The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System.

The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-ß-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.

Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients.

BACKGROUND: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis. METHODS: We performed a case-control study of consecutive ischaemic stroke survivors aged ≤45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction-restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke. RESULTS: 204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P=.03), tobacco use (P=.02), and the polymorphisms Glu298Asp (genotype: P=.001, allele frequency: P=.001) and C677T (genotype: P=.01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P=.03) and T (P=.01) alleles, hypertension (P=.03), tobacco use (P=.01) and family history of stroke (P=.04) were identified as independent risk factors. CONCLUSION: The polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors.

Interethnic variation of the MMP-9 microsatellite in Amerindian and Mexican Mestizo populations: considerations for genetic association studies.

We studied the interethnic variation of the MMP-9 microsatellite in the Mestizo and Amerindian populations using blood samples collected from 435 healthy unrelated individuals from the Central Valley of Mexico. DNA samples were genotyped using the -90 (CA)12-27 repeat near the MMP transcriptional start site using capillary electrophoresis. Our data were compared with those from African, Asian, and European populations (N = 729). Both Mestizo and Amerindian populations were in Hardy-Weinberg equilibrium (P ≥ 0.05). However, strong genetic heterogeneity was found within the Mestizo population (94%, P ≤ 0.0001), which exhibited the highest frequency of Amerindian, African, and European alleles. Likewise, Amerindians showed 6.7% variation among populations (P ≤ 0.0001), suggesting a genetic substructure potentially associated with linguistic affiliations. These findings were corroborated with principal component and population differentiation analyses, which showed relative proximity among the Mestizos and their historical parental populations: Asian (FST ≥ 0.05), European (FST ≥ 0.09), and African (FST ≥ 0.02). Nevertheless, important differences were found between Mestizo and Nahuas (P ≤ 0.0001), and between Mestizo and Me'Phaas (P ≤ 0.0001). These findings highlight the importance of determining local-specific patterns to establish the population variability of MMP-9 and other polymorphic markers. Validation of candidate markers is critical to identifying risk factors; however, this depends on knowledge of population genetic variation, which increases the possibility of finding true causative variants. We also show that dissimilar ethnic backgrounds might lead to spurious associations. Our study provides useful considerations for greater accuracy and robustness in future genetic association studies.

von Willebrand's disease in Mexico: a pilot study.

von Willebrand's disease (VWD) is the most commonly inherited bleeding disorder. For a long time, it has been said that VWD was absent in some countries due to ethnical differences. Information about the prevalence of VWD in Mexico remains unclear, owing largely to poor awareness and diagnosis of the disease. The aim of this study was to objectively diagnose VWD in a cohort of highly selected Mexican patients with a chronic history of bleeding. Mexican Mestizos were recruited between July 2010 and August 2011. Included were 133 adult and paediatric patients with a high suspicion of VWD. Fifty-three were diagnosed with VWD: 47 (88.7%) with type 1 VWD, four (7.5%) with type 2a VWD and two (3.8%) with type 3 VWD. Mean age for female patients was 19.5 years (range 3-44 years) and 18.5 years (range 4-63 years) for male patients. Mean age at start of bleeding symptoms was 8.8 years (range 1-61). The most frequent clinical symptoms were epistaxis (84.9%), ecchymosis (79.2%), haematomas (71.7%), gum bleeds (62.3%) and petechia (50.9%). Severe transoperative or postoperative bleeding was found in 17 patients (32.1%). Twenty-six women at childbearing age had a history of abnormal gynaecological bleeding. Our results clearly demonstrate the presence of VWD in Mexican and underscore the importance of a more detailed description of VWD. Efforts to increase the awareness and diagnosis of VWD could help in better identification of patients with bleeding disorders and lead to early, appropriate management with safe and efficacious therapies such as desmopressin and plasma concentrates.

Awareness regarding venous thromboembolism among internal medicine practitioners in Mexico: a national cross-sectional study.

BACKGROUND: Venous thromboembolism (VTE) affects millions of patients worldwide and is responsible for thousands of hospitalisations annually. AIMS: To evaluate the awareness regarding VTE among Mexican internists. METHODS: We designed a cross-sectional survey using a questionnaire applied to Mexican internists mainly during academic meetings. RESULTS: We collected 1220 questionnaires. VTE was considered a potential complication for medical inpatients by 85% of the respondents, whereas 69% and 63%, respectively, considered pulmonary embolism to be a complication of deep vein thrombosis (DVT) and a cause of death. Awareness of some VTE risk factors was adequate, and 85% of those physicians surveyed routinely observed patients for these risk factors, although only 58% performed global risk stratification. Only 12% of the respondents considered length of hospital stay as a risk factor, and 58% assumed that the risk decreases after hospital discharge; 64% and 49% responded that the risk is higher, and VTE risk factors are more frequent in surgical versus medical inpatients respectively. VTE diagnosis was reported as easy or very easy for 59% of the respondents, but only 41% regarded phlebography as the gold standard for diagnosing DVT, although 85% of the respondents reported that d-dimer + Doppler ultrasound was an alternative. Pulmonary arteriography or helical computed tomography CT scan was the gold standard for diagnosing pulmonary embolism for 60% of the physicians, but 55% responded that electrocardiogram, arterial gasometry and chest X-ray are also useful. CONCLUSIONS: Awareness regarding VTE risk factors and the degree of diagnostic skills among Mexican internal medicine specialists are low.

[Joint position statement of the Mexican College of Orthopedics and Traumatology: prophylaxis for venous thromboembolic disease in high-risk orthopedic surgery]. / Declaración de posición conjunta del Colegio Mexicano de Ortopedia y Traumatología: profilaxis de la enfermedad tromboembólica venosa en cirugía ortopédica de alto riesgo.

Venous thromboembolic disease (VTED) is a public health problem worldwide. In the United States it causes 2 million annual cases. Its annual incidence is 1-2 cases per 1,000 individuals in the general population. It is a disease frequently associated with life threatening complications and its mortality rate is 1-5% of cases. Due to its high complication rate, its slow recovery, and the need for prolonged disability, it is considered as a high-cost disease. VTED may occur in both surgical and medical patients; the known associated risk factors include prolonged rest, active cancer, congestive heart failure, atrial fibrillation, and stroke, among the major medical conditions. Orthopedic surgery represents the main surgical risk factor for VTED, including mainly hip and knee replacements, as well as polytraumatized patients with severe spinal lesions, and major fractures. VTED may be prevented with the appropriate use of antithrombotics. The participants in this consensus defined thromboprophylaxis as the strategy and actions undertaken to reduce the risk of VTED in patients undergoing high risk orthopedic surgery. The position of the Mexican College of Orthopedics and Traumatology regarding the prevention of VTED in orthopedic surgery is described herein.

Lamivudine-induced pure red cell aplasia.

The aim of this report is to describe five patients with lamivudine-induced pure red cell aplasia, an association not previously described. We describe patients with unresponsive anemia in whom a complete study including blood cell counts, reticulocyte counts, hemolysis tests, and bone marrow aspiration was performed. Pure red cell aplasia was considered when anemia was associated with normal leukocyte and platelet counts with a corrected reticulocyte count below 1% and less than 5% bone marrow erythroid progenitors in the absence of positive hemolysis tests. Complete remission was considered when bone marrow erythroid progenitors were at least 16%. Five male patients had pure red cell aplasia with a median age of 32 years (range 29 to 37 years). Before lamivudine, they had hemoglobin >11.8 g/dl without transfusion requirements. After receiving the drug, hemoglobin dropped to 5.2 g/dl (4.3 to 6.1 g/dl) with high transfusion requirements and mean bone marrow erythroid progenitors of 1.84% (0 to 4%). Withdrawal of lamivudine was attempted to confirm the diagnosis. Seven weeks after stopping lamivudine, hemoglobin rose up to 12.8 g/dl (11 .3 to 13.8 g/dl) and bone marrow erythroid progenitors increased up to 25.6% (21 to 40%) without transfusion requirements. Lamivudine-induced pure red cell aplasia may be a cause of anemia unresponsive to conventional treatment in AIDS. Since lamivudine use in Mexico has been relatively short, we expect more cases to appear in the future.

Serum erythropoietin levels in kidney donors after renal transplantation.

BACKGROUND: Renal transplantation is the treatment of choice for many patients with end-stage renal disease. In the donor, renal excretory function is not affected after nephrectomy; however, little is known about other functions such as erythropoietin production. We studied the erythropoietin production in renal donors after nephrectomy. METHODS: We included healthy individuals fulfilling the criteria for kidney donation. Blood samples were collected before and monthly from 1 to 6 months after nephrectomy. Complete blood cell counts and erythropoietin were assayed. RESULTS: Eight kidney donors were studied. A significant increase in erythropoietin levels was observed during the first 3 months, but no difference was observed by the 4th month as compared with basal values. CONCLUSIONS: Erythropoietin production rose during the first 3 months after nephrectomy. However, erythropoietin was normal by the 4th month. Unchanged hemoglobin levels may suggest that the compensatory production of erythropoietin could participate in the preservation of an adequate physiological status of the donor after nephrectomy.

[Thrombophilia, thromboembolism and the use of the unfractionated and low-molecular-weight heparins]. / Trombofilia, tromboembolia y el uso de las heparinas no fraccionadas y de bajo peso molecular.

An overview of the key concepts about detection of thrombophilic states, establishment of risk factors for thrombosis, the current strategies on diagnosis of thrombophilia, as well as an analysis of the current experience with the use of fractionated and unfractionated heparins, is presented. It is well known that thrombotic disease is multifactorial and that its treatment must be interdisciplinary and multidisciplinary in order to perform an opportune diagnosis and to establish an adequate prophylaxis and anti-thrombotic therapy. Even though several advantages are observed when low molecular weight heparins are used, unfractionated heparins still have some specific indications. Furthermore, under specific conditions, they can work synergistically to achieve a maximal effect on the thromboembolic states. We propose that every medical unit should establish its own criteria and diagnostic and therapeutic algorithms that allow to detect, to diagnose, and to treat the thrombotic events in the best way thus diminishing the morbidity and mortality associated with these thrombotic events.

External quality control program of four blood cell counters.

OBJECTIVE: To evaluate an internal-external quality control program of four automated counters. METHODS: Every one or two weeks during 14 months, six direct cell parameters were measured in three fresh blood samples in four Coulter counters. The median per parameter of the working day was used to detect inaccuracies and if the participants' internal control program confirmed it, a recalibration of the parameter was performed. RESULTS: In 21 of 22 instances, the internal program confirmed an inaccuracy and a recalibration was done (4 leukocyte and 5 erythrocyte counts, 5 hemoglobins, 7 red-cell volumes). In these four parameters there were no large differences between the lowest and highest counter upon analyzing all results whereas all counters differed from one another in the parameters that cannot be recalibrated by the user (platelet volume, red-cell distribution width). CONCLUSIONS: 1. The program contributed to good accuracy and precision within-counters and good concordancy between-counters in the parameters that can be recalibrated. 2. The counter differences in red-cell distribution width were sufficiently large (up to 9%) to affect clinical interpretation. This poses the need of width distribution reference ranges for each counter.

Usefulness of a low-dose intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS.

Infection with the human immunodeficiency virus (HIV) frequently is complicated with thrombocytopenia (HIV-Thr) during all stages of the infection. The treatments for autoimmune thrombocytopenic purpura (ITP) are used in HIV-Thr; however, their effects upon the immune status of patients with acquired immunodeficiency syndrome (AIDS) are unknown. Intravenous immunoglobulin (IVIg) is used in patients with ITP and HIV-Thr; however, its usefulness in thrombocytopenic AIDS patients has not been directly addressed. We used a low-dose IVIg regimen (0.04 g/kg per week during five weeks) for the treatment of HIV-Thr complicating AIDS. Thirteen patients received IVIg. We observed a response to IVIg in 13 patients by the end of week one and in 10 patients by the end of week five. Long-term response, evaluated three months after stopping IVIg, was present in four cases. IVIg was well tolerated and no opportunistic infections were observed during the study period. Compared with previous reports, we used 10% of the previously proposed dosage with an important decrease in the cost of treatment. Our results suggest that this low-dose IVIg regimen is a highly effective, nonexpensive alternative in treating HIV-Thr in AIDS. If sustained responses can be obtained with a similar low-dose maintenance regimen, IVIg may be the first choice for the treatment of HIV-Thr in AIDS patients.

[Changes in blood coagulation in HIV infection]. / Alteraciones de la coagulación en la infección por VIH.

The human immunodeficiency virus (HIV) infection is becoming more complex. Hemostatic abnormalities occur frequently in the patient with HIV. HIV-related thrombocytopenia (Tr-HIV) is the most common hemostatic disorder with a high morbidity and affects patients from every risk group independently of age, sex, or stage of infection. Two mechanisms are responsible for the Tr-HIV: bone marrow failure and immunological disorders, namely, circulating immune complex deposited on the platelet membrane and the production of autoantibodies directed against platelets. The treatment of choice is zidovudine; other available options are not as effective as zidovudine. In addition, there are some abnormalities in the fluid phase of the coagulation cascade which can produce bleeding or thrombosis in the HIV patient. The most common are a prolonged partially activated thromboplastin time test, the production of a lupic anticoagulant and anticardiolipin antibodies, and several abnormalities in the natural-occurring anticoagulants. The thrombotic thrombocytopenic purpura recently associated with HIV has a clinical presentation and treatment alternatives that closely resemble those for the classical disease. The knowledge of these hemostatic abnormalities in the HIV seropositive patient allows a more rational care of these patients.

The incidence of protein C deficiency in thrombosis-related portal hypertension.

OBJECTIVE: To know the incidence of protein C deficiency associated with noncirrhotic, thrombosis-related portal hypertension. METHODS: Thirty-six patients were studied who had thrombosis-related portal hypertension diagnosed by means of hepatic venography or abdominal echocardiography or during abdominal surgery. Liver disease was excluded in 20 patients based on normal liver function tests and normal histology on liver biopsy. At the time of protein C assays, these patients were not receiving oral anticoagulation, and, in those recently diagnosed, the assays were performed more than 14 days after the last thrombotic event. Antigenic and functional assays for protein C were performed by ELISA and chromogenic assay, respectively. RESULTS: We found 11 patients with protein C deficiency who had a median age of 28 yr (range 19-55 yr) at time of diagnosis. Five patients had a history of systemic thromboembolism, and upper GI bleeding was the most frequent symptom related to portal hypertension (six cases). Antigenic protein C levels were measured in nine of the 11 patients (mean 31.88%, range 10-49%). Functional protein C level was assayed for all 11 patients (mean 40.90%, range 15-58%). After diagnosis, all patients received oral anticoagulants (ideally International Normalized Ratio: 2-3). CONCLUSION: We suggest that protein C screening should be performed in patients with thrombosis-related portal hypertension.

[Essential thrombocythemia: a 35-year experience and review of the literature]. / Trombocitemia esencial: experiencia de 35 años y revisión de la literatura.

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by an uncontrolled rise in peripheral blood platelet count. The aim of this report was to determine the clinical and laboratory data of this disease in a 35 years revision. Of the patients with the diagnosis of ET, we selected those who fulfilled five of the six diagnostic criteria proposed by the Poli Vera Study Group. We found 14 cases (10 female and 4 male) with a median age of 54.5 years (range 29-74). The most frequent initial clinical finding was hemorrhage and in four cases the diagnosis was preoperative. Median platelet count was 1,355 x 10(9)/L (range 600 to 3,750). One case had iron deficiency which was corrected before ET was diagnosed. None has evolved to acute leukemia. Initially, most of the cases were treated with busulphan and two received alpha-interferon which was promptly changed to busulphan because of secondary effects. Three patients have died due to hemorrhagic complications and one due to thrombosis. ET has a low frequency in our country and must be considered an exclusion diagnosis. Iron deficiency may mask the diagnosis specially in the cases with a platelet count not very high. Treatment can provide in general a long survival of good quality of life.

[Reference values for protein C activity in healthy adults in Mexico]. / Valores de referencia de la activadad de proteína C en adultos sanos en México.

Protein C (pC) is a natural-occurring anticoagulant and its acquired or hereditary deficiency has been associated with thrombosis. For its screening, technics that appraise both its plasmatic concentration and biological activity are used. The quantitative deficiency is important, but some characteristics of pC activity (pCA) suggest an essential role of the functional deficiency. Because reference levels have not been previously described in Mexico, we report here the results of a pCA assessed by a chromogenic assay in 88 adult healthy mexican people between 15 and 69 years of age. The pCA values at the 2.5 and 97.5% percentiles in our population were 75 and 137% in normal plasma. Functional disorders of this protein have been described in the presence of normal pC quantitative levels and, therefore, there are individuals with low pC concentrations and a normal pCA without thrombosis. These data suggest that the pCA could be a more important screening test than the quantitative determination as the first step in the study of a possible deficiency state of protein C.

Drug-induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor.

Drug induced agranulocytosis (DIA) is a potentially lethal disorder characterized by selective neutropenia. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been utilized for its treatment. We report four cases of DIA treated with GM-CSF at the dose of 5 micrograms/kg/day. The patients presented infectious diseases at diagnosis. Median days to obtain 1 x 10(9)/L neutrophils and a normal neutrophil count (NNC), were 7(5-9) and 7.5 (6-10) days, respectively. The infectious disease at diagnosis improved and all patients are alive at the moment of this report. No other adverse effects than thrombocytosis (two cases) and thrombocytopenia (one case) were observed. We consider that GM-CSF could be a safe and effective alternative in the treatment of DIA.

[The international normalization ratio in the monitoring of oral anticoagulant therapy]. / El cociente de normalización internacional en la vigilancia de la terapia anticoagulante oral.

Oral anticoagulants are employed very frequently in the prophylaxis and treatment of several diseases. For their optimal effectiveness, many vigilance schedules have been proposed but none has proved to be 100% effective. The international normalization ratio (INR) can be a safer way to monitor oral anticoagulation, and our objective was to determine its clinical usefulness. A prothrombin time test (PT) was carried out by means of either a chromogenic or a coagulometric method, and an INR was obtained using the ratio of the PT patient/PT control elevated to an exponential given by the international sensitivity index (ISI) of our thromboplastin. Our objective was to maintain our patients in a therapeutical INR range between two and three. We present our experience with 77 patients and 810 results during an 18 months period. We observed 26 cases of hemorrhage and three of thrombosis. In all these cases, the INR was out of the desired therapeutical range. No deaths occurred in our patients. Our analysis showed a significative disagreement between the INR and the prothrombin time ratio (PTR) but a better correlation with hemorrhage and thrombosis was seen with the INR than with the PTR. Our experience supports the use of INR in the clinical vigilance of oral anticoagulation as a useful method.