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PubMed1983

Contributions to the optimal use of human blood. IX. Elimination of hepatitis B transmission by (potentially) infectious plasma derivatives.

Investigations were performed concerning the elimination of the risk of hepatitis B transmission of potentially infectious plasma derivatives by the addition of a low dose of hepatitis B immunoglobulin (HBIg). To this end, clotting factor VIII concentrate, prothrombin complex, C1 esterase inhibitor concentrate, plasminogen and antithrombin III were prepared from plasma strongly positive for hepatitis B surface antigen (HBsAg). To one half of every preparation, HBIg was added up to a final concentration of 0.4 IU anti-HBs/ml (test preparations), the other half was not treated (control preparations). Furthermore, to 10(-3) diluted infectious reference plasma (Bureau of Biologics, FDA, USA), an overdose HBIg was added to a final concentration of about 0.4 IU anti-HBs/ml. 6 chimpanzees, injected either with the control plasma derivatives or with the untreated infectious reference plasma, were infected with hepatitis B virus, whereas 5 chimpanzees, injected either with the test plasma derivatives or the infectious reference plasma to which the HBIg had been added, did not show any evidence of hepatitis B infection during the follow-up of 1 year. Addition of a low dose of HBIg to potentially infectious plasma derivatives appears to be a reliable measure to eliminate the hepatitis B transmission and is preferred to other methods for labile plasma derivatives.

Animals↗

PubMed1993

Postpartum factor VIII inhibitors. Report of two cases with special reference to the efficacy of various treatments.

Two cases of postpartum inhibitors to F VIII are described. One patient had a severe bleeding tendency (iliopsoas bleeding, forearm bleeding). The maximum inhibitor titer was 800 BU/ml in case 1 and 120 BU/ml in case 2. Bleeding was controlled by treatment with human and porcine factor VIII concentrate and with activated prothrombin complex concentrate (FEIBA, Immuno AG, Vienna, Austria) in case 1, while no replacement therapy was given in case 2. Prednisone (given in both cases) and high-dose immunoglobulin (given in case 2) was without effect. Cyclophosphamide (100 mg per day), combined with small doses of prednisone led to complete disappearance of the inhibitor and normalization of factor VIII in case 1. In the other patient who refused treatment with cyclophosphamide the inhibitor titer remained high over a period of 13 months.

Adult↗

PubMed2006

Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature.

Myocardial infarction and other arterial occlusions are considered to be rare in hemophilia A. However, a systematic study of the subject has never been attempted. All case reports of myocardial infarction or other arterial occlusions have been now gathered and properly evaluated from a cardiological point of view. Thirty-six patients with myocardial infarction and 6 patients with documented cerebrovascular event were retrieved from the literature. The age of the patients varied between 7 and 79 years, with a mean of 44 years. In 16 cases, the arterial occlusion occurred in men <40 years of age. The majority of myocardial infarctions (MIs) were anterolateral (12 cases). Posterior-inferior MI was present in 6 cases whereas it was of the non-Q type in 4 patients. It was multiple in 6 cases, and in the remaining patients the type of infarction could not be determined. In 26 cases, the thrombotic event (22 myocardial infarctions and 4 ischemic cerebrovascular accidents) occurred during or after the infusion of factor VIII concentrates and, more frequently, after prothrombin complex concentrates (activated or non-activated ones) or recombinant factor VIIa preparations. In 3 cases, the vascular complication occurred after intravenous desmopressin administration. MI was fatal in 7 instances. After the event, signs and symptoms of heart failure were seen as sequels in 7 patients. One patient had to undergo cardiac transplant 5 months after the MI. No death occurred after ischemic cerebrovascular accidents. Since not all hemophilia patients develop inhibitors and therefore are not usually treated with activated concentrates, this series of patients is somewhat biased and does not allow general conclusions. The high prevalence of MI and other arterial complications which occurred after transfusion therapy, usually in patients with inhibitors, clearly indicates the need for a careful evaluation of the appropriate therapeutic approach in each single patient.

Adolescent↗

PubMed1977

Treatment of anti-factor VIII antibodies.

Bleeding episodes in patients with hemophilia A with anti-factor VII antibodies are frequently difficult to treat. Factor VIII concentrates administered by continuous infusion or prothrombin complex concentrates (PCC) have been used for treatment. Hemophilia A patients with inhibitors who respond to factor VIII concentrates generally have low to moderate inhibitor titers (generally less than 20 Bethesda units). Those patients who receive PCC are quite difficult to evaluate but promising clinical responses have clearly been observed. This paper describes our experience with both modalities of therapy and will offer specific guidelines for such therapy.

Adult↗

PubMed1986

Thermal inactivation of human immunodeficiency virus in lyophilised blood products evaluated by ID50 titrations.

Inactivation of human immunodeficiency virus (HIV) in lyophilised small pool cryoprecipitate, factor VIII concentrate, prothrombin complex and C1-esterase inhibitor concentrate by prolonged heat treatment (72 h, 60 degrees C) was studied. Plasma products, inoculated prior to lyophilisation, had infectious titres ranging from 10(7) to 10(10.5). Residual infectivity (TCID50) was assessed by multiple titrations on H9 cells in a macro system and subsequent detection of virus replication by determining reverse transcriptase activity. Kinetics of inactivation showed a biphasic pattern: during the first 8 h a variable TCID50 reduction up to 10(4.3) was observed, followed by an additional loss of 10(1)-10(2.7) during the next 64 h. Heat treatment for 72 h resulted in a mean TCID50 reduction of 10(5). It is concluded that prolonged heat treatment may lead to the adequate prevention of HIV transmission by lyophilised plasma products.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Preparation and heat-treatment of factor-IX-concentrates.

The stability to dry heat of different prothrombin complex concentrates depends on their composition, i.e. on the way of preparation and on additives such as reducing or non-reducing sugars. Alcohol precipitation, for instance, and addition of fructose or sorbitol as stabilizers is unsuitable for products which are intended to be heat-treated in the lyophylized state. Among the tests applied, only clotting-factor activities and--to a minor degree--turbidity, measured at 650 nm, responded significantly to small changes in heat-treatment. Finally, we were able in good yield to produce a factor IX high potency concentrate by adsorption on DEAE-Sephadex and ammonium sulphate precipitations. The freeze dried material can be heated for up to 96 hours and 70 degrees C without any sign of denaturation.

Drug Stability↗

PubMed1998

Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates.

In 1994, shortly after a heat-treated prothrombin complex concentrate (PCC) had been withdrawn from the German market due to transmission of hepatitis B, the license of another brand was withdrawn, due to 3 acute fatalities associated with the use of this product. We report on the clinical data of altogether 5 patients, who died during a 3 month period in Germany after having received this brand of PCC. All patients had surgery, acquired deficiencies of coagulation factors, and underlying diseases predisposing for thrombosis or disseminated intravascular coagulation. PCC was administered for the prevention of bleeding. In three patients, a drug interaction of PCC with aprotinin may also have played a role. Several points, however, are suspicious of a major causative effect of the respective product, (a) the close temporal correlation between administration of the drug and the subsequent clinical as well as laboratory deterioration, (b) the accumulation of these adverse events in a short period of time, when the use and market share of this brand increased due to the shortage of other products, and (c) laboratory abnormalities of this brand which have been consistently observed in several in vitro studies.

Adult↗

PubMed1992

Management of factor VIII inhibitors: evolution and current status.

Management of patients with factor VIII (and IX) inhibitors includes management of acute bleeds and methods to induce immune suppression and tolerance and to detect patients at risk of developing inhibitors. The methods used over the years to treat acute bleeding have been more or less successful. The best method is to raise factor VIII levels by human or porcine factor VIII concentrate, but this is not usually possible. Prothrombin complex concentrates, activated or non-activated, have enjoyed some success as factor VIII by passing agents, but the development of recombinant activated factor VII represents a new and promising method of inducing haemoslasis at the site of bleeding whilst minimizing the risk of disseminated intravascular coagulation. Alternatively, the use of tissue factor is under consideration to exploit the extrinsic system. Methods to induce immunological tolerance by use of the 'Bonn' regime or by the introduction of immunomodulation with the 'Malmö' regime of extracorporeal immunodepletion, cyclophosphamide, and intravenous immunoglobulin continue to be attempted with significant but variable success. Gradually the inhibitor problem is being contained, but it is still an important complication of haemophilia therapy.

Animals↗

PubMed1992

Effect of antithrombin concentrate on haemostatic variables in critically ill patients.

In a controlled pilot study of 32 critically ill patients, we have attempted prospectively to identify laboratory variables which can be used to select and monitor patients on antithrombin (AT) therapy. Patients with plasma AT levels less than 70% of normal were randomized to receive (AT group) or not to receive AT concentrate (non-AT group). The groups did not differ in median age, sex, median APACHE II and TISS scores, number of days spent in the Intensive Care Unit or mortality rate. At the time of inclusion all patients had activated coagulation and fibrinolysis demonstrated as high levels of soluble fibrin, thrombin-antithrombin complexes and fibrin-D-dimers (twice, four and ten times the upper reference range, respectively). In the AT group these levels decreased faster and the prothrombin complex concentration increased more rapidly to normal (i.e. the prothrombin time decreased). The level of C-reactive protein which was high in both groups on inclusion (139 and 98 mg/l, respectively) decreased by 40% in the AT group but did not change in the control group. Our study indicates that laboratory variables normalize faster in seriously ill patients who have activated coagulation and fibrinolysis when they receive AT concentrate and that the variables mentioned above seem to be useful for monitoring the treatment.

Aged↗

PubMed1991

Perspectives on the use of factor IX complex concentrates in the treatment of bleeding in persons with acquired factor VIII inhibition.

In contrast to the type of bleeding encountered in congenital hemophilia with inhibitors, the diathesis toward bleeding exhibited by patients with spontaneously acquired factor VIII (FVIII) inhibitors often is severe and life threatening. Large hematomas and retropharyngeal or central nervous system hemorrhage may appear suddenly. Thus, a high premium is placed on rapid therapeutic intervention. Several treatment options are at the physician's disposal. The role of factor IX (FIX) complex concentrates, both standard and purposely activated, is discussed. The FIX products are also known as prothrombin complex concentrates (PCCs). Prudent choice of any treatment modality requires weighing its benefits and shortcomings. Advantages of PCCs--particularly the activated products--include availability, ease of reconstitution and administration, and at least partial efficacy; control of bleeding episodes can be achieved with PCCs in many (but not all) instances. One salient disadvantage of therapy with FIX complex concentrates is that they are not subjected to such rigorous viral-attenuation processes as are most of the currently marketed FVIII products. Therefore, a small but definite risk of infection with hepatitis B or C (HBV, HCV) remains. An assay that detects antibodies against HCV has been licensed and is being used to screen blood donors. Nevertheless, up to the present time the U.S. Food and Drug Administration (FDA) has ruled that HCV screening of plasmapheresis donors should not be performed for plasma collections destined to be pooled for fractionation and that units of HCV-positive source plasma (e.g., that provided by American Red Cross donors) found to be HCV positive be sent for fractionation. The starting plasma from which FIX complex concentrates and human FVIII concentrates are made thus contains some HCV and may also contain some HBV. Because nonhemophiliacs with acquired antibodies against FVIII are unlikely to have had prior exposure to blood products and are unlikely to have been vaccinated against HBV, they are at risk of viral hepatitis and its sequelae when treated with FIX complex concentrates. Furthermore, therapy with FIX complex concentrates is not always effective in controlling bleeding in persons with FVIII inhibitors, its mechanism of action in bypassing the need for FVIII remains unclear, very large doses are required, and it has an attendant risk of several adverse effects when used in large, repeated doses. These include disseminated intravascular coagulation, thromboembolism, and acute myocardial infarction. Thus, FIX complex concentrates may play a useful role in the treatment of bleeding in nonhemophiliacs with acquired inhibitors against FVIII, but one must carefully consider their disadvantages profile.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoantibodies↗

PubMed2006

Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases.

All reported cases of non-catheter induced venous thrombosis in patients with hemophilia A or B have been carefully evaluated. A total of 27 cases were reported,12 patients with hemophilia A and 15 patients with hemophilia B. The age of patients varied between 9 and 67 years. There were 10 cases of deep vein thrombosis, 8 patients with pulmonary embolism accompanied or not by deep vein thrombosis, 5 cases of superficial vein thrombosis. In addition, there were 3 cases of thrombosis in unusual sites (1 retinal central vein thrombosis and 2 portal vein thrombosis). Finally, in one case, venous thrombosis was multiple. There was a fatality in a hemophilia B patient with pulmonary embolism. The most frequent risk or triggering factor in hemophilia A was the administration of Feiba or rFVIIa concentrates in patients with inhibitors. Surgery together with Prothrombin Complex concentrates was the most frequent cause in hemophilia B patients. Congenital associated prothrombotic risk factors were present in two patients. No or very few therapeutic procedures were initiated in these patients but for a suspension or reduction of concentrates infusion. In a few instances low molecular weight heparin was given for a few days. The frequent association of venous thrombosis with infusion of concentrates indicates the need for a careful evaluation of patients about to receive such therapy.

Hemophilia A↗

PubMed1998

Clinical picture and treatment strategies in factor VII deficiency.

Factor VII is a trace protein required for normal haemostasis. Deficiency of factor VII comprises a highly heterogeneous disease group. Factor VII deficiency can cause bleeding, in particular if factor VII is extremely low, but a few cases lacking factor VII function entirely or subtotally may not present with a history of bleeding. Bleeding problems are not often reported in patients having a factor VII:C level at 10-15% of normal or more. Bleeding is frequently of mucocutaneous type, but the whole array of haemophilic bleeding may also occur. To control bleeding, during surgery in particular, substitution is required in the severe case of factor VII deficiency, but clinical studies documenting which correctional levels of factor VII:C to aim are lacking. It appears that a critical low level (trough) value at 10-15% may be anticipated, but clear documentation does not exist. Substitution programmes may include plasma or plasma derived factor IX concentrates of lower degrees of purity, so-called prothrombin complex concentrates that also are relatively impure, and pure factor VII concentrates. An alternative is a recombinant factor VIIa molecule. However, this concentrate has not received license in a number of countries. Thrombotic manifestations appear to occur more often than expected in the factor VII deficient patients, some have been linked to the use of impure concentrates, others to preexisting thrombophilic risk factors, but some are unexplained and may bear a relationship to the deficiency state of factor VII itself. Controlled clinical trials are highly warranted in this rare bleeding condition.

Factor VII Deficiency↗

PubMed1986

HTLV-III/LAV antibodies and virus in hemophilia patients in Nebraska: survey and initiation of a prospective study.

Thirty-nine patients from the Nebraska Regional Hemophilia Center were studied for the prevalence and titers of antibodies to HTLV-III/LAV, and for clinical symptoms of possible progression toward the acquired immunodeficiency syndrome (AIDS). Fourteen of 26 (54%) patients with hemophilia A were positive for HTLV-III/LAV antibodies as determined by immunofluorescence and Western blotting. Retrovirus was detected in cultured lymphocytes of two out of three seropositive individuals by reverse transcriptase assay and molecular hybridization with cloned HTLV-III/LAV probe. Of the twelve factor VIII-deficient patients who were seronegative, one had received only heat-treated factor VIII concentrates, six only cryoprecipitate or fresh frozen plasma, two prothrombin complex concentrates, one had not been transfused since 1983, and two had never been transfused. None of the patients treated only with factor IX concentrates, volunteer donor plasma, or cryoprecipitate had HTLV-III/LAV antibodies. In 12 of 14 seropositive hemophiliacs, titers of serum antibodies to HTLV-III/LAV ranged from 1:1,280 to 1:10,240, indicating a strong immune response against HTLV-III/LAV antigens and/or persistent infection with the virus. In spite of the possible exposure to HTLV-III/LAV during the past four years, none of the patients in this group had AIDS. Whether or not this group of patients has developed immunity to the AIDS retrovirus remains to be determined.

Antibodies, Viral↗

PubMed1982

Clinical evaluation of the hepatitis safety of a beta-propiolactone/ultraviolet treated factor IX concentrate (PPSB).

The association of viral hepatitis, type B, with the use of prothrombin complex concentrates (PPSB) has been well documented. PPSB prepared from cold-sterilized plasma (beta-propiolactone treated and UV irradiated) has been shown not to induce hepatitis in chimpanzees. 500 U of cold-sterilized PPSB were infused into 5 healthy male volunteers. Previous to, and up to 6 months after, PPSB-application in addition to careful clinical investigations, the following hepatitis parameters were determined: SGOT, SGPT, y-GT, alkaline phosphatase, total serum bilirubin, HBsAg, HBcAb and HBsAb. On the basis of all of the above parameters there was no indication of induction of viral hepatitis following the application of PPSB prepared from beta-propiolactone/UV treated plasma.

Adult↗

PubMed1998

Congenital deficiencies and abnormalities of prothrombin.

Prothrombin (factor II) deficiency was first described in 1947 by Quick et al., although the first prothrombin abnormality was reported in 1969 by Shapiro et al. The condition is still considered very rare. In spite of its rarity, the defect has allowed important improvements in our understanding of both congenital and acquired prothrombin deficiencies. The diagnosis of prothrombin deficiency or abnormality can be made using a combination of clotting, chromogenic and immunological assays. In cases of true deficiency, a parallel decrease in all these assays is observed, regardless of the activating agent. If discrepancies among the clotting assays are noted, particularly using viper venoms, a dysprothrombinemia should be suspected. Usually, activity levels less than 10% of normal are found in homozygotes, and between 40 and 60% in heterozygotes. Factor II levels in congenital dysprothrombinemias are more variable since one may encounter homozygotes, heterozygotes and compound heterozygotes between a heterozygous abnormality and heterozygous 'true' deficiency or between two distinct abnormalities. Usually the levels of factor II vary between 1 and 50% of normal. Antigen levels in congenital dysprothrombinemias will be normal, near normal or slightly decreased but always higher than the clotting counterpart. Cases with a parallel decrease in prothrombin activity and antigen should not be considered as examples of hypoprothrombinemia. The gene involved in the synthesis of prothrombin is located in chromosome 11. It is composed of 10 exons and 8 introns. Molecular biology studies have discovered several point mutations in some of the dysprothrombinemias. Bleeding manifestations may be severe in homozygous 'true' deficiency and may be more variable in dysprothrombinemias. Heterozygotes are usually asymptomatic. Prognosis is variable and generally in agreement with the prothrombin activity level. In homozygous true deficiency, hemarthroses and intracranial bleeding have been described. Substitution therapy is based on the administration of prothrombin complex concentrates or of plasma. The long half-life of prothrombin injected, about 70 h, allows the achievement of hemostatically effective levels (about 50% of normal) without difficulty.

Adolescent↗

PubMed1991

No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate.

Purer factor IX concentrates, containing very little or no factor II or X, have been developed in an attempt to avoid the thromboembolic complications that occur with prothrombin complex concentrates (PCC), which also contain factors II and X and variable amounts of factor VII. To evaluate ex vivo the thrombogenic potential of one of these purer concentrates, we studied whether large single doses produced signs of activation of the coagulation cascade in patients with haemophilia B, and compared the results with those obtained after infusion of a PCC. Seven patients were infused with 50 IU/kg of factor IX concentrate and seven additional patients were subsequently infused with 100 IU/kg of the same concentrate. After the infusions, factor IX levels rose in proportion to the administered dose while the concentrations of factor II and factor X did not rise at all. At both doses of concentrate, we did not observe significant post-infusion increments in the levels of the factor X activation peptide (a measure of the activity of the factor VIIa-tissue factor complex and/or the factor IXa-VIIIa-activated surface complex), prothrombin fragment 1 + 2 (a measure of factor Xa activity), and fibrinopeptide A (a measure of thrombin activity). We also infused 10 patients with a PCC (50 IU/kg). After the infusions, significant rises in the concentrations of the factor X activation peptide and prothrombin fragment were observed. Therefore, it appears that the infusion of a PCC to patients with haemophilia B can augment factor X activation and subsequently thrombin generation in vivo and that this process can be abrogated by the administration of more pure factor IX concentrate.

Adolescent↗

PubMed2006

Manipulation of prothrombin concentration improves response to high-dose factor VIIa in a cell-based model of haemophilia.

Clinical reports suggest that treatment regimens employing both activated prothrombin complex concentrates (aPCCs) and recombinant activated factor VII (rFVIIa) may control the bleeding in patients with haemophilia who fail to respond to either agent alone. We hypothesised that increased concentrations of prothrombin, as may be observed after the infusion of aPCCs, favourably influence parameters of thrombin generation in haemophilia treated with high-dose rFVIIa. We examined the effect of varied prothrombin and rFVIIa concentrations on thrombin generation in a model of haemophilia. At all concentrations of rFVIIa, increased prothrombin concentrations led to increases in the peak and rate of thrombin generation. In assays with the highest concentrations of prothrombin and rFVIIa, peak thrombin actually equalled that measured in the model of normal haemostasis. The significant impact of prothrombin concentration on the effect of rFVIIa in vitro may explain the improved haemostasis reported with concurrent use of aPCCs and rFVIIa. These results imply that persons with plasma prothrombin levels at either end of the 'normal' range could have significantly different responses to similar rFVIIa doses. Furthermore, these results suggest that increasing plasma prothrombin concentration prior to rFVIIa administration may offer advantages over the use of rFVIIa alone in the treatment of haemophilic bleeding.

Blood Platelets↗

PubMed1998

Management of oral anticoagulant-induced intracranial haemorrhage.

Intracranial haemorrhage is an infrequent but often fatal complication of oral anticoagulant therapy which will become more common as anticoagulant use increases. The risk of anticoagulant-induced intracranial haemorrhage may be reduced by judicious prescribing, identification of patients at high risk of bleeding, and close monitoring by experienced staff. The presenting features of intracranial haemorrhage are often vague and physicians should be aware of the need for urgent investigation of all anticoagulated patients with neurological symptoms. Current guidelines for immediate reversal of anticoagulation recommend administration of vitamin K1 and factor replacement with either factor concentrates or fresh frozen plasma. In this review we discuss recent evidence suggesting prothrombin complex concentrates lead to faster, and more complete, correction of coagulation and, in the context of intracranial bleeding, may be associated with improved neurological status. Evidence for the risks of short-term cessation of anticoagulants, in the immediate period following an intracranial haemorrhage, and their subsequent reintroduction is also discussed.

Administration, Oral↗