bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical management of endosalpingiosis with tubovaginal fistulization after hysterectomy by a combined laparoscopic‐vaginal route, and histological findings
Authors: Fleckenstein Georg , Heyl Wolfgang , Brinck Ulrich , Pauer Ulrich , Viereck Volker , Emons Günter
Published: March 2003

Background

Isolated endosalpingiosis with vaginal fistulization after histerectomy is an extremely rare event.

Case

We present the interesting case of a female patient with persistent ‘menstrual bleeding’ after an abdominal hysterectomy. The cause was found to be an isolated endosalpingiosis with vaginal fistulization. Postoperative confirmation of the presumptive diagnosis was obtained by seamless histomorpholgical analysis of the tube and fistula and surrounding tissue. The situation was managed using a combined laparoscopic‐vaginal approach.

Conclusion

The cyclic occurrence of vaginal bleeding after hysterectomy should by clarified endoscopically.
Open laparoscopy utilizing either a 5 mm or 10 mm standard intra‐umbilical trocar
Authors: Gordon Simon J. , Maher Peter J. , Seman Elvis I.
Published: March 2003

To describe a technique for open entry for laparoscopic procedures, utilizing either a standard 5‐ or 10 mm trocar through an 8‐ or 12 mm intra‐umbilical incision, respectively.

Two teaching hospitals.

A total of 237 patients. The first 186 patients had a 10‐mm trocar inserted, and the latter 51 patients a 5‐mm trocar entry.

The average time required to achieve pneumoperitoneum was 3.5 min with no complications encountered. Gas leakage overall occurred in 4.2% of patients, though in no case was remedial fascial suturing required. There were two cases of wound infection (0.8%), including an infected umbilical haemotoma. All minor complications occurred in the first 20 patients undergoing surgery.

Open laparoscopy using this technique is safe, quick, and cosmetically excellent with minimal complications and no major disadvantages. It provides an improved safety margin for vascular injury in comparison to closed peritoneal entry, though it is theoretically capable of causing type II visceral injuries.
Fragmentation of a disposable trocar during laparoscopy
Authors: Cosson Michel , Hautefeuille Jerome , Querleu Denis
Published: March 2003

Objective

To report a case of breakage of the tip of a disposable trocar in the course of laparoscopic surgery, and to seek to establish the causes of the incident, analyse the incident itself, and to attempt to draw conclusions, in order to prevent recurrences.

Results

This was an generally difficult laparoscopic procedure in an obese patient, but no notable incident occurred. Towards the end of surgery, we noticed the presence of small plastic fragments and saw that the 10‐mm disposable trocar was broken at its tip. Because it would be difficult to locate the small clear fragments, even if the abdomen were incised, and despite the fact that the fragments were sharp, we decided not to convert to laparotomy. We retrieved as many fragments as possible via laparoscopy. The postoperative course was completely normal.

Conclusions

The case illustrates the actual occurrence of a theoretical risk. In order to reduce the risk to a minimum, impacts between plastic trocars and metallic instruments should be avoided. Despite the lack of reaction from the manufacturers, it may be useful to raise the standard of robustness demanded for this product.
Hysteroscopic and immunohistochemical findings in endometrial lesions unresponsive to medroxyprogesterone acetate: a report on four cases
Authors: Maia Hugo , Maltez Amélia , Fahel Paulo , Oliveira Maíta , Athayde Célia , Coutinho Elsimar
Published: March 2003

Objective

This is a case report showing an association between c‐erbB2 over‐expression in the endometrium and lack of response to progesterone.

Patients and methods

Determinations of oestrogen and progesterone receptors by immunohistochemistry were carried out in four patients with endometrial lesions that did not respond to the administration of progestins, and results were correlated with the presence of c‐erbB2 over‐expression.

Results

The presence of c‐erbB2 over‐expression in the endometrium was associated with a lack of response to progesterone even in the presence of receptors for this hormone.

Conclusion

The presence of c‐erbB2 over‐expression in the endometrium may be an early event in the development of some forms of atypical complex hyperplasia or carcinoma that may not regress with progesterone treatment.
Tensile strengths of extracorporeal slip knots tied with poliglecaprone and polydioxanone
Authors: Ind Thomas , Chou Danny , Lam Alan , Carlton Mark
Published: March 2003

To compare the tensile strengths of commonly used extracorporeal slipknots when tied with poliglecaprone and polydioxanone.

The tensile strength of seven extracorporeal slip knots and the flat square knot were tested using a tensiometer. Knots were tied in random order with 2/0 poliglecaprone and polydioxanone. The study was designed to demonstrate a 5‐newton difference in knot strength with 95% confidence at 80% power. Five knots were studied in each arm of the experiment.

A laboratory experiment.

Force required to break or cause slippage of knots.

Knots tied with polydioxanone had a marginal yet significantly stronger tensile strength of 2.3 N (95% CI 0.1–0.75 N, P = 0.0332). The Tayside, Blood, Hutchon and Western knots had lower tensile strengths than the flat square knot in both poliglecaprone and polydioxanone. The modified Roeder knot was also stronger than the other ligatures when tied in poliglecaprone and more secure than the Western and Tayside knots when tied in polydioxanone.

Slip knots tied in poliglecaprone are marginally less strong than those tied in polydioxanone. No extracorporeally tied slip knot is stronger than the modified Roeder knot.
Hysteroscopic uterine septum incision: is endometrial preparation mandatory to reduce operative complications and failure?
Authors: Simsek Tayup , Uner Mine , Trak Bilal
Published: March 2003

Objective To evaluate the effect of preoperative endometrial preparation on operative complications and failure rate in hysteroscopic uterine septum incision.

Design Prospective study.

Setting Department of Obstetrics and Gynaecology, Akdeniz University School of Medicine.

Subjects 46 patients with septate uteri were enrolled into the study. In 34 patients incision of the septum was done without endometrial preparation with gonadotrophin‐releasing hormone analogues or progestins, for example, and in 12 patients there was preoperative suppression of the endometrium. Operative complications were recorded and the patients underwent hysterosalpingography after the operation, to evaluate the endometrial cavity. The two groups were compared for operative complications and failure.

Results The mean age was 29.2 (range 22–42) and the mean parity was 1.4 (range 0–5). Hysteroscopic incision of the septum was successful (providing an adequate endometrial cavity) in all patients. Operative complications occurred in three patients (6.5%). No statistically significant difference was found between the two groups with regard to operative complications or failure.

Conclusion Preoperative endometrial preparation for reduction of operative complications and failure rate is not necessary.
Hysteroscopic resection of submucous fibroids: clinical analysis of 99 cases
Authors: Feng Zuan Chong , Shi Yong Peng , Liu Su Ping
Published: March 2003

Objective To evaluate the efficacy of hysteroscopic resection of submucous fibroids.

Design A retrospective study of 99 cases.

Setting Shanghai Institute of Planned Parenthood Research, Shanghai First Maternity and Infant Health Hospital and the Shanghai Jiading Gynaecological Endoscopy Centre.

Subjects The study included 99 patients with submucous fibroids. Out of these, 84 had menorrhagia, 13 had menorrhagia with irregular bleeding and two had postmenopausal bleeding.

Interventions Transcervical hysteroscopic resection was used to treat submucous myoma in all patients on one or two occasions. All patients were followed up, for between 6 months and 6 years. Those patients who desired a child underwent hysteroscopic tubal catheterization and hydrotubations to check whether the shape of the uterine cavity recovered after surgery.

Results In 94 out of 99 patients, the menstrual pattern became normal; five patients remained hypermenorrhoeic. Two patients were treated with endometrial ablation using a thermal balloon, because of retained myoma within the uterine wall and persistent hypermenorrhoea. Both of these patients experienced hypomenorrhoea for more than 12 months. Only one patient required hysterectomy after 34 months, because of a retained intramural myoma, which had enlarged and caused a recurrence of her menorrhagia. Seven out of the 12 women who desired a child became pregnant.

Conclusion Hysteroscopic resection is an effective method for the treatment of submucous fibroids and could replace hysterectomy for some patients. It can shorten the operation time and patients can recover more quickly. For those patients who desire a child, this technique is not only organ‐sparing, but also avoids the intra‐abdominal adhesions induced by laparotomy.
Heamoperitoneum caused by heamorrhagic corpus luteum in a patient with type 3 von Willebrand’s disease
Authors: Gomez  , Lucia  , Perella  , Aguilar
Published: March 2003

In female patients affected by congenital coagulation disorders heamorrhagic corpus luteum must be considered for the differential diagnosis of acute abdomen. We report the complication in a 22‐year‐old woman with type 3 von Willebrand’s disease who presented with abdominal pain and heamorrhagic shock. Along with adequate factor VIII replacement therapy oral contraceptive treatment is the key for the management of this potentially life‐threatening complication and the long‐term prevention of future bleeding episodes of this origin.
Development of a subdural vein thrombosis following aggressive factor VII replacement for postnatal intracranial haemorrhage in a homozygous factor VII‐deficient infant
Authors: Worth L. L. , Hoots W. K.
Published: March 2003

Congenital factor VII deficiency is a rare (1:500 000) autosomally recessive coagulopathy with variable expression and high penetration. In infants the most devastating presentation is that of intracranial haemorrhage. An infant is described with severe factor VII deficiency who developed post‐natal intracranial haemorrhage. The baby was treated with factor VII concentrate (ImmunoA.G.) ViennaAustria). Three weeks after the haemorrhage he developed a dural venous sinus thrombosis. Although factor VII‐deficient patients may need treatment with factor VII concentrate this needs to be carefully monitored because of the thrombotic risk.
The molecular basis of haemophilia A
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , PEAKE IAN
Published: March 2003

Summary. The cloning and isolation of the human factor VIII (FVIII) gene in the mid‐1980s has lead to 10 years of increasing understanding of the genetic and hence the molecular basis of haemophilia A. These studies are not only of enormous potential benefit for accurate carrier detection and prenatal diagnosis in families with haemophilia A, but provide insights into the relationships between genetic defects and their clinical manifestations. These latter studies not only explain and even predict the severity of the disease but may also help towards a better understanding of the basis of inhibitor development.
Can we improve on nature?“Super molecules” of factor VIII
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , KAUFMAN R. J. , PIPE S. W.
Published: March 2003

Summary. Treatment of heamophilia A requires frequent infusion of plasma‐ or recombinant‐derived factor VIII. This regimen is limited due to the high cost and inconvenient access to peripheral veins. In addition, patients frequently develop inhibitory antibodies that limit available therapeutic regimens. Two major advances in factor VIII research over the past 15 years were the ability to isolate homogeneous preparations of factor VIII and the isolation of the factor VIII gene that provided for a detailed biochemical and structural characterization of the factor VIII molecule. With an increased understanding of the requirements for factor VIII function, studies have attempted to produce improved factor VIII molecules for replacement therapy. These findings have produced forms of factor VIII that are more efficiently produced, that are less immunogenic, and that have higher specific activity. The future will see the engineering of novel factor VIII molecules with increased therapeutic efficiency while minimizing inhibitor antibody development. In addition, there are now structural models of factor VIII available that should in the future direct development of novel peptidomimetics that may eventually overcome the requirement for replacement therapy with factor VIII protein.
Novel delivery systems for coagulation proteins
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , MIEKKA S. I. , JAMESON T. , SINGH M. , WOOLVERTON C. , LIN H.‐M. , KRAJCIK R. , MACPHEE M. , DROHAN W. N.
Published: March 2003

Summary. Long‐term haemophilia prophylaxis with clotting factors administered by alternative delivery modes requires stable liquid formulations of these factors. We developed an aqueous‐formulated human coagulation factor IX (hCFIX) with in vitro half‐life (T1/2) of 6 weeks at 37°C and 18 months at 4°C. Upon bolus subcutaneous (SC) injection in animals, hCFIX had a bioavailability of up to 16% compared to intravenous (IV) dose. When delivered by SC implanted pumps, hCFIX attained >2% of normal human levels in the animal plasma. Hydrogels of hCFIX in a chitosan derivative, N,O‐carboxymethyl chitosan (NOCC), released hCFIX slowly in vitro, and when injected SC, gave prolonged plasma levels over those obtained by bolus IV or SC injection. Freeze‐dried human coagulation factor VIII (hCFVIII) formulated in non‐aqueous solvents had in vitro T1/2 up to 80 days at 37°C.
Haemophilia and advanced fibrin sealant technologies
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , TOCK B. , DROHAN W. , HESS J. , PUSATERI A. , HOLCOMB J. , MACPHEE M.
Published: March 2003

Summary. Fibrin sealant, which consists mainly of fibrinogen and thrombin, provides rapid haemostasis as well as tissue sealing and adhesion. Commercial, viralinactivated products are available in Europe, Canada, and Japan. Liquid fibrin sealant (LFS) has been used clinically in haemophiliacs to perform dental procedures, orthopedic surgeries, non‐orthopaedic surgeries, and circumcisions. LFS use is expected to increase as commercial products will soon be available in the US. Recombinant sources and transgenic animal bioreactor systems will replace plasma‐derived products and become the predominant sources for this product in the next decade. Other areas of innovation include the development of fibrin sealant bandages or dressings, expandable foams, and spray powders which will provide the haemophiliac the ability to rapidly attain control of traumatic haemorrhages prior to hospital treatment with a significant reduction in the use of IV clotting factors. Fibrin sealant products have the potential to provide life‐saving control of haemorrhage, reduction in factor dependency, lower viral exposure risk, and medical care cost reduction.
The natural history of the immune response to exogenous factor VIII in severe haemophilia A
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , SCANDELLA D. , MONDORF W. , KLINGE J.
Published: March 2003

Summary. The development of inhibitory antibodies to factor VIII (fVIII) in severe haemophilia A patients is a serious therapeutic complication. Using a highly sensitive immunoprecipitation (IP) assay which measures all anti‐fVIII antibodies, we have tested severe haemophilic plasmas from two clinical studies. Inhibitor titres in the range of 0.4 to 1 Bethesda units/ml (BU/ml) could not be verified by IP as being due to an immune response to fVIII in 35% of plasmas tested. Low fVIII recoveries were likewise correlated with the presence of antibodies in 29% of plasmas tested. However, 16% of plasmas without inhibitor titres had immune responses as measured by IP. The rapidity of antibody appearance did not allow their effective detection by IP before development of inhibitor titres. These results suggest that the IP assay can provide a valuable confirmation of anti‐fVIII antibody production when the Bethesda assay is low or negative and where clinical observations suggest their presence, but they cannot be used reliably to detect early immune responses.
HIV treatment — a rational approach to the use of antiretroviral agents
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , VELLA S.
Published: March 2003

Summary. Over the last 2 years, advances in many areas of HIV clinical research and data on the effectiveness of potent combination therapy have substantially influenced the overall perspective of long‐term management of HIV disease. However, the progress against HIV also came as a result of the better understanding of HIV pathogenesis. Research work in basic science has contributed considerably to obtain a clearer picture of the mechanisms of HIV infection, mainly through the understanding of key steps in the dynamics and kinetics of viral replication in vivo. Molecular biology also revealed much about the mechanisms of HIV virulence and the emergence of drug resistance. This article will give a short overview of the most recent advances in the field.
Influence of phospholipids on the assessment of factor VIII activity
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , MIKAELSSON M. , OSWALDSSON U. , SANDBERG H.
Published: March 2003

Summary. In view of reported discrepancies between different factor VIII assays, the influence of phospholipids on the performance of one‐stage clotting (OS) and chromogenic substrate (CS) assays was evaluated. The B domain deleted recombinant factor VIII, rVIII SQ, two full‐length recombinant products and a plasma derived factor VIII concentrate were each diluted into severe haemophilia A plasma and assayed against a plasma standard. The one‐stage activity was 50, 80, 75 and 106%, respectively, of the chromogenic result. Variations in the phospholipid concentration did not affect the chromogenic assay, except at very low levels where the apparent activity increased. In contrast, dilution of the phospholipid reagent had a substantial influence on the activity measured by OS assays, especially in the case of rVIII SQ. At low levels of phospholipid, the one‐stage activity of rVIII SQ exceeded the chromogenic result. When mixtures of phosphatidylserine (PS) and phosphatidyl‐choline (PC) were used as a source of phospholipid, the OS results for rVIII SQ agreed well with the CS activity as long as the content of PS was below 10%, i.e., closer to the physiological level. At higher levels of PS, as in most commercial APTT reagents, the OS activity decreased. When the APTT reagent was replaced by platelets in the OS assay, the results compared well with those obtained by the CS assay for both t‐VIII SQ and full‐length factor VIII products.
Haemophilia B Brandenberg‐type promoter mutation
Authors: HEIT  , KETTERLING  , ZAPATA  , ORDONEZ  , KASPER  , SOMMER
Published: March 2003

We report the second confirmed case of the haemophilia B `Brandenberg' phenotype. At the time of testing, patient HB530 was a 17‐year‐old post‐puberty male with a persistent, clinically severe bleeding disorder and markedly reduced plasma procoagulant factor IX activity (< 1%). Sequencing studies revealed a G→A transition at bp − 26 within the promoter region of the factor IX gene. This case report confirms the observation that not all patients with promoter mutations improve after puberty and supports the hypothesis that bp − 26 is a critical binding site within the factor IX gene promoter region for both constitutive as well as androgen‐inducible transcription factors.
Pharmacokinetics and acute tolerance of a double virus inactivated plasma derived factor VIII concentrate
Authors: Saez  , Bosh  , Boadas  , Arguello  , Horvat  , Dinapoli  , Lisciani
Published: March 2003

To further reduce the risk of possible viral disease transmission, an additional virucidal step was performed in the manufacturing process of a solvent/detergent treated factor VIII concentrate, which consisted of heating the lyophilized preparation at 100 °C for 30 min (Emoclot DI®; ISI, Italy). Because thermal treatment may modify factor VIII bioavailability, the pharmacokinetic parameters and the acute tolerance of the single viral inactivated concentrate (preparation A) were compared with that of the double viral inactivated one (preparation B). Fifteen patients with severe haemophilia A and positive for HAV Ab were enrolled in a double‐blind cross‐over study and injected with 32.5 IU kg−1 of preparation A and 27 IU kg−1 of the preparation B. No significant differences between terminal half‐life, area under the curve/dose, clearance/kg, volume of distribution at the steady state, in vivo recovery and acute tolerance of the two preparations was observed. The only statistical difference was restricted to Cmax.
Efficient adenoviral vector transduction and expression of functional human factor VIII in cultured primary human hepatocytes
Authors: Andrews  , Weaver  , Kaleko  , Connelly
Published: March 2003

Hemophilia A is a severe bleeding disorder caused by a deficiency in blood coagulation factor VIII (FVIII). Adenoviral vectors containing a potent human FVIII expression cassette encoding a truncated FVIII cDNA were developed that mediated sustained FVIII expression in normal and haemophiliac mice and complete phenotypic correction of the bleeding disorder in haemophiliac mice and dogs (Connelly and Kaleko, Haemophilia, 1998; 4: 380–8). Here, we evaluated two E1/E2a/E3‐deleted adenoviral vectors encoding human FVIII, one containing the full‐length cDNA and the second containing a truncated cDNA lacking the B‐domain. Viral vectors encoding the human full‐length FVIII cDNA have not been described previously. Hepatocyte transduction was efficient and dose dependent, ranging from 50% to 100%. High levels of functional FVIII were secreted from transduced cells at amounts up to 6000 mU−1 106cells−1 60 h. B‐domain deleted FVIII was expressed at levels at least 8‐fold higher than the full‐length FVIII protein, whereas FVIII RNA levels were similar with both vectors. These data provide the first demonstration of FVIII adenoviral vector function in primary human cells and verify the potential clinical utility of adenoviral vectors for the treatment of haemophilia A.
Kinetics of factor IX activity differ from that of factor IX antigen in patients with haemophilia B receiving high‐purity factor IX replacement
Authors: Liebman  , Rosenwald‐Zuckerman  , Retzios  , Yasmin  , Kasper
Published: March 2003

Pharmacokinetic studies in haemophilia B have found in vivo recovery of FIX (FIX) to be uniformly lower than the factor VIII recovery in haemophilia A. We hypothesized that this lower recovery could result from rapid binding to high‐affinity receptors on platelets and endothelium. To test this hypothesis, we evaluated the kinetics of FIX activity and protein in haemophilia B patients. Twelve patients were enrolled in a double dosing, crossover study with two high‐purity FIX concentrates, AlphaNine® SD and MonoNine®. Subjects were given 40 U kg–1 of FIX concentrate and blood samples were taken at 15, 30, and 60 min. A second infusion of 40 U kg–1 was given after the 60 min blood sample and further blood samples removed at 15, 60, 120, and 360 min after the second dose. Patients were infused with the alternate concentrate at least 7 days later. Plasma samples were assayed for FIX activity by coagulation assay and antigen by RIA. FIX antigen in the infused concentrates was measured and quantified as μg U–1. There was no difference between the two FIX concentrates (AlphaNine® vs. MonoNine®) in the initial (15 min) activity (57% ±1 19% vs. 53% ±1 12%) and antigen (62% ±1 16% vs. 55% ±1 19%) recoveries. Recoveries after the second FIX dose were not statistically different than those observed after the first FIX dose. In one patient, a doubling of the initial infusion dose did not increase FIX recovery after the second FIX dose. However, the recovery of FIX antigen was significantly greater than the recovery of FIX activity and the differences became more significant in the post‐15 min samples. We calculated a ratio of plasma FIX antigen to FIX activity in μg U–1. Average antigen to activity ratio increased from 5.8 ±1 1.9 μg U–1 at 15 min to 7.1 ±1 2.2 μg U–1 at 60 min. At 420 min the ratio increased to 9.3 ±1 2.4 μg U–1. Although these studies failed to demonstrate a significant FIX receptor pool, they did demonstrate a phenomenon of progressive loss of biologic activity of the FIX protein after infusion of FIX concentrates.
Use of recombinant factor VIIa (NovoSeven) in a haemophilia A patient with inhibitor in Kuwait
Authors: Kanyike  , Abdul–salam  , Prakash  , Sharhan  , Wahib  , Youssef
Published: March 2003

Development of inhibitors is a known complication in some haemophiliacs receiving coagulation factor replacement therapy. We report on the successful management of a young boy with haemophilia A with inhibitor using recombinant factor VIIa. We had failed to control bleeding in this patient following his circumcision, despite infusion with high doses of factor VIII concentrate for 2 weeks. Recombinant factor VIIa is a useful ‘factor VIII bypassing agent’ for the control of bleeding in patients with haemophilia A and B who develop inhibitors. We suggest that severely affected haemophiliacs should be absolved of ritual circumcision as a protective measure against what might become a life‐threatening haemorrhage – especially in those with inhibitors.
Expanding portal haematomata as a complication of knee arthroscopies in persons with haemophilia
Authors: Heim  , Israeli  , Varon  , Chechic  , Engelberg  , Martinowitz
Published: March 2003

Recurrent haemarthroses stimulate the hypertrophy of synovial tissues that if left in situ will eventually cause joint destruction. Synovectomies have been the cornerstone of joint preservation and a number of different methods exist. We report two patients who suffered complications after an arthroscopic procedure. No previous complications of this nature have been reported in the literature.
Safety and efficacy of high‐purity concentrates in haemophiliac patients undergoing surgery by continuous infusion
Authors: Tagariello  , Davoli  , Gajo  , De Biasi  , Risato  , Baggio  , Traldi
Published: March 2003

In this study we explore the feasibility of high‐purity double‐inactivated concentrates by continuous infusion for the treatment of haemophiliacs in a group of patients undergoing different surgical procedures. The patients were enrolled in the study on the basis of their transfusion history, which was well known due to their long‐term follow up at our Haemophilia Center. We did not perform a pre‐operative pharmacokinetic study because one of the aims of this study was to demonstrate that continuous infusion can become a first choice standard treatment in patients with haemophilia. Fourteen haemophilia A and one haemophilia B patients who needed at least 5 days of replacement therapy were monitored for haemostatic efficacy, post‐operative factor VIII and factor IX levels and evaluated for safety and flexibility of the products.

The infusion rate of 3 IU kg–1 h–1 was demonstrated to be sufficient to ensure haemostasis and patients did not need additional bolus infusion during the post‐operative period. Our study demonstrates the safety and feasibility of high‐purity concentrates in patients undergoing surgery by continuous infusion, also in the absence of a previous pharmacokinetic study.
Severe haemophilia A in a female: a compound heterozygote with nonrandom X‐inactivation
Authors: Seeler  , Vnencak‐Jones  , Bassett  , Gilbert  , Michaelis
Published: March 2003

We report a case of severe haemophilia A (<1% factor VIII level) in a female resulting from an interesting and improbable combination of events. The patient inherited a factor VIII intron 22 inversion from her carrier mother, as well as a second factor VIII inversion involving intron 22 that arose de novo on her paternally derived X chromosome. In addition, the patient’s paternally derived X chromosome had been preferentially inactivated in 95+% of her somatic cells. The patient’s mother, who was clinically unaffected, carried an intron 22 inversion as well and also showed nonrandom X‐inactivation. The patient’s mother had a brother with severe haemophilia A. It is therefore likely that the mother’s inversion was on her maternally derived X chromosome. Since she was unaffected, it is likely that her inversion‐bearing X was the one that was preferentially inactivated.
Diagnosis of von Willebrand Disease
Authors: Ingerslev J. , Gürsel T.
Published: March 2003

The haemorrhagic diathesis in von Willebrand disease (vWD) is caused by a quantitative deficiency or a qualitative defect in the von Willebrand factor (vWF) in plasma and/or platelets causing insufficient primary haemostasis. Since vWF binds and protects factor VIII (FVIII) towards random proteolysis, coagulation may also be impaired in patients with a low plasma level of vWF, and in instances where vWF displays insufficient binding capacity to FVIII. The entity of vWD displays a vast heterogeneity. Apart from rarely occurring acquired cases, vWD is an inherited disorder of autosomal linkage. The major clinical hallmark in vWD is an increased tendency to mucocutaneous bleeding that rarely reach life‐threatening proportions, unless vWF is severely reduced or completely absent. Increased bleeding may also occur in sites such as muscles and joints when the level of FVIII is particularly low.

Significant progress has recently been achieved through extensive molecular genetic exploration of various forms of vWD. In order to guide treatment and to form a platform for genetic investigation, however, accuracy in diagnosis and phenotypic characterization is important. By means of various laboratory methods, major subclasses of vWD can be differentiated, as presented in another article of this series. Whereas most of the cases of vWD can quite easily be diagnosed and classified using today’s diagnostic methods, the most frequently occurring bleeding disorder of all, vWd type 1 of mild degree, continues to challenge clinicians and diagnostic laboratories. The aim of this paper is to review the laboratory methods most commonly used in diagnostic investigation of the patient suspected of vWD.
Effect kinetics of desmopressin‐induced platelet retention in healthy volunteers treated with aspirin or placebo
Authors: Lethagen  , Olofsson  , Frick  , Berntorp  , Björkman
Published: March 2003

Desmopressin is often used for haemostatic treatment in platelet dysfunction, but the effect kinetics of platelet responses and the mechanism of action are poorly known. This study aimed to determine the kinetics of platelet function responses induced by desmopressin in healthy volunteers treated with aspirin or placebo. Another aim was to correlate platelet responses to changes of von Willebrand factor (vWF) in plasma. We measured platelet function with a glass bead retention test, Ivy bleeding time, vWF:Ag and multimeric structure in plasma. Median baseline platelet retention was 12% (normal reference range 16–27%) during aspirin treatment and 18% during placebo. Median peak platelet retention after desmopressin was 33% during aspirin treatment and 34% during placebo. After about 3 h platelet function had returned to baseline. A second desmopressin dose after 3 h stimulated platelet retention to a similar extent as the first dose. There was no correlation between platelet responses and quantitative or qualitative changes of vWF in plasma. Platelet count did not change significantly. Thus, desmopressin’s effect on platelet function lasts for about 3 h, but may be prolonged by a second dose immediately thereafter. These findings may have important clinical implications for patients with aspirin‐induced platelet dysfunction undergoing surgery.
Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with Haemophilia
Authors: Ragni  , Lusher  , Koerper  , Manco‐Johnson  , Krause
Published: March 2003

Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection through exposure to blood products. Havrix®, an intramuscular hepatitis A vaccine, is currently recommended for the prevention of disease caused by hepatitis A virus. Because bleeding may complicate intramuscular injections in those with bleeding disorders, we conducted a randomized, Phase IV clinical trial to compare the safety and immunogenicity of Havrix® given by the subcutaneous (s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6 months. All children were anti‐HAV and anti‐HIV negative at baseline, and the haemophilic group did not differ from their siblings in alanine aminotransferase (ALT; 25 IU L−1 vs. 22 IU L−1), or in age; 8.5 years vs. 8.7 years. The vaccine was well tolerated, with minor adverse events being similar between groups; 21 (47%) vs. 24 (58%), P > 0.05. Local symptoms included soreness in 39 (45%), erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no differences between groups. The proportion seroconverting to anti‐HAV IgG positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre was lower in those with Haemophilia, 185 vs. 233 mIU mL−1 at month 1; 68 vs. 94 mIU mL−1 at month 6; and 584 vs. 1082 mIU mL−1 at month 8, respectively. We conclude that Havrix® is safe and immunogenic when administered s.c. in children with Haemophilia.
High responding factor VIII inhibitors in mild Haemophilia – is there a link with recent changes in clinical practice?
Authors: White  , Cotter  , Byrne  , O’Shea  , Smith
Published: March 2003

The development of high responding inhibitors is an increasingly recognized complication of mild Haemophilia. Inhibitors tend to develop in adolescence and adulthood and this is frequently preceded by high‐intensity factor replacement therapy. We report two patients with mild Haemophilia who developed high responding inhibitors after continuous infusion with recombinant factor VIII (Kogenate) as prophylaxis for surgery. We discuss whether recent changes in clinical practice could be responsible for the apparent increase in high responding inhibitors in mild Haemophilia.
The history of synoviorthesis in haemophilia
Authors: Gilbert M.S. , Cornwall R.
Published: March 2003

The history of synoviorthesis and recent studies have shown that it is a safe procedure and that the results are similar to those seen following open surgical and arthroscopic synovectomy. If the safety of this procedure is definitively proven in long‐term studies it will become the procedure of choice for treatment of recurrent haemarthroses and synovitis. That is, until the time when the haematologists and geneticists eliminate the need for orthopaedic intervention in the care of persons with haemophilia.
Chemical synoviorthesis with osmic acid in haemophilia
Authors: Ayral X.
Published: March 2003

Based on previous experience in inflammatory arthritis, a small number of open studies have evaluated the usefulness of chemical synoviorthesis with osmic acid in haemophilia, with various assessment criteria and a wide range of follow‐up periods. Based on these studies, the efficacy of osmic acid seems modest, with 30–44% of good clinical and radiological results, but with fair or poor clinical results in other patients with a possible deleterious effect on cartilage. Osmic acid was found inferior to Yttrium‐90 in one retrospective study. Synoviorthesis with osmic acid seems particularly indicated in haemophilic arthritis with no or mild radiological deterioration in children between 8 and 15 years of age. However, prospective randomized studies are clearly required to evaluate the symptomatic and structural effects of chemical and radioactive synoviorthesis in haemophilic arthritis.
Knee joint arthroplasty in a patient with haemophilia A and high inhibitor titre using recombinant factor VIIa (NovoSeven®): a new case report and review of the literature
Authors: Faradji A. , Bonnomet F. , Lecocq J. , Grunebaum L. , Desprez D. , Kern O. , Barbier L. , Sibilia J.
Published: March 2003

Elective orthopaedic surgery is regularly withheld from patients with haemophilia and high inhibitor titre despite the presence of severe arthropathy and urgent medical need. A knee joint arthroplasty was performed in a patient with severe haemophilia A and a high inhibitor titre using recombinant factor VIIa (rFVIIa) as the sole coagulation factor. There was no abnormal bleeding during surgery although an increased blood loss through surgical drains did occur during the first 6 h postoperatively. Rehabilitation was started on day 1 and continued for 3 months. Walking commenced on day 4. After 1 year of follow‐up, the clinical outcome of surgery was considered excellent with no pain, knee mobility at 0–5‐90°, and an International Knee Society score of 95/100. No rFVIIa‐associated side‐effects or thrombotic complications were reported. In conclusion, knee joint arthroplasty is now an option for haemophilia patients with a high inhibitor titre. An international review of all available data on elective orthopaedic surgery in inhibitor patients is required so that the optimal treatment regime can be defined and the short‐ and long‐term risk–benefit ratio of surgery compared to that of noninhibitor patients.
Long‐term follow‐up after intertrochanteric varus osteotomy for haemophilic arthropathy of the hip
Authors: WALLNY T. , BRACKMANN H. H. , HEß L. , SEUSER A. , HOFMANN P. , KRAFT C. N.
Published: March 2003

In view of an increasing tendency in prosthetic management of haemophilic arthropathy, we intended to evaluate the efficacy of corrective osteotomy of the hip, specifically taking long‐term clinical and radiographic results into consideration. Eleven hips affected by haemarthropathy in nine patients suffering from severe haemophilia A were treated with an intertrochanteric varus osteotomy. The average follow‐up period was 15·4 years. The preoperative clinical score of the Advisory Committee of the World Federation of Haemophilia was 5·3 points (range 4–7) and the Pettersson score was 6·4 points (range 2–10). The average WFH score at follow‐up had increased to 3·6 points. Seven hips showed clinical improvement, two hips showed a postoperative deterioration while a further two hips remained unchanged. The Petterson score increased to an average of 7·7 points. Here the radiographs of six patients indicated postoperative deterioration, three remained unaltered and two showed improvement. Our study cannot conclusively answer whether intertrochanteric varus osteotomy for haemophilic arthropathy of the hip is always a feasible alternative to joint arthroplasty. The decision for or against this procedure must be individually assessed and the patient must be thoroughly informed about the advantages and disadvantages of both procedures.
The use of haemostatic drugs in haemophilia: desmopressin and antifibrinolytic agents
Authors: Villar A. , Jimenez‐Yuste V. , Quintana M. , Hernandez‐Navarro F.
Published: March 2003

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.

 By contrast, pharmacological options for the treatment of the haemophilia remain very limited. The only therapeutic alternatives of real practical value which have been available in the last 30 years for the treatment of haemophilic patients are desmopressin, antifibrinolytic agents, aprotinin, concentrated oestrogens, and local haemostatic agents such as topical thrombin or fibrin glue.

 This article aims to assess the pharmacological basis and accumulated experience relating to these drugs when used for the prevention and treatment of bleeding in patients with haemorrhagic disorders.
Desmopressin is not always effective in mild haemophilia Apatients undergoing urological surgery: the need of standardized protocols
Authors: Renom P. , Wibaut B. , Rigot J. M. , Coupez B. , Goudemand J.
Published: March 2003

Summary.  Desmopressin may be an efficient haemostatic treatment for mild A haemophiliacs because its infusion raises plasma factor VIII level. We report the use of desmopressin in five mild haemophilia A patients undergoing urological surgery. They all received a preoperative infusion (0.3 µg kg−1, i.v.) 1 h before incision followed by repeated injections at 12‐ or 24‐h intervals according to the severity of the procedure. Nevertheless, four patients presented a postoperative bleeding requiring again surgery performed for 3 of them under clotting factor concentrate instead of desmopressin. The occurrence of haemorrhage was not always correlated with particularly low plasma factor VIII level. Surgical management of urological procedures with desmopressin in mild haemophilia A patients requires standardized protocols.
Guidelines for the diagnosis and management of von Willebrand disease in Italy
Authors: Federici A. B. , Castaman G. , Mannucci P. M. ,   for the Italian Association of Hemophilia Centers (AICE)
Published: March 2003

Summary.  von Willebrand disease (vWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (vWF). The molecular basis of type 2And 3 vWD are now known and those of type 1 vWD are being understood. Phenotypic diagnosis is based on the measurements of plasma and platelet vWF, of the ability of vWF to interact with platelet receptors and the analysis of the multimeric structure of vWF. Due to the heterogeneity of vWF defects and the variables that interfere with vWF levels, a correct diagnosis of types and subtypes may sometimes be difficult but is very important for therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal intrinsic coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion. Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 70% of cases, because it corrects FVIII–vWF levels and the prolonged bleeding time (BT) in the majority of these patients. In type 3 and in severe forms of type 1 and 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and safe, but they cannot always correct BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of BT after plasma concentrate treatment is associated with continued bleeding.
Treatment of chronic haemophilic synovitis in humans with D‐penicillamine
Authors: Corrigan J. J. , Damiano M. L. , Leissinger C. , Wulff K.
Published: March 2003

Summary. Chronic proliferative synovitis secondary to haemathroses is a major complication in patients with severe haemophilia. Current management strategies include prophylactic infusions of the missing coagulation factor, corticosteroids, synoviorthesis and/or synovectomy with variable degrees of benefit. In addition, patients with coagulation factor inhibitors are not amenable to the invasive therapeutic modalities. The gross and microscopic findings of the synovitis in haemophilic arthritis are remarkably similar to those seen in patients with rheumatoid arthritis, although the pathophysiology of these two conditions are quite different. Haemophilic arthropathy, in the later stages, resembles degenerative rather than inflammatory joint disease. Oral d‐penicillamine, a drug effective in the proliferative synovitis of rheumatoid arthritis, was evaluated in 16 patients. Ten patients had an unequivocal response, while three had a reduction in palpable synovium and three had no response. Thus 81% of the patients had a beneficial response. Minor reversible drug side‐effects occurred in two patients (proteinuria in one and a rash in the second). The results of this study suggest that d‐penicillamine is an effective and safe drug for the treatment of haemophilic chronic synovitis.
Surgery in severe factor XIII deficiency: report of a case of epilepsy neurosurgery and review
Authors: Pernod G. , Barro C. , Arnutti B. , Blanc‐Jouvan F. , Garrel S. , Kahn P. , Minotti L. , Koudsie A. , Benabid A. L. , Wrobleski I. , Joannard A. , Polack B.
Published: March 2003

Summary. Factor XIII (FXIII) deficiency is a rare autosomal recessive congenital disorder of haemostasis, associated with a high risk of intracranial haemorrhage. Intracranial haemorrhage can result in neurological sequelae including seizure disorders. In some cases, medically intractable epilepsy led to epilepsy surgery. Little has been reported on the management of FXIII deficiency during surgery, and there is only a few data on the management, safety and efficacy of epilepsy surgery in the patients with haemostatic disorder. We report here an epilepsy neurosurgery in a case of severe FXIII deficiency.
What causes the vegetation types on Mount Bloomfield,a coastal tropical mountain of the western Philippines?
Authors: Proctor J. , Bruijnzeel L. A. , Baker A. J. M.
Published: March 2003

Mount Bloomfield has been shown to have several vegetation types, including medium stature forest on greywacke, small stature forest on serpentinized peridotite, and scrub and Gymnostoma woodland on dunite. The causes of the large physiognomic and floristic differences among these vegetation types have been investigated by soil chemical analyses, soil physical studies, and by a phytometer experiment involving the crop plant Zea mays. There was no relationship between maximum tree height and the soil chemical factors analysed (P, K, Ca, Mg, Ni) but there was a directly proportional relationship between maximum tree height and soil water retention. The phytometer experiment supported the idea that there is no acute soil toxicity in spite of the high soil Ni and Mg/Ca quotients recorded in this study. It is concluded that soil water retention, perhaps in combination with fire, is the major cause of stature differences among the vegetation types and together with soil chemistry is an important determinant of floristic composition.