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Biomedical subjects

M Magallón

Publications and source records attributed to M Magallón.

At least 19 recordsLinked to original sources
PubMed2001

Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII.

In order to determine the difference in reactivity of factor (F) VIII inhibitors against the FVIII/von Willebrand factor (vWF) complex and against vWF-deficient FVIII, we investigated a panel of 10 antibodies to FVIII from multitransfused individuals with severe haemophilia A and other pathologies. Immunoblotting of purified FVIII and purified thrombin-cleaved FVIII revealed that in all cases inhibitor epitopes could be localized in the heavy chain (A2 subunit) while in four cases they were also present in the light chain. One of the FVIII inhibitors remained unclassified. The effect on FVIII:C of purified IgG from inhibitor plasmas was tested against a high purity FVIII/vWF concentrate and a monoclonally purified FVIII concentrate with only trace contents of vWF, by two different functional assays. Our results suggest that for those inhibitors showing A2 plus light chain (LC) reactivity, the IgG concentration required to inhibit 50% of FVIII activity in vitro is higher for the FVIII/vWF complex than for the vWF-deficient FVIII. We conclude that there might be a protective role of vWF (at least in vitro) against FVIII inhibitors with A2 and LC subunit specificity.

Antibodies↗
PubMed2000

The orthopaedic status of severe haemophiliacs in Spain.

This paper provides an outline of the results obtained in a cross-sectional study conducted primarily with the aim of ascertaining orthopaedic complications in a group of young severe A and B haemophiliacs, the effects which these complications have on the medical resources used with these patients, and the impact of severe haemophilia on their quality of life. Its secondary aim was to link their current orthopaedic status to the type of treatment they had received prior to the study. Eleven Spanish hospitals took part in this study, monitoring 70 severe haemophiliacs (FVIII:C <2%) without inhibitors who had a mean age of 21.6 years and a median age of 22. Retrospective data collected from birth to the conclusion of the study were used and, for certain variables, data from the last 12 months. The type of treatment given had been on-demand treatment, together with prophylaxis of variable time periods, which in 32 cases (45.7%) were prolonged (>6 months). In 40 cases (57.1%) the patients underwent one or more periods of prophylaxis. Thirty-three patients (47.8%) had over 1000 days of administration of factors VIII and IX. The analysis of the total study group reveal an average of 348 bleeding episodes per patient. The findings of this study revealed that 84.3% of these patients suffer from articular complaints on the Gilbert scale, and 85.7% on the Pettersson scale. In addition, pain was reported in 16.1% of the joints, the most frequently affected being the ankle joints. Twenty-six patients (37%) had undergone orthopaedic surgery from the time of birth to the conclusion of the study. The quality of life of the severe haemophiliacs reviewed seems to have been affected. During the last 12 months, there were 216 outpatient haematological visits and 176 orthopaedic-rehabilitation visits, as well as 12 radiological explorations and two hospitalizations. During these 12 months, medical expenditure totalled $55 473 per patient per year, the most important item being factor concentrates VIII/IX ($54 119 per patient per year). The type of treatment given to these patients (on-demand and/or as secondary prophylaxis) was found to be incapable of preventing haemophilic arthropathy or guaranteeing an acceptable quality of life, although both the administration of coagulant factor concentrate to such patients and the financial resources dedicated to their treatment was very high. Consequently, a strategic change is to be considered for the prevention of haemophilic arthropathy, based on the introduction of replacement treatment involving continuous administration of factors VIII and IX in primary prophylaxis regimens from the first years of life.

Adolescent↗
PubMed1999

Identification of twenty-one new mutations in the factor IX gene by SSCP analysis.

In this study we have analyzed the factor IX gene from 84 hemophilia B patients of Spanish origin. It included single-strand conformation polymorphism (SSCP) analysis of all functional regions of the gene and further sequencing of all fragments showing abnormal migration. In 76 patients (90.4%), it was possible to identify molecular alterations leading to the appearance of the disease. Twenty-one new mutations were identified, including 13 missense mutations, two nonsense mutations, three splice-site mutations, one frameshift deletion, one frameshift insertion, and one non-frameshift deletion. The approach appears to be very suitable for molecular diagnosis of hemophilia B.

DNA Mutational Analysis↗
PubMed1999

Therapeutic embolization and surgical excision of haemophilic pseudotumour.

Haemophilic pseudotumour is a rare complication of haemophilia. Few cases of iliac haemophilic pseudotumour have been reported in the literature. These tumours can act as a focus for infection and cause cutaneous fistulas. When they present perforations and infections of endogenous origin their course is usually fatal. Suitable treatment has been investigated on numerous occasions, most of the literature agreeing that the only curative treatment is surgical resection. We present a case of haemophilic pseudotumour of the iliac and caecum with cutaneous fistulas, with a septic process of endogenous origin. It was treated with surgical resection after performing arterial embolization to reduce the vascularization of the pseudotumour, thereby reducing its size and the risk of bleeding complications during surgery.

Cecal Diseases↗
PubMed1999

Hepatitis G virus infection markers (RNA and anti-E2 antibodies) in a multicenter cohort of hemophiliacs.

BACKGROUND AND OBJECTIVE: To investigate the prevalence and evolution of hepatitis G virus (HGV) infection in hemophiliacs and to correlate evolution of HGV infection markers with immunologic parameters in those patients co-infected with HIV. DESIGN AND METHODS: HGV RNA and anti-E2 antibodies were studied in 124 patients. Serial samples were drawn every 4 months from 1992 to 1996. Lymphocyte subsets including T-helper lymphocytes, T-suppressor lymphocytes, T-cytotoxic lymphocytes, activated T-lymphocytes and natural killer cells were analyzed. RESULTS: Prevalences were 22.6% for HGV RNA and 18.5% for anti-E2. Four patients had both HGV RNA and anti E2, so the overall prevalence of HGV infection in hemophiliacs was 37.9% (11.5% in 200 controls, p<0.0001). After a median follow-up of 36.6 months 20 patients remained HGV RNA positive, whereas HGV RNA had cleared in 8, with an actuarial probability of clearance at 36 months of 34.6%. Only 2 patients developed anti-E2 antibodies. Four patients cleared anti-E2, with an actuarial probability at 36 months of 24.8%. In patients with HIV infection, both lower CD4+ lymphocyte count (p=0.01) or higher CD8+ lymphocyte count (p=0.03) showed predictive value for probability of clearing HGV-RNA. CD4+/CD8+ ratio (p=0.002) was the only variable included in the best model for HGV-RNA disappearance. INTERPRETATION AND CONCLUSIONS: A more accurate estimation of the prevalence of HGV infection can be achieved with the determination of both HGV RNA and anti-E2. Anti-E2 response can be undetectable or transitory after disappearance of HGV-RNA, giving therefore rise to the possibility of underestimating HGV prevalence with currently diagnostic methods. In HIV-positive patients, cellular immune function seems to be involved in the resolution of HGV infection, following the significant correlation found between clearance of HGV-RNA and CD4+/CD8+ lymphocyte populations.

Adolescent↗
PubMed1998

von Willebrand factor contained in factor VIII concentrates of different purities supports platelet adhesion in blood samples from a heterogeneous group of patients with von Willebrand disease.

BACKGROUND AND OBJECTIVE: Plasma derived FVIII-VWF concentrates in which the VWF structure is reasonably maintained are recommended as substitutive therapy in VWD. Our aim was to assess platelet deposition and binding to subendothelial structures of VWF present in FVIII concentrates. DESIGN AND METHODS: Cryoprecipitate (CRY), intermediate-purity (IPC), or high-purity (HPC) FVIII concentrates were added in vitro to citrated blood samples from 11 patients affected by different subtypes of VWD, with the aim of normalizing VWF levels. Measurements of VWF:Ag, ristocetin cofactor (RiCof) activities, FVIII coagulant activity (FVIII:C), and platelet interaction with subendothelium under flow conditions (Baumgartner's perfusion method, computer-assisted morphometry, shear rate 1000 s-1, 10 min, 37 degrees C) were determined. Binding of VWF to the luminal surface of the perfused vessels was assessed by immunofluorescence microscopy. Paired t-test statistics were performed. RESULTS: Addition of FVIII-VWF preparations raised VWF:Ag from baseline (BSL) values of 0.3 (SD 0.2) to averages of 1.4 (SD 0.5, p < 0.001), 1.2 (SD 0.6, p < 0.001), and 0.4 (SD 0.3) IU mL-1 after CRY, IPC, and HPC, respectively. A positive labeling for VWF was observed by immunofluorescence in vessels perfused with blood containing any of the concentrates. Platelet adhesion of 13.2 (SD 7.6), 22.4 (SD 10.8), 24.8 (SD 7.8, p < 0.03), or 22.5 (SD 4.8)% was measured in BSL, CRY, IPC, or HPC tests, respectively. INTERPRETATION AND CONCLUSIONS: Our observations support the hypothesis above the mechanisms involved in the beneficial effects of commercial concentrates in von Willebrand disease: the VWF in these concentrates has functional capacity to bind to subendothelium and to support platelet adhesion.

Adult↗
PubMed1997

Hemophilic synovitis of the knee and the elbow.

A prospective study from 1974 to 1996 was done to determine optimal treatment for chronic hemophilic synovitis of the knee and synovitis of the elbow. Sixty-five patients with synovitis affecting 65 knee joints and 40 patients who had synovitis of the elbow (44 elbows), despite a 3-month trial of prophylactic substitution therapy, were treated by synovectomy. Radiation synovectomies (Au-198 synoviorthesis) were done on 38 knees, open surgical synovectomy on 18, and nine had an arthroscopic procedure. Radioactive gold synoviorthesis was performed on 29 elbows, and 15 had a resection of the radial head and partial open synovectomy. Synovectomy (by any method) significantly reduced bleeding episodes, but did not halt the radiographic deterioration of the joints. It is thought that radiation synovectomy is the best choice for patients with persistent synovitis of the knee and synovitis of the elbow unresponsive to a 3-month trial of prophylactic factor replacement. If two to three consecutive synoviortheses with 3 to 6 months intervals had been ineffective, or when the radiographic score is more than two points, an open synovectomy is indicated.

Adolescent↗
PubMed1997

Hamstring release for fixed knee flexion contracture in hemophilia.

Sixteen hamstring tenotomies and posterior capsulotomies were assessed retrospectively in 10 patients with hemophilia. The average age of the patients was 17 years (range, 16-24 years). The main indication for surgery was a fixed knee flexion contracture of 30 degrees to 45 degrees, associated with repeated hemarthroses, and failure of conservative treatment after 6 months. A posterior transverse capsulotomy and a Z shaped hamstring tenotomy were performed. The postoperative treatment consisted of repeated stretching exercises for a 6-month period. An average decrease of 25 degrees in the amount of fixed knee flexion contracture was obtained (range, 10 degrees-40 degrees). Followup for an average of 9.5 years showed 11 good, four fair, and one poor result regarding their joint scores. It is concluded that hamstring release is an effective surgical procedure for fixed knee flexion contracture in hemophilia. It seems to reduce the incidence of hemarthrosis relating to such a deformity.

Adolescent↗
PubMed1996

Antibodies to factor VIII in plasma of patients with hemophilia A and normal subjects.

Non-neutralizing factor VIII (FVIII) antibodies (FVIII-Ab) in hemophilia A may be associated with an abnormal clinical response to FVIII concentrates. Patients with FVIII inhibitors may develop noncoagulation FVIII-Ab after the induction of immunotolerance. Natural FVIII-Ab may be detected in the plasma of some healthy subjects. The aim of this study was to analyze the presence of FVIII-Ab in the plasma of 53 normal blood donors and 124 patients with hemophilia A (18 patients had a previous history of FVIII inhibitor, but only 12 had inhibitor at the moment this study was performed). FVIIII inhibitor was measured using the Bethesda method. FVIII-Ab were analyzed by a specific ELISA assay using purified FVIII from a monoclonal concentrate and a standard plasma containing 26 Bethesda units (BU) of FVIII inhibitor. Purified FVIII was used to coat wells of a microtiter plate and was incubated with dilutions of plasma to be tested. Bound human IgG FVIII-Ab were detected by incubation with polyclonal sheep anti.human IgG alkaline phosphatase conjugate, and the OD405 was quantitated. A linear fit was obtained (by plotting FVIII-Ab positivity [OD 405nm] versus BU titer) when serial dilutions of this standard inhibitor plasma, containing titers of 0.5 BU or higher, were used. Four different levels of FVIII-Ab positivity [OD 405nm] were distinguished in this assay: Negative levels (-) were obtained with dilutions of the standard inhibitor containing < 0.5 BU. Mild levels (+) were obtained with dilutions of 0.5-5 BU. Moderate levels (+2) were obtained for dilutions ranging from 5-25 BU. Maximum positivity (+3) was obtained for dilutions of titers > 25 BU. FVIII-Ab positivity was detected in eight of the normal subjects (15%): three were found to be moderately positive (+2) and five mildly positive (+). No inhibitory activity was detectable when whole plasma was used. All the hemophilic patients with a presence of FVIII inhibitor at the time of the study were found to be positive for FVIII-Ab. In addition, the level of positivity correlated with the corresponding BU. Four of the six patients who had a history of inhibitory were negative and two positive. Twenty additional patients (16.12%) in whom no inhibitory activity was detected were found to be positive for FVIII-Ab: 16 + and four +2. The mean age of patients with FVII-Ab positivity was significantly higher than that of patients of the FVIII-Ab negative group (p < 0.005). In conclusion, FVIII-Ab positivity in patients with hemophilia A was 17.7% higher than the level of positivity detected by an inhibitory assay. We propose that this method for FVIII-Ab analysis could be used for patients with hemophilia A, at least to complement the functional inhibitor assay. FVIII recovery or half-life should be assessed in patients who test positive for FVIII-Ab and who show no evidence of inhibitor.

Adolescent↗
PubMed1994

Hemophilic pseudotumor: multicenter experience over a 25-year period.

Pseudotumor is an infrequent manifestation of bleeding diathesis seen in hemophiliacs, the management of which is still controversial. To ascertain the effectiveness of the main therapies of choice, we have reviewed 1,831 patients affected by hemophilias A (1,108) and B (172), von Willebrand's disease (329), and other miscellaneous coagulopathies (222) diagnosed between 1965 and 1990 in a multicentric, retrospective study. Pseudotumor was proven in 21 patients. Replacement therapy was given in 15 cases as the first therapeutic approach, with complete success attained in only two, whereas surgery, which was carried out in 14 patients, completely resolved the process in eight (P = 0.017). Patients over 40 years of age demonstrated worse prognosis than younger patients (P = 0.02), but no other clinical parameters were shown to have influenced the patients' evolution. Surgical management was the most effective treatment for pseudotumor, although more conservative therapies cannot be overlooked in selected cases.

Adolescent↗
PubMed1994

[Intra-articular methylprednisolone therapy in chronic hemophilic synovitis of the knee].

This prospective study evaluates the effectiveness of intraarticular methylprednisolone (IAMP) (80 mg) in 10 knees of 10 hemophilic patients with chronic synovitis. This treatment was prescribed because the lack of sensitivity to substitutive therapy with the deficient coagulation factor during 2 months. The patients average age was 25 years (range, 18 to 30) and the minimum follow up was 1 year. The patients were radiographically and ultrasonographically (US) evaluated before starting any kind of treatment and periodically until finishing the follow up. The results one year after the injection were excellent in 4 cases, good in 3 cases, fair in 2 cases and poor in 1 case. Correlation between results and previous radiographic status of the knee has not been found. A close correlation between clinical features and US examination findings was demonstrated. This study has demonstrated that IAMP is an useful procedure for medically treating the chronic hemophilic synovitis of the knee, even with radiographic signs of arthropathy. IAMP must be born in mind before applying other methods more aggressive. US is very useful for diagnosing and following up the effects of IAMP on this condition.

Adolescent↗
PubMed1992

Factor IXMadrid 2: a deletion/insertion in factor IX gene which abolishes the sequence of the donor junction at the exon IV-intron d splice site.

DNA from a patient with severe hemophilia B was evaluated by RFLP analysis, producing results which suggested the existence of a partial deletion within the factor IX gene. The deletion was further localized and characterized by PCR amplification and sequencing. The altered allele has a 4,442-bp deletion which removes both the donor splice site located at the 5' end of intron d and the two last coding nucleotides located at the 3' end of exon IV in the normal factor IX gene; this fragment has been replaced by a 47-bp sequence from the normal factor IX gene, although this fragment has been inserted in inverted orientation. Two homologous sequences have been discovered at the ends of the deleted DNA fragment.

Adolescent↗
PubMed1991

Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients.

Platelet von Willebrand factor (vWF) has been suggested to play an important role in the hemostatic process. Clinical and experimental data indicate that bleeding time (BT) and platelet-vessel wall interaction cannot be normalized unless the defect of platelet vWF is also corrected. We have examined the effect of normal platelet concentrate transfusion 1 hour after cryoprecipitate infusion in five type III von Willebrand disease (vWD) patients. The cryoprecipitate infusion attained normal circulating levels of ristocetin cofactor, vWF antigen, and factor VIII activity. In two patients, cryoprecipitate infusion did not modify the BT (greater than 30 minutes), whereas in the remaining three patients BT was only partially corrected (from greater than 30 to 12, 18, and 21 minutes). However, the immediate platelet transfusion completely corrected the BT in four cases, and in one case it shortened the BT to 8.30 minutes (n = 3 to 8 minutes). In the perfusion study, cryoprecipitate infusion only resulted in a slight increase in platelet deposition (surface coverage range: 2.4% to 11.3%), whereas the platelet concentrate transfusion elicited a more marked improvement (range: 8.2% to 26.4%; P less than .02 v post-cryoprecipitate). These results suggest an important in vivo role of the platelet vWF in supporting platelet-vessel wall interaction. They also give support to the occasional addition of normal platelet transfusion to the cryoprecipitate infusion for the control of serious bleeding episodes resistant to cryoprecipitate in severe vWD patients.

Bleeding Time↗
PubMed1991

Identification of a new haemophilia BM case produced by a mutation located at the carboxy terminal cleavage site of activation peptide.

We describe a novel point mutation due to C----G transversion at nucleotide 20518 in the exon VI of factor IX gene, resulting in the substitution of glycine (GGG) for arginine (CGG) at position 180 in the polypeptide. This point mutation was found in a patient with a haemophilia BM variant. We designated the altered factor IX produced by this new mutation as factor IXMadrid. This mutation blocks the cleavage site involved in the release of the activation peptide at Arg180-Val181. It also abolishes the Aval site (CTCGGG) in exon VI, which can be directly detected with the enzymatic DNA amplification technique (PCR) and offers the possibility of direct analysis in carrier and prenatal diagnosis in kindreds with this mutation.

Amino Acid Sequence↗