A bodyweight-dependent allometric exponent model for scaling clearance of clotting factor VIII and IX from infants to adults

Abstract Introduction Hemophilia A and B are hereditary genetic disorders caused by deficiency of clotting factor VIII and IX respectively. Infusions of clotting factors constitute the mainstay of treatment. Before availability of recombinant factor VIII and IX, patients with hemophilia received products derived from human plasma and were at risk of blood-borne infections exposure. Since then, ongoing advances have yielded not only safer recombinant clotting factors but also effective treatment of infections. Hepatitis C infection and its complications constitute a common cause of morbidity and mortality in older hemophilia patients. In the last few years, FDA approved various antiviral medications which allow achievement of sustained virologic response and even cure hepatitis C infection. Goal of our study is to show prevalence of hepatitis C infection and virus clearance at our hemophilia treatment center. Methods We performed retrospective chart review of patients followed at a single hemophilia treatment center in the United States. We included 59 patients with factor VIII or IX deficiency, age 30 and older, followed in clinic between 2005 and 2014. Patients with acquired hemophilia were excluded from study. Data was collected from physician notes and laboratory tests results which included hepatitis C antibodies and viral load. Results 39 (66.1%) patients had history of hepatitis C infection. 21 (35.6%) patients had detectable hepatitis C viral load [95% CI 0.24-0.49] while 18 (30.5%) patients cleared the virus [95% CI 0.19-0.44]. Conclusions Our study showed that 66.1% of hemophilia patients followed at our institution had current or past hepatitis C infection. More than half of them were virus carriers during their last viral load check. Many of them had refused interferon-based treatment due to the requirement of being on it for long duration and concerns about side effects. Others had received the treatment but failed it. This constituted as much as 35.6% of hemophilia patients at our hemophilia treatment center. Availability of the newer antiviral agents that are better tolerated and yield high cure rates provide an opportunity to further reduce the disease burden in these patients. Disclosures No relevant conflicts of interest to declare.

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Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia

Blood ◽

10.1182/blood.v68.3.673.673 ◽

1986 ◽

Vol 68 (3) ◽

pp. 673-679 ◽

Cited By ~ 8

Author(s):

P Saidi ◽

BZ Lega ◽

HC Kim ◽

K Jr Raska

Keyword(s):

Factor Viii ◽

Plasma Levels ◽

Fibrinolytic Activity ◽

Clotting Factor ◽

Clotting Factors ◽

Double Blind ◽

Immune Parameters ◽

Plasma Factor ◽

Viii And Ix ◽

Mucosal Bleeding

Abstract Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia.

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Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia

Blood ◽

10.1182/blood.v68.3.673.bloodjournal683673 ◽

1986 ◽

Vol 68 (3) ◽

pp. 673-679

Author(s):

P Saidi ◽

BZ Lega ◽

HC Kim ◽

K Jr Raska

Keyword(s):

Factor Viii ◽

Plasma Levels ◽

Fibrinolytic Activity ◽

Clotting Factor ◽

Clotting Factors ◽

Double Blind ◽

Immune Parameters ◽

Plasma Factor ◽

Viii And Ix ◽

Mucosal Bleeding

Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia.

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The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO)

British Journal of Haematology ◽

10.1046/j.1365-2141.2000.02327.x ◽

2000 ◽

Vol 111 (1) ◽

pp. 78-90 ◽

Cited By ~ 98

Author(s):

C. R. M. Hay ◽

T. P. Baglin ◽

P. W. Collins ◽

F. G. H. Hill ◽

D. M. Keeling

Keyword(s):

Factor Viii ◽

Diagnosis And Management ◽

Viii And Ix ◽

The Uk

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Antibody to Hepatitis G Mrus after a Vapour-Heated Factor Vlll Goncentrate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647291 ◽

1990 ◽

Vol 64 (02) ◽

pp. 232-234 ◽

Cited By ~ 21

Author(s):

P M Mannucci ◽

A R Zanetti ◽

M Colombo ◽

A Chistolini ◽

R De Biasi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hepatitis B ◽

Factor Viii ◽

Alanine Aminotransferase ◽

Household Contact ◽

Clotting Factor ◽

Double Infection ◽

Marked Elevation ◽

Clotting Factor Concentrates

SummaryTo evaluate whether or not clotting factor concentrates exposed to virucidal procedures transmitted hepatitis C, sera obtained in 1984–1986 from 27 previously untreated hemophiliacs infused with a vapour-heated factor VIII concentrate were tested retrospectively for the antibody to the hepatitis C virus (anti- HCV). A 2-year-old hemophiliac, negative for anti-HCV before administration of concentrate, seroconverted at week 12 and remained anti-HCV positive thereafter. Both his parents were anti-HCV negative and he had no other household contact. The patient had also become HBsAg positive at week 8 and had at the same time a marked elevation of alanine aminotransferase. His double infection with the hepatitis B and C viruses indicates that hot vapour was not completely effective in inactivating these viruses.

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The Effect of Adrenaline Infusions on Blood Coagulation in Normal and Haemophilia B Dogs

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649437 ◽

1966 ◽

Vol 15 (03/04) ◽

pp. 349-364 ◽

Cited By ~ 5

Author(s):

A.H Özge ◽

H.C Rowsell ◽

H.G Downie ◽

J.F Mustard

Keyword(s):

Body Weight ◽

Factor Viii ◽

Factor Ix ◽

Clotting Factor ◽

Blood Ph ◽

Order Of Magnitude ◽

Dose Dependent ◽

Generation Test ◽

Plasma Activity

SummaryThe addition of trace amounts of adrenaline to whole blood in plasma in vitro increased factor VIII, factor IX and whole plasma activity in the thromboplastin generation test. This was dose dependent.Adrenaline infusions less than 22 (μg/kg body weight in normal dogs accelerated clotting, increased factor IX, factor VIII and whole plasma activity in the thromboplastin generation test and caused a fall in blood pH. In a factor IX deficient dog, there was no increase in factor IX activity. After adrenaline infusions, however, the other changes occurred and were of the same order of magnitude as in the normal. Adrenaline in doses greater than 22 μg/kg body weight did not produce as great an effect on clotting in normal or factor IX deficient dogs. The platelet count in the peripheral blood was increased following the infusion of all doses of adrenaline. These observations suggest that the accelerating effect of adrenaline on clotting is not mediated through increase in activity of a specific clotting factor.

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