Common Units for Clotting Factors Assayed Against Different Standards

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

Blood ◽

10.1182/blood.v110.11.496.496 ◽

2007 ◽

Vol 110 (11) ◽

pp. 496-496 ◽

Cited By ~ 2

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.

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Reversible Factor VIII-Abnormalities in Reye’s Syndrome

10.1055/s-0038-1665837 ◽

1979 ◽

Author(s):

J. H. Joist ◽

J. Vargo ◽

M. W. Haymond ◽

J. P. Keating ◽

D. C. DeVivo

Keyword(s):

Factor Viii ◽

Coagulation Factors ◽

Clotting Factor ◽

Metabolic Disturbances ◽

Clotting Factors ◽

Reye's Syndrome ◽

Blood Coagulation Factors ◽

Qualitative And Quantitative ◽

Quantitative Studies ◽

Slow Moving

Reye’s syndrome, an acute and frequently fatal viral infection with severe metabolic disturbances is frequently associated with marked hemostatic alterations. Hypopro-thrombinemia and deficiencies of other clotting factor activities as well as findings suggestive of disseminated intravascular coagulation have been reported. This report deals with detailed sequential qualitative and quantitative studies of blood coagulation factors in four children with this disorder. Depression of factors IX, X, VII, V and II and marked disproportionate elevation of VIIIAHF, VIIIAGN and VIIIvWF associated with a loss of the slow moving component of VIIIAGU on crossed immunoelectro phoresis were consistently observed during the initial phase of the illness. in three of the four children who survived, the changes were fully reversible. Since laboratory evidence for DIC was lacking (normal fibrinogen, consistently negative protamine sulfate precipitation test) the findings seem to indicate that Reye’s syndrome is associated with an acute, transient stimulation of synthesis of normal and abnormal factor VIII as well as decreased synthesis or synthesis of functionally abnormal clotting factors by the liver.

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

Blood ◽

10.1182/blood.v126.23.4706.4706 ◽

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.

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Clinical case of an acquired hemophilia

The Clinician ◽

10.17650/1818-8338-2019-13-3-4-74-77 ◽

2020 ◽

Vol 13 (3-4) ◽

pp. 74-77

Author(s):

P. N. Barlamov ◽

E. R. Vasilyeva ◽

M. E. Golubeva ◽

V. G. Zhelobov ◽

A. A. Shutylev ◽

...

Keyword(s):

Factor Viii ◽

Blood Clotting ◽

Clinical Case ◽

Hemophilia A ◽

Clotting Factor ◽

Clotting Factors ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Left Femur ◽

Submandibular Region

The aim of the work is to describe the clinical case of formation, diagnosis and treatment of the acquired form of blood clotting factor VIII deficiency – of acquired hemophilia A.Material and methods. Patient R., 71 years, from April 2018, was found an acute hemorrhagic syndrome in the hematomic type of large hematomas manifested submandibular region, neck, chest, right breast, pubic and inguinal regions on the right, the anterior-medial surface of the left femur, anterior surface of left tibia. Standard laboratory tests, computed tomography of soft tissues of the neck, lungs, abdomen; coagulogram; blood clotting factors; inhibitor of factor VIII were evaluated in dynamics during the patient’s stay in the hospital; platelet aggregation function.Results. Typical gematomny type of bleeding, prolongation of coagulation indicators, the presence of the inhibitor factor VIII (7,0 BAA), the decrease in factor VIII (2 %) allowed diagnosis of acquired hemophilia A. Anti-inhibitory coagulant complex, fresh frozen plasma was successfully used for treatment. The patient is under observation in the regional Hematology center. The hematomas were not renewed.Conclusion. Our clinical observation demonstrates the features of the course, the algorithm of diagnosis and management of patients with of acquired hemophilia A.

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Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors

Hematology ◽

10.1182/asheducation-2015.1.33 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 33-40 ◽

Cited By ~ 13

Author(s):

Paul E. Monahan

Keyword(s):

Gene Therapy ◽

Factor Viii ◽

Standard Of Care ◽

Factor Ix ◽

Clotting Factor ◽

Gene Correction ◽

Clotting Factors ◽

Igg Antibody ◽

Coagulation Protein ◽

Interfering Rna

Abstract For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. At the same time that gene therapy is gaining momentum, suggesting the possibility of relief from regular intravenous coagulation protein replacement, a number of innovative technologies that enhance hemostatic potential independently of replacement factor administration are demonstrating success in human clinical application. Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies.

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Evaluation of Potential Clinical Surrogate Markers of a Trauma Induced Alteration of Clotting Factor Activities

BioMed Research International ◽

10.1155/2016/5614086 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Manuel Burggraf ◽

Arzu Payas ◽

Carsten Schoeneberg ◽

Alexander Wegner ◽

Max Daniel Kauther ◽

...

Keyword(s):

Factor Viii ◽

Multiple Trauma ◽

Base Deficit ◽

Clotting Factor ◽

Control Group ◽

Surrogate Markers ◽

Factor Viii Activity ◽

Clotting Factors ◽

Contrast Factor ◽

Hemostatic Therapy

Objective.The aim of this study was to identify routinely available clinical surrogate markers for potential clotting factor alterations following multiple trauma.Methods.In 68 patients admitted directly from the scene of the accident, all soluble clotting factors were analyzed and clinical data was collected prospectively. Ten healthy subjects served as control group.Results.Patients showed reduced activities of clotting factors II, V, VII, and X and calcium levels (allP<0.0001to 0.01). Levels of hemoglobin and base deficit correlated moderately to highly with the activities of a number of clotting factors. Nonsurvivors and patients who needed preclinical intubation or hemostatic therapy showed significantly reduced factor activities at admission. In contrast, factor VIII activity was markedly elevated after injury in general (P<0.0001), but reduced in nonsurvivors (P<0.05).Conclusions.Multiple trauma causes an early reduction of the activities of nearly all soluble clotting factors in general. Initial hemoglobin and, with certain qualifications, base deficit levels demonstrated a potential value in detecting those underlying clotting factor deficiencies. Nevertheless, their role as triggers of a hemostatic therapy as well as the observed response of factor VIII to multiple trauma and also its potential prognostic value needs further evaluation.

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Homoeopathic Management of a Case of Severe Haemophilia Type A with Inhibitor Positive: Case Report

Homœopathic Links ◽

10.1055/s-0040-1718775 ◽

2020 ◽

Vol 33 (04) ◽

pp. 302-308

Author(s):

Hiral Shah ◽

Tapas Kumar Kundu ◽

Afroz Farooque Shaikh

Keyword(s):

Case Report ◽

Factor Viii ◽

Replacement Therapy ◽

Psychological Status ◽

Clotting Factor ◽

Factor Viii Inhibitor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Clotting Factors ◽

Bleeding Episodes

AbstractHaemophilia is an X-linked inherited immunogenetic bleeding disorder resulting from deficiency of clotting Factor VIII (haemophilia A) or Factor IX (haemophilia B). Haemophilia patients suffer from complication of developing autoantibodies/inhibitor against clotting factors used for the treatment; most commonly patients are treated with Factor VIII replacement therapy. In modern medicine, haemophiliacs with inhibitor positive status are treated with bypassing agents such as Factor VIII inhibitor bypassing agent and immune tolerance induction therapy (ITI) because such patients do not respond to traditional factor replacement therapy during an event of active bleeding. Treatment with ITI is very expensive and it requires medical expertise. Moreover, high cost of such treatment is one part of the problem, while its availability is another problem especially in developing countries. The inhibitor status among haemophilia patients is identified by conducting a blood test which measures the Bethesda units (BU) levels in the blood. In this case report, the homoeopathic management of a patient with haemophilia A severe type (Factor VIII <1%), inhibitor positive (4 BU/mL), is presented. The patient underwent treatment for a span of 4 years. After closely assessing the patient's condition and applying the principles of homeopathy medicine selection, his frequent bleeding episodes were treated with homoeopathic medicines such as Hamamelis Virginica Q, Phosphorus, Arnica montana, Rhus toxicodendron, Calendula officinalis, and Pulsatilla nigricans. Intercurrent medicine—Tuberculinum bovinum—was given when the most indicated medicine failed to relieve the symptoms of the case and was given during non-bleeding phase. The medicines not only helped in reducing haemophilia-related bleeding episodes but also improved complaints of pain, relieved skin complaints, and showed improvement in overall psychological status of patient. It can be concluded that homeopathy medicines were able to successfully reduce the frequency of bleeding and intensity of pain in this patient. Owing to reduced bleeding, he required relatively a smaller number of factor replacement treatment compared with earlier when he was not taking homeopathy. Homoeopathy proved to be effective in managing severe haemophilia patient as a supportive therapy and was able to contribute toward reduced inhibitor levels in severe haemophilia patient.

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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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Reversible Factor VIII-Abnormalities in Reye’s Syndrome.

10.1055/s-0039-1684565 ◽

1979 ◽

Author(s):

J. H. Joist ◽

J. Vargo ◽

M. W. Haymond ◽

J. P. Keating ◽

D. C. DeVivo

Keyword(s):

Factor Viii ◽

Coagulation Factors ◽

Clotting Factor ◽

Metabolic Disturbances ◽

Clotting Factors ◽

Reye's Syndrome ◽

Blood Coagulation Factors ◽

Quantitative Studies ◽

Crossed Immunoelectrophoresis ◽

Slow Moving

Reye’s syndrome, an acute and frequently fatal viral infection with severe metabolic disturbances is frequently associated with marked hemostatic alterations. Hypoprothrombinemia and deficiencies of other clotting factor activities as well as findings suggestive of disseminated intravascular coagulation have been reported. This report deals with detailed sequential qualitative and quantitative studies of blood coagulation factors in four children with this disorder. Depression of factors IX, X, VII, V and II and marked disproportionate elevation of VIIIAHF, VIIIAGN VIIIVWF associated with a loss of the slow moving component of VIIIAGN on crossed Immunoelectrophoresis were consistently observed during the initial phase of the illness. In three of the four children who survived, the changes were fully reversible. Since laboratory evidence for DIC was lacking (normal fibrinogen, consistently negative protamine sulfate precipitation test) the findings seem to indicate that Reye's syndrome is associated with an acute, transient stimulation of synthesis of normal and abnormal factor VIII as well as decreased synthesis or synthesis of functionally abnormal clotting factors by the liver.

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Detection of hepatitis A virus from clotting factors implicated as a source of HAV infection among haemophilia patients in Korea

Epidemiology and Infection ◽

10.1017/s0950268805004632 ◽

2005 ◽

Vol 134 (1) ◽

pp. 87-93 ◽

Cited By ~ 17

Author(s):

Y. M. JEE ◽

U. GO ◽

D. CHEON ◽

Y. KANG ◽

J.-D. YOON ◽

...

Keyword(s):

Factor Viii ◽

Blood Clotting ◽

Hepatitis A ◽

Hepatitis A Virus ◽

Epidemiological Studies ◽

Clotting Factor ◽

Clotting Factors ◽

Matched Case ◽

Relationship Of ◽

Blood Clotting Factors

SUMMARYTo investigate the causal relationship of blood clotting factors and hepatitis A virus (HAV) infection in haemophilia patients during 1998–1999 in Korea, we performed a 1:3 matched case-control study and molecular detection of HAV from clotting factors and patients. The epidemiological investigation showed that one lot of clotting factor VIII was related epidemiologically to patients with hepatitis A with an odds ratio of 35·0, or 38·4 when adjusted for the interval between injections. We examined 17 sera collected from seven patients and 124 lots of blood clotting factors (factor VIII and factor IV) by HAV reverse transcriptase–polymerase chain reaction (RT–PCR). HAV RNA was detected in five clotting factors and six sera. The HAV sequence of one of the factor VIII samples was identical to the sequences found in three patients' sera. Findings from the laboratory and epidemiological studies suggested that the clotting factor was causally related to HAV infection in three haemophilia patients.

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