[Von Willebrand disease. Molecular biology and diagnosis]. / Enfermedad de von Willebrand, biología molecular y diagnóstico.

BACKGROUND: Von Willebrand disease is the most common inherited disorder of the coagulation proteins in humans. There are three types: 1, 2A, 2B, 2N, 2M and 3. It is associated with mutations on chromosome 12 in the region p13.2, encoding the von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes. DISCUSSION: The VWF gene has been characterised using molecular biology techniques, which have acquired an important role in diagnosis von Willebrand disease, as well as in the investigation of alterations in other genes, which may be involved in regulating the synthesis, processing, and secretion of VWF. However, there are still no strategies to integrate the molecular biology diagnostic tests available. Analysis of VWF multimers is a methodology that meets the characteristics for diagnosis, but it is not easy to standardise. Considering that even in tertiary centres in our country, von Willebrand patients do not have a definitive diagnosis, it is necessary to implement these methodologies to study and improve diagnosis. CONCLUSIONS: Von Willebrand disease is highly heterogeneous due to the molecular mechanisms that produce the various clinical and laboratory phenotypes. In Mexico there are few studies related to this disease; therefore it is essential to conduct a comprehensive study including clinical, basic, and special testing laboratory tests, in order to establish a correct diagnosis, develop new therapeutic approaches, and offer the appropriate medical care and genetic counselling.

[Type 2N von Willebrand disease (Normandy)]. / Enfermedad de von Willebrand tipo 2N "Normandy"

INTRODUCTION: the results of the laboratory test for 2N von Willebrand disease (2N vWD) are indistinguishable from those of light or moderate haemophilia A, until the technique that evaluates the operation of the vWF: FVIII binding is performed. OBJECTIVE: to determine the prevalence of type 2N vWD in patients diagnosed with light or moderate haemophilia A and type 1 vWD. MATERIAL AND METHODS: twelve healthy donors and twenty-five patients diagnosed with haemophilia A (a carrier) and five suspected of type 1 vWD were included in the study. The common tests of haemostasis for this condition plus the technique of the relationship of the vWF: FVIII recombinant (F VIIIr) binding was performed. RESULTS: the laboratory results of the 30 patients were concordant with the previous diagnosis. However, three with a previous diagnosis of haemophilia A demonstrated a rate of relationship of the vWF: F VIIIr binding lower than the reference interval obtained from the healthy donors, which means it corresponds to 2N vWD. CONCLUSIONS: the screening method of 2N vWD employed in this study allowed to identify for first time in Mexico, the first cases of this variant with a prevalence of 10%. In our country, this method will allow to establishing accurate diagnosis of 2N vWD and to providing specific treatments.

Fc receptor blockade in patients with refractory chronic immune thrombocytopenic purpura with anti-D IgG.

BACKGROUND: This is an evaluation of the treatment of 63 patients with chronic immune thrombocytopenic purpura (54 splenectomized and nine nonsplenectomized) with weekly doses of anti-D (IgG)-coated red blood cells (RBCs). METHODS: All patients were given one 5-15 microg/kg/dose of intravenous (i.v.) anti-D (IgG)-coated RBCs per week (average of 300 microg/dose/week) for a median 3-month period (3-6 months). Treatment modality was evaluated on a weekly basis by platelet counts, measuring of hemoglobin levels, and performance of Coombs tests. RESULTS: All patients presented a clinical response. Fifty-two patients (82.5%) increased their platelet count (PC) and 45 (69.8%) increased their PC >50 x 10(9)/L. In 34 cases, response was sustained. Six of nine nonsplenectomized patients (67%) increased PC, thus avoiding splenectomy; four patients attained a stable complete response (CR). Similar platelet responses were observed in homozygous and heterozygous Rh (D)-positive patients (Rh/Hr phenotypes). Currently, after >10 years, 43 patients present a now permanent complete response with platelet count >50 x 10(9)/L. Ten patients subsequently decreased their platelet count, although they were able to attain CR after receiving six doses of anti-D (IgG)-coated RBCs. CONCLUSIONS: Based on our study of Fc receptor blockade treatment with anti-D (IgG)-coated RBCs with the most difficult cases of ITP, which resulted in a 69.8% successful response rate, we concluded that weekly prescription of anti-D (IgG)-coated RBCs is an effective approach to treating chronic refractory ITP.

Utilidad de la desmopresina en cuatro casos de trombocitopatías asociadas a plaquetas gigantes / Utility of desmopressin in four cases of thrombocytopathy with giant platelets

La agresión plaquetaria requiere de complejos glucoproteicos plaquetarios (Gp), del factor de von Willebrand y del ADP. Los síndromes de Bernard-Soulier (BS) y de la plaqueta gris (SPG) son defectos hereditarios de la función plaquetaria caracterizados por ausencia del Gp lb-lX y ausencia de gránulos alfa, respectivamente, con presencia en ambos síndromes de hemorragias mucocutáneas, tiempo de sangrado (TS) prolongado, trombocitopenia moderada y plaquetas gigantes. Existen informes que la desmopresina (DDAVP) acorta el TS en algunos pacientes con defectos de la función plaquetaria. El objetivo de este estudio fue evaluar la respuesta a DDVAP en cuatro mujeres (2 con SPG + enfermedad de marfán y 2 con BS). Todas presentaron hemorragias mucocutáneas de intensidad variable con TS> 10 minutos, cuenta de plaquetas (CP) entre 40 y 88 X 10/L y defectos en la agregación plaquetaria. El DDAVP se administró a dosis de 0.3µg X kg/dosis única en solución salina, por vía intravenosa durante 30 a 45 minutos. Todas las pacientes fueron estudiadas antes y después de la administración del DDAVP (TS, CP, factor 4 plaquetarios volumen plaquetario medio, factores F.VIII:C, FvW:Ag, FvW:RiCof y agregación plaquetarías). El TS se corrigió a < 6 minutos y se incrementaron los niveles de F.VIII:C, FvW:Ag y FvW:RiCof (> 100 UI/dL); las manifestaciones hemorrágicas desaparecieron. Concluímos que hubo una buena respuesta al DDAVP, la cual puede estar relacionada con mejoría de la adhesión plaquetaria e incremento de multínumeros del factor de von Willibrand

Treatment of patients with hemophilia A and inhibitors to factor FVIII with cimetidine

In this study, cimetidine was used to treat patients with hemophilia A and inhibitors to factor VIII who presented with acute hemorrhages (Group A) and those without hemorrahges (Group B). The dose of cimetidine was 15 mg/kg/day. Group A consisted of five patients with inhibitors between 156 and > 10,000 Bethesda Units (BU), all with serious hemorrhagic problems. The control of hemorrhaging was effective in 100 per cent of these patients, although inhibitor levels remained high (25-380 BU). Group B consisted of seven patients who did not have hemorrhages, whose inhibitor levels were 41-358 BU. Five of these patients no longer had anamnestic responses to Factor VIII after several months of treatment with cimetidine. No difference in the response to cimetidine was seen between HIV positive and HIV negative patients. The results suggest that cimetidine is useful to suppress inhibitores to Factor VIII in patients with hemophilia A

Informe de dos casos con enfermedad de von Willebrand adquirida y uno con hemofilia A adquirida / Report of two cases of acquired von wiellebrand disease and one of acquired hemophilia a

Se informan tres mujeres con inhibidores adquiridos de la coagulación contra el complejo F VIII:C/F vW:Ag que se diagnosticaron como enfermedad de von Willebrand adquidida (vWA) en los casos 1 y 2, y como hemofilia A adquirida en el caso 3. Las edades son de 19, 40, y 38 años para los casos 1, 2 y 3, respectivamente. No tenían historia familiar de padecimientos hemorrágicos, pero sí de enfermedad autoinmune asociada (enfermedad de Graves, lupus eritematosos sistémico y artritis reumatoide + postparto, respectivamente); las tres pacientes presentaban manifestaciones hemorrágicas. En las pruebas de hemostais, el nivel del FVII:C fue menor de 8 U/dL en los tres casos y el F vW:Ag, F vW:RiCof y la agregración plaquetaria con ristocetina estuvieron disminuidos en los dos casos de vWA; la búsqueda del anticoagulante lúpico (Exner) fue positiva en un caso, pero no se confirmó ya que la prueba de neutralización con fosfolípidos plaquetarios fue negativa. La dosificación de los inhibidores contra el F VIII:C, con el método de unidades Bethesda, fue de 50, 38 y 20 para los casos 1 a 3 respectivamente. Al administrar crioprecipitados y DDAVP (desmopresina), las pacientes tuvieron respusta clínica con respuesta parcial en sus parámetros de laboratorio. Con el tratamiento de córticosteroides se obtuvo respuesta; en la paciente con hemofilia adquirida fue necesario un tratamiento inmunosupresor