Thomas Löfqvist

Bio: Thomas Löfqvist is an academic researcher from Lund University. The author has contributed to research in topics: Haemophilia & Tolerance induction. The author has an hindex of 8, co-authored 9 publications receiving 1420 citations.

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B

Abstract: In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.

Haemophilia prophylaxis in young patients–a long‐term follow‐up

Abstract: Objectives. To review long-term prophylactic factor treatment in young patients with severe haemophilia A and B, focusing on the orthopaedic and radiological outcome. Design. We received 34 patients with severe haemophilia A (n=29) and B (n=5), aged 7–22 years. Age at start of treatment was 1–4.5 years. Dosages of factor concentrate (F VIII and F IX, respectively) were 25–40 IU/kg body weight, three times a week for haemophilia A and twice a week for haemophilia B. The patients had been checked annually over a 5-year period (1990–95). Orthopaedic and radiological joint scores were evaluated according to recommendations by the World Federation of Haemophilia. Setting. All results were obtained at the Department for Coagulation Disorders, University of Lund, Malmo University Hospital, Malmo, Sweden. Results. Orthopaedic and radiological joint scores were found to have remained unchanged during follow-up in almost all patients and to be still zero (i.e. no unaffected joints) in 79% (n=27) of the patients. Conclusion. There is a growing international consensus haemophilic arthropathy can be prevented by administering early high-dose prophylaxis. The results of the present investigation strongly support this opinion.

Total hip replacement in patients with hemophilia. 13 hips in 11 patients followed for 1-16 years.

Abstract: During 1973-88, we performed 13 total hip replacements in 11 hemophilia patients, mean age 46 (25-65) years. During the operation, blood loss averaged 920 mL, and a mean of 120,000 units of factor VIII/IX were used. The mean duration of follow-up was 7 (1-16) years. 5 hips became loose within 6 years, and a further one after 13 years. 4 hips were revised, 2 of them due to infection in patients who were also seropositive for HIV. At the latest follow-up, 10 patients were alive. 6 had no hip pain and 7 could walk at least 1,000 meters at a time. Although these results are inferior to those obtained in arthrosis, total hip replacement should be considered in hemophiliac patients.

Radioactive synoviorthesis in patients with hemophilia with factor inhibitor : Prevention and treatment of chronic hemophilic synovitis

Abstract: In nine patients with hemophilia and factor inhibitor (six with hemophilia A; three with hemophilia B), 19 joints were treated with radioactive synoviorthesis using Au-198. Ages ranged from 3 to 40 years. Synoviorthesis was performed when the antibody titer was low (< 10 Bethesda units), thus making hemostasis possible by factor administration for 2 to 4 days. On five occasions, radioactive synoviorthesis was performed simultaneously with tolerance induction according to the Malmo protocol. A bleeding free interval of more than 6 months was obtained in 11 joints, six of which remained bleeding free for more than a year. At long term followup (range, 18-182 months) five joints were rated good, one joint was fair, and 11 joints were poor. Although the results are inferior to those for patients with hemophilia without inhibitor, radioactive synoviorthesis should be considered because of its ease of performance and the definite decrease in joint bleeding frequency that it brings about. This is of particular interest in patients with hemophilia caused by factor inhibitor who otherwise are difficult to treat.

Orthopaedic surgery in hemophilia. 20 Years' experience in Sweden.

Abstract: At the International Hemophilia Center, Malmo, Sweden, which serves a large proportion of the Swedish hemophilia population, 98 orthopaedic surgical procedures were performed from 1970 to 1989 in 66 patients ranging in age from 6 to 71 years. The most common procedures were knee synovectomy, elbow synovectomy in combination with resection of the radial head, and total hip replacement. Comparing the 2 decades of the period, 3 differences were observed: a decreasing need of surgery, an increasing average age of the patients, and a change in the kinds of operations performed. Knee synovectomy and achillotenotomy were most frequent during the 1970s, whereas elbow synovectomy with resection of the radial head and total hip replacement were most frequent during the 1980s. Owing to the availability of regular factor replacement therapy as practiced at the Malmo Center, the situation of patients with hemophilia has improved dramatically during the last 2 decades. In the authors' opinion, it is now possible to avoid hemophilic arthropathy almost completely by giving effective continuous prophylaxis from an early age. In all likelihood, this is the explanation of the changing picture of orthopaedic surgery in patients with hemophilia today.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

Abstract: We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Guidelines for the management of hemophilia.

Abstract: Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.

Abstract: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597.)

Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector

Abstract: Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.

Therapeutic genome editing: prospects and challenges

Abstract: Recent advances in the development of genome editing technologies based on programmable nucleases have substantially improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges.