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

Blood ◽  
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

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.

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

Blood ◽  
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.

Prevalence of Hepatitis C Infection and Virus Clearance in Patients with Hemophilia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4706-4706
Author(s):  
Kamila Izabela Cisak ◽  
Jianmin Pan ◽  
Shesh Nath Rai ◽  
Patricia Ashby ◽  
Vivek R. Sharma
Keyword(s):  
Viral Load ◽  
Hepatitis C ◽  
Factor Viii ◽  
The United States ◽  
Treatment Center ◽  
Clotting Factor ◽  
Hepatitis C Infection ◽  
Clotting Factors ◽  
Virus Clearance ◽  
Viii And Ix

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.

Impaired Fibrinolysis in Sickle Cell Disease

1970 ◽  
Vol 24 (01/02) ◽  
pp. 010-016 ◽  
Author(s):  
D Green ◽  
H. C Kwaan ◽  
G Ruiz
Keyword(s):  
Sickle Cell Disease ◽  
Factor Viii ◽  
Plasminogen Activator ◽  
Sickle Cell ◽  
Fibrinolytic Activity ◽  
Endothelial Damage ◽  
Cell Disease ◽  
Clotting Factors ◽  
Platelet Counts

SummaryCoagulation studies were performed in 52 patients with sickle cell disease during asymptomatic periods and during episodes of crisis and infection. Platelet counts averaged 473,000, 469,000, and 461,000 per mm3 in these 3 groups, and factor VIII concentrations were elevated in all. Fibrinogen was increased to the same extent in both sickle cell and non-sickle cell patients with infection. Fibrinolytic activity, as measured by euglobulin lysis times and zones of lysis on fibrin plates, was markedly reduced during periods of infection in sickle cell patients but not in non-sickle patients. Impairment of fibrinolysis in most patients was not on the basis of overutilization or consumption, since no decrease in the levels of clotting factors or plasminogen was observed. It was suggested that generalized intravascular sickling in these patients may have caused widespread endothelial damage, resulting in decreased production of plasminogen activator.In addition, several sickle cell patients with infection were found to possess elevated levels of an inhibitor directed against urokinase.

EXPRESSION IN MAMMALIAN CELLS OF FUSION PROTEINS BETWEEN HUMAN FACTORS IX AND VII

1987 ◽  
Author(s):  
K L Berkner ◽  
S J Busby ◽  
J Gambee ◽  
A Kumar
Keyword(s):  
Fusion Protein ◽  
Fusion Proteins ◽  
Factor Ix ◽  
Biologically Active ◽  
Factor Vii ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Mammalian Expression ◽  
Plasma Factor ◽  
Gla Domain

The vitamin K-dependent plasma proteins demonstrate remarkable similarities in their structures: all have multiple domains in common and extensive homology is observed within many of these domains. In order to investigate the structure-function relationship of these proteins, we have interchanged domains of one protein (factor IX) with that of another (factor VII) and have compared the expression of these fusion proteins with recombinant and native factors IX and VII. Oligonucleotide-directed mutagenesis was used to generate four fusion proteins: factor IX/VII-1, which contains the factor IX leader and gla domain fused to the growth factor and serine protease of factor VII; factor VII/IX-1, a reciprocal fusion protein of factor IX/VII-1; factor IX/VII-2, which contains the factor IX leader adjoined to the mature factor VII protein sequence; and factor VII/IX-2, the reciprocal fusion protein of factor IX/VII-2. The cDNAs encoding all four proteins were cloned into mammalian expression vectors, and to date three of these (factors IX/VII-1, 2 and VII/IX-1) have been transfected into baby hamster kidney (BHK) cells or 293 cells and characterized. Factors IX/VII-1 and VII/IX-1 were both secreted at levels comparable to recombinant factors IX and VII. The factor IX/VII-1 was identical in molecular weight to native or recombinant factor VII (i.e., 53 K). Factor VII/IX-1 was expressed as two proteins with molecular weights around 68 kd, as observed with recombinant factor IX. The factor IX/VII-1 protein has been purified to homogeneity and has been found to possess factor VII biological activity, but at a specific activity approximately 20% that of plasma factor VII. Thus, the gla domain of one clotting factor is capable of directing the activation of another and of generating biologically active protein. In contrast, no activity was observed with the factor IX/VII-2 fusion protein, indicating that there are limits to the interchanges which can generate functional blood clotting factors.

Extravascular Clotting Factor Activity within Joint Tissues Protects Against Progression of Hemophilic Arthropathy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 496-496 ◽  
Author(s):  
Junjiang Sun ◽  
Narine Hakobyan ◽  
Leonard A. Valentino ◽  
Paul E. Monahan
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Joint Capsule ◽  
Factor Ix ◽  
Clotting Factor ◽  
Needle Puncture ◽  
Factor Activity ◽  
Clotting Factors ◽  
Hemophilic Arthropathy ◽  
Human Factor Viii

Abstract Hemophilic arthropathy is the major morbidity of congenital factor VIII and IX deficiency. Therapies localized to hemophilic joints could provide adjunctive protection, in addition to that provided by systemic factor replacement. However, the ability of extravascular clotting factors to contribute to hemostatic protection within joint tissue is unknown. We hypothesized that replacing deficient factor VIII or IX within the injured joint capsule of mice with hemophilia A (FVIII −/ −) or hemophilia B (FIX −/ −), respectively, would decrease the progression of synovitis. We developed a bleeding model consisting of a unilateral knee joint capsule needle puncture to induce hemorrhage in hemophilic mice. Pathology of the joint at two weeks after the injury is graded 0 to 10 using a murine hemophilic synovitis grading system (Valentino, Hakobyan. Haemophilia, 2006). Hemostatically normal mice do not develop synovitis following this injury, but > 95% of FIX −/ − mice develop bleeding and synovitis with a mean grade of 3–4 or greater. Coincident with needle puncture, recombinant human coagulation factor doses ranging from 0 to 20 IU/kg body weight of factor IX or 0 to 25 IU/kg of factor VIII were instilled intraarticularly (I.A.). Comparison groups received the same injury and intravenous (I.V.) factor IX or VIII doses of 25 IU/kg to 100 IU/kg (n= 4–7 mice per study group). Joint bleeding phenotype of the two strains of mice was similar. Mice receiving only saline injection at the time of needle puncture developed mean synovitis scores of 5 ±0.5 in the FVIII −/ − mice and 6 ±0.5 in the FIX −/ − mice. Protection by human clotting factor in the mouse coagulation system was incomplete; mice receiving 100 IU/kg I.V. of factor VIII or factor IX developed synovitis scores of 2.6 ± 1.7 and 2.1 ± 0.2, respectively. In contrast, pathology grade of FVIII −/ − mice dosed with 25 IU/kg I.A. was 0.67 ± 0.3 (p = 0.05 for comparison of 25 IU/kg I.A. with 100 IU/kg IV); FIX−/ − mice receiving 20 IU/kg I.A. had synovitis scores of 0.45 ± 0.58 (p < 0.01 for comparison of 25 IU/kg I.A. with 100 IU/kg I.V.). We next ruled out the possibility that I.A. factor was entering the circulation, and via that route resulting in joint protection, either through technical error at the time of injection, or from a depot effect in the joint with late equilibration into the circulation. Additional groups of mice received factor VIII or IX intravenously at 100 IU/kg, or intraarticularly at 4 times the doses used in the hemarthrosis challenge (80 IU/kg FIX or 100 IU/kg FVIII), and factor activity assays were performed at 1, 4, 12, 24, and 48 hours. Expected circulation kinetics were seen following I.V. dosing; no increase in circulating factor VIII or IX activity were seen in the intraarticular dosing groups at any timepoint. In considering the potential immunogenicity of an intraarticular therapy approach for hemophilic joint therapy, factor VIII −/ − mice were treated with three doses of human factor VIII 100 IU/kg at five day intervals either I.V. or I.A. At two weeks after exposure, 5/5 I.V.-treated mice developed inhibitor antibodies with titers ranging 0.8–7.2 BU; 2/5 I.A.-treated mice had detectable low-titer antibodies (1.3 BU), indicating no greater immunogenicity in the I.A. model. Extravascular factor VIII and factor IX can contribute to protection against blood-induced joint deterioration; enhancing local tissue hemostasis with protein or gene therapy may prove a useful adjunct to systemic replacement.

TT Virus Is Present in a High Frequency of Italian Hemophilic Patients Transfused With Plasma-Derived Clotting Factor Concentrates

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4333-4336 ◽  
Author(s):  
Benjamin P. Chen ◽  
Maria Grazia Rumi ◽  
Massimo Colombo ◽  
Yu-Huei Lin ◽  
Latha Ramaswamy ◽  
...  
Keyword(s):  
Factor Viii ◽  
Odds Ratio ◽  
Causal Effect ◽  
Clotting Factor ◽  
Hepatitis Viruses ◽  
Tt Virus ◽  
Plasma Factor ◽  
Immunodeficiency Virus ◽  
Factor Viii Concentrates ◽  
Clotting Factor Concentrates

The prevalence of the blood-borne TT virus (TTV) in Italian hemophiliacs treated with different preparations of factor VIII was determined. Of the 178 hemophilic patients (mean age, 29 years), TTV-DNA was found in 123 (69%), in comparison to 22 of 100 (22%) blood donors (P < .0001). Of the 123 patients who tested positive for TTV, significant numbers were also infected with human hepatitis viruses and/or human immunodeficiency virus (HIV): 31% had TTV and hepatitis C virus (HCV), 22% had TTV, and at least 2 of the 4 known human blood-borne viruses tested, whereas 15% had TTV alone. The risk of acquiring TTV alone was only slightly higher in recipients of unmodified plasma factor concentrates (78%, odds ratio, 1.24; 95% confidence interval [CI], 0.27 to 5.79) than in patients treated with virus inactivated concentrates (67%), whereas the risk was significantly lower in recipients of recombinant factors (11%, odds ratio, 0.09; 95% CI, 0.01 to 0.52). Serum alanine aminotransferase (ALT) levels were elevated in 2 of 27 patients (7%) with TTV alone compared with 43 of 56 patients (77%) coinfected with TTV and HCV and compared with 16 of 21 patients (76%) with HCV alone. Taken together, these results indicate that TTV frequently infects Italian hemophiliacs treated with plasma-derived factor VIII concentrates, both unmodified and virus-inactivated. Our results do not suggest a causal effect of TTV on chronic liver disease in these patients.

Further Evidence for a Humoral Control of Factor VIII Plasma Levels

1973 ◽  
Vol 30 (03) ◽  
pp. 460-470
Author(s):  
Ricardo H. Landaburu ◽  
Delicia E. Castellanos
Keyword(s):  
Factor Viii ◽  
Adrenal Cortex ◽  
Plasma Levels ◽  
Adrenergic Stimulation ◽  
Negative Results ◽  
Plasma Factor ◽  
Humoral Control ◽  
Acth Release

SummaryFactor VIII increase after stress or adrenergic stimulation appears to be justified by ACTH release, which in turn liberates a principle other than steroids, from the adrenal cortex. A substance isolated from adrenal cortex and denominated S3 increase, when injected, the level of plasma factor VIII. The rise in factor VIII after S3 also occurs in adrenalectomized animals where ACTH or catecholamines administration gives negative results.

Common Units for Clotting Factors Assayed Against Different Standards

1982 ◽  
Vol 48 (03) ◽  
pp. 270-273 ◽  
Author(s):  
W R S North ◽  
Y Stirling ◽  
T W Meade
Keyword(s):  
Factor Viii ◽  
Personal Characteristics ◽  
Population Based ◽  
Clotting Factor ◽  
Clotting Factors ◽  
The Third ◽  
Epidemiological Method ◽  
Heart Study ◽  
Study Participants

SummaryThere are no generally accepted units for clotting factors except factor VIII. Results are usually expressed as percentages of the standards used in the assays and standards vary in their potency. Over a six year period, factors V, VII and VIII were measured in over 3000 participants in the Northwick Park Heart Study. Six different standards had to be used. For comparative purposes, all results were expressed in terms of the first standard (71/11). This paper describes how appropriate conversion values were derived. Three different methods were compared. One consisted of the assay of each standard against its replacement. Another was based on the use of a reference plasma spanning the use of two successive standards. The third was a population-based, or epidemiological method using the data from all the participants in the study. This method is based on the assumption that results would be the same in comparable groups of study participants. In order to ensure comparability, personal characteristics which affect clotting factor levels, such as age and degree of obesity, were taken into account. The three methods gave similar results but the population method was, in general, the most satisfactory for factor VIII as well as factors V and VII, and has been adopted for routine use.

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