treated severe hemophilia A. Both groups were followed up for12 months from study entry and all were treated on demand therapy with a single plasma-derived factor VIII product. Hemophilic patients who underwent circumcision were inhibitor negative except two with low- titer inhibitor(3.3 and 4.4 BU/ml) respectively. One hour before the operation, intravenous tranexamic acid (25 mg/ kg) and first dose of factor concentrate (25 unit / Kg) were given to the patients. After reaching a trough plasma factor level more than 90%, patients underwent circumcision using general anesthesia and same surgical technique for all. Bolus injections of factor VIII concentrate were repeated in a dose of (25 units / Kg ) twenty four hours after operation. However, the two patients with inhibitors were given factor VIII concentrate in a dose of (50 units /Kg) with an extra dose at forty-eight hours. Another dose of factor concentrate (25 units/ Kg) was given just before removal of gauze dressing at 5th −7th day post operative. Follow up for inhibitor development was assessed every 8 exposure days (EDs) for 12 months or 100 EDs whichever comes first. Results: Of the eighteen patients enrolled, only one of the 2 patients with low- titer inhibitor had postoperative bleeding at day 5 and 7 respectively. First attack responded to a single dose of factor administration (50 units/Kg), whereas haemostasis was achieved in the second episode after a single dose of Recombinant Factor VIIa (90 microgram/kg) and applying absorbable haemostatic agent (gelatin sponge) and binding. None of the other patients had any bleeding or infection at site of surgery. High -titer inhibitors developed in three patients (16.6 % ) during the follow-up; after 8, 16 and 40 EDs respectively in contrast to four patients (16.6 %) developed high titer inhibitor in the non circumcised group; after a median of 16 exposure days (range 8– 60 EDs). Conclusion: Our study has shown that bleeding following circumcision was absent except in low- titer inhibitor patient necessitating administration of Recombinant Factor VIIa. Moreover, circumcision was not a risk for development of inhibitor where the incidence of high- titer inhibitors during12 months follow up was low in this cohort of minimally treated patients and comparable to non circumcised group. Disclosures: No relevant conflicts of interest to declare.

Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3615-3620 ◽  
Author(s):  
Mikael Tranholm ◽  
Kim Kristensen ◽  
Annemarie T. Kristensen ◽  
Charles Pyke ◽  
Rasmus Røjkjær ◽  
...  
Keyword(s):  
Blood Loss ◽  
Bleeding Time ◽  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Intrinsic Activity ◽  
Hemostatic Effect ◽  
Therapeutic Doses ◽  
Hemostatic Effects

AbstractIt is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, Novo-Seven) relies on the tissue factor (TF)-independent activity of the enzyme. The present study was conducted to investigate the in vivo hemostatic effects of rFVIIa and 3 analogs thereof with superior intrinsic activity (FVIIaIIa, K337A-FVIIaIia, and M298Q-FVIIa) in mice with antibody-induced hemophilia A. A highly significant dose response was observed for the bleeding time and blood loss for each of the rFVIIa variants. The bleeding time and blood loss were normalized after administration of 10 mg/kg rFVIIa, 3 mg/kg K337A-FVIIaIia, and 3 mg/kg M298Q-FVIIa, indicating a potency of these FVIIa analogs 3-4 times above that of rFVIIa in FVIII-depleted mice. The different in vivo potencies of the various forms of FVIIa could not be explained by the pharmacokinetics. Histopathological evaluation of kidneys revealed no signs of treatment-related pathological changes even after treatment with the superactive variants. The fact that FVIIa analogs with enhanced intrinsic activity are more efficacious in the murine hemophilia A model strongly suggests that the TF-independent procoagulant activity of FVIIa contributes to its clinical hemostatic effect. (Blood. 2003; 102:3615-3620)

scholarly journals Total knee replacement with and without emicizumab: a unique comparison of perioperative management

2020 ◽  
Vol 4 (5) ◽  
pp. 855-857
Author(s):  
Matthew S. Evans ◽  
Charles Davis ◽  
M. Elaine Eyster
Keyword(s):  
Total Knee Replacement ◽  
Knee Replacement ◽  
Perioperative Management ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Cost Savings ◽  
Knee Surgery ◽  
Severe Hemophilia ◽  
Key Points ◽  
Total Knee

Key Points Prophylaxis with emicizumab was used in a patient with severe hemophilia with an inhibitor who underwent knee surgery. Use of emicizumab during surgery led to less recombinant factor VIIa and less bleeding, in addition to cost savings, for this patient.

Abstract 2051: Recombinant Factor VIIa Affects Vein Graft Patency and Flow in Rabbits

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
David Mazer ◽  
Howard Leong-Poi ◽  
Zuhair Alfardan ◽  
Zhilan Wang ◽  
Beiping Qiang ◽  
...  
Keyword(s):  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Postoperative Bleeding ◽  
Rabbit Model ◽  
Graft Patency ◽  
Vessel Diameter ◽  
Factor Vii ◽  
Activity Levels ◽  
Graft Occlusion ◽  
Plasma Factor

INTRODUCTION: Recombinant factor VIIa (rVIIa) has been used to decrease postoperative bleeding in cardiac surgical patients. However, there is potential for rVIIa to interact with tissue factor expression at the site of new anastomoses resulting in early graft occlusion. This safety study tested the hypothesis that the administration of rVIIa dose-dependently reduces graft patency at the site of new vascular anastomoses comparable in size to human coronaries, in a rabbit model. METHODS: After ACC approval, a reversed venous graft was fashioned in the right carotid artery using autologous right jugular vein with 9 – 0 sutures in 64 anesthetized and heparinized rabbits. Animals were then given either one of three doses of rVIIa (300 ug/kg, 90 ug/kg or 20 ug/kg IV) or placebo (n=16/group). The primary outcome was graft patency, measured by a blinded observer 24 hours postoperatively using vascular ultrasound (HDI 5000cv, 15 MHz probe) and/or direct inspection. Factor VII activity levels were measured from citrated plasma samples with a 1-stage prothrombin time-based assay using rabbit thromboplastin. Data was analyzed using chi-square, fishers exact test, or ANOVA where appropriate, with p<0.05 considered significant. RESULTS: Physiologic variables (ACT, hemoglobin, pH, pCO2) and vessel diameter were similar between groups. Graft patency and flow were significantly reduced, and plasma factor VII levels significantly increased in the rVIIa treated rabbits in a dose-dependent fashion. DISCUSSION: The study suggests that high doses of rVIIa (300 and 90 ug/kg) are associated with an increased incidence of occlusion of new vascular grafts. A clear dose-response effect was observed, suggesting that higher doses may be associated with increased thrombotic outcomes.

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