Continuous intravenous infusion of a plasma-derived factor IX concentrate (Mononine) in haemophilia B.

This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset of 13 non-emergency patients 7-21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for 107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.

Recombinant factor IX (BeneFix) by adjusted continuous infusion: a study of stability, sterility and clinical experience.

The safety and efficacy of adjusted continuous infusion (CI) of recombinant factor IX (FIX; BeneFix) was assessed in vitro and in a clinical study. BeneFix was reconstituted at 100 IU mL-1 with or without unfractionated heparin (4 U mL-1) and stored at either 4 degrees C or room temperature. Reconstituted BeneFix retained at least 90% activity over 14 days if stored at 4 degrees C but stability was reduced at room temperature. BeneFix reconstituted in a sterile pharmacy was free of bacterial contamination. Six patients with haemophilia B received seven CIs of BeneFix to cover routine surgery and severe bleeding episodes. The CIs lasted between 3 and 10 days. In all cases, haemostasis was excellent and the desired therapeutic FIX level was easily maintained. No thrombotic episodes or inhibitor development occurred but two patients developed thrombophlebitis at the infusion site when heparin was not added to the infusion. BeneFix is not currently licensed for CI and we suggest that studies to enable licensing should be established as soon as possible.

Acquired haemophilia in recipients of depot thioxanthenes.

We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.

Long-term follow up of patients treated with intermediate FVIII concentrate BPL 8Y.

Long-term surveillance studies of clotting factor concentrates are important to detect infrequent or delayed complications and to provide data against which newer products can be compared. We have assessed the long-term use of BPL 8Y factor VIII (FVIII) concentrate (Bio Products Limited, Elstree, UK) in a cohort of 33 patients. These patients have been treated for a median of 96 months. They have received between one batch (in total) and 10 batches per year and between 1020 units (in total) and 116,700 units per year of BPL 8Y concentrate. No patient has developed a clinically significant FVIII inhibitor. There has been no evidence of transmission of hepatitis C, hepatitis B or HIV 1 or 2. Parvovirus B19 IgG antibody was present in 100% of the patients screened. Analysis of CD4 and CD8 lymphocyte subsets, using age-related normal ranges, showed persistently depressed values in five patients, one of whom had a consistently low CD4/CD8 ratio.

Absence of intrafamilial transmission of hepatitis C in patients with inherited bleeding disorders.

Hepatitis 'C' virus (HCV) infection has caused significant anxiety in patients with inherited bleeding disorders. A significant number of patients with HCV have developed chronic liver disease, cirrhosis and hepatocellular carcinoma. The exact risk of heterosexual and contact transmission is unclear at the moment. A test for antibody to hepatitis 'C' was offered, after counselling, to spouses and family members of 118 known hepatitis 'C' antibody positive patients with inherited bleeding disorders. Two hundred and fifteen family members were tested, 73 partners and 142 household contacts; all were found negative for hepatitis 'C'. Our experience confirms the low risk of heterosexual and contact transmission of hepatitis 'C' virus.

A lesson from persistently elevated aspartate transaminases (AST) in a patient with severe haemophilia A.

Prior to the availability of test for hepatitis 'C' in 1989, any elevated AST in a pooled blood product recipient was presumed to be from non-A-non-B hepatitis. We report a patient who received pooled factor VIII in 1984 and had persistently elevated AST which proved to be of nonhepatic origin.

Hepatocellular failure from hepatitis C infection in two recipients of a single batch infusion of plasma-derived blood products.

We report two patients with mild inherited bleeding disorders who acquired hepatitis C infection after receiving single infusion of plasma-derived concentrates prior to the introduction of donor screening and viral inactivation procedures. Both these patients became clinically jaundiced at the time of hepatitis C infection. Despite being HIV antibody negative, an absence of other risk factors of chronic liver disease and treatment with interferon, they progressed to hepatocellular failure in 5 and 12 years following seroconversion. The natural history of hepatitis C infection is still uncertain [1], although it is usually considered that hepatitis C infection progresses slowly, only resulting in clinically manifest liver disease after several decades. In view of the apparent rapidity of onset of liver damage in these two patients, we wonder if older age at time of infection, jaundice during the seroconversion illness or a mild coagulopathy with consequent infrequent exposure to blood products are adverse prognostic features.

Clinical experience with a highly purified factor IX concentrate in patients undergoing surgical operations.

The haemostatic efficacy of a new highly purified factor IX concentrate, prepared by metal chelate affinity chromatography, was assessed in 13 patients with haemophilia B undergoing a variety of surgical operations. Four of the patients had developed post-operative thromboembolic complications following previous operations, when treated with a prothrombin complex concentrate. None of the patients in the present series developed any evidence of post-operative thrombotic complications. Effective haemostasis was achieved in all patients, with the exception of a surgical bleed in one case, and late post-operative bleeding in a second patient when the factor IX activity fell below 20iu/dl. The product is treated with a solvent-detergent process that destroys lipid-enveloped viruses, while the affinity chromatography process during manufacture removes in excess of 4 log10 of a non-lipid-enveloped virus. In follow-up studies, none of the patients has shown evidence of fresh infection from the concentrate, when assessed by virological markers. It is concluded that this high-purity concentrate (tradenane 'Replenine') is effective for the treatment of patients with haemophilia B who undergo surgical operations.

Obstetric management in von Willebrand's disease: a report of 24 pregnancies and a reivesw of the literature.

The case records of 13 patients (24 pregnancies) with von Willebrand's disease (vWD) were studies rettospectively. The overall incidence of primary and secondary post-partum haemorrhage (PPH) was 15.8% and 25% respectively, all primary PPH occurring in tyre 2 discase (3/14 deliveries, 21.4%). The risk of primary PPH in type 2 patients who did not receive prophylactic factor VIII was 37.5% (3/8 deliveries). Factor VIII coagulant activity (VIII:C) and von Willebrand factor antigen (vWF:Ag) rose above bascline values by a factor of at least 1.5 during the pregnancy in most case. More severely affected patients were less likely to benefit significatntly. A baseline VIII:C of <15 iu/dl (4/14 cases) was predictive of a third trimester level of <15 iu/dl. Improvements in the von Willebrand factor activity were less marked. The baseline von Willebrand factor activity was <15 iu/dl in all patients with serial data, none of whom achieved a third-trimester von Willebrand factor activity of >50 iu/dl. The bleeding times were unaltered significantly in all but one of the cases, reflecting a general failure of the primary haemostatic defect to improve with pregnancy. The findings demonstrate that coagulation parameters do not universally improve in pregnancy in vWD, especially when preconception levels are low. The risk of primary PPH is generally higher in type 2 diseases. The level of factor VIII:C is not a good predictor of the risk of primary PPH in type 2 patients. Secondary PPH is a significatnt risk in both type 1 and type 2 patients.

PCP pneumonia with bilateral pneumothoraces in a haemophiliac with factor VIII inhibitors.

Pneumocystis carinii pneumonia (PCP) infection is a well-recognized feature of advanced HIV infection in all risk groups. This serious opportunistic parasitic infection is almost invariably fatal if left untreated. When associated with bilateral pneumo-thoraces in a patient with severe haemophilia A and factor VIII inhibitors, it poses a critical management problem and can be life-threatening. We report the case of a young man with severe haemophilia A with factor VIII inhibitors presenting with bilateral pneumothoraces which was successfully managed with conservative therapy only.

A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate.

A prospective cross-over study was carried out on 19 patients with haemophilia B. comparing the pharmacokinetics of a purified factor IX concentrate prepared by metal chelate affinity chromatography (9MC) with a conventional three-factor prothrombin complex concentrate (9A). The highly purified factor IX concentrate was shown to have a half-life comparable to the PCC; the in vivo recovery of the purified concentrate was significantly greater than that of the complex (P < 0.01). The 20% change in the value of the International Standard for Factor IX Concentrate, introduced in 1988, might have been expected to lower the recovery values. However, the in vivo recovery for both concentrates was somewhat higher than reported previously, particularly in the older literature. In nine patients, serial assays for fibrinopeptide A, prothrombin fragment F1+2 and thrombin-antithrombin complexes (TAT) were performed to assess the potential thrombogenicity of the two concentrates. Evidence was obtained that there was significantly less activation of coagulation following administration of purified factor IX (9MC), as compared to the activation that occurred after the PCC.

The relationship of HIV-1 viral sequences detected by the polymerase chain reaction in haemophilic patients to clinical and other markers of infection.

A nested primer polymerase chain reaction (PCR) of pol gene sequences of human immunodeficiency virus-1 (HIV-1) was applied to whole blood of 31 haemophiliacs who were, or had been, positive for HIV p24 antibody (HIVAb) by enzyme linked immunosorbent assay (ELISA) and samples from 22 persistently HIVAb negative haemophiliacs who had been at risk of contracting HIV from treatment. The results were compared with those of p24 HIV antigen determination, T4 cell counts beta 2 Microglobulin (beta 2M) levels and clinical evidence of progression of HIV disease. There was no discrepancy between the PCR results and past or present seropositivity for HIVAb. The qualitative PCR was more sensitive than the p24 antigen assay but the presence of the latter was predictive of progression of infection as determined clinically and by falling T4 cell counts and rising levels of beta 2M. The results of the PCR are reassuring for HIVAb negative haemophiliacs at risk from treatment and to HIVAb negative sexual contacts of HIVAb positive persons.