bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiotherapy for the prevention of articular contraction in haemophilia
Authors: Buzzard B.M.
Published: March 2003

The idea of prevention and preventative care is not new. History and culture have given us many examples of the importance of physical well‐being and the prevention of illness and disease. The ancient societies of China focused on the balance of Yin and Yang in promoting health; Greece and Rome valued the importance of health and physical culture; the earliest Hebrew societies documented the importance of diet and dietary restrictions as a means towards good health. Throughout this century health professionals have advocated the importance of preventative care as an integral element of the quality of health. Haemophilia is a life‐long condition with a high potential towards disability, handicap and impairment if not adequately treated. It is therefore essential that those with haemophilia are taught the importance of physical fitness at an early age as a means of preventing articular contractures. Physiotherapy is of great importance in this field, especially in third‐world countries where the supply of replacement products are scarce or non‐existent.
Haemostatic treatment in connection with surgery in patients with von Willebrand disease
Authors: Lethagen S.
Published: March 2003

Haemostatic treatment in patients with von Willebrand disease (vWD) in connection with surgery aims at normalizing the haemostatic defect in order to avoid bleeding complications. Factor VIII (FVIII) levels in plasma must be normalized in connection with major surgery, whereas the bleeding time is more important for mucous membrane bleedings. Most patients respond well to treatment with desmopressin which stimulates the endogenous release of FVIII and von Willebrand factor (vWF) and shortens the bleeding time. Non‐responders to desmopressin are substituted with a plasma‐derived factor concentrate which contains vWF and FVIII. This paper includes a summary of retrospective data from the last 10 years on haemostatic treatment in connection with surgery from four haemophilia centres in Sweden and Denmark on 40 invasive procedures in 27 vWD patients and on one normal delivery. If a FVIII‐containing concentrate is given prior to surgery a dose of 30–40 IU VIII:C kg−1 will normalize FVIII levels in most severe cases. If a pure vWF concentrate is used, a dose of 40–50 IU RCoF kg−1 will normalize RCoF in most cases, but FVIII levels will not be normalized until after about 12 h or later. Repeated doses of FVIII‐vWF concentrate may lead to very high levels of FVIII in plasma because of the combined effect of the exogenous FVIII‐substitution and the endogenous FVIII‐release induces by the infused vWF. Dosage should be adjusted according to FVIII levels in plasma.
Gene therapy for the haemophilias
Authors: Thompson
Published: March 2003

A variety of approaches for transferring genes for factors VIII and IX are being investigated. No single technique has emerged as superior, but considerable progress has been made in factor expression after in vivo delivery of vectors into animal models, which has led to considerations of clinical trial development for both factors. The last decade has seen several major contributions to the field from many different laboratories. In early attempts coding DNAs (cDNAs) for factor IX or VIII were inserted into cells grown in culture, then the modified cells were returned to the donor animal. Unfortunately, the modified cells expressed clotting factor better in culture (ex vivo) than in the animal (in vivo). This led to attempts to transfer cDNAs by inserting them into vectors that were then administered directly to animals, by either intravenous or intramuscular routes. There was some success with either long‐term expression of subtherapeutic amounts of expressed protein or even normal amounts that circulated transiently for up to a few months. However, it has only been within the last year that improved vectors have provided sufficiently encouraging results to allow contemplation of clinical trials in humans. Recent advances that are likely to lead to human clinical trials are summarized in this monograph.
Pitfalls in the management of a child with mild Haemophilia A and a traumatic hyphaema
Authors: Hallet  , Willoughby  , Shafiq  , Kaye  , Bolton‐Maggs
Published: March 2003

A 12‐year‐old boy presented with a traumatic hyphaema that failed to settle with the standard treatment. Subsequent investigation showed that despite a normal APTT, he had a low factor VIII:C. Treatment with DDAVP precipitated further bleeding despite correction of the fVIII:C to normal, possibly caused by the vasodilation induced by the therapy. Bleeding was effectively treated with recombinant fVIII concentrate. DDAVP may be contraindicated in mild Haemophilia and von Willebrand patients for treatment of traumatic hyphaema.
MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage
Authors: Nuss R. , Kilcoyne R. F. , Geraghty S. , Shroyer A. L. W. , Rosky J. W. , Mawhinney S. , Wiedel J. , Manco‐Johnson M.
Published: March 2003

We hypothesized that magnetic resonance imaging (MRI) scans taken prior to radiosynoviorthesis may be predictive of response to the procedure in persons with haemophilia. Specifically, response would be inversely related to the severity of synovial hyperplasia. Radiosynoviorthesis was administered to 21 joints with recurrent haemorrhage (target joints). A detailed self‐report of haemorrhage history, joint evaluation with scoring according to the World Federation of Haemophilia orthopaedic joint and pain scales, plain radiographs, and MRI studies of the joints were performed pre‐ and post‐radiosynoviorthesis. To augment comparison of the MRI findings to those assessed using the Arnold‐Hilgartner and Pettersson scales, a provisional MRI scale for evaluation of haemophilic arthropathy was designed. We found the MRI findings prior to the procedure were not predictive of clinical response; independent of the severity of synovial hyperplasia, most joints bled less and showed improvement by the WFH orthopaedic score. There was generally no change in the severity of synovial hyperplasia after the procedure. We conclude that MRI evaluation is not routinely indicated prior to radiosynoviorthesis.
Use of the dual force system to correct chronic knee deformities due to severe haemophilia
Authors: Kale J. S. , Ghosh K. , Mohanty D. , Pathare A. V. , Jijina F.
Published: March 2003

In this study, the use of the dual force system to correct recent or relatively longstanding knee deformities in ten patients is described. (Nine of the patients had severe haemophilia and one had severe von Willebrand’s disease.) The mean duration of deformity in these patients was 10 months. The mean range of movement at the affected knee joints increased from 50° at pre‐intervention to 110° following 6 weeks of application of the dual force system. In nine of ten patients (90%) the residual flexion deformity ranged from 0° to 10°. The dual force system offers an easily affordable and effective means of correcting a flexion deformity of the knee joint in severely affected haemophilia and allied disorders. More extensive use of this technique in different centres is required to determine its place in the day‐to‐day management of such patients.
Protease inhibitor therapy and bleeding
Authors: Wilde
Published: March 2003

Shortly after the introduction of protease inhibitor drugs (PIs) for the treatment of human immunodeficiency virus infection an association between these drugs and an increased bleeding tendency in patients with hereditary bleeding disorders was observed. Not only do patients experience an increased bleed frequency in usual sites, but bleeds can also occur in unusual places such as the finger joints. Mucus membrane bleeding and haematuria are also common. Ritonavir appears to be associated with the highest risk of bleeding followed by indinavir. As yet there has not been enough experience with the newer PIs to assess fully their potential to induce increased bleeding, although nelfinavir seems to pose less of a risk than the original PIs. PI‐associated bleeds tend to be more resistant to factor concentrate treatment and periods of prophylaxis may be required in individuals with frequent persistent bleeds. Patients continuing on PI therapy tend to develop a tolerance to this adverse effect with time. The mechanism of the bleeding tendency has not been elucidated. There is no consistent evidence of a disturbance of coagulation, fibrinolysis or platelet function which raises the possibility that PIs may exert a direct local effect on blood vessels. It is very important that this class‐specific side‐effect is recognized and understood by both treaters and patients.
Unexpected presentation of type 2N von Willebrand disease in pregnancy
Authors: Dennis M. W. , Clough V. , Toh C. H.
Published: March 2003

The finding of low factor VIII levels in pregnancy immediately raises concern of haemophilia A carriage, especially with a history of bleeding in the maternal grandfather. However, the diagnosis of type 2N von Willebrand disease (2N vWD) should also be considered as illustrated here. This is also the first reported case of the management of 2N vWD in pregnancy.
Haemophilia and the forbidden abdomen
Authors: Ingram G. I. C.
Published: March 2003

Abdominal surgery became routinely possible over a hundred years ago, after the introduction of general anaesthesia and sterile procedures. Abdominal surgery for haemophiliacs had to wait another 60 or 70 years for adequate control of haemostasis. This paper traces its gradual achievement from the 1920s to the 1970s through a series of reports of appendectomies, gastric and intestinal operations, gall bladder operations and splenectomies in patients with haemophilia of varying degrees of severity. A short‐lived flurry of interest in splenectomy as a proposed treatment for haemophilia is also mentioned.
Chemical synoviorthesis with rifampicin in haemophilia
Authors: Caviglia H.A. , Fernandez‐Palazzi F. , Galatro G. , Perez‐Bianco R.
Published: March 2003

Rifampicin is an antibiotic that has been currently used for the treatment of noninfectious articular lesions with satisfactory results. The first experience was performed with patients who presented rheumatoid arthritis, and later with haemophilic patients. The clinical experience of three haemophilia centres which used rifampicin for the treatment of chronic haemophilic synovitis is presented here. The protocols were different. It was observed that rifampicin is more effective when it is used in small joints (elbows and ankles), than when used in bigger ones (knees), and that a high number of injections predicts failure. Mention is also made of experimental studies in animals where it was shown that the healing pattern of rifampicin is similar to that of NSAIDs.
On the safety of synoviorthesis in haemophilia
Authors: Fernandez‐palazzi F. , Caviglia H.
Published: March 2003

One of the best procedures to prevent haem‐arthrosis has been radioactive synovectomy (synoviorthesis). Since the first report of radioactive synovectomy in haemophilia of Ahlberg in 1971 [1], many centres adopted this procedure as the one of choice, through fibrosing the synovial membrane, prevent further haemarthrosis.

Since 1976 we have performed 104 such radioactive synoviorthesis in 97 patients, age ranging from 6 to 40 years with a mean of 10 years. Sixty‐five of these patients were under 12 years of age. The knees were injected in 61 cases, elbow in 26 cases, ankles in 14 cases and shoulders in three cases. The clinical results of this procedure show 80% of excellent results with no further bleeding. In case of failure, a new injection can be given in the same joint at a 6‐month interval, or an injection for the same purpose in other joint. One of the criticisms against this method is the possible chromosomal damage induced by the radioactive material.

In our centre, four studies have been carried out in order to see whether these changes, when they occur, are everlasting; all have demonstrated that chromosomal changes are reversible. The radioactive material used in the two first studies was Gold‐189 (189Au). In 1978, 354 metaphases were studied with 61 ruptures, 17.23% (nonpremalign) and six structural changes, considered premalign (1.69%). Any number below 2% is considered not to be dangerous. A further study was done in 1982, in the same group of patients with a result of 21 ruptures (3.34%) and no structural changes. This demonstrated that the possible premalign changes disappeared with time. A third study was performed in a series of 13 patients that sustained radioactive synoviorthesis with Rhenium‐186 (186Re) in November 1991. For comparison, we carried out a chromosomal study just before and 6 months after the radioactive material injection. The results confirmed that changes that could be linked to the radiation, appeared equally in nonirradiated patients, and those changes due to the radiation disappear with time, never reaching the dangerous zone of 2%. In the group treated with186Re we studied an additional number of 130 metaphases with identical results and no structural changes. In a study on patients where90Y was the radiocolloid, no premalign change was found before or after the synoviorthesis. It seems, in view of these results, that radioactive synovectomy is safe and gives great benefits to the haemophilic patients.
Viral safety of a pasteurized, monoclonal antibody‐purified factor VIII concentrate in previously untreated haemophilia A patients
Authors: Philipp C. S. ,   FOR THE MONOCLATE‐P STUDY GROUP
Published: March 2003

The efficacy and viral safety of a pasteurized, immunoaffinity‐purified procoagulant factor VIII protein (FVIII:C; Monoclate‐P) was studied in two multicentre, prospective, open‐label trials in 30 previously untreated patients, 18 with severe (< 1% FVIII:C activity), and 12 with moderate (1% to 5% FVIII:C activity) haemophilia A. Clinical assessments, performed at screening and regularly thereafter for 6 to > 24 months (maximum 34 months), showed that none of 24 assessable patients acquired illnesses consistent with monitored transfusion‐transmissible diseases. No patients acquired hepatitis B surface antigen, or antibodies against hepatitis B core antigen, hepatitis C, or human immunodeficiency virus. Likewise, no patients acquired treatment‐related hepatitis A antibodies or sustained elevations of alanine aminotransferase levels. The safety profile for Monoclate‐P is brought about by a multi‐step safety system that incorporates viral inactivation (through a combination of immunoaffinity chromatography and pasteurization) plus donor screening, plasma testing, and quality assurance. The inhibitor development rate (13% low titre, 10% high titre) was similar to that reported in the literature for other FVIII concentrates (24% to 52%). The most frequently reported adverse events were related to typical infant and childhood diseases. Monoclate‐P was effective in all patients treated according to protocol, except in two, who developed inhibitors.
Heart transplant in a factor VIII‐deficient patient with a high‐titre inhibitor: perioperative management using high‐dose continuous infusion factor VIII and recombinant factor VIIa
Authors: Sheth S. , Dimichele D. , Lee M. , Lamour J. , Quaegebeur J. , Hsu D. , Addonizio L. , Piomelli S.
Published: March 2003

Four years prior to transplantation, a 14‐year‐old boy with severe haemophilia A and a high‐responding factor VIII (FVIII) inhibitor developed an anteroseptal myocardial infarct while receiving high doses of an activated prothrombin complex concentrate (PCC). Cardiac transplantation was required for survival because of the ensuing cardiomyopathy. At surgery, the patient’s inhibitor titre was 1.8 Bethesda units (BU). High‐dose bolus therapy, followed by a continuous infusion of FVIII provided excellent operative and initial postoperative haemostasis without additional blood‐product support. Once anamnaesis developed on day 6 postoperatively, recombinant factor VIIa (rFVIIa) therapy was initiated. Haemostasis remained excellent, except for the transient increase in chest‐tube bleeding that was noted on day 7. ɛ‐aminocaproic acid was added and haemostasis was re‐established. On day 15, rFVIIa was replaced with alternate day infusions of prothrombin complex concentrates (PCCs). On day 21 following the transplant, the patient was discharged, remaining on daily FVIII immune tolerance and thrice‐weekly PCC prophylaxis. He remains well 24 months after transplant with an inhibitor titre of 39 BU. This paper describes the second case of cardiac transplantation complicated by haemophilia and an inhibitor, and discusses preoperative planning and operative and postsurgical haemostasis management.
Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America
Authors: Cohen A. J. , Kessler C. M. , Ewenstein B. M. ,   ON BEHALF OF THE HEMOPHILIA RESEARCH SOCIETY OF NORTH AMERICA
Published: March 2003

The optimal treatment of patients with von Willebrand’s disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety‐nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF‐containing FVIII product, type 3 patients with vWF‐containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.
Discontinuation of prophylactic therapy in severe haemophilia: incidence and effects on outcome
Authors: Fischer K. , Van Der Bom J. G. , Prejs R. , Mauser‐Bunschoten E. P. , Roosendaal G. , Grobbee D. E. , Van Den Berg H. M.
Published: March 2003

A cohort study was performed to assess adherence to early prophylactic therapy and its effects on outcome in 49 patients with severe haemophilia born 1970–1980. Median age at start of prophylaxis was 5.5 years. The majority (69%) of patients interrupted prophylactic treatment one or more times of their own accord (median total interruption 2.2 years). Patients who discontinued prophylaxis at any point tended to have more arthropathy as measured by the Pettersson scale (median 8 points versus 4 points). One‐third of these patients interrupted prophylaxis for longer periods and had permanently stopped taking prophylaxis at a mean age of 20.1 years (mean ± SD duration 4.1 ± 4 years) and consequently experienced 5.4 ± 3.4) joint bleeds per year. This subgroup could be identified by a predictive score based on age at start of prophylaxis, weekly dose of prophylaxis, and joint bleed frequency on prophylaxis. In conclusion, while on prophylaxis, more than two‐thirds of patients with severe haemophilia try to discontinue treatment, resulting in slightly more arthropathy. One‐third of these patients permanently discontinue prophylaxis in adulthood, while maintaining a low number of joint bleeds.
Descriptive epidemiology of haemophilia in Maharashtra, India
Authors: Kar A. , Potnis‐Lele M.
Published: March 2003

Secondary data on haemophilia cases in the state of Maharashtra, India were compiled and analysed. A total of 2192 haemophiliacs could be accounted from case papers and pedigrees, representing approximately 60% of the estimated number of cases in the state. Ratio of haemophilia A to haemophilia B was 4.2:1. Severe haemophiliacs constituted the majority of haemophilia A and B cases. About 70% of patients did not report any family history. Age distribution of cases suggested that the longevity of severe haemophiliacs was less than 30 years. Geographical distribution revealed clustering of cases around three established haemophilia clinics, with large parts of the state showing no cases. Although the cumulative number of cases showed an ascending trend, there was a 90% decrease in the number of cases registered between 1989 and 2000, suggesting that case recruitment from areas around the facilities had been achieved. Most cases showed delayed diagnosis, as the majority of severe haemophiliacs was being diagnosed at around 11–15 years of age. However, increasing awareness about haemophilia was reflected in a four‐fold increase in referrals of severe cases over a 10‐year period and increased registration of cases under 5 years of age. This study highlights that haemophilia services in India are still in their infancy, and increased awareness among healthcare providers as well as expansion of treatment facilities are still the primary areas for improvement of treatment.
Management of spontaneous inhibitors in children with porcine factor VIII
Authors: Kobrinsky N.L. , Stegman D. , Sjolander D.
Published: March 2003

Acquired factor VIII (FVIII) inhibitors are rare, typically occurring in the postpartum period or in the elderly. Their occurrence in childhood is distinctly unusual. Acquired FVIII inhibitors are often life‐threatening and refractory to treatment with high doses of human FVIII concentrate. Alternative strategies for control of haemostasis include the use of products with FVIII ‘bypassing’ activity or porcine FVIII (pFVIII) concentrate if the pFVIII titre is sufficiently low (<10–20 porcine Bethesda Units). Corticosteriods and other immunosuppressive therapies are inconsistently effective in eliminating FVIII inhibitors. Accordingly, acquired FVIII inhibi‐tors often require long‐term haemostatic management.
Porcine factor VIII: current status and future developments
Authors: Hay C.R.M.
Published: March 2003

High‐purity porcine factor VIII (pFVIII) (Hyate:C, Ipsen, UK), with a specific activity of > 125 U mg−1 protein, has been shown to be effective in up to 90% of bleeds in patients with FVIII inhibitors. These inhibitors have been shown to have a median 15% cross‐reactivity to pFVIII, and even less cross‐reactivity in patients with acquired haemophilia. Its use is sometimes associated with a transient fall in platelet count and with transfusion reactions. Furthermore, it is not virally attenuated. Although pFVIII has not been shown to transmit any viral illness to its human recipients, it is extensively screened for porcine viruses using a 4‐cell line general screen. The source plasma is also screened for porcine parvovirus. To satisfy the demand for ever‐improved side‐effect profile and viral safety a third‐generation pFVIII is under consideration by Ipsen. This product will be purified from porcine plasma screened for porcine parvovirus, using immuno‐purification, ion‐exchange chromatography and washing. Spiking experiments using human FVIIIC (hFVIIIC) suggest that these purification steps may be associated with a 6‐log viral reduction. The product is also virally attenuated using the solvent‐detergent method. This should yield an ultra‐pure concentrate, lacking porcine von Willebrand factor, with a specific activity of approximately 5000 U mg−1 protein which does not require added albumin as stabilizer and which may be stored at 2–4°. One would anticipate that this product should be clinically effective and should be associated with enhanced viral safety and an improved side‐effect profile. It should not affect the platelet count and should be associated with a much reduced risk of transfusion reactions. Clinical trials are planned.
Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs
Authors: SALVIATO R. , BELVINI D. , ARE A. , RADOSSI P. , TAGARIELLO G.
Published: March 2003

Haemophilia A displays a broad heterogeneity of genetic defects and of clinical severity. Inhibitor development is the main complication of replacement therapy in severe cases and most patients with inhibitors have gross gene rearrangement or point mutations, which hamper the production of normal circulating factor VIII (FVIII). We have investigated three related severe haemophilia A patients, all of whom have high titre inhibitors. By using long‐range polymerase chain reaction (PCR) for FVIII gene inversion, we observed an unusual pattern in these patients. We therefore decided to screen the whole FVIII gene by conformation‐sensitive gel electrophoresis. A large FVIII gene deletion spanning exon 2 to exon 25 was identified and we were able to obtain a 18.5 kb PCR product, which is specific for this mutation and useful for determining the carrier state in this family. All three haemophiliacs carrying this very large gene deletion show similar clinical history and very high‐titre inhibitors, supporting the observation that inhibitor development seems to be an inherited characteristic. On the basis of our observations we think that this subgroup of patients at very high risk of inhibitor development should be identified by mutation analysis whenever possible, before the beginning of replacement therapy.
Quality‐of‐life differences between prophylactic and on‐demand factor replacement therapy in European haemophilia patients
Authors: ROYAL S. , SCHRAMM W. , BERNTORP E. , GIANGRANDE P. , GRINGERI A. , LUDLAM C. , KRONER B. , SZUCS T. ,   FOR THE EUROPEAN HAEMOPHILIA ECONOMIC STUDY GROUP
Published: March 2003

The European Study on the Clinical Outcomes and Resource Utilization associated with Haemophilia Care was designed to compare various health outcomes associated with on‐demand and prophylactic factor substitution methods in European haemophilia patients. While the primary objective of this research is to conduct an economic analysis, an important component of this study is to evaluate quality‐of‐life differences that may exist between patients who utilize these two styles of therapy. Quality‐of‐life research has emerged as a primary measure of health outcomes because it allows the augmentation of traditional clinical indicators of health with data gathered from the patient's perspective. A total of 1033 haemophilia patients from 16 European haemophilia treatment centres were enrolled in this study. The SF‐36, a multidimensional quality‐of‐life instrument, was administered to all participants. This instrument measures eight health‐related quality‐of‐life dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. All haemophilia subjects enrolled in the study scored significantly lower than the population normative means in the three physical dimensions and in the general health dimension. HIV‐negative haemophiliac subjects differed significantly by factor substitution type in a multivariate analysis examining all eight health dimensions. Univariate analyses testing each dimension separately indicated that patients treated prophylactically reported significantly less bodily pain, better general health, and scored significantly higher in the physical functioning, mental health, and social functioning dimensions. While these results suggest that health‐related quality‐of‐life may be better for haemophilia patients treated prophylactically, future prospective studies that gather periodic quality‐of‐life data over time should be conducted.
Efficacy of desmopressin as surgical prophylaxis in patients with acquired von Willebrand disease undergoing thyroid surgery
Authors: FRANCHINI M. , DE GIRONCOLI M. , LIPPI G. , MANZATO F. , BRAZZAROLA P. , BOTTURA D. , APRILI G. , GANDINI G.
Published: March 2003

Coagulation abnormalities may occur in patients with thyroid diseases. We report on 14 patients undergoing thyroid surgery for a thyroid disease with an alteration of coagulation parameters resembling von Willebrand disease. Subcutaneous desmopressin was first tested and then used successfully in these patients as surgical prophylaxis, with no side‐effects or bleeding complications during or after surgery. This study highlights the need for coagulation studies in patients with thyroid diseases undergoing thyroid surgery. Subcutaneous desmopressin may be used in these patients in order to prevent a surgically related bleeding risk.
von Willebrand disease: still an intriguing disorder in the era of molecular medicine
Authors: RODEGHIERO F.
Published: March 2003

von Willebrand disease (vWD) is a single‐locus disorder resulting from a deficiency of von Willebrand factor (vWF): a multimeric multifunctional protein involved in platelet adhesion and platelet‐to‐platelet cohesion in high shear stress vessels, and in protecting from proteolysis and directing circulating factor VIII (FVIII) to the site of injury. vWD is the most frequent bleeding disorder, with an estimated prevalence in the general population of 1%. Almost all these cases are represented by a partial quantitative deficiency of von Willebrand factor (vWF) (type 1 vWD). Type 1 is transmitted as an autosomal dominant trait with an extremely variable penetrance and expressivity. A consensus figure for the prevalence of cases with significant bleeding symptoms, requiring some form of treatment, is approximately 100 cases million−1. Among these cases, more than 70–80% are represented by type 1 and respond to deamino‐D‐arginine vasopressin (DDAVP; desmopressin) administration. The remaining cases are represented by type 2 vWD (qualitative), some of which require substitutive treatment. Only 3–5 cases million−1 result from a total deficiency of vWF in plasma and platelets because of the recessive inheritance of two defective alleles. These cases may have severe bleeding episodes and may require frequent substitutive treatment. The molecular basis of type 2 (missense mutation in the functional domains of the vWF subunit) and type 3 (nonsense or large deletions) is quite well understood. On the contrary the molecular basis for most type 1 cases remains largely unknown, and many genetic factors (e.g. ABO blood group) and environmental or circumstantial factors (e.g. age, stress, drugs, pregnancy, and inflammation) are superimposed on to the genetic background determined by the vWF gene to produce a continuous spectrum from normality to mild type 1 cases. It is extremely difficult to make a clear distinction between mild type 1 cases and normal people because of the wide `normal' range of laboratory measurements (e.g. length of bleeding time, and levels of vWF and FVIII) and of bleeding symptoms. Molecular testing is useless in this situation, and only good history‐taking and repeated laboratory testing of vWF‐related measurements in the propositus and his/her family members can help in clinical diagnosis, albeit imprecisely. This difficult task is the main focus of this review which is aimed at alerting the physician toward a balanced approach that should take into consideration both the risk of over‐ and under‐diagnosis of this frequent disorder and the unavoidable production of a number of false positive and false negative cases.
Continuous infusion of coagulation factors
Authors: Batorova A. , Martinowitz U.
Published: March 2003

Summary.  Continuous infusion (CI) of coagulation factor concentrate is aimed at maintaining a steady haemostatic level of the missing factor in circulation, preventing dangerous troughs below the haemostatic level and unnecessary high peaks, which increase the safety and decrease the consumption of factor concentrate replacement therapy. This can be achieved by the administration of the coagulation factor at a rate corresponding to its elimination. CI has been used in wider extent since the early 1990s, after the resolution of basic questions such as the stability of factor concentrates after reconstitution, the risk of contamination and bacterial overgrowth in these biological materials during either preparation of infusion bags or prolonged administration, the frequent local thrombophlebitis, the knowledge of pharmacokinetics of coagulation factors in the conditions of CI and the developement of adequate minipumps. The increasing clinical experience with CI used in haemophilia A and B and von Willebrand disease has proven the advantages of this mode of replacement therapy, providing improved margins of efficacy and safety in various clinical settings requiring the maintenance of haemostatic levels over prolonged periods, as well as reduction in treatment cost compared with the traditional therapy via intermittent injections of coagulation factors.Keywords: continuous infusion, factor VIII, factor IX, haemophilia, recombinant FVIIIa, von willebrand disease.
Hepatitis G virus in clotting factor concentrates
Authors: Alonso‐Rubiano E. , Gerber M. , Friedman P. , Hodges S. , Leissinger C.
Published: March 2003

Summary. Blood‐borne hepatitis is a well‐known complication in patients with bleeding disorders. A recently discovered parentally transmitted virus, hepatitis G [GB virus C (GBV‐C)] has an increased prevalence in patients with haemophilia. Clotting factor concentrates derived from pools of human plasma currently undergo viral inactivation techniques known to be effective against hepatitis B, C and HIV; however, the effectiveness of current purification and viral inactivation techniques against newly discovered viruses such as GBV‐C is unknown. A total of 37 vials of clotting factor concentrates manufactured in the USA from 1981 to 1995 were tested for the presence of GBV‐C virus. All samples that did not undergo a specific viral inactivation step were positive for GBV‐C. Viral inactivation techniques that did not uniformly remove GBV‐C included vapour heat treatment and dry heat treatments for less than 144 h. All samples treated by pasteurization, solvent detergent or dry heat for 144 h, were negative for the presence of GBV‐C.
Inherited bleeding disorders in Indian women with menorrhagia
Authors: Saxena R. , Gupta M. , Gupta P. K. , Kashyap R. , Choudhry V. P. , Bhargava M.
Published: March 2003

Summary.  In order to define the prevalence of haemostatic defects in women presenting with menorrhagia in our region, the coagulation data on women bleeders investigated in the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200 menorrhagic women investigated were characterized to have an inherited bleeding disorder; 221 of these 337 women presented with menorrhagia alone while 116 also had other associated bleeding manifestations as prolonged bleeding from injury site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and major bleeds like intracerebral bleeding. The tests performed included bleeding time (BT), platelet count, prothrombin time (PT), prothrombin consumption index (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin. Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor assay and electron microscopy were performed wherever necessary.

Inherited platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these, isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and Bernard–Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the platelet function defect could not be classified into any specific subtypes. Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst these, von Willebrand disease (vWD) was the most frequent being seen in 40 (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII deficiency in one (0.3%) of the patients.

It is concluded that although hereditary platelet function defects constitute a large majority of women bleeders in India but among the coagulation defects, vWD is the commonest as reported from the caucasian population. It is thus suggested that in women presenting with menorrhagia, screening tests for haemostasis especially for vWD and inherited platelet function defects must be performed.
Haemophilic arthropathy of the hip in children – prognosis and long‐term follow‐up
Authors: Wallny T. , Brackmann H. H. , Seuser A. , Diedrich O. , Kraft C. N.
Published: March 2003

Summary.  The aim of this study was to report on the long‐term follow‐up of haemophilic children with avascular femoral head necrosis and to determine whether radiographic findings at initial diagnosis have any prognostic value. Seven patients with avascular necrosis of the femoral head were clinically and radiographically observed over a period of 5–50 years. The average age of patients at first diagnosis was 7.1 years. At follow‐up, three of seven patients claimed to have occasional mild pain in the affected hip, four of seven showed loss of range of motion in the hip joint and two of seven patients showed a limp. Only one patient was clinically completely inconspicuous. The radiographically measured caput–collum–diaphysis angle at follow‐up was pathologic in four cases and in one case a lateral subluxation of the femoral head was found. There was marked deformation of the femoral head in three of seven cases and a further two hips showing slight incongruency. Owing to the small patient‐number, a statement concerning the prognostic value of defined radiographic signs cannot be made. As expected, the more ‘risk signs’ radiographically found, the higher the likelihood that patients will suffer arthrosis at a later stage. We propose that a clear distinction between haemophilic arthropathy of the hip and Legg–Calvé–Perthes disease should be made. In cases where radiographic changes are also found in the vicinity of the acetabulum, it is indicative for haemophilic arthropathy.
Monitoring forest degradation in tropical regions by remote sensing: some methodological issues
Authors: Lambin Eric F.
Published: March 2003

Key issues related to the monitoring by remote sensing of open forest degradation in a tropical context are discussed. Degradation of forest‐cover is often a complex process, with some degree of ecological reversibility and a strong interaction with climatic fluctuations. Only a representation of land cover as a continuous field of several biophysical variables can lead to an accurate detection of forest degradation. For this purpose, repetitive measurements of spectral, spatial and temporal indicators of the land surface have to be performed. Each set of indicators brings a specific type of information on the land cover. These indicators must therefore be combined to achieve a comprehensive description of the surface processes. The detection of inter‐annual changes in landscape spatial structure is more likely to reveal long term and long lasting land‐cover changes, while spectral indicators are more sensitive to fluctuations in primary productivity associated with climatic fluctuations. Different monitoring systems may be optimal for different ecosystems. A long time series of observations is always required. The monitoring of the spatio‐temporal distribution of biomass burning may also give indications of open forest degradation.
Rainfall and topo‐edaphic influences on woody community phenology in South African savannas
Authors: Shackleton Charlie M
Published: March 2003

Woody community phenology was studied in the central lowveld, South Africa, over a twelve month period at three sites along a rainfall gradient, with both toplands and bottomlands sampled at each site. Each month, individual plants, in replicated samples, were scored into a number of categories describing their phenological state. Position on the rainfall gradient influenced: (1) onset and magnitude of leaf emergence, (2) onset and duration of mature leaves, and (3) the proportion of leafless trees. Generally, the moist site demonstrated earlier leaf growth than the intermediate or arid sites. Emergent and mature leaves were recorded earlier, and in the case of mature leaves, retained longer. Overall, there was a lower proportion of leafless trees during the dry season at the moist site, followed by the semi‐arid site, followed by the arid site. Differences with respect to catenal position were evident for the proportion of trees in winter with mature leaves, and the proportion of trees with senescent leaves. Bottomlands had a greater proportion of trees with leaves during winter, but a lower proportion of trees recorded with senescent leaves. Both of these findings were a result of the greater proportion of evergreen species in bottomlands, as well as increased leaf retention by the deciduous species. Phenological activity of leaves was related to plant stem size. In particular, there was greater leaf retention during the dry period by small stems, relative to large stems.
Toll‐like receptors: their role in allergy and non‐allergic inflammatory disease
Authors: Sabroe I. , Parker L. C. , Wilson A. G. , Whyte M. K. B. , Dower S. K.
Published: March 2003

The human TLRs comprise an important and interesting group of receptors that regulate pathogen‐related responses, and play as yet uncharacterized roles in the amplication of sterile inflammation. Signalling through these receptors, which are powerfully coupled in gene transcription processes, has powerful immunostimulatory and immunomodulatory effects. Exploitation of TLR signalling will probably lead to novel effective therapies for allergic disease, in the first instance through more efficient mechanisms of immunotherapy. The likelihood of adverse consequences of such treatments, though possible, may be minimized by use of conjugated vaccines.
Granulomatous slack skin
Authors: Pai Kanthilatha ,   md, Rao Ravikala ,   md, Devadiga Rama ,   dvd, Shenoi Shrutakirthi ,   md,   dvd, Pai Sathish ,   md,   dvd
Published: March 2003

A 32‐year‐old man presented with multiple subcutaneous swellings of 6 years' duration. A biopsy performed 6 years earlier, when the patient presented with papules and plaques, was reported as tuberculoid Hansen's disease. The patient received dapsone, but showed no improvement. The disease was progressive. The patient currently has bilateral parotid enlargement ( Fig. 1), enlarged submandibular, submental, and axillary lymph nodes, multiple subcutaneous swellings over the axillae and arms of cricket ball size, loose skin folds in the axillae (
Fig. 2) and groin, and dry, scaly, and ichthyotic skin all over the body. Clinical differential diagnoses of mycosis fungoides and cutis laxa were made. The patient was discharged on request and then was lost to follow‐up.

Patient with bilateral parotid enlargement

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Patient showing loose skin folds in axillae

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Biopsies taken from the axillary fold, right arm, and face revealed dense infiltration of the dermis and subcutis by aggregates of small lymphocytes, some exhibiting nuclear convolutions along with one or two Langhans‐type giant cells ( Fig. 3). A few giant cells showed evidence of lymphophagocytosis. Blood vessel walls were infiltrated by lymphocytes. Epidermotrophism was seen in biopsies from the arm and face (Fig. 4). There was partial loss of elastic fibers in the dermis. A histopathologic diagnosis of granulomatous slack skin (GSS) was made.

Photomicrograph showing dense infiltration of the dermis and subcutis by lymphoid aggregates with one or two Langhans‐type giant cells. Epidermotropism was also noted (hematoxylin and eosin, × 10)

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The Californian urban butterfly fauna is dependent on alien plants
Authors: Shapiro Arthur M.
Published: March 2003

Abstract. Using the unusually well‐documented butterfly fauna of Davis, Yolo County, California, it is shown that the mainly native species commonly observed in gardens breed mostly or entirely on alien plants, especially naturalized weeds. Over 40% of the fauna has no known native hosts in the urban–suburban environment. Were certain alien weeds to be eradicated or their abundance greatly reduced, the urban‐suburban butterfly fauna would disappear. This might be regarded as an unfortunate, and perhaps intolerable, side‐effect of such programs.
‘It’s the best of two evils’: a study of patients’ perceived information needs about oral steroids for asthma
Authors: Stevenson Fiona A. , Wallace Gwen , Rivers Peter , Gerrett David
Published: March 2003

Objectives To explore the sources of patients’ knowledge about the potential side‐effects of oral steroids prescribed to treat asthma.

Methods Seventeen in‐depth interviews were conducted with patients taking prescribed oral steroid medication (prednisolone) for asthma. The interviews were transcribed verbatim and the data organized according to common themes.

Results All the respondents acknowledged they had no choice but to take oral steroids but they wanted to be informed about the potential side‐effects. Respondents reported that they had not received sufficient information about side‐effects from their general practitioner (GP). Information was sought from both medical sources (pharmacists and asthma nurses) and non‐medical sources (friends and family, self‐help groups and the media) to supplement their knowledge. The conclusions drawn about the risks of taking oral steroids were also influenced by respondents’ existing beliefs.

Conclusions Respondents drew upon information about oral steroids from a variety of professional and lay sources. The findings add weight to calls for doctors and patients to share their respective knowledge in consultations. Developing an understanding of the views of GPs about the provision of information about side‐effects would help to identify any perceived barriers to a more open exchange of information in the consultation.
Decision‐making role preferences and information needs: a comparison of colorectal and breast cancer
Authors: Beaver Kinta , Bogg Janet , Luker Karen A.
Published: March 2003

Objective An exploratory study has been carried out to examine decision‐making role preferences and information needs for a sample of people with colorectal cancer (n=48). The work replicated a larger study carried out for women with breast cancer (n=150), and this paper compares and contrasts findings for both disease groups.

Design A cross‐sectional design was employed, involving structured interviews. The main variables investigated were decision‐making preference (using a decisional role preference card sort), perceived decisional role and information need (using an information needs questionnaire).

Results The majority (78%) of the colorectal cancer patients preferred to play a passive role in decision making, in contrast to 52% of women with breast cancer in previous work. Eighty per cent of the colorectal sample and 61% of the women with breast cancer perceived that the doctor had made treatment decisions. Priority information needs for both groups related to cure, spread of disease and treatment options.

Conclusions The two most striking findings from the comparison between the two disease groups relate to the differences in decision‐making role preferences and the similarities in information needs. The process of involving people with colorectal cancer in treatment decision making warrants further investigation. The similarity in information needs of the two disease groups has implications for health care professionals providing information to people with cancer.