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.

Long term follow up of haemophilic arthropathy treated by Au-198 radiation synovectomy.

Intra-articular injection of Au-198 (gold synoviorthesis) has been used in the treatment of repeated haemarthroses of the elbows, knees, or ankles in 64 haemophiliacs. These patients had continued to have joint haemorrhages despite appropriate, episodic, substitutive therapy over a period of more than six months. Follow-up for an average period of 14 years in one knee in 38 male haemophiliacs showed 8 good, 23 fair, and 7 poor results with regard to their joint scores. It is concluded that Au-198 is an effective agent for radiation synovectomy, particularly in the early stages of the disease with minimal radiographic changes. It appears to reduce the incidence of haemarthrosis and to slow the rate of evolution of radiographic changes.

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.

Septic arthritis in HIV positive haemophiliacs. Four cases and a literature review.

Septic arthritis is rare in haemophiliacs. Four new cases who were also HIV positive are reported. In three, the knee was involved, and in the fourth the elbow. The organism was streptococcus pneumoniae and staphylococcus aureus in one patient each, and salmonella in two. Although all the patients were human immunodeficiency virus (HIV) positive at the time of diagnosis, only two patients developed autoimmune deficiency syndrome (AIDS) after their septic arthritis. These two died later due to AIDS complications. Treatment was conservative in all cases with antibiotic therapy and prompt rehabilitation. The results were fair in two and good in two. Therefore nonoperative management is advocated before surgical drainage is considered. It seems likely that a positive HIV status is related to the appearance of septic arthritis in haemophiliacs.

La Paz Hemophilia Center, 1967-1992: people, events, and memories.

In 1967, once urgent blood requirements had been resolved in La Paz Hospital, Madrid, Spain, and adequate supplies of plasma for cryoprecipitation, therefore, being available, a Hemophilia Unit (later Hemophilia Center) was set up to attend to the comprehensive care of hemophilia patients and patients with other coagulopathies. This Center covers a regional area and also a national area for referrals and normally attends 600 patients. In this Center the Spanish Social Security Hemophilia Association was created. In 1983 the first cases of AIDS appeared, occasioning the change from standard factor VIII concentrates to the heat-treated concentrates that had recently appeared on the market. At present the Center is responsible for the medical attention of those hemophilia patients affected by HIV.

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.

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.

[Pathogenesis of peripheral cytopenias in hemophiliac patients]. / Observaciones sobre la patogenia de las citopenias periféricas en pacientes hemofílicos.

The frequent occurrence of peripheral cytopenias is a common clinical fact in patients with HIV-1 infection, and its pathogenetic mechanism is not clear, although several hypotheses have been proposed. Such cytopenias are frequently observed in haemophilic patients, in whom the immunologic alteration induced by continuous antigenic stimulants derived from plasma concentrate therapy has been postulated as an additional causative factor. One-hundred and forty five haemophiliacs treated with commercial antihaemophilic concentrates were studied. The patients were divided into three therapeutic groups according to the mean number of units of therapeutic factor VIII administered per Kg every year in the four years prior to the study (group I: less than 500 U; group II: between 501 and 1500 U; group III: more than 1500 U). The occurrence of cytopenias in the patients was co-ordinated with the presence or absence of HIV infection and the therapeutic group. The statistical studies showed clear correlation between peripheral cytopenias and presence of anti-HIV markers, regardless of the amount of concentrates perceived (except for the total neutrophil count).

Síndrome de inmunodeficiencia adquirida: estudios clínicos, inmunológicos y microbiológicos en pacientes hemofílicos / Acquired immunodeficiency syndrome: clinical, immunolofical and microbiological studies in hemophilic patients

La reciente constatación de que el síndrome de inmunodeficiencia adquirida (SIDA) podría afectar en forma especial a homosexuales, drogadictos por vía intravenosa y hemofílicos motivó el inicio, en marzo de 1983, de un seguimiento clínico, inmunológico y microbiológico en 67 pacientes hemofílicos que reciben atención en la Unidad de Hemofilia de la Ciudad Sanitaria La Paz de Madrid. De ellos, 31 eran asintomáticos y 36 portadores de alguno de los signos o síntomas prodrómicos del SIDA. Los resultados obtenidos demostraron, em primer lugar, que un alto número de pacientes hemofílicos presentaban inversión del cociente de linfocitos T inductores/linfocitos T supresores sin que existiera una relación clara con la presencia de signos y síntomas asociados con el SIDA; en segundo lugar, la presencia de infecciones recientes y pasadas en proporciones similares en pacientes sintomáticos y asintomáticos, así como la mayor frecuencia de infecciones recientes por virus del grupo herpes en los hemofílicos con síntomas clínicos, y, en tercer lugar, que uno de los casos evolucionó hacia un cuadro compatible con SIDA. Estos resultados sugieren la existencia del riesgo de que los enfermos de hemofilia padezcan el SIDA, por lo debe mantenerse un control médico especial sobre ellos

Frequency and clinical and transfusional significance of rheumatoid factor in patients with haemophilia and von Willebrand's disease.

Using a solid-phase radioimmunoassay for IgM rheumatoid factor, increased levels were found in 24% or 82 patients with haemophilia A, in 4 of 11 patients with haemophilia B, in 2 of 11 patients with haemophilia A with inhibitors and in 4 of 12 with von Willebrand's disease. The levels of rheumatoid factor increased significantly (p less than 0.02) after factor VIII concentrate or cryoprecipitate transfusions. No clinical or transfusional side effects could be attributed in these patients in relation to the presence of rheumatoid factor.

Effect of circulating immune complexes on transfusional therapy in patients with hemophilia or von Willebrand's disease.

Circulating immune complexes were examined in patients with hemophilia or von Willebrand's disease in order to determine the immediate or long-term side effects after transfusion. The conglutinin binding assay which allows quantitation of C3bi-bearing immune complexes was used for 82 patients with hemophilia A. Immune complexes were detected in 37 (45%) of these cases prior to transfusion. Immune complexes also were detected in four of 11 patients with hemophilia A and factor VIII inhibitors, in five of 11 patients with hemophilia B, and in three of 10 patients with von Willebrand's disease. The levels of circulating immune complexes in 21 patients with hemophilia A and seven with von Willebrand's disease significantly increased 24 hours after concentrate or cryoprecipitate transfusions. Purified immune complexes from three patients with hemophilia A were shown to contain IgG, IgM, and complement components. No factor VIII coagulant or antigenic protein or fibrinogen was identified in the immune complexes using specific antisera. Side effects immediately after transfusion were not associated with immune complexes. The levels of factor VIII or IX after transfusion were not particularly decreased in relation to the presence of immune complexes. Finally, the presence of circulating immune complexes in the patients studied did not correlate with the number of transfusions, the units of concentrates injected, the presence of HBsAg or HbsAb, the levels of plasma aspartate transferase, or the presence of rheumatoid factor. Proteinuria was absent in all the patients studied.