Haemophilia (HAEMOPHILIA)

Publications in this journal

• Article: Treatment for life for severe haemophilia A- A cost-utility model for prophylaxis vs. on-demand treatment.

  Farrugia A, Cassar J, Kimber MC, Bansal M, Fischer K, Auserswald G, O'Mahony B, Tolley K, Noone D, Balboni S
  [show abstract] [hide abstract]
  ABSTRACT: Prophylaxis has been established as the treatment of choice in children with haemophilia and its continuation into the adult years has been shown to decrease morbidity throughout life. The cost of factor therapy has made the option questionable in cost-effectiveness studies. The role of prophylaxis in pharmacokinetic dosage and tolerization against inhibitor formation were used to model the cost utility of prophylaxis vs. on-demand (OD) therapy over a lifetime horizon in severe haemophilia A. The model was applied to a single provider national health system exemplified by the United Kingdom's National Health Service and a third party provider in the United States. The incremental cost-effectiveness ratio (ICER) was estimated and compared to threshold values used by payer agencies to guide reimbursement decisions. A cost per quality-adjusted life year (QALY) was also estimated for Sweden. Prophylaxis was dominant over OD treatment in the UK. The model resulted in an ICER - $68 000 - within the range of treatments reimbursed in the USA. In Sweden, a cost/QALY of SEK 1.1 million was also within the range of reimbursed treatments in that country. Dosage- and treatment-induced inhibitor incidence were the most important variables in the model. Subject to continuing clinical evidence of the effectiveness of pharmacokinetic dosage and the role of prophylaxis in decreasing inhibitor incidence, treatment for life with prophylaxis is a cost-effective therapy, using current criteria for the reimbursement of health care technologies in a number of countries.
  Haemophilia 03/2013;
• Article: What should men living with severe haemophilia need to know? The perspectives of Canadian haemophilia healthcare providers

  S. Lane, E. Arnold, K.E. Webert, A. Chan, I. Walker, N. M. Heddle
  Haemophilia 01/2013;
• Article: M. SOLANO, A. LINARES, C. SOSSA, S . CASTAÑO, C. CASAS ,M. CORTE´ S, I . SARMIENTO and A. PEÑA Secondary prophylaxis with anti-inhibitor coagulant complex (AICC): From anecdote to reality, Haemophilia (2012), 18 (Suppl. 3), 163

  M. SOLANO, A. LINARES, C. SOSSA, S . CASTAÑO, C. CASAS, M. CORTE´ S, I . SARMIENTO, A. PEÑA
  Haemophilia 01/2012;
• Article: History of haemophilia.

  L M Aledort
  [show abstract] [hide abstract]
  ABSTRACT: Haemophilia, an ancient disease, now has sophisticated methods for diagnosis and treatment. The genetically missing factors can now be supplied by fractionation of human-derived (HD) plasma or with recombinant technology (r). Making therapeutic choices is complicated by past transfusion-transmitted diseases. HD and r products now have similar safety profiles. Several diseases have only HD products for treatment. These products remain important in our treatment armamentarium.
  Haemophilia 01/2008; 13 Suppl 5:1-2.
• Article: Fanhdi, efficacy and safety in von Willebrand's disease: prospective international study results.

  I F Bello, V J Yuste, M Q Molina, F H Navarro
  [show abstract] [hide abstract]
  ABSTRACT: Recently, three multicentre prospective international studies have been carried out to evaluate the clinical efficacy and safety of Fanhdi [high-purity, double-inactivated plasma-derived factor VIII/von Willebrand factor (VWF) concentrate] in patients with von Willebrand's disease (VWD). Pharmacokinetic parameters, clinical efficacy and safety of Fanhdi in acute bleedings episodes or invasive procedures were determined in this population. RESULTS: Pharmacokinetic parameters observed were similar to previous reported for other highly purified plasma-derived FVIII/VWF concentrate. The mean in vivo recovery (IU dL(-1) per IU kg(-1)) was 1.9 +/- 0.6 for VWF:RCof; 2.1 +/- 0.6 for VWF:Ag and 2.6 +/- 0.6 for FVIII:C. The mean half-life (h) was 14.4 +/- 10.5 for VWF:RCof; 27.5 +/- 11.0 for VWF:Ag and 33.4 +/- 16.4 for FVIII:C. Therapeutic benefit of Fanhdi in VWD patients treated during bleeding episodes was clearly demonstrated. The achievement of haemostasis was excellent or good in 100% of the cases (major or minor bleeding episodes). Also, the clinical efficacy of Fanhdi in preventing excessive bleeding during surgery showed a very good profile. Efficacy was rated as excellent in six cases (three major/three minor surgical procedures) and good in three cases (two major/one minor surgical procedures). In addition, the product was well tolerated and no adverse events potentially related to the study drug were reported. CONCLUSIONS: Fanhdi is an effective and safe plasma-derived FVIII/VWF concentrate that can be used as an alternative to the current replacement therapy in patients with VWD to provide an adequate haemostasis during surgical procedures and treatment of bleeding episodes.
  Haemophilia 01/2008; 13 Suppl 5:25-32.
• Article: Inhibitor development in haemophilia A: the role of von Willebrand factor/factor VIII concentrates.

  J Goudemand
  [show abstract] [hide abstract]
  ABSTRACT: The presence of inhibitors that neutralize the function of factor VIII (FVIII) decreases the haemostatic efficacy of replacement clotting factor concentrate and increases morbidity among patients with haemophilia A. Certain genetic and environmental variables have been linked to a higher incidence of inhibitors. Conversely, the presence of von Willebrand factor (VWF) in some plasma-derived FVIII products may provide some measure of protection against inhibitor development, although the evidence is not conclusive. Clinical trials are needed to resolve this issue and determine the appropriate role of VWF-containing FVIII concentrates in the treatment of haemophilia A patients.
  Haemophilia 01/2008; 13 Suppl 5:47-51.
• Article: Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers).

  P M Mannucci, A Gringeri, F Peyvandi, E Santagostino
  Haemophilia 01/2008; 13 Suppl 5:65-8.
• Source

  Available from: bayerkogenate.com.cn

  Article: Diagnosis and treatment of von Willebrand disease: new perspectives and nuances.

  C M Kessler
  Haemophilia 01/2008; 13 Suppl 5:3-14.
• Article: VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice.

  E Berntorp
  [show abstract] [hide abstract]
  ABSTRACT: We and others have previously shown that inhibitor containing plasma from patients with congenital haemophilia A sometimes reacts less with von Willebrand factor (VWF) containing concentrates compared with highly purified plasma-derived or recombinant factor VIII (FVIII) concentrates. To further substantiate the haemostatic role of a variation in inhibitor reactivity with different FVIII concentrates, we compared the inhibitor titres from 11 plasma samples against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested: Fandhi (Grifols) which contains VWF with a final ratio of approximately 1 (VWF IU per IU FVIII:C); Haemate (CSL Behring) with a ratio of 2.5 and Haemofil M (Baxter), a monoclonal antibody-purified concentrate containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer (Bayer) containing no VWF was included in the panel. A statistically significant difference in measured titres against the four concentrates was found. The inhibitor titre needed to inhibit 50% maximum thrombin generation was lowest for Kogenate Bayer and highest and similar for Fandhi and Haemate. This study confirms the results from previous research regarding variation of inhibitor reactivity against different concentrates and further shows that the VWF containing concentrates Fandhi and Haemate added to FVIII-deficient plasma with the presence of inhibitor generate more thrombin than do the purified concentrates Haemofil M and Kogenate Bayer. A further interesting aspect could be that bypass therapy may have an increased efficacy when infused together with FVIII concentrates containing VWF. However, the clinical implications of all these findings in vitro need to be established.
  Haemophilia 01/2008; 13 Suppl 5:69-72.
• Article: Safety procedures of coagulation factors.

  J I Jorquera
  [show abstract] [hide abstract]
  ABSTRACT: Two main types of safety procedures must be applied to biological products, including plasma derivatives: (i) preventive procedures and (ii) elimination procedures. Prevention includes epidemiological control of donor populations; checks on each donor's health condition; analysis of each donation for the main pathogens using serological methods; additional analysis of all plasma for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis A virus (HAV) and the B19 virus, using nucleic acid amplification techniques (NAT). A 60 days or longer inventory hold of all plasma donations is applied, to allow additional time to discard previous donations from potential seroconverting or otherwise rejectable donors. Elimination procedures minimize the low residual risk of transmitting pathogens, including unknown or previously undetected ones. Since the introduction 20 years ago of solvent-detergent treatment, very effective against enveloped viruses (HIV, HBV, HCV, West Nile virus, SARS, avian influenza virus etc), there have been no known cases of transmission of this type of pathogens by products manufactured according to this procedure. Other inactivation procedures such as pasteurization, dry-heat or nanofiltration may prove equally effective. In addition, dry-heat treatment and nanofiltration are capable of effectively eliminating non-enveloped viruses (HAV, B19 virus). Recent studies show that the B19 virus is much more sensitive to heat (in lyophilized state or by pasteurization) and acid pH than previously thought. Although there is no evidence for the transmission of classic transmissible spongiform encephalopathies (TSEs) through blood or blood-products transfusion, four possible cases have been reported in the United Kingdom involving transmission by non-leukoreduced blood components of the agent that causes variant Creutzfeldt-Jakob Disease (vCJD), a disease linked to the outbreak of bovine spongiform encephalopathy (BSE) which took place in that country. However, there are no cases of human TSE (classic or variant) transmission by plasma-derived products. Analytical methods capable of detecting the vCJD agent in patients' brains (where high titres are found) and other tissues (such as the spleen, appendix and lymph nodes, where much lower concentrations are found) are unable to detect the agent in blood or plasma from patients with vCJD, even in the clinical phase of the disease. Experiments by Grifols and other groups show that the capacity of the production processes to eliminate vCJD agent models is many orders of magnitude greater than the maximum expected load of the agent. In this regard, the efficacy of precipitation, affinity chromatography, depth filtration and nanofiltration are particularly notable.
  Haemophilia 01/2008; 13 Suppl 5:41-6.
• Article: Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO. WILL Study.

  A B Federici
  [show abstract] [hide abstract]
  ABSTRACT: Two therapeutic approaches are available to manage patients with von Willebrand disease (VWD): (i) the release of endogenous von Willebrand factor (VWF) from endothelial compartments induced by desmopressin (DDAVP); (ii) the transfusion of exogenous VWF contained in VWF/FVIII plasma-derived concentrates. Only a few high-purity VWF/FVIII concentrates have been extensively evaluated in pharmacokinetic (PK) trials as well as in retrospective or prospective efficacy studies in VWD. The Alphanate Study Group published results of PK and clinical efficacy studies in 2002. Efficacy results showed that 75% of bleeding episodes were controlled with one or two infusions, and 71% of patients who received prophylactic treatment for surgeries or invasive procedures had good clinical responses. In another retrospective study, 22 VWD patients in Italy received Fanhdi, a VWF concentrate similar to Alphanate. Excellent-good clinical responses were seen in 92% of bleeding episodes and in 93% of surgical procedures. More recently, the efficacy and safety of Fanhdi have been evaluated retrospectively in a larger cohort of Italian patients (n = 103) with 97% (bleedings) and 99% (surgeries) of excellent/good clinical responses. The largest experience on secondary prophylaxis in VWD has been collected in Sweden in 35 patients with severe forms of VWD. Secondary prophylaxis was also implemented in a cohort of Italian patients with VWD. Prophylaxis was started because of GI bleeds in seven patients with types 3 (n = 1), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) and for joint bleeds in four patients with type 3 VWD (n = 4). Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalization for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on demand therapy will be now investigated in one large prospective study (PRO.WILL) organized in Italy.
  Haemophilia 01/2008; 13 Suppl 5:15-24.
• Article: Creutzfeldt-Jakob disease: reflections on the risk from blood product therapy.

  P Brown
  [show abstract] [hide abstract]
  ABSTRACT: Creutzfeldt-Jakob disease (CJD) was first described as a clinical entity in the 1920s, first transmitted experimentally in 1968, and first transmitted iatrogenically in 1972 (corneal transplant). Numerous experimental studies in rodents, sheep and primates have since revealed very low levels of infectivity in blood (about 1/100 000th the level in brain tissue) that can appear as early as half-way through the incubation period, with 5-10 fold higher concentrations in leucocytes than plasma. Transfused blood from individuals incubating the variant form of CJD has transmitted infection to four recipients in the United Kingdom, and several dozen other recipients remain at risk. Plasma and plasma proteins have not been implicated in any transmissions, and no instance of transmission from the blood of individuals incubating other forms of CJD has been recognized. Strategies to prevent iatrogenic transmissions include low-risk sourcing, leucodepletion, and a variety of infectivity-reducing plasma processing steps; screening tests to detect infection in preclinical donors are under development.
  Haemophilia 01/2008; 13 Suppl 5:33-40.
• Article: VWF/FVIII concentrates in high-risk immunotolerance: the RESIST study.

  A Gringeri
  [show abstract] [hide abstract]
  ABSTRACT: Immune tolerance induction (ITI), through the regular infusion of coagulation factor concentrates over a time period ranging from 1 to more than 24 months, is successful in about 75% of high responders. Among the issues of ITI treatment that are still open, the choice of the product to use is one of the most difficult. In fact, common practice is to start with the same product that induced the inhibitory response, but recent findings indicated that plasma-derived products containing large amounts of von Willebrand factor (VWF) can play a positive role. Two retrospective cohorts in Germany and in France and one prospective cohort have shown a high rate of success when VWF/factor VIII (FVIII) products are used to induce ITI. For these reasons, two prospective studies have been planned to complement the international ITI study already started: an observational study in patients who had already experienced a failure with a VWF-free FVIII concentrate, called RESIST(exp) (experienced); a randomized, controlled study in patients who have never tried an ITI treatment before and at high risk to fail, called RESIST(naïve) (naïve).
  Haemophilia 01/2008; 13 Suppl 5:73-7.
• Article: Inhibitors in haemophilia A: current management and open issues.

  S Haya, A Moret, A R Cid, V Cortina, P Casaña, N Cabrera, J A Aznar
  [show abstract] [hide abstract]
  ABSTRACT: The incidence of inhibitors in haemophilia A is 21-33%. The development of inhibitors to factor VIII (FVIII) is one of the most serious complications in haemophilia therapy and is an important challenge in haemophilia care. The main short-term objective of the treatment of haemophilic patients with inhibitors is to control bleeding episodes, and the long-term one is to eradicate the inhibitor by means of immune tolerance induction (ITI). The choice of treatment for bleeding in inhibitor patients is dictated by the current inhibitor titre, the severity of the bleed and the previous anamnesic response to FVIII. In low responder inhibitor patients the best treatment is large doses of concentrates of FVIII to attain haemostatic levels of the factor infused. The same approach can also be considered in high responders who have a temporarily low inhibitor level and major haemorrhage. High responders patients with high inhibitors titre or with minor haemorrhage must be treated with bypassing agents, such as FEIBA (factor VIII inhibitor bypassing activity) or recombinant activated FVII (rVIIa); there is no agreement which of both agents should be chosen in the different clinical situations. Only in patients waiting to start ITI treatment the rFVIIa use is clearly recommended, in order to avoide an anamnesic responce. In case of failure with this agents, extracorporeal immunoadsortion may be considered. All haemophiliac children who develop an inhibitor should be considered for ITI. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda units/mL (BU ml(-1)) where possible. Starting the treatment when inhibitor titre is below 10 BU ml(-1) is the strongest predictor of success. However, there are many other points to clarify: recommended FVIII doses in the ITI; if the results can be affected by concomitant infections during ITI; if there are any differences using plasma derived or recombinant concentrates, even more if the plasma-derived concentrate contains large amounts von willebrand factor or not; age of starting the ITI and the delay in beginning it; if using immunosupresors can help in the treatment of patients with a bad prognosis; and when the treatment must be left in patients without a clear failure.
  Haemophilia 01/2008; 13 Suppl 5:52-60.
• Article: Prevention of haemophilic synovitis: prophylaxis.

  C A Lee
  [show abstract] [hide abstract]
  ABSTRACT: It has been proven that early prophylactic therapy can prevent bleeding and arthropathy. Numerous retrospective non-randomized cohort studies have demonstrated that prophylaxis, if started early in life, is associated with a considerable reduction of the mean number of joint bleeds and the rate of joint deterioration. It is quite extraordinary that despite the considerable evidence base it has been considered necessary by investigators to pursue the ideal of the controlled randomized trial and expose children to the risk of cerebral bleed. This questionable ethical approach is driven by the reluctance of the 'willingness to pay' but it is important that patients are not subjected to unnecessary investigation at either the behest of the Cochrane Database or those who control the financing of haemophilia care.
  Haemophilia 12/2007; 13 Suppl 3:20-5.
• Article: Rehabilitation of synovitis in patients with haemophilia.

  A Seuser, P Berdel, J Oldenburg
  [show abstract] [hide abstract]
  ABSTRACT: Monitoring the synovium is a central requirement in haemophilia. In cases of acute synovitis, a sufficiently high dosage of coagulation factor should be used immediately, and pain control and anti-inflammatory treatment are essential. Severe effusion should be aspirated and persistent inflammation should be treated with steroid injections. In relation to physical therapy, cryotherapy with CO(2), and CP current after Bernhard should be used, if appropriate in combination with ultrasound and phonophoresis with Voltaren [Voltarol] Emulgel. Early functional treatment is essential following a short individually variable period of immobilization, with the aim of restoring flexibility, coordination and strength (closed chain). If the treatment is insufficient and chronic synovitis develops, consideration must be given after 2-3 month of early synovectomy, by chemical, radio-active, arthroscopic techniques, or by arthrotomy. The physical therapy following operations of this sort should be regarded as the same as for acute synovitis. The rehabilitation of synovitis is independent of co-infections.
  Haemophilia 12/2007; 13 Suppl 3:26-31.
• Article: Prophylaxis and treatment of chronic synovitis in haemophilia patients with inhibitors.

  E C Rodriguez-Merchan, L Valentino, M Quintana
  [show abstract] [hide abstract]
  ABSTRACT: Prophylaxis is paramount to try to avoid the development of haemophilic synovitis. The best treatment for synovitis in patients with inhibitors is radioactive synoviorthesis (rhenium for ankle and elbows, yttrium for knees). With both methods (prohylaxis and radioactive synoviorthesis), we can delay the development of severe haemophilic arthropathy, that eventually will require major orthopaedic surgery.
  Haemophilia 12/2007; 13 Suppl 3:45-8.
• Article: Total joint arthroplasty: the final solution for knee and hip when synovitis could not be controlled.

  E C Rodriguez-Merchan
  [show abstract] [hide abstract]
  ABSTRACT: In severely affected haemophilic patients knee and hip arthropathy is a common problem, which can leads to considerable pain and functional deficit. Surgical management, including total knee and hip arthroplasty, can be undertaken if conservative management fails. This paper reviews the functional outcome of arthroplasty in the knee and hip, the postoperative and long-term complications, and the impact of HIV. Although complications are commonly described and the surgery is technically demanding, the results of the author of this paper and the review of the literature suggest that arthroplasty of the hip and knee can be a valuable option in the management of severe haemophilic arthropathy.
  Haemophilia 12/2007; 13 Suppl 3:49-58.