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Haemophilic arthropathy (HA) is one of the main complications of recurrent bleeding episodes in patients with severe haemophilia. However, the precise reasons making joints the predilected site of bleeding in patients with haemophilia are not fully understood. The objective of this project was to study the potential effect of synovium-derived thrombomodulin (TM) on the pathophysiology of haemarthroses. The concentration of TM and tissue factor pathway inhibitor (TFPI) was measured in knee synovial fluid of patients with haemophilia and controls. We used these concentrations of TM and TFPI in a thrombin generation (TG) model to analyse their in vitro effects on coagulation in plasma of six male controls and six severe haemophiliacs. The expression of TM in synovial tissue was also studied in controls and haemophiliacs. Patients with HA had significantly higher synovial fluid TFPI and TM levels, with a mean of 47 ± 27 ng/mL (P = 0.033) and 56 ± 25 ng/mL (P = 0.031), respectively, compared to the control group which presented lower levels of synovial fluid TFPI (26 ± 9 ng/mL) and TM concentrations (39 ± 21 ng/mL). TG capacity was significantly reduced in the presence of TM 56 ng/mL (P = 0.02), concentration observed in the synovial fluid of patients with HA. The concomitant addition of TM 56 ng/mL and TFPI 47 ng/mL induced a highly significant inhibition of TG in the same samples (P = 0.008).No significant inhibition of TG capacity was observed in the presence of control synovial concentration of TM (P > 0.05). Our results showed increased TM levels in synovial fluid and dramatically impaired expression of TM on synovial cells, suggesting a massive release of TM into the synovial fluid induced by a concerted action of neutrophils and cytokines on synovial cells as previously described in patients with rheumatoid arthritis., (© 2012 Blackwell Publishing Ltd.)

Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor-screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high-purity FVIII product with von Willebrand factor, Optivate(®). Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long-term studies. Seventy previously treated patients with severe haemophilia A, with ≥ 20 exposure days, were recruited into two long-term, multicentre, open-label studies. The protocols were virtually identical. Patients received Optivate(®) either prophylactically or on-demand. A mean of 159.0 EDs were experienced over 11,320 infusions. Under both conditions, Optivate(®) was well tolerated. Only 10% of patients experienced a treatment-related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on-demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on-demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate(®) in both prophylactic and on-demand management of patients with haemophilia A., (© 2011 Blackwell Publishing Ltd.)

The efficacy and safety of Optivate(®) was assessed in 23 surgical operations, orthopaedic (12) including 5 revision arthroplasties, ophthalmic (1), ENT (1), dental (6), liver biopsy (2), and removal of portacath (1) on 15 teenagers and adults with severe haemophilia A. The preoperative dose was calculated to raise the FVIII concentration to 100 IU dL(-1). Subsequent doses were targeted to maintain at least 50 IU dL(-1). There were 11 major and 12 minor operations categorized as receiving intensive replacement therapy for ≥ 5 days or < 5 days respectively. The median preoperative dose was 50.4 (range 18.2-88.2) IU kg(-1). The median incremental recovery based on this first dose in 10 procedures (5 patients) was 2.9 (range 2.4-3.4 IU dL(-1) ) per IU kg(-1). The daily doses decreased during the first 4 days of the study. The patients in this study received 173 infusions in total. Outcome was 'good' or 'excellent' for 19 (83%) of 23 operations, 'uncertain' in three procedures because an antifibrinolytic agent was used as well and for one procedure outcome was not assessed. Tolerance was good. There were no excessive bleeds, no inhibitors and no virus transmissions., (© 2011 Blackwell Publishing Ltd.)

Optivate(®) is a high purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate, which is manufactured using two antiviral processes: solvent/detergent and terminal dry heating (80 °C for 72 h). A multicentre, non-randomized open-label study in 15 patients was conducted to test the pharmacokinetics (PK) of Optivate(®). PK variables were analysed for the patients' prior FVIII product (PK1), their first dose of Optivate(®) (PK2) and at 3 months therapy (PK3). Mean non-compartmental half-lives (h) were 14.1, 12.4 and 12.1, respectively (P = 0.45), mean clearances (mL h(-1) kg(-1)) were 3.6, 3.2 and 3.1, respectively (P = 0.051), MRTs (h) were 19.0, 17.3 and 17.4, respectively (P = 0.39) and mean AUC(0-48h) (h IU mL(-1)) were 14.3, 15.4 and 16.6, respectively (P = 0.051) and mean AUC(0-∞) (h IU mL(-1)) were 15.9, 16.4 and 17.9, respectively (P = 0.18). The recovery data from this PK study was aggregated with recovery data collected from another study, with similar design but devoid of the other PK measurements. A total of 309 recoveries were conducted in 70 patients. The overall mean recovery per subject across 27 Optivate(®) batches was 2.7 IU dL(-1) per IU kg(-1). There were no clinical differences between Optivate(®) and other FVIII products, and except for volume of distribution (Vd), no statistically significant differences were seen with respect to any of the other PK variables, or in recovery between weeks 0 and 12. Therefore, the PK of FVIII is not affected by the processes used to manufacture Optivate(®), which can be expected to be effective in the management of patients with haemophilia A., (© 2010 Blackwell Publishing Ltd.)

The thrombin-platelet feedback loop was examined at low concentration tissue factor using calibrated automated thrombography in combination with the elimination of contact factor activation by corn trypsin inhibitor. The results indicated that, when contact factor activation was eliminated, the thrombin-platelet feedback loop was a major determinant of thrombin generating capacity and that platelets had a greater role in regulating the propagation of thrombin generation than its initiation. This method has potential application to the measurement of platelet-dependent thrombin generation in clinical diagnostic laboratories and hence the investigation of patients with apparent hypo- or hypercoagulable phenotypes.

Assessment of chronic hepatitis C virus infection requires a liver biopsy in most circumstances. There is a reluctance to perform liver biopsy in haemophiliacs because of a perceived risk of haemorrhage, although with adequate factor concentrate replacement in patients without factor concentrate inhibitors it should be safe. We report a 4-year experience of liver biopsy in patients with haemophilia infected with chronic hepatitis C virus. Of 55 patients seropositive for anti-HCV, 35 have undergone liver biopsy; the median age of this group was 33 years (range 13-68). Seven patients had a normal liver. 22 had portal tract inflammation, four with lymphoid aggregates. Mild piece-meal necrosis was observed in only two and no bile duct injury was found. 11 patients had mild mixed micro- and macro-vesicular fat. 19 patients had no evidence of fibrosis despite an estimated median duration of disease of 20 years (range 8-43). In the remaining 16 patients the maximum degree of fibrosis achieved was stage III. Patients with more significant fibrosis could not be identified on the basis of ALT or HCV RNA. There were no complications of liver biopsy in this series. Liver biopsy following a well-defined protocol in chronic hepatitis C virus haemophiliac carriers is safe in the absence of factor concentrate inhibitors. In this young group of patients without HIV infection there was no evidence of significant liver disease despite a considerable duration of disease. Performing liver biopsy allows accurate information to be given to the patient and avoids unnecessary therapy. The relative youth of this group may be important in the light of the benign histology.