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PubMed1996

Why prescribe highly purified factor VIII and IX concentrates?

The aftermath of the HIV catastrophe and hepatitis virus transmission to hemophiliacs has been characterized by continuous efforts to improve the purity of factor VIII and factor IX concentrates, increasing sophistication of the virucidal methods used, and the introduction of recombinant factor VIII. The cost of hemophilia care is substantial and there is a large price difference between products depending on their purity; generally, the purer the concentrate, the higher the price. The use of expensive highly purified concentrates may be questioned if these products are not superior in terms of safety, efficacy or convenience. The properties of concentrates used in hemophilia care are discussed in this review, as are their safety and side effects. The available data do not clearly reveal any clinical difference between factor VIII concentrates, although the highly purified products may be of theoretical benefit. With regard to factor IX, purified products do not seem to carry any risk of the well-known thromboembolic complications which occur in certain situations after treatment with prothrombin complex concentrates.

Drug Contamination↗

PubMedDate not supplied

The response of an acquired Factor V inhibitor to activated Factor IX concentrate.

A 91-year-old man developed a severe bleeding diathesis postoperatively. Laboratory studies showed an inhibitor to factor V which was identified as IgG. The patient failed to respond to fresh-frozen plasma and platelet transfusions, but demonstrated both clinical and laboratory improvement after transfusion with an activated prothrombin complex concentrate (Autoplex). Patients with refractory inhibitors to factors VIII or IX have been managed successfully with this concentrate; however, this case demonstrates that is also may be of value in managing patients with refractory inhibitors to factor V.

Aged↗

PubMed2001

Acquired haemophilia: experiences with a standardized approach.

Acquired haemophilia is a rare, life-threatening, acquired bleeding diathesis. No general consensus exists on the best therapeutic approach. We report on the standardized approach at our institution evaluated in ten patients with acquired haemophilia. Factor VIII inhibitors were found in all patients, activities ranging from 1 to 648 Bethesda units (BU). Eight of the ten patients presented with severe bleeding. Two patients died during the acute phase, one from intracranial bleeding and one due to Mycoplasma pneumonia. One patient with mild bleeding was treated with immunosuppression alone. Two patients with factor VIII inhibitor activities below 5 BU were started on factor VIII concentrate therapy. Therapy was successful in one and was changed to recombinant human activated factor VII infusion (rFVIIa) in the other, owing to insufficient factor VIII recovery. Six patients with factor VIII inhibitor activities above 5 BU were started on activated prothrombin complex concentrate (APCC) therapy. APCC treatment was successful initially in all six patients and was changed to rFVIIa infusion in one for rebleeding. One patient did not receive any specific therapy. Immunosuppression with prednisolone (2 mg kg(-1)) was begun in nine patients and was continued with cyclophosphamide (2 mg kg(-1)) in six. A complete remission of the acquired haemophilia was found in seven of the eight patients surviving the acute phase, one had a partial remission. All patients with acquired haemophilia could be managed effectively following our standardized approach. Routine administration of immunosuppression was associated with high inhibitor elimination rates.

Acute-Phase Reaction↗

PubMed1984

Apparent intrinsic prothrombinase activity of human Factor X zymogen: identification with Factor VIII inhibitor bypassing activity (FEIBA).

Steady state kinetic studies have provided evidence for intrinsic prothrombinase activity of human factor X zymogen in a chromogenic assay system. Using a prothrombin substrate, kinetic parameters have been obtained for the action of factors X and Xa. The Km for prothrombin is of a different order of magnitude for the zymogen as compared with the active enzyme. Using a kinetic approach, we have obtained evidence for the binding of factor Xa zymogen to cofactors essential for the coagulant activity of factor Xa. Zymogen enzymatic activity is not inhibited by a specific serine proteinase inhibitor, (p-amidino-phenyl)methanesulfonyl fluoride (p-APMSF), a potent inhibitor of factor Xa. The apparent slow rate of zymogen inhibition by antithrombin III (AT III) as compared with the active enzyme suggests a different kind of zymogen-antithrombin interaction. Blood clotting studies paralleled the kinetic data. Factor X zymogen evidences factor VIII inhibitor bypassing activity (FEIBA) in an in vitro direct clotting system employing factor VIII deficient inhibitor plasma as substrate in both activated or nonactivated partial thromboplastin assay. Most significantly, zymogen coagulant is refractory to inhibition by p-APMSF or AT III. We conclude that a system consisting of factor X zymogen-phospholipid-factor Va can physiologically initiate blood clotting in the presence of inhibitors and may have a major role in the bypass mechanism of therapeutic prothrombin complex concentrate (PCC).

Antithrombin III↗

PubMed1984

Inverse correlation between age related abnormalities of T-cell immunity and circulating thymosin alpha 1 levels in haemophilia A.

T-cell immunity and serum levels of thymosin alpha 1, beta 2-microglobulin, circulating immune complexes, serum immunoglobulin levels, antibodies to hepatitis surface or core antigen, and to cytomegalovirus, and Epstein-Barr virus were investigated in 51 patients with haemophilia A ranging in age from 2 to 52 years. All patients had received commercial U.S. lyophilized concentrates of antihaemophilic factor (AHF). The mean helper/cytotoxic-suppressor (OKT4/OKT8) ratio of 11 pre-adolescents (1.6 +/- 0.4 SE) was not significantly different from that of age matched normal controls. In contrast, the mean OKT4/OKT8 ratios of 13 adolescent (1.2 +/- 0.2 SE) and 23 adult (0.8 +/- 0.1 SE) haemophiliacs were significantly reduced. Abnormalities of lymphocyte mitogenic responses were found only in adult haemophiliacs. Nine individuals treated with commercial U.S. prothrombin complex concentrates for antibodies directed against AHF or for haemophilia B had normal mean OKT4/OKT8 values. The mean serum thymosin alpha 1 levels for each age category was similar to that of age matched controls; however, regression analysis revealed a significant relationship between elevated thymosin alpha 1 levels and decreased OKT4/OKT8 ratios in adult haemophiliacs (P = 0.012). Although the mean serum level of beta 2-microglobulin was significantly increased in the adult haemophiliac group, there was no correlation between OKT4/OKT8 ratios and any of the other serologic parameters studied.

Adolescent↗

PubMed2000

NovoSeven in immune tolerance therapy.

The development of inhibitors in haemophilia patients is one of the most serious challenges to effective treatment. The effect of factor (F) concentrate and treatment regimen on titre levels was studied in nine patients with haemophilia A or B and inhibitors. Patients with haemophilia A were subdivided into those treated with recombinant activated factor VII (rFVIIa) on demand or those treated prophylactically with activated prothrombin complex concentrate (aPCC) and rFVIIa. A third group comprised haemophilia B patients receiving rFVIIa prophylaxis and on-demand aPCC or rFVIIa. On-demand therapy with rFVIIa proved to be effective and safe treatment for acute bleeding episodes in haemophilic patients. In group 1, inhibitor titres decreased markedly 0.5-21 months prior to immune tolerance therapy (ITT) and remained low for a further 1-19 months. However, use of rFVIIa instead of aPCC as prophylactic treatment in group 2 patients undergoing ITT failed to show favourable results for rFVIIa. This may be due to the short half-life of rFVIIa (2.3-2.9 h). The data presented suggest that exclusive use of rFVIIa in acute bleeding episodes prior to commencing ITT is an effective method of decreasing inhibitor titre, thereby optimizing conditions for ITT.

Adolescent↗

PubMed2001

Parvovirus B19 DNA in plasma pools and plasma derivatives.

BACKGROUND AND OBJECTIVES: Human parvovirus B19 (B19) has been transmitted by various plasma-derived medicinal products. The aim of this study was to determine the frequency and the level of B19 DNA contamination in plasma pools destined for fractionation and in a broad range of plasma derivatives. In addition, removal of B19 DNA by the manufacturing process was investigated in cases where corresponding samples from plasma pool and product were available. MATERIALS AND METHODS: Plasma pool samples and blood products were tested for B19 DNA by nested polymerase chain reaction (PCR), and the viral DNA content was determined by TaqMan quantitative PCR. RESULTS: Two-hundred and twenty two of 372 plasma pools for fractionation contained B19 DNA at concentrations of 10(2)-10(8) genome equivalents/ml (geq/ml). While approximately 65% of the DNA-positive plasma pools were only moderately contaminated (< 10(5) geq/ml), 35% contained > 10(6) geq/ml. High frequencies of contamination were detected in Factor VIII (79 of 91), prothrombin complex concentrates (38 of 43) and Factor IX (41 of 62), where the concentration of B19 DNA ranged between 102 and 107 geq/ml. A lower level of B19 DNA contamination was found in antithrombin III (five of 26 samples), in anti-D immunoglobulins (three of 37 samples) and in albumin (four of 51 samples), with levels ranging between 10(2) and 10(3) geq/ml. Furthermore, investigation of plasma pools for solvent/detergent plasma (S/D plasma), from two manufacturers, revealed B19 DNA in 15 of 66 batches at concentrations of 10(2)-10(8) geq/ml. Similar concentrations were detected in the corresponding final S/D plasma products. Anti-B19 immunoglobulin G (IgG) was found in plasma pools and S/D plasma at concentrations of approximately 40 IU/ml. CONCLUSION: Although positive PCR results do not necessarily reflect infectivity, these data show that B19 is a common contaminant in plasma pools and in plasma-derived medicinal products. Considering the resistance of animal parvoviruses to inactivation by heat and chemical agents, and the absence of specific information for B19, the risk of B19 transmission by plasma products should be considered. Physicians should be aware of this problem when treating patients of B19-related risk groups. The plasma fractionation industry should continue their efforts to avoid B19 contamination of plasma derivatives and develop methods which are effective in removing/inactivating parvovirus B19.

Blood↗

PubMed1985

Lymphocyte subset ratios and factor VIII usage in haemophilia.

Type and quantity of replacement treatment, together with haematological and immunological parameters were determined in 37 boys with severe haemophilia A and 41 children with other bleeding disorders. The quantity of factor VIII concentrate given to boys with severe haemophilia A (mean U/year) showed a significant inverse correlation with total white cell counts, lymphocyte counts, platelet counts, and the ratio of monoclonal antibody defined T lymphocyte subsets, T4 and T8 (T4:T8). Of the boys with severe haemophilia A, 49% had inversed T4:T8 ratios and 24% had thrombocytopenia. Treatment with high dose factor VIII concentrate (more than 25 000 U/year) was associated with low platelet counts, low lymphocyte counts, low T4:T8 ratios, and hypergammaglobulinaemia. In addition, six patients with severe haemophilia A and factor VIII inhibitors had inversed T4:T8 ratios. Patients treated exclusively with cryoprecipitate or prothrombin complex concentrates had normal T4:T8 ratios and platelet counts. The severity of the haematological and immunological abnormalities observed seems to be associated with high usage of factor VIII concentrates. Similar abnormalities have been described in patients with the acquired immune deficiency syndrome (AIDS). Prospective study of haemophiliacs is required to assess long term sequelae of factor concentrate usage, including the possible development of AIDS.

Child↗

PubMed2003

[Hyperpyrexia and rhabdomyolysis after ecstasy (MDMA) intoxication].

Abuse of 3,4-methylenedioxymethamphetamine (MDMA,Ecstasy) is still growing over the last years and reports of severe or even fatal complications, such as arrhythmias, hyperpyrexia, rhabdomyolysis, disseminated intravascular coagulopathy (DIC), acute renal or liver failure or brain oedema are also increasing. We report the case of a 21-year-old male who took a suicidal overdose of MDMA and subsequently developed severe hyperpyrexia (>43 degrees C/109.4 degrees F), rhabdomyolysis with an initial myoglobin level of 88,000 microg/l, disseminated intravascular coagulation (DIC) and beginning renal and liver failure. Infusing dantrolene 140 mg (2.5 mg/kg body weight) i.v. and using supportive cooling was effective in treating hyperpyrexia. To support renal function and diuresis we increased the intravenous fluid supply up to 5 l per day which led to a raised elimination of myoglobin, urea nitrogen and creatinine within 1 week. Hemodialysis was not necessary. DIC was treated according to laboratory parameters by supply of antithrombin (AT) III, fresh frozen plasma, prothrombin complex concentrates (PPSB) and continuous aprotinin 100,000 IE/h.

Acute Kidney Injury↗

PubMed2000

Prevalence of human parvovirus B19 and TT virus in a group of young haemophiliacs in South Africa.

A well recognized hazard of transfusion with blood or blood products is the acquisition of a viral infection. Parvovirus B19 and transfusion transmitted virus (TTV) are two of several non-enveloped viruses that may on rare occasions be present in coagulation factor concentrates. The prevalence of these viruses in the South African Haemophilia population has not previously been studied. Thirty-nine Haemophiliac children were investigated for evidence of parvovirus and TTV infection. 26 boys with Haemophilia A had been treated with cryoprecipitate or intermediate purity factor VIII, and 13 boys with Haemophilia B had received prothrombin complex concentrates. All the plasma products were prepared from South African donors and were virally inactivated by heat or solvent/detergent since 1992. A control group of 32 children who had not been transfused were also studied. IgG antibodies to B19 were present in 29 of the 39 patients (74%), 18/26 (69%) with Haemophilia A and 12 of the 13 (85%) with Haemophilia B. None of the patients was IgM antibody positive but two children were PCR positive for B19 DNA. Of the control children, 47% had IgG antibodies to B19, but none were IgM antibody or B19 DNA positive. TTV viral DNA was found in 10.2% of patients and in 9% of the control group. The results indicate that our locally produced plasma products are not a significant source of TTV transmitted infection but may contribute to infection by B19 parvovirus.

Adolescent↗

PubMed1994

Preparation and properties of a therapeutic inter-alpha-trypsin inhibitor concentrate from human plasma.

Inter-alpha-trypsin inhibitor (ITI) is a serine protease inhibitor found in human plasma. Its antiprotease activity is due to bikunin which is effective in various types of experimental shock and pancreatitis. Therefore ITI, which releases bikunin by proteolytic cleavage, could be of therapeutic interest. A method for the large-scale isolation of ITI from human plasma is described. ITI was purified from the prothrombin complex concentrate (PCC) by diethylaminoethyl-Sepharose fast-flow chromatography followed by a chromatographic step on immobilized heparin designed to remove C4, factor X and protein C. With this procedure, which was performed under mild conditions, a homogeneous preparation of native ITI was obtained, as demonstrated by electrophoretic and chromatographic analyses. ITI maintained its biological activity, as exhibited by its specific antitryptic activity of 420 +/- 65 IU/g. In order to decrease or eliminate the risk of transmission of viral disease due to lipid-enveloped viruses, the process incorporated a solvent-detergent treatment. Animal studies on the final product revealed no adverse side-effects in terms of toxicity, thrombogenicity or hypotension. This preparation appears suitable for therapeutic evaluation in animal experimental models.

Alpha-Globulins↗

PubMed1982

Surgery for a chronic cystic hematoma on the right thigh in a hemophiliac A with a potent factor VIII inhibitor.

A surgical case is described of a 40-year-old hemophilia A patient with a potent factor VIII inhibitor (40 Bethesda units) suffering from a chronic cystic haematoma in the right thigh. Surgery was performed after extensive plasmapheresis and administration of a large amount of factor VIII concentrate (42,500 U on the day of operation). During the five post-operative days, the factor VIII level was maintained above 25%, which allowed control of hemorrhage. However, two serious problems, i.e., hemolytic anemia and anamnestic response of factor VIII inhibitor titer, occurred on the 6th post-operative day. The hemolytic anemia was circumvented by administering prothrombin complex concentrate every 8 hours for 12 days until the sutures were removed. There was no bleeding although the inhibitor titer rose to 460 Bethesda units.

Adult↗

PubMed1994

Products for the treatment of hemophilia A and B prepared by ion exchange chromatography.

In France, since 1988, factor VIII concentrate are prepared by ion exchanged chromatography from plasma cryoprecipitate. The final product is a very high purity factor VIII with a specific activity (SA) between 150 and 250 IU/mg of proteins. Viral inactivation is obtained after solvent detergent method with TNBP and Tween 80. Since 1989 hemophilia B patients are treated with a factor IX preparation purified from a prothrombin complex concentrate and after solvent detergent inactivation. Factor IX concentrate is a high purity product with a SA of 50 to 100 U/mg of protein.

Chromatography, Ion Exchange↗

PubMed1986

Affinity chromatography of thrombin on modified polystyrene resins.

Insoluble polystyrenes substituted with sulphonate and L-arginyl methyl ester (PAOM) present substituents mimicking the reactive binding site of antithrombin III. These materials have a specific affinity for thrombin. The binding of the enzyme is reversible and the eluted thrombin remains active. Consequently, these resins can be used as stationary phases in affinity liquid chromatography in order to purify thrombin with a high biological activity. The influence of different characteristics of such polymers (substitution ratio, average particle size, affinity constant, synthesis conditions) on the purification performance is studied. Human prothrombin complex concentrate is activated and applied onto the gel. A purified human thrombin of high specific activity is separated with a high recovery of biological activity of the enzyme.

Chromatography, Affinity↗

PubMed1999

Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies.

BACKGROUND AND OBJECTIVES: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma-derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. MATERIALS AND METHODS: Twenty-seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ig/kg body weight. RESULTS: A mean dose between 22 and 26 Ig/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4-5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. CONCLUSION: This recombinant concentrate is efficacious in FVII-deficient patients. It is safe since any risk of transmission of blood-borne viruses is eliminated.

Adult↗

PubMed1985

[Articular and muscular hemorrhages in hemophilia A with anti-factor VIII antibodies. Treatment with selected batches of PPSB (factor IX concentrate)].

Over a 10-month period, 65 bleeding episodes in 14 hemophilia A patients with anti-Factor VIII antibodies were treated with a non-activated Factor IX concentrate (PPSB). A single dose of 58-102 U/kg of Factor IX (average 80 U/kg) was used in 51 hemarthroses, 13 muscle hematomas and one dental bleed. Overall clinical results were satisfactory in 51% of cases. Forty nine per cent of acute hemarthroses were clinically improved. Safety tests were unchanged and no significant elevation of anti-VIII: C titers was recorded. These preliminary results ae similar to those obtained with single doses of activated prothrombin complex concentrates given to the same patients (Autoplex and FEIBA).

Adolescent↗

PubMed1992

[The role of HCV in the pathogenesis of post-transfusion hepatitis].

Between January 1987 and April 1988 following 462 open heart surgery operations, 83 patients with icteric hepatitis were seen. Among them 59 patients were anti-HCV positive with the Ortho anti-HCV test, these findings suggested a hepatitis C virus infection. The source of viral infection was searched, and a prothrombin complex concentrate which had been used during that period, seemed to be the potential cause of bloodborne hepatitis C. The results suggest that special care is required when using such blood products.

Cardiac Surgical Procedures↗

PubMed1994

[Extracorporeal shock wave lithotripsy in a patient with hemophilia A. A case report].

We treated a 25-year-old hemophilia A patient (FVIII:C activity 2%) with left ureteral stone by means of extracorporeal shock wave lithotripsy under replacement therapy of concentrated Factor VIII material. The patient was attacked by sudden onset of left renal colic with gross hematuria on the 12th postoperative day. Renal ultrasonography and computed tomography demonstrated subcapsular bleeding of the left kidney. In spite of usual antihemophiliac replacement therapy, bleeding was extended from the retroperitoneal space to intraperitoneal and intrapleural space because potent Factor VIII inhibitors (14 Bethesda Unit) was produced. After embolization of the left renal artery, double filtration plasmapheresis and bypassing therapy using prothrombin complex concentrate were performed effectively to save the patient's life.

Adult↗