scholarly journals Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 715-720 ◽  
Author(s):  
GF Gjerset ◽  
PJ Martin ◽  
RB Counts ◽  
LD Fast ◽  
JA Hansen
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Absolute Number ◽  
Factor Ix ◽  
Clotting Factor ◽  
Lymphocyte Function ◽  
Laboratory Evidence ◽  
Group I ◽  
The Mean

Abstract We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.

scholarly journals Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 715-720
Author(s):  
GF Gjerset ◽  
PJ Martin ◽  
RB Counts ◽  
LD Fast ◽  
JA Hansen
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Absolute Number ◽  
Factor Ix ◽  
Clotting Factor ◽  
Lymphocyte Function ◽  
Laboratory Evidence ◽  
Group I ◽  
The Mean

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.

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

1966 ◽  
Vol 15 (03/04) ◽  
pp. 349-364 ◽  
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.

Blood Induced Cartilage Changes in a Hemophilia A Murine Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1152-1152
Author(s):  
Amy L. Dunn ◽  
Bahig M. Shehata
Keyword(s):  
Articular Cartilage ◽  
Factor Viii ◽  
Hemophilia A ◽  
Age Groups ◽  
Clotting Factor ◽  
Blue Staining ◽  
Mankin Score ◽  
The Mean ◽  
Bleeding Score ◽  
And Control

Abstract Background: Hemophilia A results from a congenital deficiency of clotting factor VIII. Patients with hemophila are unable to generate adequate thrombin during blood coagulation and therefore have a bleeding diathesis. Degenerative joint disease is the largest source of morbidity for hemophilic patients. The pathophysiology of this process is poorly understood but clinically, repeated bleeding into a joint leads to changes in the synovium, articular cartilage and underlying bone. It is not well known how quickly cartilage changes occur or if animal age has any impact on susceptibility to blood induced cartilage damage. Materials and Methods: The E16 fVIII knockout mouse is a well-established model for hemophilia research. These mice contain a targeted disruption of the factor VIII gene at exon 16 (E16) in a C57BL/6 background. Despite having no detectable circulating fVIII activity they rarely suffer from spontaneous hemarthroses. Therefore hemarthroses was mimicked by injecting 5 μL of autologous whole blood into the hind knee. Six male mice per group in each of three ages; 12, 24 and 52 weeks were utilized. The animals were sacrificed 48 hours after injection. The injected and control contralateral knee joint from each animal was fixed in 10% formalin and then mounted in paraffin. After decalcification, five micrometer sections through the joint were obtained. Joint architecture was examined after hematoxylin and eosin staining. Proteoglycan content of articular cartilage was evaluated after alcian blue staining as part of the modified Mankin score. The pathologic specimens were also scored utilizing Valentino’s visual bleeding score. The Student’s t-test was utilized for significance testing. Results: All mice showed evidence of blood remaining in the injected joint at 48 hours. The mean visual bleeding score was significantly higher for the injected knees versus the control knees of all age groups p<0.001. The mean visual bleeding score was significantly between the 12 and 24 week animals p=0.0112 and the 12 and 52 week animals p=0.0379, but not between the 24 and 52 week animals p=0.5423. The modified Mankin score was significantly higher between the injected and control knees of all age groups as seen in Figure 1 where the mean and standard deviation is shown for 6 animals in each group. Interestingly, one control knee in a 24 week old animal demonstrated synovial hyperplasia and decreased proteoglycan staining but had no evidence of blood in the joint. This likely represented a previous spontaneous hemorrhage. The modified Mankin score was highest for the 12 week old animals and lowest for the 52 week animals but did not achieve statistical significance p=0.5746. Conclusions: Injection of autologous blood mimicked clinical hemarthrosis. Evidence of decreased proteoglycan staining of articular cartilage was evident within 48 hours of blood exposure. Additionally, there was a trend toward more prominent proteoglycan loss in the youngest animals. Figure Figure

Is the Detection of Factor IX Inhibitors in Hemophilia B Orphan than Factor VIII Inhibitors in Hemophilia A? A Concise, Systematic Review

2020 ◽  
Vol 20 (3) ◽  
pp. 185-190
Author(s):  
Hassan Mansouritorghabeh ◽  
Seyedeh T. Mohades
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
World Federation ◽  
Health Provider ◽  
Comprehensive Review ◽  
Significant Challenge ◽  
The World ◽  
The Mean

Objective: Development of inhibitors in hemophilia A and B comprise significant challenge for patients, hematologists, and health provider systems. It has recommended by the World Federation of Hemophilia (WFH) to check inhibitors every 3-4 months. The incidence of inhibitor in hemophilia B is lower than hemophilia A. Here, it tried to unravel whether the detection of inhibitors in hemophilia B neglected compared to hemophilia A or not? Methods: A comprehensive review carried out using six international and local medical search engines on published contributions about inhibitors in hemophilia A and B in Iran. Results: From 699 titles, 12 relevant papers were selected. The mean of factor VIII inhibitors in hemophilia A was 14.8%. The mean of factor IX inhibitors in hemophilia B was 6%. The minimum and maximum reported percentages of factor VIII inhibitors were 4% and 19.6%, while the minimum and maximum of reported percentages of factor IX inhibitors were 0% and 11.8%, respectively. The inhibitors in hemophilia A had reported in 6 papers. One paper had covered the inhibitors in hemophilia B. There were five papers on inhibitors in both hemophilia A and B. The comparison between the reported patients showed that 3020 patients with hemophilia A and 314 patients with hemophilia B had studied. Conclusion: Consistent with the lower frequency of hemophilia B and the lower development of inhibitors in hemophilia B compared to hemophilia A, it was concluded that hemophilia B had not neglected in Iran. It seems to be rational that each country, check rates of detection of inhibitors in hemophilia B to identify whether it has neglected or not.

Immunologic aberrations, HIV seropositivity and seroconversion rates in patients with hemophilia B

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 276-281
Author(s):  
DB Brettler ◽  
F Brewster ◽  
PH Levine ◽  
A Forsberg ◽  
S Baker ◽  
...  
Keyword(s):  
Factor Viii ◽  
Male Volunteer ◽  
Hemophilia A ◽  
High Titer ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Immunodeficiency Virus ◽  
And Function ◽  
Factor Concentrate

Because there have been reports that factor IX concentrate is less immunosuppressive and therefore factor IX users have less immunologic aberrations, we have studied a group of 22 patients with hemophilia B and six patients with factor VIII deficiency and high titer inhibitors with respect to lymphocyte numbers and function, human immunodeficiency virus (HIV) serology, and factor usage. This group was compared to 111 patients with hemophilia A and a group of 28 healthy male volunteer controls. When the study began in 1983, the majority of patients with hemophilia B and with higher titer factor VIII inhibitors were seronegative, 77% and 83% respectively, as compared to only 30% of patients with hemophilia A. At that time the factor IX users also had milder immune aberrations than the hemophilia A group. However, with time and increasing clotting factor concentrate usage, seroconversion and more striking abnormalities in immune function have occurred in the hemophilia B group. In a subgroup of 16 patients with hemophilia B studied twice, the incidence of seropositivity increased from 31% in 1983 to 69% in 1985. We thus conclude that factor IX concentrate in itself is not less immunosuppressive than factor VIII concentrate. Seroconversion in factor IX concentrate users appears to be lagging behind seroconversion in factor VIII concentrate users, perhaps secondary to the lower cumulative dosage of concentrate that patients with hemophilia B utilize.

Gene Therapy for Hemophilia A and B: Patient Selection and Follow-up, Requirements for a Cure

1999 ◽  
Vol 82 (08) ◽  
pp. 572-575 ◽  
Author(s):  
Jeanne Lusher
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hepatitis A ◽  
Hemophilia A ◽  
The United States ◽  
Factor Ix ◽  
Clotting Factor ◽  
R Factor ◽  
New Variant ◽  
Clotting Factor Concentrates

IntroductionThe treatment of hemophilia A and B has improved considerably in recent years. The availability of hepatitis A and B vaccines, safer clotting factor concentrates (particularly recombinant factor VIII and recombinant factor IX concentrates), and synthetic agents, such as desmopressin,1 has resulted in earlier, more aggressive treatment and prophylactic regimens aimed at preventing chronic, debilitating joint disease.2-8There have been no new cases of human immunodeficiency virus (HIV) disease attributable to clotting factor in North America since 1987, and documented instances of hepatitis transmission by clotting factor concentrates have been rare in the 1990s. Concerns remain that certain nonenveloped viruses, such as human parvovirus B19 and hepatitis A virus, can still be transmitted by some plasma-derived clotting factor concentrates,9and questions linger as to whether the agents causing Creutzfeld-Jacob disease (CJD) and new variant CJD might also be transmitted. Overall, however, the products available to treat hemophilia today are safer than ever before.An increasing number of persons with hemophilia are receiving exclusively recombinant (r) products, and manufacturers are now producing new, second-generation r-factor VIII products that are stabilized with sugars, rather than albumin, or are smaller, truncated molecules.10 Scientists are now designing specific changes into the factor VIII genes in an attempt to derive unique and improved forms of r-factor VIII.11 The next logical areas of focus are to bring to fruition the promise of an “unlimited supply” of r-factor VIII and r-factor IX products, to meet the needs of persons with hemophilia, not only in developed countries, but throughout the world, and to be able to cure hemophilia through gene therapy.As gene therapy trials begin in humans with hemophilia, the scientists involved, the United States Food and Drug Administration (FDA), and perhaps most importantly, members of the hemophilia community must decide which categories of affected individuals should be entered in these trials, particularly the earliest, Phase I trials. Who is most likely to benefit if gene therapy proves to be both effective and safe? Who should be the first patients to be enrolled in each new trial? Who is at greatest risk if something unexpected happens? What would be considered a good outcome? Clearly, some of these questions are more difficult to answer than others.

T-Cell Alterations in Hemophiliacs Treated with Commercial Clotting Factor Concentrates

1983 ◽  
Vol 50 (02) ◽  
pp. 552-556 ◽  
Author(s):  
K Lechner ◽  
H Niessner ◽  
P Bettelheim ◽  
E Deutsch ◽  
I Fasching ◽  
...  
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Hemophilia A ◽  
Indirect Evidence ◽  
Absolute Number ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
T Helper ◽  
Immunological Parameters

SummaryVarious immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.

scholarly journals A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2335-2340
Author(s):  
Toufik Abache ◽  
Alexandre Fontayne ◽  
Dominique Grenier ◽  
Emilie Jacque ◽  
Alain Longue ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Viia ◽  
Rabbit Model ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Factor X ◽  
Factor Viiia

Rendering coagulation factor X sensitive to thrombin was proposed as a strategy that can bypass the need for factor VIII. In this paper, this non-replacement strategy was evaluated in vitro and in vivo in its ability to correct factor VIII but also factor IX, X and XI deficiencies. A novel modified factor X, named Actiten, was generated and produced in the HEK293F cell line. The molecule possesses the required post-translational modifications, partially keeps its ability to be activated by RVV-X, factor VIIa/tissue factor, factor VIIIa/factor IXa and acquires the ability to be activated by thrombin. The potency of the molecule was evaluated in respective deficient plasmas or hemophilia A plasmas, for some with inhibitors. Actiten corrects dose dependently all the assayed deficient plasmas. It is able to normalize the thrombin generation at 20 μg/mL showing however an increased lagtime. It was then assayed in a rabbit antibody-induced model of hemophilia A where, in contrast to recombinant factor X wild-type, it normalized the bleeding time and the loss of hemoglobin. No sign of thrombogenicity was observed and the generation of activated factor X was controlled by the anticoagulation pathway in all performed coagulation assays. This data indicates that Actiten may be considered as a possible non replacement factor to treat hemophilia's with the advantage of being a zymogen correcting bleedings only when needed.

scholarly journals Immunologic aberrations, HIV seropositivity and seroconversion rates in patients with hemophilia B

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 276-281 ◽  
Author(s):  
DB Brettler ◽  
F Brewster ◽  
PH Levine ◽  
A Forsberg ◽  
S Baker ◽  
...  
Keyword(s):  
Factor Viii ◽  
Male Volunteer ◽  
Hemophilia A ◽  
High Titer ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Immunodeficiency Virus ◽  
And Function ◽  
Factor Concentrate

Abstract Because there have been reports that factor IX concentrate is less immunosuppressive and therefore factor IX users have less immunologic aberrations, we have studied a group of 22 patients with hemophilia B and six patients with factor VIII deficiency and high titer inhibitors with respect to lymphocyte numbers and function, human immunodeficiency virus (HIV) serology, and factor usage. This group was compared to 111 patients with hemophilia A and a group of 28 healthy male volunteer controls. When the study began in 1983, the majority of patients with hemophilia B and with higher titer factor VIII inhibitors were seronegative, 77% and 83% respectively, as compared to only 30% of patients with hemophilia A. At that time the factor IX users also had milder immune aberrations than the hemophilia A group. However, with time and increasing clotting factor concentrate usage, seroconversion and more striking abnormalities in immune function have occurred in the hemophilia B group. In a subgroup of 16 patients with hemophilia B studied twice, the incidence of seropositivity increased from 31% in 1983 to 69% in 1985. We thus conclude that factor IX concentrate in itself is not less immunosuppressive than factor VIII concentrate. Seroconversion in factor IX concentrate users appears to be lagging behind seroconversion in factor VIII concentrate users, perhaps secondary to the lower cumulative dosage of concentrate that patients with hemophilia B utilize.

Differentiation of BM-HSCs Into FVIII Producing Hepatocytes: Approach to Haemophilia Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4388-4388
Author(s):  
Amal M. El-beshlawy ◽  
Hala Gabr ◽  
Rania Zayed ◽  
Laila Hegaz ◽  
Rania Fawzy ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Alpha Fetoprotein ◽  
Control Group ◽  
P Value ◽  
Rt Pcr ◽  
Significant Difference ◽  
The Mean

Abstract Abstract 4388 Background: Hemophilia is caused by a single-gene defect in which a small increase in gene products could transform a severe form of hemophilia into a mild one. Hemophilia treatments are readily available in developed countries, however In Egypt, Most hemophilia patients are treated with plasma or cryoprecipitate, where the treatment is associated with a high risk of blood-borne diseases. Liver transplantation in human and canine hemophilia A results in an increase in factor VIII levels to normal. Studies showed that BMCs not only differentiated into hepatic and liver cells, but they did express the intact gene of the FVIII A3 domain. Objective: In this work we studied the ability of bone marrow derived stem cells from hemophilia patients' relatives (carrier or normal) to be differentiated into hepatocytes expressing FVIII m-RNA in vitro as a step towards transplantation in haemophilia patients. It was necessary to prove that the applied culture conditions were successful not only to obtain hepaotocyte morphology but also hepatocyte ability to produce FVIII. Methods: The study was conducted on family relatives of five hemophilia A patients attending the hematology clinic, Cairo University hospitals. From each family, one hemophilia A carrier and one healthy person were subjected to the study. Informed consent was obtained from the participants. BM-HSCs were cultured in liquid culture containing HGF for 6 days. Differentiation into hepatocytes was evaluated by alpha-fetoprotein (AFP) expression using immunohistochemistry, albumin synthesis in culture supernatant using microalbumin assay kit, factor VIII activity by one stage clotting assay and expression of FVIII mRNA by RT-PCR. Results: Cell morphology changed after 6 days culture; round or polygonal-shaped cells with moderate cytoplasm and a medium-sized nucleus were observed. Morphologic confirmation of hepatocyte differentiation was done by immunocytochemistry; human alpha fetoprotein positive cells were detected in the culture. The positive cells appeared round or pear shaped, most of them contained one nucleus. However, few cells were binucleated with brown stained cytoplasm and bluish nuclei (Figure 1 A, B). By image analysis, the mean number of alpha fetoprotein positive cells estimated in10 random high power fields was 11 ± 1.6, 11 ±1.8 cells/HPF in the carriers and controls respectively. Immunophenotyping after culture; the percentage of CD 34+ve cells for the carrier group ranged from 0.5 to 2.5 with the mean of 1.2 ± 0.8 and from 0.7 to 2.1 with the mean of 1.5 ± 0.7 for the control group. There was no statistically significant difference between the two groups (p > 0.05) and the percentage of CD 90+ve cells for the carrier group ranged from 11.1 to 14.2 with the mean of 12.7 ± 1.2 and from 12.6 to 13.8 with the mean of 13.3 ± 0.6 for the control group. There was no statistically significant difference between the two groups (p > 0.05). On comparison between immunophenotyping before and after culture in both groups, statistical analysis showed highly significant decrease in CD34 positivity (p value 0.002 and 0.001) in the carriers and controls respectively associated with highly significant increase in the percentage of CD90 positive cells (p value 0.000) in the two groups. Albumin secretion was detected in the culture supernate at the 6th day culture, the mean albumin level was 0.52 mg/L ± 0.32 and 0.6 mg/L ± 0.4 in the carriers and controls respectively. F VIII activity was estimated; with the mean of 0.14%±0.021% and 0.5%±0.4% in the carriers and controls respectively. Transcription of FVIII m-RNA was detected by qualitative RT-PCR in 2 carriers and all controls (Figure 2). Conclusion: BM derived hepatocytes showed positive AFP expression. Functional tests performed showed their ability to produce albumin and perform FVIII activity. Also FVIII mRNA expression was detected. Induction of HSCs differentiation by in vitro manipulation may become a valuable tool to provide a cell source for liver transplant procedures and treatment of haemophilia patients. Disclosures: No relevant conflicts of interest to declare.

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