Consenso mexicano para el diagnóstico y tratamiento de la trombastenia de Glanzmann / Mexican consensus on the diagnosis and treatment of Glanzmann thrombasthenia

Resumen Las plaquetas tienen un papel central en diferentes escenarios fisiológicos, incluyendo la hemostasia; se unen unas con otras en la agregación plaquetaria, lo cual permite formar un coágulo plaquetario. Para que la agregación sea apropiada se requiere del complejo glicoproteico IIb/IIIa (GPIIb/IIIa) en la superficie plaquetaria. Toda alteración funcional plaquetaria, hereditaria o adquirida, impide la formación adecuada del coágulo y se manifiesta como hemorragia. Las enfermedades plaquetarias hereditarias son raras y, hasta recientemente, fueron ignoradas. Una de las más reconocidas y estudiadas es la trombastenia de Glanzmann (TG), entidad en la cual el número de plaquetas puede ser normal pero la función está alterada. Es un padecimiento autosómico y recesivo que causa hemorragia de diferente intensidad toda la vida y en la cual el problema radica en precisamente en la GPIIb/IIIa. Las hemorragias son típicamente mucocutáneas: equimosis, púrpura, epistaxis, gingivorragia; menos frecuentes son la hemorragia gastrointestinal, hemartrosis o en sistema nervioso central. La hiperpolimenorrea es común en las mujeres y llega a ser tan importante que amerita transfusiones en la menarca. La TG afecta a todos los grupos étnicos y su prevalencia varía entre 1/40,000 y 1/400,000. A pesar de esta información acerca de la TG en el mundo, hay pocas guías o recomendaciones basadas en la opinión de expertos y experiencias unicéntricas. En México la TG es rara y no se cuenta con una recomendación general para su diagnóstico y tratamiento. El objetivo de este documento fue establecer un consenso y hacer sugerencias generales para su diagnóstico y tratamiento.

Abstract Platelets have a central role in several physiological scenarios including hemostasis. Platelets bind each other during platelet aggregation allowing the proper formation of the clot; to be appropriate, platelet aggregation requires the glycoproteic complex IIb/IIIa (GPIIb/IIIa). Every platelet function abnormality both, congenital or acquired, impedes clot formation and favors bleeding episodes. Hereditary platelet abnormalities are rare and, until recently, they were almost ignored. Among these disorders, Glanzmann Thrombasthenia (GT) is a widely recognized abnormality in which platelet counts may be normal, but their function is affected. GT is an autosomal, recessive disease that causes life-long bleeding of different intensity. Main biochemical abnormality resides in GPIIb/IIIa. Bleeding is typically mucocutaneous: easy bruising, purpura, and nose and gum bleeds; less frequently are gastrointestinal bleeds, hemarthrosis, or intracranial. Menorrhagia and hyperpolymenorrhea are common findings in in women and may be the cause of anemia requiring blood transfusions at fertile age. GT affects all ethnic groups and its prevalence ranges between 1/40,000 to 1/400,000. Despite this worldwide information regarding GT, only a few guidelines and recommendations have been published, most of them based on expert opinions. In Mexico, GT is rare and there is not a general recommendation regarding its diagnosis and treatment. The aim of this document was to establish a consensus to suggest a general guideline for the diagnosis and treatment of GT in Mexico.

Effects of Rivaroxaban on Platelet Aggregation.

Rivaroxaban is a direct oral anti-factor Xa anticoagulant. It has recently been suggested that rivaroxaban may affect platelet function in vitro; however, little is known about the clinical impact of this likely antiplatelet effect and whether this probable phenomenon is dose-dependent. Our aim was to determine whether rivaroxaban at 4 different doses inhibits direct platelet aggregation. We included adult patients of both sexes and who were allocated to one of the following groups depending on the prescribed daily dose of rivaroxaban: 5, 10, 15, and 20 mg. In 80 patients (20 patients/group), the percentage of platelet aggregation was determined by means of platelet aggregometry tests before and after rivaroxaban use. Basal samples were obtained before starting rivaroxaban and 1 month after treatment, both 2 and 24 hours after the last dose of the drug (12 hours after in the case of rivaroxaban 5 mg). We used 5 platelet agonists: adenosine diphosphate, epinephrine, arachidonic acid, collagen, and thrombin. There were no significant changes in the percentage of platelet aggregation before and after rivaroxaban use independently of the dose administered and the agonist used. Our results have clearly shown that rivaroxaban, even at a high dose, does not directly affect platelet aggregation.

von Willebrand Disease and other hereditary haemostatic factor deficiencies in women with a history of postpartum haemorrhage.

INTRODUCTION: Postpartum haemorrhage (PPH) is the main cause of maternal morbidity and mortality globally, but it is far more important in non-developed countries. PPH represents 25% of all maternal deaths worldwide. Women with von Willebrand disease (VWD) and other inherited haemorrhagic disorders are at increased risk of PPH. Our aim was to establish a probable association of severe PPH in women with a history of haemostatic abnormalities. METHODS: An observational, controlled study of adult women with a one or more episodes of severe PPH requiring treatment in an intensive care unit or >10 units of blood products during the 24-hour period after diagnosis and their controls. The tests performed were blood cell count, blood group, renal, viral, liver function and haemostatic tests, fibrinogen, activity of the plasma factors and specific test to diagnose and classify VWD. RESULTS: We included 124 women with 133 PPH events and their controls. The median age at the first event was 25.5 years old. Results were significantly different between the groups in terms of fibrinogen concentration, VWF:Ag, VWF:RCo and FVIII. A specific diagnosis was established in 69 (55.6) and 4 (3.2%) patients in the PPH group and controls, respectively. Of 61 patients with VWD, 57 had type 1, two had type 2A, and another two had type 2B. CONCLUSION: Our results show a relationship between PPH and inherited haemostatic disorders. VWD was the most frequent diagnosis. Appropriate and opportune diagnosis before pregnancy of inherited haemostatic disorders may be important to effectively prevent and treat PPH.

Impact of Classical Risk Factors for Arterial or Venous Thrombosis in Patients With Antiphospholipid Syndrome.

There are classical risk factors associated with arterial thrombosis (AT) or venous thromboembolic disease (VTD). However, less is known about these risk factors and AT or VTD episodes in patients with antiphospholipid syndrome (APS). Our aim was to elucidate whether APS-related thrombotic episodes are associated with the same risk factors as the non-APS population. We gathered demographics, medical history, complications, and causes of death associated with the risk factors for AT or VTD in patients with APS. We analyzed 677 thrombotic events in 386 patients. Type 2 diabetes mellitus and grade 3 obesity were associated with VTD instead of AT. There were no significant differences between the groups for almost all laboratory tests analyzed, although lupus anticoagulant was significantly higher in the VTD group. We suggest that thrombosis in APS is due to the APS itself and that the risks factors for AT or VTD do not have a main role. Our findings may have an ethnical background. Therefore, it may be difficult to elaborate predictive thrombotic clinical scores applicable to patients with different ethnical background.

Effects of the contraceptive skin patch and subdermal contraceptive implant on markers of endothelial cell activation and inflammation.

Changes in blood coagulation factors may partially explain the association between hormonal contraceptives and thrombosis. Therefore, the likely effects of the contraceptive skin patch and subdermal contraceptive implant on levels of inflammatory markers and endothelial activation were analyzed. This was an observational, prospective, longitudinal, nonrandomized study composed of 80 women between 18 and 35 years of age who made the decision to use the contraceptive skin patch or subdermal contraceptive implant. vascular cell adhesion molecule-1 (VCAM-1), endothelial cell leukocyte adhesion molecule-1 (ELAM-1), von Willebrand factor (VWF), and plasminogen activator inhibitor type 1(PAI-1) as well as high-sensitivity C-reactive protein (hsCRP) were assayed before and after 4 months of use of the contraceptive method. VCAM-1, VWF, and PAI-1 remained unchanged in the contraceptive skin patch group; however, a significant increase in hsCRP (0.29-0.50 mg/dL; P =.012) and a significant decrease in ELAM-1 (44-25 ng/mL; P =.022) were observed. A significant diminution in VCAM-1 (463-362 ng/mL; P =.022) was also found in the subdermal contraceptive implant group. Our results strongly suggest that these contraceptive methods do not induce endothelial activation after 4 months of use. Increase in hsCRP levels was unrelated to changes in markers of endothelial activation.

Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: a prospective study.

BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out.

[Reference values for blood coagulation factor activity in the Mexican population].

INTRODUCTION: During the fluid phase of hemostasis, fibrinogen is converted into fibrin, but other hemostatic factors are required. Reference values of hemostatic factors are established by manufacturers producing reagents using individuals with a specific genetic background. OBJECTIVE: To establish reference values for hemostatic factors in the Mexican indigenous and Mestizo populations. MATERIAL AND METHODS: We carried out a cross-sectional, descriptive study of healthy adult Mexicans. Clotting activity was evaluated using coagulometric assays. Blood donors were informed about the nature of the study and informed consent was obtained prior to blood being drawn. The protocol was approved by the Ethics Committee of our institution. RESULTS: One hundred and twenty samples were assayed (60 females and 60 males). Fibrinogen was higher in mestizos and in females. Reference values for factor XII ranged from 40-170% in indigenous subjects and from 36-159% in mestizos. Factor VIII ranged from 57-160% in indigenous subjects and from 51-209% in mestizo subjects. Reference values for the other hemostatic factors were also clearly different from the commercial reference values. Reference values for hemostatic factors in the Mexican population are different from traditionally used commercial reference values. There were significant differences between indigenous and mestizo Mexicans in the concentration of hemostatic factors with a tendency among mestizos to have higher factor concentrations. Low levels of plasma factor XII are frequent and perhaps may represent a risk factor for thrombotic events. Using these reference values may individualize the reposition of factors in Mexican hemophiliac patients.

Safety of the oral methionine load test: effects on the clinical performance and laboratory tests.

INTRODUCTION: Hyperhomocysteinemia is a prothrombotic risk factor. Homocysteine is evaluated during fasting and after an oral methionine load (OML). AIM: To determine the safety of the OML test according to the general performance status and clinical laboratory tests. We studied healthy nonsmoking volunteers and patients with several thrombotic conditions. Before and after receiving an OML, blood samples were obtained to perform several laboratory tests. We also evaluated acute and subacute adverse effects and 30-day associated morbidity and mortality. Of 353 individuals, three were eliminated because they did not tolerate the OML. We studied 175 healthy individuals and 175 patients without age differences. After OML, mild to moderate clinical abnormalities were recorded in 78 subjects (22.1%): nausea (n = 69; 88.5%), dizziness (n = 13; 16.7%) and decreased or increased blood pressure (n = 8; 10.2%). Nausea always disappeared after breakfast in affected individuals. Prevalence of complications was similar in patients and controls. No patient required hospitalization and there was no mortality during the 30-day study period. In conclusion, OML test had no significant undesirable effects on the clinical status or the general laboratory tests of patients and healthy controls. Some mild and moderate symptoms associated with OML tests were observed, and OML test did not negatively affect general laboratory tests. OML test is a safe diagnostic procedure in patients with previous thrombotic events (and with the consequent associated risk factors such as diabetes mellitus or dyslipidemia) and in healthy subjects.

[Reference values for the blood coagulation tests in Mexico: usefulness of the pooled plasma from blood donors]. / Valores de referencia para las pruebas de coagulación en México: utilidad de la mezcla de plasmas de donadores de sangre.

INTRODUCTION: The blood coagulation system maintains the blood in a liquid state and bleeding and thrombosis are the manifestations of its malfunction. Blood coagulation laboratory evaluates the physiology of this system. OBJECTIVE: To establish both, the reference values for several tests performed at the blood coagulation laboratory as well as the utility of the pooled plasma to perform these assays. MATERIAL AND: METHODS: In this descriptive, cross-sectional, randomized study, we collected plasma from Mexican Mestizos. Each pooled plasma was prepared with the plasma from at least 20 blood donors. We performed screening and special tests and the Levey-Jennings graphs were built and interpreted after each pass. Results of the tests were analyzed and their distribution was established using the Kolmogorov-Smirnov test. To establish the reference values we used 95% confidence intervals. RESULTS: We collected 72 pooled plasmas. The distribution for PT, APTT, and TT tests was abnormal. Although the PT test showed a bimodal distribution it was normal for factor VII. The reference values for the hemostatic, anticoagulant, and fibrinolytic factors were different from those suggested by the manufacturers. CONCLUSION: We established the reference values for the blood coagulation tests in the adult Mexican population. We have shown that the pooled plasma must be used for the screening tests. We suggest that each clinical laboratory should establish its own reference values (at least for the screening tests). To reach this objective, we encourage the use of the pooled plasma.

[Factor VIII activity among young Mexican patients with acute myocardial infarction]. / Actividad del factor VIII en jóvenes mexicanos con infarto agudo del miocardio.

BACKGROUND: Atherothrombotic disease is the leading cause of death worldwide. Most casualties are due to acute myocardial infarction (AMI). Patients younger than 45 years account for 5-10% of AMI cases. These patients generally do not display typical atherothrombotic risk factors. METHODS: Our cross-sectional study included adult patients under 45; men and women with AMI were included. A control group of healthy individuals matched for age, sex, and blood group was included to determine the role of several atherothrombotic risk factors on AMI. One hundred and sixty patients were included, the control group was comprised by 77 males (m) and 83 females (f) RESULTS: Our results indicate that 25% of patients (23 m and 18 f) had increased FVIII compared with 8.8% of control subjects. Mean FVIII activity for patients and controls was 134 mg/dl (95%CI=114) vs. 118 mg/dl (95%CI=128-140), respectively (p=0.001). Prevalence of elevated FVIII was higher than the one found for hypertension or diabetes mellitus. HDL cholesterol was higher among patients than controls. Quantitative variables associated with AMI were high FVIII activity, blood monocyte count and HDL cholesterol. CONCLUSIONS: Classical atherothrombotic risk factors do not fully explain AMI events in the young. High levels of FVIII activity is a moderate but common risk factor in young people suffering AMI.

Actividad del factor VIII en jóvenes mexicanos con infarto agudo del miocardio / Factor VIII activity among young Mexican patients with acute myocardial infarction

Antecedentes: La enfermedad aterotrombótica es la causa de muerte más frecuente y la mayoría corresponde a infarto agudo del miocardio (IAM). Los menores de 45 años representan 5 a 10% de los IAM y es común que no sean portadores de factores de riesgo aterotrombótico clásicos. Métodos: Este estudio transversal analítico incluyó pacientes menores de 45 años con IAM, de uno y otro sexo, pareados por edad, sexo y grupo sanguíneo con sus respectivos controles, para analizar el impacto de diferentes factores de riesgo aterotrombótico sobre el IAM. Incluimos 160 casos y controles, 77 hombres y 83 mujeres. Resultados: El 25% de los pacientes tuvo aumento del factor VIII de la hemostasia (FVIII) vs. 8.8% en los controles. El FVIII promedio para pacientes y controles fue 134 mg/dl (IC 95%=114) vs. 118 mg/dl (IC 95%=128-140), respectivamente (p=0.001). La prevalencia de actividad alta del FVIII fue mayor que la de diabetes mellitus o hipertensión arterial. Paradójicamente, el colesterol HDL fue mayor en los pacientes que en los controles. Las únicas variables cuantitativas asociadas a IAM fueron la actividad alta del FVIII, la cuenta de monocitos en sangre periférica y el colesterol HDL. Conclusiones: Los factores de riesgo aterotrombótico clásicos no explican totalmente el IAM en jóvenes. El aumento de FVIII es un factor de riesgo moderado pero frecuente en la población joven con IAM.

BACKGROUND: Atherothrombotic disease is the leading cause of death worldwide. Most casualties are due to acute myocardial infarction (AMI). Patients younger than 45 years account for 5-10% of AMI cases. These patients generally do not display typical atherothrombotic risk factors. METHODS: Our cross-sectional study included adult patients under 45; men and women with AMI were included. A control group of healthy individuals matched for age, sex, and blood group was included to determine the role of several atherothrombotic risk factors on AMI. One hundred and sixty patients were included, the control group was comprised by 77 males (m) and 83 females (f) RESULTS: Our results indicate that 25% of patients (23 m and 18 f) had increased FVIII compared with 8.8% of control subjects. Mean FVIII activity for patients and controls was 134 mg/dl (95%CI=114) vs. 118 mg/dl (95%CI=128-140), respectively (p=0.001). Prevalence of elevated FVIII was higher than the one found for hypertension or diabetes mellitus. HDL cholesterol was higher among patients than controls. Quantitative variables associated with AMI were high FVIII activity, blood monocyte count and HDL cholesterol. CONCLUSIONS: Classical atherothrombotic risk factors do not fully explain AMI events in the young. High levels of FVIII activity is a moderate but common risk factor in young people suffering AMI.

Activated protein C resistance and factor V Leiden in Mexico.

A common cause of hereditary thrombophilia is activated protein C resistance (APCR), and most cases result from factor V Leiden mutation. An APCR phenotype without association with factor V Leiden has been described. This transversal, observational, nonrandomized study evaluated these 2 phenomena in healthy indigenous and mestizo Mexican subjects (n = 4345), including 600 Mexican natives. No indigenous subjects had APCR, but 82 mestizo subjects did. After retesting, 50 subjects had a negative test. The remaining 32 subjects had factor V Leiden, giving a 0.85% prevalence of factor V Leiden in the mestizo Mexican population. Only 31% of APCR carriers had factor V Leiden. These results show a very low prevalence of APCR and factor V Leiden in Mexico. Except for factor V Leiden, there are no other mutations in the factor V gene responsible for the APCR phenotype. Acquired APCR is nearly twice as prevalent as the inherited variant.