Abrogating fibrinolysis does not improve bleeding or rFVIIa/rFVIII treatment in a non‐mucosal venous injury model in haemophilic rodents

Essentials

• The efficacy of systemic antifibrinolytics for hemophilic non‐mucosal bleeding is undetermined.
• The effect of systemically inhibiting fibrinolysis in hemophilic mice and rats was explored.
• Neither bleeding nor the response to factor treatment was improved after inhibiting fibrinolysis.
• The non‐mucosal bleeding phenotype in hemophilia A appears largely unaffected by fibrinolysis.

Summary

Background

Fibrinolysis may exacerbate bleeding in patients with hemophilia A (HA). Accordingly, antifibrinolytics have been used to help maintain hemostatic control. Although antifibrinolytic drugs have been proven to be effective in the treatment of mucosal bleeds in the oral cavity, their efficacy in non‐mucosal tissues remain an open question of significant clinical interest.

Objective

To determine whether inhibiting fibrinolysis improves the outcome in non‐mucosal hemophilic tail vein transection (TVT) bleeding models, and to determine whether a standard ex vivo clotting/fibrinolysis assay can be used as a predictive surrogate for in vivo efficacy.

Methods

A highly sensitive TVT model was employed in hemophilic rodents with a suppressed fibrinolytic system to examine the effect of inhibiting fibrinolysis on bleeding in non‐mucosal tissue. In mice, induced and congenital hemophilia models were combined with fibrinolytic attenuation achieved either genetically or pharmacologically (tranexamic acid [TXA]). In hemophilic rats, tail bleeding was followed by whole blood rotational thromboelastometry evaluation of the same animals to gauge the predictive value of such assays.

Results

The beneficial effect of systemic TXA therapy observed ex vivo could not be confirmed in vivo in hemophilic rats. Furthermore, neither intravenously administered TXA nor congenital knockout of the fibrinolytic genes encoding plasminogen or tissue‐type plasminogen activator markedly improved the TVT bleeding phenotype or response to factor therapy in hemophilic mice.

Conclusions

The findings here suggest that inhibition of fibrinolysis is not effective in limiting the TVT bleeding phenotype of HA rodents in non‐mucosal tissues.

     

A COMPARISON OF "CARRIER SCREENING" OF HEMOPHILIA BY THE RATIO OF FACTOR VIII COAGULANT ACTIVITY OR ANTIGEN TO FACTOR VIII RELATED ANTIGEN

Abstract: The ratio of factor VIII coagulant activity (VIIIC) or antigen (VIIICAg) to that of factor VIII related antigen (VIIIRAg) was measured in 15 normals, 21 obligatory and 23 possible carriers of hemophilia. Factor VIII coagulant was measured on fresh plasma samples whereas antigenic properties were measured on frozen and thawed samples. In obligatory carriers only, the mean level of VIIICAg was significantly lower than VIIIC and there was a tendency for low VIIICAg levels to be associated with raised VIIIRAg levels. Using both ratios, 13 obligatory carriers were outside the normal tolerance ellipse. In possible carriers, neither ratio showed superior discriminating power. In reference laboratories that perform carrier studies on stored or transported specimens, measurement of VIIICAg/VIIIRAg is a suitable test for diagnosis of carriers.     

Suppression of hepatitis C virus (HCV) replication by hepatitis D virus (HDV) in HIV-infected hemophiliacs with chronic hepatitis B and C

Most hemophiliacs who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have high serum levels of HCV RNA. To study the impact of multiple hepatitis virus infections, we evalated all eight chronic carriers of hepatitis B surface antigen (HBsAg) from a previously studied cohort of 99 hemophiliacs with chronic HIV and HCV infections. Stored serum or plasma samples were tested for antibody to hepatitis D virus (anti-HDV) by ELISA; qualitatively for HCV RNA, HBV DNA, and HDV RNA by the polymerase chain reaction (PCR); and quantitively for HIV RNA, HCV RNA, and hepatitis B virus (HBV) DNA by a quantitative branched DNA signal amplification assay. HCV RNA was detected in only one of five patients with HDV infections on a cross-sectional study, and this individual had low levels (<3.5×10⁵ genome eq/ml) of HCV RNA. In contrast, all three without HDV infections had high levels (>1.5×10⁷ genome eq/ml) of HCV RNA. HIV RNA was present in all eight patients. There was no correlation between the level of HIV RNA and the presence of hepatitis viruses. Three of the eight patients (38%) died of liver failure and another has hypersplenism with hypoprothrombinemia. We conclude that HDV infection appears to suppress HCV replication and that liver failure is common in adult HIV-infected hemophiliacs with chronic HCV and HBV infections. These findings have implications for the therapy of HCV-infected hemophiliacs who are HBsAg positive.This study was supported by the Brandywine Valley Hemophilia Foundation, and the Alice Livingston Trout Family Fund.Dr. Battegay was supported by the Swiss National Science Foundation, the Conrad Gessner Stipendium, and the Schweizerische Stiftung fur medizinisch biologische stipendien.     

药代动力学与血友病的个体化预防治疗

血友病是一种由基因突变导致凝血因子缺乏引起的出血性疾病。由于血友病管理理念的不断发展,现在首选的治疗方案是预防治疗。凝血因子在不同患者体内的药代动力学以及不同患者的出血类型存在明显差异,可以根据患者药代动力学相关数据为其量身定做治疗方案,尽量减少患者的不便、不适以及尽可能避免高昂的治疗费用。因此,个体化预防是重要的。它可能使预防治疗的剂量更加准确,形成精准化治疗。     

Setting the scene: Historical overview of challenges and what led to advances in comprehensive care in developed countries,the Canadian experience

The history of the development of comprehensive care for hemophilia and other inherited bleeding disorders in Canada has been long and full of challenges. From limited in‐patient treatment with plasma and cryoprecipitate in a few major centres in the 1950s and 1960s, a network of Hemophilia Treatment Centres (HTCs) offering multi‐disciplinary comprehensive care, home infusion and prophylaxis was established across the country by the late 1970s and early 1980s, only to be shaken by the widespread contamination of factor concentrates with HIV and HCV in the 1970s and 1980s. In recent years the mission of HTCs has expanded to better serve people with von Willebrand disease, rare factor deficiencies and other rare bleeding disorders, and more fully recognize the needs of women with bleeding disorders. In 2020, challenges remain, notably maintaining the resources and expertise in HTCs and gaining access to the latest innovations in treatments.     

Immune tolerance induction using a factor VIII/von Willebrand factor concentrate (BIOSTATE®), with or without immunosuppression,in Australian paediatric severe haemophilia A patients with high titre inhibitors: A multicentre,retrospective study

Introduction

It has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors.

Materials and methods

We conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE®) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis.

Results

BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1–11.5 years) and for salvage ITI in 7 patients (9.9 years, range 1.1–15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21 months (range 5–85 months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI.

Conclusion

BIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor.     

Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Background

Hemophilia is caused by deficiencies in coagulation factor VIII or IX, resulting in direct blockade of the intrinsic tenase complex and indirect blockade of the extrinsic tenase complex which is rapidly inhibited upon binding of factor Xa to tissue factor pathway inhibitor. We evaluated the ability of Gla-domainless factor Xa, a truncated form of factor Xa devoid of procoagulant properties, to bind to tissue factor pathway inhibitor and to alleviate the physiological inhibition of the extrinsic tenase.

Design and Methods

Using a thrombin generation assay triggered by a low concentration of tissue factor, we evaluated the ability of Gla-domainless factor Xa to restore blood coagulation in plasma from hemophilia A and B patients without and with inhibitors. We then compared its efficacy to generate thrombin to depletion of antithrombin or tissue factor pathway inhibitor by specific antibodies. Finally, we compared the kinetics of neutralization of factor Xa and Gla-domainless factor Xa by antithrombin and tissue factor pathway inhibitor.

Results

Gla-domainless factor Xa was able to restore thrombin generation in plasma samples from hemophiliacs. This effect was observed for plasma from hemophilia A patients without or with inhibitors and for plasma from hemophilia B patients. Gla-domainless factor Xa had a lower affinity than factor Xa for tissue factor pathway inhibitor whereas the affinities of both proteins for antithrombin were similar. Finally, despite a short half-life in plasma, the effect of Gla-domainless factor Xa on thrombin generation was sustained for at least 1 hour.

Conclusions

As Gla-domainless factor Xa was able to restore thrombin generation in plasma from hemophilia patients, our results suggest that it may be an effective alternative to current treatments for hemophilia with or without an inhibitor.     

Effect of a self‐help program for mothers of hemophilic children in Korea

Mothers of hemophilic children are under stressful situations because of the characteristics of disease and inheritance. The purpose of this study was to evaluate the effect of the self‐help group program for the mothers of hemophilic children. Fifty one mothers of hemophilic children were participated. The experiment group (n = 24) participated in the self‐help group program for 5 weeks, while the control group (n = 27) received a self‐help booklet only. Knowledge, self‐efficacy, depression, parenting stress, and quality of life were evaluated using questionnaires. Data were analyzed using χ²‐test, t‐test, and analysis of covariance (ancova ). The experiment and control groups were homogeneous in general characteristics and depending variables except knowledge (P < 0.05; P > 0.05, respectively). Knowledge, self‐efficacy, and quality of life in the experiment group were increased after the program (P < 0.001). Especially, the knowledge in the experiment group was lower than the control group in pretest, but higher in the posttest (P < 0.001). Depression and parenting stress were reduced in the experiment group compared to the control group (P < 0.001). It is suggestive that the self‐help group program can be a useful opportunity for mothers of hemophilic children to improve knowledge and self‐efficay of child care and quality of life of themselves; to decrease depression and parenting stress. Extended application of the program to fathers or all family members may be needed to investigate in the future.