M. Quintana

European Study on Orthopaedic Status of haemophilia patients with inhibitors

Summary.   Development of inhibitors against factor VIII (FVIII) or factor IX (FIX) in haemophilia patients is one of the most serious complications of repeated exposure to replacement therapy and has major clinical and economic consequences. To evaluate the relationship between inhibitor status of haemophilia patients and their quality of life (QoL) and degree of arthropathy and to compare the orthopaedic status of patients with/without inhibitors. An observational, cross‐sectional, case control study enrolling: group A (n = 38), males aged 14–35 years, with severe congenital haemophilia A or B who had inhibitors against FVIII/FIX >5 years; group B (n = 41), as group A, but aged 36–65 years and group C (n = 49), as group A, but without inhibitors. Socio‐demographics: medical history, clinical characteristics and QoL were assessed. In groups A and B, 16% and 27% were hospitalized for orthopaedic procedures vs. 4% in group C. Patient mobility was also severely reduced in groups A and B, with 24% and 22% using wheelchairs vs. 4% in group C, and 50% and 51% needing a walking aid vs. 29% in group C. Significantly more joint pain was reported by patients in group A vs. those in group C; clinical/radiological orthopaedic scores were also worse in group A vs. group C. Significantly more joint abnormality was reported by patients in group A vs. group C. The burden of orthopaedic complications and the impact on QoL are more severe in haemophilia patients who have developed inhibitors than in those without inhibitors.

Prophylactic treatment effects on inhibitor risk: experience in one centre.

Summary.  Nowadays, the elective treatment for children with haemophilia is prophylaxis. There is a common consensus that this modality of therapeutic approach is not associated with a higher risk of inhibitor development. We analysed the inhibitor incidence in 50 haemophiliac children and its relationship with mutations, type of clotting factor used and treatment modality. There was a significant correlation between receiving on‐demand treatment and an increased incidence of inhibitors, independently of mutations or factor used. We advise putting haemophiliac children under prophylactic treatment as soon as possible, especially if they have mutations associated with high risk of inhibitor development, as prophylaxis is negatively associated with the development of inhibitors.

Prophylaxis in 10 patients with severe haemophilia A and inhibitor: different approaches for different clinical situations.

Summary.  The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the "Seville Document".

Grade 1A recommendations We recommend: The use of restrictive transfusion strategies in nonbleeding, euvolaemic anaemic patients. Perioperative administration of tranexamic acid to patients undergoing cardiac surgery. The administration of intravenous iron to cancer patients, as an adjuvant to erythropoiesis-stimulating agents, for correcting chemotherapy-induced anaemia. Preoperative administration of erythropoiesisstimulating agents to anaemic, orthopaedic surgical patients expected to have moderate blood losses. We do not recommend: The administration of desmopressin to patients undergoing elective surgery. The administration of erythropoiesis-stimulating agents to critically ill patients who do not have a previous indication for this therapy.

Orthopaedic surgery for inhibitor patients: a series of 27 procedures (25 patients)

Summary.  We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8–53) and the average follow‐up time was 2.5 years (range:1–5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9–26) and the average follow‐up was 4.5 years (range: 1–7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg−1, except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg−1. In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11–53) and the average follow‐up was 2.5 years (range: 1–5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high‐titre inhibitors, leading to an improved quality of life for these patients.

The use of haemostatic drugs in haemophilia: desmopressin and antifibrinolytic agents

Summary.  Over the last 4 decades, there have been very significant advances in the treatment of haemophilia. Plasma products first became available in the 1960s, beginning with cryoprecipitate and then intermediate‐purity plasma concentrates, for the treatment of haemophilia A and B. The disasters of viral infections amongst people with haemophilia in the 1980s served to stimulate both the development of techniques of viral inactivation of concentrates and the manufacture of purer products. We therefore now have safe plasma products that are also pure in that they are concentrates of only the deficient protein responsible for the congenital coagulopathy. Preparations of specific coagulation proteins obtained using recombinant biotechnology techniques have been available since 1995.

Progression of HIV infection and mortality by hepatitis C infection in patients with haemophilia over 20 years

Summary.  Hepatitis C virus (HCV) infection is an important cause of mortality in human immune deficiency virus (HIV)‐positive haemophiliacs. This study describes progression to AIDS, death from HCV end‐stage liver disease (ESLD) and all‐cause mortality over 20 years. All HIV‐positive haemophiliacs in La Paz University Hospital were included in this cohort. HIV seroconversion was estimated using mathematical techniques for interval‐censored data from 1979 to 1985. Poisson regression was used to estimate rates of AIDS, death from ESLD and all causes in different periods: before 1988, 1988–89, 1990–91, 1992–93, 1994–95, 1996–97 and 1998–2001 using competing risk models. Among 383 cohort members, global AIDS incidence was 9.7 per 100 person‐years, peaking in 1992–93 and dropping by 87% in 1998–2001 compared with before 1988 [incidence rate ratio (IRR) 0.13; 95% CI: 0.03–0.53]. Overall mortality was 7.5 per 100 person‐years, was highest from 1992 to 1997, and fell by 66% in 1998–2001 compared with before 1988 (IRR 0.34; 95% CI: 0.14–0.81). Eighteen (5%) persons died of ESLD which represented 19% of deaths before 1988, 4% during 1988–89, 1990–91 and 1992–93, 2% in 1994–95, 10% in 1996–97 and 33% in 1998–2001. Overall death rate from ESLD was 0.5 cases per 100 person‐years with no statistically significant trend observed over time. Important reductions in HIV disease progression to AIDS and death have been observed from 1998 to 2001, and can be attributed to highly active antiretroviral therapy. Although no increase in the rate of HCV‐related deaths can be demonstrated, HCV accounts for an increasing proportion of deaths in the recent years.

Controversies and Challenges in Elective Orthopedic Surgery in Patients With Hemophilia and Inhibitors

Until recently, orthopedic surgery was strongly contraindicated in patients with hemophilia and inhibitors. However, recent advances in our knowledge of bypassing agents (particularly recombinant activated factor VII [rFVIIa]) that provide effective surgical hemostasis have allowed us to successfully perform major orthopedic procedures in these patients. Adequate hemostasis during surgery and postoperative rehabilitation is crucial, as development of a wound hematoma may jeopardize long-term outcomes. It also should be noted that success depends not only on appropriate drug therapy but also on preoperative preparations and adequate perioperative surveillance. Preoperative assessment of vascular status is very important, and strong motivation--on the part of the patient, the surgeon, and the hematologist--is needed to ensure a satisfactory result. Although inhibitor patients undergoing surgery face a higher risk of bleeding and other complications than their non-inhibitor counterparts, outcomes are generally good if a multidisciplinary team approach is applied.

Acquired hemophilia: a single-center survey with emphasis on immunotherapy and treatment-related side-effects.

Abstract: Objectives: Acquired hemophilia is a rare disease caused by the development of autoantibodies against factor VIII. Since 1981 we have observed 17 patients with this disorder in our institution. The objective of this survey was to assess the epidemiological features, clinical course, and mortality rate of these patients, with special emphasis on therapy‐related side‐effects. Also, we present our results with an immunosuppressive approach based on the severity of bleeding episodes. Methods: Clinical records of all patients with acquired hemophilia due to factor VIII inhibitor admitted or referred to our hospital between 1981 and 2001 were reviewed retrospectively. We collected each patients sex, age, medical history, presenting symptoms, activated partial thromboplastin time, factor VIII activity, and inhibitor titre. Patients clinical courses, including their bleeding episodes, response to therapy, and therapy‐related side‐effects, were also recorded. Results: Complete and partial responses were achieved in 14 and one patient, respectively (overall response rate 88%) after a median time to complete response of 3.5 months (range 30 d − 25 months). The inhibitor‐related and overall mortality rates were 12% and 29%, respectively. Side‐effects were frequent: two patients had blood‐borne infections, three patients had thrombotic complications, and nine patients had immunosuppressive therapy‐related side‐effects. In five patients, discontinuation of cyclophosphamide or prednisone was required. Conclusions: Although our response rates were remarkable, this survey showed that treatment‐related morbidity could also be very important. Therefore, it is pertinent to bear in mind these potential side‐effects in order to decide the most appropriate therapy for each particular patient.

Clinical efficacy in bleeding and surgery in von Willebrand patients treated with Fanhdi® a highly purified, doubly inactivated FVIII/VWF concentrate

Summary.  Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi®) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi®. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi® was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi® a highly purified, doubly virus‐inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.