bluuebunny/crossref_metadata_2025 huggingface dataset:
Ureteral endometriosis
Authors: Nisolle Michelle , De La Osa Escribano Inigo Lopez , Squifflet Jean , Donnez Jacques
Published: March 2003

Objective

To evaluate the prevalence of ureteral endometriosis and to describe the laparoscopic surgery.

Design

This is a prospective study.

Results

In a series of 306 patients with rectovaginal adenomyotic nodules, preoperative intravenous pyelography revealed ureteral stenosis with ureterohydronephrosis in 14 cases (4.5%). In four patients, complete ureteral stenosis was observed, and kidney scintigraphy revealed damaged kidney parenchymal function varying from 18% to 42%. Laparoscopic ureterolysis was possible in 13 women, and a significant postoperative decrease in ureterohydronephrosis was noted. In only one case, ureteral resection and uretero‐ureterostomy were needed.

Conclusion

In cases of rectovaginal adenomysois more than 3 cm, the prevalence of ureteral endometriosis is high. The preoperative IVP is needed before laparoscopic ureterolysis which will avoid the silent loss of real function.
Human immunodeficiency virus infection in Haemophiliacs in Taiwan: the importance of CD4 lymphocyte count in the progression to acquired immunodeficiency syndrome
Authors: Shen Ming‐Ching , HU FU‐Chang , Lin Jen‐Shiou , Hsie Suan‐Wan , Hung Chien‐Ching , Chung Che‐Yuan
Published: March 2003

From July 1984 to December 1996, we tested and studied 303 haeophilic patients for the infection of the human immunodeficiency virus (HIV). Among the 261 Haemophilia A patients 44 were HIV positive (16.9%), while none of the Haemophilia B patients was HIV positive. The mean age of the 44 HIV‐seropositive patients in 1984 was 20.6 years (2–37 years). Seven who had known seroconversion dates and 29 whose first seropositive dates were known seroconverted before 1986. Acquired immunodeficiency syndrome (AIDS) has developed in 16 patients, nine of whom presented with Pneumocystis carinii pneumonia, three with tuberculosis infection, and 13 had died. The Kaplan–Meier estimate of the progression rate to AIDS after the date of first seropositive test is about 30% at the 10th year. The median survival time after development of AIDS obtained from the Kaplan–Meier estimate of the survival curve was 11.7 months. Statistical analysis for the covariate effects on the risk of developing AIDS by the Cox proportional hazards model revealed that there was a statistically significant negative association of the risk for progression to AIDS with the logarithm of initial CD4 cell counts (P = 0.027) and the rate of decline of CD4 cell counts (P = 0.040), but not with age (P = 0.650). In conclusion, the clinical characteristics of AIDS Haemophiliacs in Taiwan were not different from that observed in western countries. Low initial CD4 cell count and sharp decline in CD4 cell counts, but not age, increased the risk of progression to AIDS.
Haemophilia A: two cases showing unusual features at birth
Authors: Pommelet  , Durand  , Laurian  , Devictor
Published: March 2003

We report two patients with severe Haemophilia A, factor VIII < 2 u dL−1, diagnosed at birth, through isolated bleeding in the adrenal gland (case 1) and through a haeatoma in the liver (case 2). In these two clinical cases, the vital emergency, with haeorrhagic shock, required early diagnosis of the hereditary coagulation defect. Generally at birth, any unexplained bleeding should prompt screening for Haemophilia. In the newborn period, the PTT is inadequate for many reasons and the laboratory evaluation must include factor VIII and IX levels.
Inhibitor development and substitution therapy in a developing country: Turkey
Authors: Kavakli  , Gringeri  , Bader  , Nisli  , Polat  , Aydinok
Published: March 2003

Prevalence of inhibitor in developing countries, such as Turkey, where fresh frozen plasma (FFP) is still in use due to high cost of concentrates, is unknown. To determine the frequency of inhibitors in Turkish Haemophiliacs exposed to blood products, 53 Haemophilia A patients (age range 1–20; median: 11 years) and 12 Haemophilia B patients (age range 3–20; median: 10 years), were evaluated; 31 Haemophilia A patients (23 severe) received plasma‐derived concentrates and 22 patients (10 severe) only FFP. No Haemophilia B patients developed inhibitor, compared with seven of 53 (13%) Haemophilia A patients, all with a severe defect (7/33; 21%) and treated with concentrates (7/23; 30%), whereas severe patients treated with FFP showed a lower risk to develop inhibitors (0/10, P = 0.07). Inhibitors were detected after 8–125 exposure days (median: 52). Intermediate‐purity concentrates and pasteurization seemed to be linked with a higher risk of inhibitor compared to high‐purity concentrates and solvent‐detergent inactivation for seven patients with inhibitor. In four of seven inhibitor patients low‐dose concentrate was administered at 25 IU kg−1 twice weekly and inhibitor disappeared in 1–4 months. This regimen might be recommended for immune tolerance in developing countries for its lower cost.
Total knee and hip arthroplasty in haemophilic patients
Authors: Heeg M. , Meyer K. , Smid W. M. , Horn J. R. Van , Meer J. Van Der
Published: March 2003

We evaluated the long‐term results of three total hip and nine total knee arthroplasties in nine haemophilic patients with disabling pain and end‐stage arthropathy. These patients have been followed over a period of 2–12 years (mean 6.9). One patient had a post‐operative haematoma, which was evacuated; two patients required manipulation of the knee because of a limited range of motion. There were no infections. At follow‐up, all but two patients were completely free of pain; two patients had occasional pain. The functional improvement was impressive with an average increase in the knee score from 37 to 80 points post‐operatively. The hip score increased from 36 to 85 points. The range of motion was increased in seven joints, unchanged in two joints and decreased in three. One total hip arthroplasty was revised after 9 years for aseptic loosening. One total knee demonstrated nonprogressive radiographic evidence of aseptic loosening. Median consumption of coagulation factor concentrate in severe haemophiliacs decreased from 47.00 U yr−1 (range 16.000–144.000) before surgery, to 25.000 U yr−1 (range 18.000–132.000) at 2 years after surgery. Conclusion: hip and knee arthroplasty is a valuable option in symptomatic haemophilic patients with disabling arthropathy, in order to obtain pain relief and functional improvement. It is associated with a low rate of complications and may reduce the need for substitution of factor VIII and IX.
Molecular characterization of haemophilia A & B in Indians
Authors: Shetty  , Ghosh  , Pathare  , Jijina  , Mohanty
Published: March 2003

Forty‐seven haemophilia A patients from 43 pedigrees and 34 haemophilia B patients from 31 pedigrees were screened for the presence of mutations by Southern blotting using factor VIII and IX cDNA and genomic DNA probes. Three deletions and two restriction site variants were detected among 47 haemophilia A patients and one deletion and two restriction site variants were detected in 34 haemophilia B patients. Overall, the frequency of mutations in haemophilia A was 10.6%; the frequency of deletions was 6.4% and that of point mutations was 4.2%. In haemophilia B, the frequency of mutations detected was 9%; deletions 9% and point mutations 6%.

The present report, the first from India, shows that like other earlier published reports from Europe and the United States, mutations in haemophilia are heterogeneous, and that RFLP using Southern blotting did not detect most of the mutations in this disorder and is an insensitive and inefficient procedure.
The management of a person with haemophilia who has a fixed flexed hip and intractable pain
Authors: Heim  , Varon  , Strauss  , Martinowitz
Published: March 2003

The clinical picture of a fixed flexed hip associated with pain in a person with haemophilia is suggestive of a haemorrhage in that area. Sonography facilitates differentiation between a haemarthrosis, intraperitoneal haemorrhage, subperiosteal bleed, a bleed into the soft tissue around the hip joint or a psoas haematoma. All these aforementioned causes may result in the same clinical presentation. Two cases are described in which coxhaemarthrosis resulted in a flexion contracture of the joint associated with severe intractable pain. Narcotic drugs failed to alleviate the severe pain. Joint aspiration produced dramatic pain relief and early joint rehabilitation.
Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease
Authors: Federici  , Mannucci
Published: March 2003

In von Willebrand disease, the main goals of treatment are to correct the dual defect of haemostasis caused by a reduced or abnormal von Willebrand factor (vWF), i.e. the prolonged bleeding time (BT) and the deficiency of factor VIII coagulant activity (FVIII:C). The synthetic vasopressin analogue, desmopressin (DDAVP), has reduced the need for transfusions in most of the mild forms of von Willebrand disease but DDAVP is ineffective in type 3 and in other severe cases of types 1 and 2 von Willebrand disease. For many years cryoprecipitate has been the mainstay of replacement therapy but, after the introduction of virucidal methods, concentrates containing FVIII/vWF have been considered much safer than cryoprecipitate and proposed in von Willebrand disease management. FVIII/vWF concentrates have been produced and tested by many authors but there is only one report describing four virus‐inactivated FVIII/vWF concentrates evaluated in a cross‐over randomized trial. According to these in vitro and pharmacokinetic data, the following information can be derived: (a) no FVIII/vWF concentrate had an intact multimeric structure similar to that of normal plasma or of cryoprecipitate; (b) all FVIII/vWF concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed in the concentrate devoid of FVIII:C; (c) no FVIII/vWF concentrate consistently normalized the BT in a sustained fashion. On the other hand, clinical haemostasis can be achieved in the management of bleeding episodes and of surgery for most of von Willebrand disease cases regardless of whether the BT is corrected; in the few rare cases with mucosal bleeding not controlled by FVIII/vWF concentrates, infusion of DDAVP or platelet concentrates can be administered in addition.
In vitro evaluation of the haemostatic value of the LFB‐von Willebrand factor concentrate
Authors: Mazurier
Published: March 2003

The structural and functional studies of the concentrate of von Willebrand factor (vWF) manufactured by LFB have been first performed as part of the preclinical development of this product specially intended for the treatment of von Willebrand disease. The electrophoretic analyses showed the high purity of LFB‐vWF concentrate (specific activity of 100 IU of ristocetin cofactor activity per milligram of protein) and the multimeric pattern attesting the presence of high molecular weight multimeters (≥15‐mers). The measurements of vWF capacity to bind to: (1) platelet glycoprotein (GP) Ib in the presence of ristocetin; (2) GPIIb/IIIa in the presence of thrombin; (3) types I and III collagen; (4) factor VIII (FVIII) gave evidence that the functional activity of purified vWF was similar to that of native plasma vWF. Furthermore the LFB‐vWF concentrate was able to promote platelet adhesion to collagen. The release of the therapeutic batches of this product rely presently on their potency measured with the ristocetin cofactor activity (40–70 IU ml−1) and the quantitative evaluation of vWF multimeric distribution studied using electrophoresis in 1.5% agarose. These validated techniques ensure the consistency and haemostatic properties of the different lots of LFB‐vWF concentrate.
New methods for inactivation of lipid‐enveloped and nonenveloped viruses
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , MIEKKA S. I. , BUSBY T. F. , REID B. , POLLOCK R. , RALSTON A. , DROHAN W. N.
Published: March 2003

Summary. Two new methods are described for inactivating lipid‐enveloped and non‐enveloped viruses in plasma‐derived products such as coagulation factors and intravenous immunoglobulin (IGIV). Iodine/Sephadex® delivers iodine to IGIV solutions in a slow, controlled way and allows for inactivation of ≥4 logs of porcine parvovirus (PPV), a hardy non‐enveloped virus, under conditions which do not measurably damage the structural or functional properties of the IGIV, and with essentially no iodination of the protein. All detectable enveloped and non‐enveloped viruses were inactivated by this treatment. Gamma irradiation has been successfully used to inactivate viruses at the final vial stage in freezedried plasma proteins. Four logs of PPV were inactivated by irradiation in the presence of fibrinogen, factor VIII and α1‐proteinase inhibitor (API) at doses of 23, 28 and 30 kiloGray (kGy) respectively, while retaining 93% of fibrinogen solubility, 67% of factor VIII activity and over 80% of API activity. Bovine viral diarrhea virus (BVDV), a lipid‐enveloped model for hepatitis C virus, was completely inactivated by radiation doses of 20–30 kGy in these products. Gamma irradiation was less effective in inactivating viruses in freeze‐dried IGIV.
Assessment and treatment of liver disease in Japanese haemophilia patients
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , FUKUDA Y. , NAKANO I. , KATANO Y. , TOYODA H. , IMOTO M. , TAKAMATSU J. , SAITO H. , HAYAKAWA T.
Published: March 2003

Summary. We studied the prevalence of the hepatitis C virus (HCV), human immunodeficiency virus (HIV) and GB virus C or hepatitis G virus (GBV‐C/HGV), and characteristics of infections in Japanese haemophilia patients. Haemophilia patients were highly infected with HCV (88.2%) because of frequent use of unheated blood concentrates. Analysis for HCV genotypes revealed characteristics of HCV infection in haemophilia patients. Japanese haemophilia patients were highly infected with rare genotypes in Japan: genotype 1a (26.5%), genotype 3 (14.5%) and genotype 4 (2.4%). HIV infection was observed in 32.3% of haemophilia patients. HCV quasispecies (clones) and direct sequencing were investigated in patients with a single HCV genotype in the hypervariable region 1 of HCV, which resulted in a high degree of diversity. This indicates that even a single genotype of HCV might have multiple origins. GBV‐C/HGV infection was noted in 20.9% of Japanese haemophilia patients. Over 40 haemophilia patients with chronic hepatitis C have been treated with interferon alpha for 6 months at total doses of 480–720 million units. About 38% showed clearance of HCV RNA from serum. Six patients with HIV infection were included in the study and they did not show eradication of HCV from the serum. This might derive from that they had high serum HCV RNA titers and genotype 1a or 1b. Histologic assessment was performed in 36 haemophilia patients with HCV. No case showed a histologically normal liver. Hepatic fibrosis in the biopsy specimens was classified into five stages of fibrosis and compared with serum hepatic fibrosis markers. Serum hyaluronic acid mostly correlated with hepatic fibrosis (γ= 0.78, P < 0.0001) followed by type IV collagen (γ= 0.38, P < 0.05). This suggests that estimation of serum fibrosis markers might be substituted for liver biopsy in haemophilia patients.
The management of factor XI deficiency
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , BOLTON‐MAGGS P. H. B.
Published: March 2003

Summary. Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used, it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.
Management of haemophilia in patients with high‐titre inhibitors: focus on the evolution of activated prothrombin complex concentrate AUTOPLEX® T
Authors: Penner
Published: March 2003

Numerous therapeutic strategies have been applied to the management of patients with inhibitors to factors VIII or IX. Different treatment approaches are analysed including prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs), porcine factor VIII concentrate, inhibitor neutralization, immune tolerance therapy, immunosuppressive regimens and recombinant factor VIIa. Clinical data are reported in the analysis of several treatments. PCCs and aPCCs have gained widespread acceptance as the standard first‐line approach for patients with inhibitors. The aPCC AUTOPLEX® T has achieved a high response rate with a low level of thrombotic events. Four case studies are presented in which AUTOPLEX® T has been used successfully. Administration of platelet concentrate or, in elective surgery, waiting for inhibitor levels to decline are useful adjuncts to some treatments. The optimal treatment depends on the patient’s inhibitor status – low responder (minimal or no increase in inhibitor levels upon administration of replacement clotting factor) or high responder (replacement clotting factor generates inhibitor production). A suggested algorithm for treating high‐responder inhibitor patients is presented.
Hepatitis C viral load, genotype and histological severity in patients with bleeding disorders
Authors: AHMED  , MUTIMER  , MARTIN  , ELIAS  , WILDE
Published: March 2003

We report the relationship between hepatitis C virus (HCV) titre, liver histology and HCV genotype in patients with bleeding disorders. One hundred and thirty‐two RIBA‐2‐positive patients, including 56 who were also HIV positive, were identified at our centre. Fifty of these patients, including nine who were HIV infected, underwent percutaneous liver biopsy. Liver histology was assessed using a modified histological activity index (HAI). Qualitative serum HCV PCR was positive in 87 (87%) of the 101 patients tested including 43 of 50 biopsied patients. HCV RNA titres, measured by quantitative PCR, were significantly higher in HIV‐positive patients compared with HIV‐negative patients (P < 0.05) but were not related to HAI, mean factor concentrate usage, duration of HCV infection or HCV genotype. There was no relationship between HCV genotype and HAI. Qualitative HCV PCR was positive in 30 of 43 liver biopsies tested. Biopsy PCR‐positive and ‐negative cohorts were not distinguished by HAI or serum HCV titre. We conclude that although serum HCV PCR is useful in confirming the presence of HCV infection in patients with bleeding disorders, little meaningful information concerning the severity of the disease can be obtained from serum HCV quantification.
Cost‐effectiveness analysis of alternative factor VIII products in treatment of haemophilia A
Authors: Hay  , Ernst  , Kessler
Published: March 2003

Manufactured factor VIII (FVIII) concentrates of varying purity are available for managing patients with haemophilia A. This study is a cost‐effectiveness analysis of ultra‐high purity and recombinant (UHP/R) FVIII products relative to intermediate and very‐high purity (IP/VHP) preparations. Because the societal (including research and development) costs of FVIII products are unknown and product prices vary with market conditions, we conducted the analysis with treatment cost as a variable quantity. We estimated the largest price premium that could be paid for a UHP/R concentrate relative to an IP/VHP concentrate such that the UHP/R product is the more cost‐effective preparation. In the analysis haemophilic patients were assumed to be seropositive for human immunodeficiency virus, seropositive for hepatitis C (HCV), or at risk for seroconversion of hepatitis A (HAV) or hepatitis B (HBV). The results showed that the maximum cost‐effective UHP/R price premium is essentially zero if the patient is only at risk of HAV or HBV infection, positive but small for the base‐case HCV+ patient, and positive and large for the base‐case HIV+ patient having a short life expectancy. Thus UHP/R preparations are not uniformly more cost‐effective than IP/VHP products across the spectrum of haemophilic patients’ health problems, and the relative cost‐effectiveness of the two classes of prepared FVIII products is sensitive to product prices. The methodology employed here can be used in other circumstances where multiple treatments exist for illnesses for which there are significant multiple comorbidities or health risks.
Haemophilia therapy: assessing the cumulative risk of HIV exposure by cryoprecipitate
Authors: Evatt  , Austin  , Leon  , Ruiz‐Sáez  , De Bosch
Published: March 2003

Most of the world’s haemophilia population live in countries with developing or emerging economies. As such, they do not have access to viral inactivated clotting product. Many are treated with cryoprecipitate made from locally supplied blood. The rationale for using cryoprecipitate instead of viral inactivated products is based on an implicit belief that because blood banks can provide reasonably safe products by using modern testing procedures, transmission of HIV and other blood‐borne viruses is rare. However, the risk of acquiring a blood‐borne infection is cumulative, and haemophilia patients treated with cryoprecipitate or fresh‐frozen plasma are exposed to hundreds or thousands of donors during their lifetime. The risk that an HIV‐infected person will be a donor during the ‘window period’ is directly related to the incidence of HIV in the country where the donation occurs. To illustrate the extent of this problem, we devise a model for estimating the risk that a person with haemophilia will encounter HIV‐contaminated cryoprecipitate as a function of years of treatment and the underlying incidence rate of HIV among blood donors. We apply the model to two countries with different incidence rates of HIV, Venezuela and the USA. Over a lifetime of treatment (60 years), the cumulative risk of HIV exposure for a person with haemophilia receiving monthly infusion of cryoprecipitate prepared from plasma of 15 donors is significant, 2% in the USA and 40% in Venezuela. Considering the cumulative risk for transmitting HIV to patients with haemophilia through cryoprecipitate treatment, medical care providers should carefully evaluate the use of cryoprecipitate in any but emergency conditions or when no virally inactivated products are available.
Acute renal failure in acquired haemophilia following the use of high dose intravenous immunoglobulin
Authors: Laidlaw  , Bainton  , Wilkie  , Makris
Published: March 2003

High dose intravenous immunoglobulin (IVIG) is a useful form of treatment in patients with acquired haemophilia, a rare bleeding disorder due to auto‐antibodies to factor VIII. We describe a patient with acquired haemophilia who developed acute renal failure rapidly after treatment with a high sucrose content IVIG preparation. We speculate that the sucrose content of the preparation was responsible for the renal failure and make recommendations on the use of IVIG in patients with acquired haemophilia.
Physiotherapy for the treatment of articular contractures in haemophilia
Authors: Heijnen L. , De Kleijn P.
Published: March 2003

Articular contractures in haemophilia are impairments that can not be cured by means of physiotherapy because of the pathophysiology of the joint. Rehabilitation, however, tries to diminish the disabilities and prevent handicaps caused by the impairments. Physiotherapy aims at pain reduction by means of manual traction. Next to manual traction the intensive physiotherapy programme includes mobilization techniques, muscle strengthening exercises and stretching, joint stability training, postural and gait training, and functional training. In all 50 haemophilia patients have undergone this intensive 4‐week clinical rehabilitation programme. Data of 20 of these severe haemophilia patients show that the mean range of motion at the start of the rehabilitation period, after 4 weeks and after 5 years do not differ. In spite of progressing arthropathy after 5 years the activities of daily living (ADL), walking range and pain are equal or better according to 13 of 15 patients.
Diagnosis and management of von Willebrand disease
Authors: Federici A.B. , Mannucci P.M.
Published: March 2003

von Willebrand disease (vWD) is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (vWF). The diagnosis is based on measurements of plasma and platelet vWF, the ability of vWF to interact with its platelet receptor and the analysis of the mutlimeric composition of vWF. Due to the heterogeneity of vWF defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion expressed by a prolonged bleeding time (BT). Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 80% of cases, because it corrects the FVIII/vWF levels and the prolonged BT in most of these patients. In type 3 and in the majority of type 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concen‐trates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and currently safe, but the BT defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the BT after concentrates is associated with continued bleeding.
The use of central venous catheters (portacaths) in children with Haemophilia
Authors: Bollard  , Teague  , Berry  , Ockelford
Published: March 2003

The experience with central venous implantable devices (portacaths) has been reviewed in children attending the Auckland Hospital Haemophilia Centre. Fourteen children had 23 portacaths inserted. Thirteen had severe Haemophilia A, of whom five had high responding inhibitors to factor VIII. All the children were HIV negative. Ages ranged from 4 months to 13 years at the time of initial placement and 12 were under 5 years. Indications for portacath placement included primary and secondary prophylaxis, induction of immune tolerance, prophylactic therapy post intracranial haemorrhage and poor venous access. Catheter‐related infections occurred in 48% of cases. Staphylococcal species were the most common organisms isolated followed by gram‐negative bacilli. 63% of the infections were successfully cleared with antibiotics. Haematoma formation occurred in 17% of catheters, primarily in patients who had high factor VIII inhibitor levels. Mechanical problems including blockage, leakage and extrusion of the portacath occurred less frequently (13%). The significant rate of infection in this immunocompetent population is consistent with other reports. Despite the obvious benefits of portacaths this complication is potentially serious and causes appreciable morbidity. In contrast, bleeding complication rates were relatively low.
Cardiac surgery and catheterization in patients with Haemophilia
Authors: Mackinlay  , Taper  , Renisson  , Rickard
Published: March 2003

The present study summarizes the results of 12 cardiac surgical procedures performed in a carrier of Haemophilia B and in six patients with Haemophilia A at a single centre from 1979 to 1998. The median age of the patients at the time of intervention was 56 years ranging from 18 years to 73 years. The six patients with Haemophilia A ranged in severity from moderately to mildly affected. Three patients were hepatitis C antibody positive. No patients were HIV antibody or hepatitis B surface antigen positive. The cardiac procedures included cardiac catheterization (n=4), coronary artery bypass surgery (n=2), percutaneous transluminal coronary angioplasty (n=1), cardiac valve replacement (AVR n=1 and AVR/MVR n=2), and closure of an atrial septal defect and subsequent drainage of a pericardial effusion (n=1). No patients had demonstrable inhibitors at the time of surgery. Haemostasis was achieved with AHF in 10/11 procedures and high purity factor IX (Immunine) in one procedure. The initial procedures involved intermittent bolus factor therapy while more recently, AHF was administered by continuous intravenous infusion. All patients demonstrated excellent intra‐ and post‐operative haemostasis. These results, although from a small and varied group of patients, demonstrate that cardiac surgical procedures can be performed safely in patients with Haemophilia.
Porcine factor VIII provides clinical benefit to patients with high levels of inhibitors to human and porcine factor VIII
Authors: Gribble  , Garvey
Published: March 2003

The development of an inhibitor against Factor VIII is an important complication of haemophilia and occurs in approximately 31% of patients [ 1]. Despite various approaches to their management, the presence of these inhibitors remains a major cause of morbidity and mortality. Inhibitors may be low level [<5 Bethesda Units (BU)] or high level [>10 BU]. Low‐level inhibitors usually remain low and do not respond to administered factor VIII with a rise of the inhibitor titre; high‐level inhibitors, in contrast, are characterized by a rapid rise in titre following treatment with factor VIII. Modalities of treatment of acute bleeding episodes in patients with inhibitors include ‘overcoming’ the inhibitor with very large doses of factor VIII, ‘bypassing’ the inhibitor blockade with products such as activated prothrombin complex concentrates or recombinant factor VIIa, ‘removing’ the inhibitor by plasmapheresis or immunoabsorption and ‘repressing’ it with immunosuppressive drugs and immune tolerance induction. An alternative approach is to use a porcine factor VIII concentrate which does not cross‐react with the human factor VIII inhibitor. Following treatment with porcine factor VIII, functional factor VIII can be detected and the therapeutic levels correlate with cessation of bleeding. The use of porcine factor VIII may, however, result in the development of antiporcine factor VIII antibodies, limiting its use. Experience in patients with high‐titre inhibitors indicates that porcine factor VIII therapy could be used in the presence of factor VIII inhibitors [
2–11], including inhibitors to porcine factor VIII [
5,
7], and that haemostasis may be obtained in the absence of detectable levels of circulating factor VIII [
7,
11].
Induction of immune tolerance and suppression of anaphylaxis in a child with haemophilia B by simple plasmapheresis and antigen exposure
Authors: Barnes C. , Rudzki Z. , Ekert H.
Published: March 2003

Anaphylaxis to factor IX (FIX) in patients with haemophilia B is a rare and life‐threatening complication that has been reported to occur in association with the development of inhibitors to FIX. Management of these patients is difficult. This report presents an 18‐month‐old boy with a frame‐shift mutation of the FIX gene and FIX coagulant level of <1% who developed anaphylactoid reactions to low and high purity plasma‐derived FIX concentration infusions and an inhibitor measuring 1.0 BU mL–1. The patient was managed with simple plasmapheresis, a short course of corticosteroids and high‐dose antigen exposure, which successfully induced long‐lasting immune tolerance to FIX concentrates.
Seventeen years’ experience with	Autoplex®/Autoplex® T: evaluation of inpatients with severe haemophilia A and factor VIII inhibitors at a major haemophilia centre
Authors: White
Published: March 2003

A retrospective case analysis of the use of Autoplex T® (anti‐inhibitor coagulant complex [heat treated]) at a major haemophilia treatment centre is described. Twenty‐three haemophilia A patients with a history of high‐titre (>10 BU), high‐response inhibitors were treated for a total of 54 bleeding episodes requiring hospital admission and/or surgical intervention. Effective or partially effective haemostatic control was achieved within 72 h in 94% of reported cases (effective 85%; partially effective 9%). The incidence of adverse reactions was low and there were no thrombotic complications. In bleeding episodes for which BU titres were determined within 6 months pre‐ and 6 months post‐treatment, there was little tendency for Autoplex T to cause an anamnestic response (1 of 19 bleeding episodes). In the three invasive surgical procedures included in the case review, coverage with Autoplex T resulted in no postoperative complications, no bleeding at the surgical site, and no postoperative haematoma. The results support the efficacy and safety of Autoplex T in the treatment of bleeding episodes and haemostatic coverage of surgical procedures in haemophilia A patients with inhibitors.
Spontaneous intracranial bleeding in two patients with congenital afibrinogenaemia and the role of replacement therapy
Authors: Parameswaran R. , Dickinson J. P. , De Lord S. , Keeling D. M. , Colvin B. T.
Published: March 2003

Congenital afibrinogenaemia and hypofibrinogenaemia are rare disorders of haemostasis. In this case report the problems posed in the management of two patients with fibrinogen levels less than 0.1 g L−1 and who developed intracranial bleeding are considered. The value of fibrinogen concentrate and the role of prophylaxis is also discussed.
Carrier analysis of a moderately affected haemophilia B family
Authors: Holoshitz N. , Kurachi K. , Kurachi S.
Published: March 2003

Here we report the successful genetic diagnosis of a pregnant caucasian female patient whose family has a history of moderate haemophilia B. While restriction fragment length polymorphism (RFLP) analysis was not informative, nucleotide sequencing of the factor IX genes of the patient’s family members determined that her mother and one of her two sisters were carriers of the mutation C31008T, which causes a Thr296Met transition. In contrast, the pregnant female herself and her other sister were found to carry only normal alleles. Plasma factor IX activity and antigen levels supported these findings.
Intrauterine correction of factor VIII (FVIII) deficiency
Authors: Gilchrist G. S. , Wilke J. L. , Muehlenbein L. R. , Danilenko‐Dixon D.
Published: March 2003

This is the first published report documenting the successful use of intrauterine infusion of factor VIII (FVIII) in order to reduce the risk of intracranial haemorrhage in a foetus with documented haemophilia A. This approach provides another option for management of newborns with documented coagulation factor deficiency. The subsequent development of an inhibitor directed against FVIII is believed to be related to exposure to exogenous FVIII in the presence of an inversion mutation and not to the intrauterine procedure.
Continuous infusion of porcine factor VIII in patients with haemophilia A and high‐responding inhibitors: stability and clinical experience
Authors: O'Gorman P. , Dimichele D. M. , Kasper C. K. , Mannucci P. M. , Santagostini E. , Hay C. R. M.
Published: March 2003

A multicentre retrospective survey was conducted to assess the efficacy and side‐effect profile of porcine factor VIII (pFVIII:C) given by continuous infusion (CI) to patients with congenital haemophilia A and inhibitors. Twenty‐nine episodes in 18 patients were treated by CI of pFVIII:C. Efficacy was graded as good in 79% of infusions and fair in 17%. There was a failed response in only one episode. Fourteen percent of patients experienced transfusion reactions with bolus doses, but no reactions were observed in patients given CI. There were no severe reactions. All the reactions resolved following interruption of the infusion and administration of steroids. Premedication did not prevent reactions. In this series the median decrease in platelet count after bolus injection of pFVIII:C was −67 × 109 L−1 compared with a median decrease of −2 × 109 L−1 during the course of CI, thus, continuous infusion of pFVIII:C appears to have less effect on platelet count than bolus injection. An anamnestic response was associated with 77% of infusions. This high rate of anamnesis reflects patient selection, in that they were all known to have high‐level high‐responding FVIII inhibitors with cross‐reactivity to pFVIII. After reconstitution, the pFVIII:C showed little loss in factor VIII activity in solution over a 24‐h period. We conclude that pFVIII:C may be effectively administered by CI to patients with haemophilia A and high‐responding FVIII inhibitors. CI is the probably the mode of administration of choice for intensive replacement therapy with pFVIII.
Successful outcome of a cirrhotic patient with postoperative haematuria treated with a single high dose of recombinant factor VIIa
Authors: Lucía J. F. , Aguilar C. , Orna E. , Allepuz C. , Giralt M. , Carrasco V. , Simón M. A.
Published: March 2003

Recombinant factor VIIa (rfVIIa) has been widely used for the treatment and prevention of bleeding episodes in haemophiliacs with high‐titre inhibitors. High single doses are the treatment of choice for joint and muscle bleeds in those patients. There are only a few reports on the value of rfVIIa in cirrhotic patients with haemostatic impairment but this drug can consistently correct the prothrombin time in these individuals. We report a case of a good response to a single high dose of rfVIIa in a patient with advanced liver disease who suffered from severe refractory postoperative haematuria.
Clinimetric instruments to assess functional health status in patients with haemophilia: a literature review
Authors: De Kleijn P. , Heijnen L. , Van Meeteren N. L. U.
Published: March 2003

Summary.  The World Federation of Hemophilia scoring system (WFH‐1) evaluates primarily body functions and structures, whereas assessment of the whole area of functional health status is considered nowadays to be a better measure. In addition, the WFH‐1 lacks psychometric properties (reliability, validity and sensitivity to change). This study aimed to gain insight into the clinimetric assessment of functional health status in patients with haemophilia by way of a systematic literature search. A standardized literature search and selection was performed on the databases of CINAHL (1982–2001), Medline (1966–2001), and PubMed (January–July 2001). Clinimetric instruments applied in the selected articles were classified based on the international classification of functioning, disability, and health (ICF) and analysed for their psychometric properties. In 19 articles published between 1979 and 2001, 34 clinimetric instruments were used to assess functional health status. Instruments were classified as measuring the ICF components body structure and function (n = 17), activities (12) and participation (4). Reliability was measured in four articles on three different instruments, the validity (construct) of the instruments for patients with haemophilia was reported in six articles on five instruments, and sensitivity to change in three articles on three instruments. The populations under study varied in number (7–9 35), mean age (21.6–50.8 years), and in the distribution of haemophilia severity. Reports on the evaluation of functional health status in patients with haemophilia are increasing. Further research on the psychometric properties of the instruments is warranted in more groups of patients with haemophilia. Development of the new core set of clinimetric instruments, the WFH‐2, might benefit from this strategy.
Unusual presentation of factor XIII deficiency
Authors: Almeida A. , Khair K. , Hann I. , Liesner R.
Published: March 2003

Summary.  Factor XIII deficiency is a rare inherited bleeding disorder that is often difficult to diagnose. The standard screening tests are normal in these patients and their bleeding phenotype may be variable. We report the case of a 3‐year‐old girl who presented with an intracranial haemorrhage. Several confounding factors, such as the suspicion of an arteriovenous malformation and the development of a deep venous thrombosis, led to a delay in the diagnosis of factor XIII deficiency. Subsequently, her brother was also found to have severe factor XIII deficiency. This case highlights the importance of a detailed history and of screening families in which index cases have been identified. It should also remind physicians that bleeding disorders may have unusual presentations and should be sought when investigating unexplained bleeding.
Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors
Authors: Mauser‐Bunschoten E. P. , Koopman M. M. W. , Goede‐Bolder A. D. E. , Leebeek F. W. G. , Van Der Meer J. , Van Marwijk Kooij G. M. , Van Der Linden P. W. G. ,   THE RECOMBINANT FACTOR VIIa DATA COLLECTION GROUP
Published: March 2003

Summary.  We have prospectively monitored treatment of haemophilia patients with inhibitors by recombinant factor VIIa (rFVIIa) administered by continuous infusion to obtain more insight in the underlying factors of the clinical efficacy of this administration method. At present, 43 treatment episodes of 14 different Dutch haemophilia inhibitor patients are included in the database. Analysis of the data showed a discrepancy between the efficacy of rFVIIa continuous infusion treatment of acute and surgical bleeds in the oral cavity [one (14%) effective, two (29%) partially effective, four (57%) not effective] and other parts of the body [29 (80%) effective, four (11%) partially effective, two (6%) not effective, one (3%) impossible to classify]. Patients who had acute or surgical oral cavity bleeds, uncontrolled by rFVIIa continuous infusion, reacted favourably to rFVIIa continuous infusion in other locations of the body. Acute bleeding episodes in the oral cavity, which could not be controlled by rFVIIa continuous infusion, stopped when the treatment regimen was switched to rFVIIa bolus injections. Finally, haemostatic control during dental extractions was excellent after the initial rFVIIa bolus injection preceding the continuous infusion, but rebleeds occurred in all patients within 48 h under rFVIIa continuous infusion coverage. These observations suggest that the efficacy of rFVIIa continuous infusion depends, at least in part, on the location of the body in which the bleeding occurs and that rFVIIa bolus injections are more effective than rFVIIa continuous infusion in the oral cavity. We hypothesize that the inability of rFVIIa continuous infusion treatment to sufficiently inhibit fibrinolysis is the underlying cause of the decreased efficacy of rFVIIa continuous infusion treatment in the oral cavity.
Significance of immune status, genotype and viral load in the severity of chronic hepatitis C in HIV infected haemophilia patients
Authors: Delladetsima J. , Katsarou O. , Touloumi G. , Vgenopoulou S. , Hatzakis A. , Karafoulidou A.
Published: March 2003

Summary. Chronic hepatitis C is associated with more severe liver disease in patients coinfected with HIV, but the pathogenic mechanism of this more aggressive course is still unclear. The aim of this study was to assess the relationship of HCV genotype, viral load and epidemiological factors with the histological severity of chronic hepatitis in haemophilia patients with HCV/HIV coinfection, taking into consideration the immune status of the patients. Twenty‐one HIV/HCV coinfected haemophilia patients, with mean age ± SD 35.7 ± 8.7 years, underwent transcutaneous liver biopsy 6–15 years (median 12 years) after HIV and 6–32 (median 21.5 years) years after HCV infection. Twelve patients were stage A (CDC), six stage B and three stage C. CD4 cells were < 50 µL−1in three patients (14.3%), 50–200 in 11(52.4%) and > 200 in 7(33.3%). Mean ± SD log10HCV‐RNA was 6.87 ± 0.7 copies mL−1(range 5.4–7.9), and mean ± SD log10HIV‐RNA was 3.75 ± 0.98 copies mL−1(range 2.7–6), at the time of liver biopsy. Minimal hepatitis was diagnosed in five patients (24%), mild in 10 (48%) and moderate in six (28%). Hepatitis stage 0–2 was found in seven cases (33%) and cirrhosis in six (29%). Statistical analysis showed a significant association of CD4 count < 50 with minimal hepatitis and of CD > 200 with mild and moderate hepatitis (P = 0.033). In addition, minimal hepatitis was found only in patients with stage C, while the majority of subjects with HIV stage A showed mild and moderate hepatitis (P = 0.003). Moreover genotype 1 was independently associated with advanced hepatitis stage (P = 0.04). No relationship was found between hepatitis severity, HIV or HCV RNA levels, patient's age and duration of HIV or HCV infection. Our results suggest that HCV/HIV coinfection may aggravate the course of hepatitis in the phase of immunocompetence, most probably through an immune mediated process. Genotype 1 seems to be associated with advanced liver disease.
First‐time development of FVIII inhibitor in haemophilia patients during the postoperative period
Authors: Ghosh K. , Jijina F. , Shetty S. , Madkaikar M. , Mohanty D.
Published: March 2003

Summary. Development of inhibitor to FVIII in haemophilia patients is well‐known and is not uncommon. However, their development for the first time during the postoperative period has hardly been reported. In a developing country such as India, where resources are limited, development of such an eventuality may prove disastrous. However, as many of our patients are sparingly treated, therefore, even if they test negative for the inhibitor preoperatively, they may get the requisite FVIII antigenic stimulation during the preoperative and immediate postoperative period, leading to the development of inhibitors during this critical time of wound healing. We describe here six patients who developed such an inhibitor, from a group of 35 patients with haemophilia A who underwent various surgical procedures (19%). We stress that such an eventuality may not remain rare in developing countries as more patients of severe haemophilia undergo surgery and are therefore challenged for the first time in their life with large amounts of FVIII concentrate during their preoperative period.
Novel prothombin mutations in Puerto Rican children
Authors: Ortiz IR , Lefkowitz JB , Weller A , Santiago‐Borrero PJ
Published: March 2003

Prothrombin (FII) deficiency is a rare congenital bleeding disorder. We have identified 8 children (7 families) with this condition, accounting for 6% of the congenital coagulation disorders (excluding VWD), followed at the Puerto Rico Pediatric Hemophilia Treatment Center.

The mean age at first significant bleeding episode was 5.9 years, ranging from 9 months to 14 years. The first bleeding symptoms were mostly mucosal, with only one child with a joint bleed. Sex distribution was even, and all but one had family history of a coagulation disorder. FII activity levels ranged from 10% to 27% with a mean FII level of 17.3%. The PT and PTT were slightly abnormal in all, with a mean PT of 14.3 sec and mean PTT of 38.4 sec. DNA sequencing has been done on four patients from three families. One patient was found to be homozygous for a prothrombin mutation previously described in a patient of Puerto Rican origin, Arg‐457→Gln (Prothrombin Denver V). Probands in two families were compound heterozygotes for the Denver V mutation and two novel mutations. One of these, named Prothrombin Puerto Rico I, is a point mutation predicting a Gla‐16→Gln substitution. The other mutation, designated Prothrombin Puerto Rico II, is a five base deletion in Exon XIII resulting in a premature stop codon.

FII deficiency is the third most common congenital coagulation factor deficiency in Puerto Rican children, suggesting a higher prevalence in our population. Our studies have identified two novel mutations in the prothrombin genes of these children.