Clinical manifestations and gene analysis of 18 cases of hereditary protein S deficiency / 中华血液学杂志

Objective: To analyze the clinical manifestations and molecular pathogenesis of 18 patients with inherited protein S (PS) deficiency. Methods: Eighteen patients with inherited PS deficiency who were admitted to the Institute of Hematology & Blood Diseases Hospital from June 2016 to February 2019 were analyzed: activity of protein C (PC) and antithrombin (AT) , PS activity were measured for phenotype diagnosis; high throughput sequencing (HTS) was used for screening of coagulation disease-related genes; Sanger sequencing was used to confirm candidate variants; Swiss-model was used for three-dimensional structure analysis. Results: The PS:C of 18 patients ranged from 12.5 to 48.2 U/dL. Among them, 16 cases developed deep vein thrombosis, including 2 cases each with mesenteric vein thrombosis and cerebral infarction, and 1 case each with pulmonary embolism and deep vein thrombosis during pregnancy. A total of 16 PROS1 gene mutations were detected, and 5 nonsense mutations (c.134_162del/p.Leu45*, c.847G>T/p.Glu283*, c.995_996delAT/p.Tyr332*, c.1359G> A/p.Trp453*, c.1474C>T/p.Gln492*) , 2 frameshift mutations (c.1460delG/p.Gla487Valfs*9 and c.1747_1750delAATC/p.Asn583Wfs*9) and 1 large fragment deletion (exon9 deletion) were reported for the first time. In addition, the PS:C of the deep vein thrombosis during pregnancy case was 55.2 U/dL carrying PROC gene c.565C>T/p.Arg189Trp mutation. Conclusion: The newly discovered gene mutations enriched the PROS1 gene mutation spectrum which associated with inherited PS deficiency.

Trombosis venosa profunda y trombofilia congénita / Deep-vein thrombosis and congenital thrombophilia

Introducción: La trombofilia es un desorden de la hemostasia congénito o adquirido que predispone al desarrollo de trombosis. Las trombofilias congénitas más frecuentes son las deficiencias de antitrombina III, proteína C y proteína S, el factor V Leiden, la mutación del gen de la protrombina (G20210A) y las mutaciones de la enzima metilentetrahidrofolato reductasa (MTHFR). Objetivo: Describir el manejo anestésico en un paciente portador de trombofilia congénita. Presentación del caso: Se reporta un paciente de 19 años de edad con antecedentes de historia familiar y personal de trombosis venosa profunda, tratamiento con doble antiagregación plaquetaria y asociación de tres mutaciones para trombofilia congénita, G20210A, A1298C MTHFR y C677T MTHFR que recibe anestesia espinal para una herniorrafia inguinal. Se mantiene tratamiento con aspirina, se suspende clopidogrel 7 días antes de la cirugía y durante ese tiempo se administra fraxiparina 0.6 Uds. subcutánea diarias hasta 12 h antes de la cirugía, se utiliza medias elásticas, deambulación precoz y reinicio de clopidogrel 24 h después de la cirugía, con evolución satisfactoria. Conclusiones: La tromboprofilaxis en pacientes portadores de trombofilia congénita es mandatoria, por eso resulta determinante la utilización de heparina de bajo peso molecular junto al resto de las medidas de prevención de la trombosis venosa profunda(AU)

Introduction: Thrombophilia is a congenital or acquired hemostasis disorder that predisposes to thrombosis development. The commonest congenital thrombophilias are deficiencies of antithrombin III, protein C and protein S, factor V Leiden, prothrombin gene mutation (G20210A), and methylenetetrahydrofolate reductase (MTHFR) mutations. Objective: To describe the anesthetic management in a patient with congenital thrombophilia. Case presentation: The case is reported of a 19-year-old patient with a family and personal history of deep-vein thrombosis, treatment with double antiplatelet therapy and association of three mutations for congenital thrombophilia (G20210A, A1298C MTHFR and C677T MTHFR), who receives spinal anesthesia for an inguinal herniorrhaphy. Aspirin treatment is maintained. Clopidogrel is suspended seven days before surgery. During this time, fraxiparin is administered subcutaneously in 0.6-mL units daily, up to twelve hours before surgery. Elastic stockings are used, early ambulation is allowed, and clopidogrel is restarted 24 hours after surgery, with satisfactory evolution. Conclusions: Thromboprophylaxis in patients with congenital thrombophilia is mandatory, a reason why the use of low-molecular-weight heparin, together with the rest of the prevention measures against deep-vein thrombosis, is decisive(AU)

Farnesoid X receptor (FXR) inhibits coagulation process via inducing hepatic antithrombin III expression in mice / 生理学报

Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.

Clinical and genetic analysis of a pedigree affected with type I hereditary antithrombin deficiency due to a g.2736dupT variant of the AT gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the phenotype and genotype of a patient affected with inherited antithrombin deficiency.@*METHODS@#All exons and exon-intron boundaries of the AT genes were subjected to PCR amplification and Sanger sequencing. The influence of variants on the disease was predicted using bioinformatic software (MutationTaster).@*RESULTS@#The results of all coagulation tests were normal, though the antithrombin activity and antigen content of the proband and his father have decreased significantly (34%, 48% and 12.97 mg/dL, 15.60 mg/dL, respectively). His mother was normal. Genetic analysis revealed that the proband and his father both carried a heterozygous g.2736dupT variant of the AT gene. Bioinformatic analysis suggested that the variant may be pathogenic.@*CONCLUSION@#The proband and his father both had type I hereditary antithrombin deficiency caused by a g.2736dupT variant of the AT gene. The variant was unreported previously.

Significance of Tissue Factor-Bearing Microparticle Procoagulation Activity and Antithrombin Ⅲ Detection in Thalassemia Patients / 中国实验血液学杂志

OBJECTIVE@#To explore whether the high risk factors possibly leading to hypercoagulative status and thrombosis exist in Thalassemia patients of Guangxi region through detecting plasma tissne factor-bearing microparticles (TFMP), procoagulatima activity, coagulation and anticoagulation function, fibrinolytic function, endothelial function and platelet count.@*METHODS@#The TFMP procoagulation activity was detected by chromogenic saubstract method, the levels of tissue factors (TF), tissue factor pathway inhibitor(TFPI), protein C (PC), protein S (PS), antithrombin Ⅲ(AT-Ⅲ), tissue plasminogen activator (tPA), thrombin-activated fibrinolysis inhibitor (TAFI), soluble E-selectin (sE-sel), intercellular adhesion molecule-1 (ICAM-1) and thrombomodulin (TM) were detected by ELISA in thalassemia group (n=71) and control group (n=20 heathy persons).@*RESULTS@#Compared with control group, the AT-Ⅲ level decreased in β-thalastemia major group (TM) (P<0.05), the AT-Ⅲ level in TM group independeutly posstiody correlated with plt count (r=0.37, P<0.05); the levels of TF and sICAM in α-thalassenia intermediate group (TA) significantly decteased (P<0.05), the procoagulatim activity of TFMP in β-thalassemia intermediate group (TI) increased sngnificantly (P<0.05)， moreover positively corretated with AT-Ⅲ level (r=0.77, P<0.05). The TF and sICAM-1 levels in normal liver functim group of Thalassemia patients were lower tham those in control group (P<0.01 and P<0.05, respectively), the TFMP activity between normal and abnormal liver function was significantly different (P<0.05), while there were no significant difference in other correspoding indexes beween thalassemia group and control group as well as between each thalassemia groups.@*CONCLUSION@#The damage of liver function and reduction of anticoagylation substances exist in patients with β-thalassenia major in Guangxi region, the procoagulation activity of plasma TFMP in patients with β-thalassemia intermedia abnormally increases. All the above-mentioned factors may increase the risk of high coagulation status or thrombosis is thalassemia patients, the decrease of TF and SICAM-1 levels in patients with α-thalassemia intermedia may be factor against thrombosis.

A Case of Pediatric Unprovoked Deep Vein Thrombosis due to Combined Hereditary Thrombophilia of Antithrombin III and Protein S Deficiency / 임상소아혈액종양

Unprovoked deep vein thrombosis (DVT) is uncommon in pediatric patients and, among those, combined hereditary thrombophilia is particularly rare. We present a 9-year-old Korean boy who developed lower extremity pain with swelling, and was diagnosed with unprovoked DVT due to hereditary (combined hereditary thrombophilia). Coagulation test revealed antithrombin III and protein S deficiency. The genetic work up confirmed the first case of combined antithrombin III deficiency and protein S deficiency by SERPINC1 heterozygous termination mutation [c.685C>T (p.Arg229*)] and PROS1 heterozygous missense mutation [c.1597G>A (p.Val533Met)]. He was treated with continuous heparin and catheter intervention but those were ineffective or transiently effective. His DVT gradually improved only after prolonged anticoagulation.

Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report / 医学前沿

Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in SERPINC1 and PROC lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of PROC and SERPINC1 were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in SERPINC1 and a short deletion variant c.572_574delAGA in PROC. This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the SERPINC1 and PROC gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE.

Differential protein expression in patients with urosepsis / 中华创伤杂志(英文版)

PURPOSE@#Urosepsis in adults comprises approximately 25% of all sepsis cases, and is due to complicated urinary tract infections in most cases. However, its mechanism is not fully clarified. Urosepsis is a very complicated disease with no effective strategy for early diagnosis and treatment. This study aimed to identify possible target-related proteins involved in urosepsis using proteomics and establish possible networks using bioinformatics.@*METHODS@#Fifty patients admitted to the Urology Unit of Lanzhou General PLA (Lanzhou, China), from October 2012 to October 2015, were enrolled in this study. The patients were further divided into shock and matched-pair non-shock groups. 2-DE technique, mass spectrometry and database search were used to detect differentially expressed proteins in serum from the two groups.@*RESULTS@#Six proteins were found at higher levels in the shock group compared with non-shock individuals, including serum amyloid A-1 protein (SAA1), apolipoprotein L1 (APOL1), ceruloplasmin (CP), haptoglobin (HP), antithrombin-III (SERPINC1) and prothrombin (F2), while three proteins showed lower levels, including serotransferrin (TF), transthyretin (TTR) and alpha-2-macroglobulin (A2M).@*CONCLUSION@#Nine proteins were differentially expressed between uroseptic patients (non-shock groups) and severe uroseptic patients (shock groups), compared with non-shock groups, serum SAA1, APOL1,CP, HP, SERPINC1and F2 at higher levels, while TF, TTR and A2M at lower levels in shock groups.these proteins were mainly involved in platelet activation, signaling and aggregation, acute phase protein pathway, lipid homeostasis, and iron ion transport, deserve further research as potential candidates for early diagnosis and treatment. (The conclusion seems too simple and vague, please re-write it. You may focus at what proteins have been expressed and introduce more detail about its significance.).

Effect of ulinastatin on serum levels of tumor necrosis factor-α, P-selectin, and thrombin-antithrombin complex in young rats with sepsis / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the effect of ulinastatin (UTI) for early drug intervention on the serum levels of tumor necrosis factor-α (TNF-α), P-selectin, and thrombin-antithrombin complex (TAT) in young rats with sepsis.</p><p><b>METHODS</b>A total of 120 male rats aged 4 weeks were randomly divided into normal control group, sham-operation group, sepsis group, low-dose UTI group (50 000 U/kg), and high-dose UTI group (200 000 U/kg), with 24 rats in each group. Modified cecal ligation and puncture was performed to establish a rat model of sepsis, and the rats in the low- and high-dose UTI groups were given caudal vein injection of UTI after model establishment. ELISA was used to measure the serum levels of TNF-α, P-selectin, and TAT at 6, 12, and 24 hours after model establishment.</p><p><b>RESULTS</b>The sepsis group had significant increases in the serum levels of TNF-α, P-selectin, and TAT at 6 hours, and the serum levels of TNF-α and TAT continued to increase by 24 hours (P<0.05); P-selectin reached the peak at 12 hours and decreased slightly at 24 hours (P<0.05). The UTI groups had similar change patterns in the levels of P-selectin and TAT as the sepsis group. The UTI groups had significant increases in the level of TNF-α at 6 hours, but gradually decreased over time. The changes in serum levels of TNF-α, P-selectin, and TAT in the UTI groups were significantly smaller than in the sepsis group (P<0.05). The high-dose UTI group had significantly smaller changes in serum levels of TNF-α, P-selectin, and TAT than the low-dose UTI group (P<0.05).</p><p><b>CONCLUSIONS</b>Early intervention with UTI can significantly improve coagulation function and inhibit the production of TNF-α, P-selectin, and TAT in young rats with sepsis. High-dose UTI has a significantly greater effect than low-dose UTI.</p>

Evaluación de la anticoagulación con rivaroxaban, en pacientes con fibrilación auricular no valvular de reciente diagnóstico / Evaluation of oral anticoagulation with rivaroxaban, in patients with new onset non valvular atrial fibrillation

Background: Atrial fibrillation (AF) generates a hypercoagulable state with an increased thrombin generation and raised levels of thrombin-antithrombin complexes, which results in a high risk of stroke and thromboembolism. Aim: To evaluate the anticoagulant effect of rivaroxaban by anti-Xa factor activity and its correlation with thrombin-antithrombin complexes, thrombin generation and prothrombin time in patients newly diagnosed with non-valvular AF. Patients and Methods: Prospective study in patients with indication of anticoagulation. Demographic variables, cardiovascular risk factors, CHA2DS2-VASc and HAS-BLED scores were recorded. Blood samples were taken at baseline, at 3 and 24 hours after the administration of the drug and at 30 days. Rivaroxaban levels, anti-Xa activity, prothrombin time, thrombin generation and plasma levels of thrombin-antithrombin complexes were determined. Results: We studied 20 patients aged 76.3 ± 8.0 years (60% female) with a CHA2DS2-VASc score > 2 points. The anti-Xa factor activity correlated with rivaroxaban plasma levels at 3 hours (r = 0.61, p < 0.01), at 24 hours (r = 0.85, p < 0.01) and at 30 days (r = 0.99, p < 0.01), with prothrombin time at 3 hours (r = -0.86, p = 0.019) and at 30 days (r = -0.63, p = 0.02) and with a sustained decrease in thrombin generation at 30 days of follow-up (r = -0.74, p < 0.01). There was no correlation with thrombin-antithrombin complexes (r = -0.02, p = 0.83). Conclusions: Rivaroxaban consistently inhibited the mild pro-coagulant state found in newly diagnosed non-valvular AF patients through the first 24 hours and this effect was maintained at 30 days. Plasma levels of the drug correlated with anti-Xa factor activity, thrombin generation and prothrombin time

Production, purification and characterization of recombinant human antithrombin III by Saccharomyces cerevisiae

Background: Antithrombin III (ATIII) is a protein that inhibits abnormal blood clots (or coagulation) by breaking down thrombin and factor Xa. ATIII helps to keep a healthy balance between hemorrhage and coagulation. The present work demonstrated the production, purification and characterization of recombinant human antithrombin (rhAT) from yeast Saccharomyces cerevisiae BY4741 was demonstrated. After expression of rhAT by S. cerevisiae, the biomass and rhAT concentration were analyzed through fed-batch fermentation process. Results: In fed-batch fermentation, the biomass (maximum cell dry weight of 11.2 g/L) and rhAT concentration (312 mg/L) of the expressed rhAT were achieved at 84 h of cultivation time. The maximum cell lysis efficiency (99.89%) was found at 8 s sonication pulse and 7 mL lysis buffer volume. The rhAT protein solution was concentrated and partially purified using cross-flow filtration with the recovery yield and purity of 95 and 94%, respectively. The concentrated solution was further purified by the single step ion exchange chromatography with the recovery yield and purity of 55 and >98%, respectively. The purified rhAT was characterized by various analytical techniques, such as RP-HPLC, FT-IR, CD, SDS-PAGE, western blotting, and Liquid chromatography mass spectrometry (LC-MS) analysis. The biological activity of rhAT was analyzed as heparin cofactor to meet the therapeutic grade applications. Conclusions: The simple, cost-effective and economically viable nature of the process used in the present study for the production of rhAT will be highly beneficial for the healthcare sector. This may also be used to produce other value-added therapeutic recombinant proteins expressed in S. cerevisiae, with greater effectiveness and ease.

The preliminary research in paroxysmal nocturnal hemoglobinuria with thrombosis / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the high risk factors of thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). It has been reported that in Chinese patients with venous thrombosis, the mutation frequency in PROC c.574_576 del (rs199469469), PROC c.565C>T (rs146922325) and THBD c.-151G>T (rs1698852) was higher than that of normal controls, indicating its importance in thrombophilia pathogenesis.</p><p><b>METHODS</b>142 patients with PNH diagnosed between 2009 and 2015 were enrolled in the study. Clinical data were analyzed and thrombophilia risk factors, such as the level of protein C, protein S, antithrombin III, APC resistance, blood fat, phospholipid antibody, were evaluated. Samples from patients and 100 normal controls were detected for the mutations of PROC c.574_576 del (rs199469469), PROC c.565C>T (rs146922325) and THBD c.-151G>T (rs1698852) by Sanger sequence.</p><p><b>RESULTS</b>Of the 142 PNH patients, 21 (14.8%) patients had at least 1 episode of thrombotic event. Only 2 patients had arterial thrombosis and 19 patients had venous thrombosis. The median age of patients with thrombosis was 35 years old, similar to those without episode (40 years old, P=0.687). The ratios of males and females were 1.33 in thrombosis group and 1.57 in non-thrombosis group (P=0.728) , respectively. Patients with thrombosis had the same disease pattern compared with those without episode. Although there was no difference in the level of hemoglobin, WBC and PLT count, and LDH level between patients with thrombosis and those without episode, patients with thrombosis showed higher RBC, higher percentage of CD59(-) granulocytes and RBC, and Flaer(-) granulocytes compared with those without episode. The routine thrombophilia screening tests did not show any difference either between PNH patients and normal controls, or between patients with or without thrombosis. There were two mutations in rs199469469 and rs16984852 sites in patients with PNH, but the mutated patients did not have any thrombosis. Mutation rs146922325 was found in PNH patients. The mutation rate was similar between PNH patients and normal controls, thrombotic PNH and non-thrombotic PNH (P>0.05).</p><p><b>CONCLUSIONS</b>Compared with non-thrombotic patients, PNH thrombotic patients have bigger PNH clone and higher RBC count. There are no differences among the routine thrombophilia factors and the three known venous eligible genes either between PNH patients and normal controls or between thrombotic and non-thrombotic PNH patients.</p>

Phenotypic and genetic analysis of two pedigrees affected with hereditary antithrombin deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the phenotype, genotype and molecular mechanism for two pedigrees affected with hereditary antithrombin (AT) deficiency.</p><p><b>METHODS</b>Clinical diagnosis was validated by assaying of coagulation parameters including prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin activity (AT:A) and specific antigen (AT:Ag), protein C activity, as well as protein S activity. To detect potential mutations in the probands, all exons, exon-intron boundaries and the 3', 5' untranslated regions were amplified by PCR and subjected to direct sequencing. Suspected mutation was confirmed by reverse sequencing and silver staining. The effect of mutations on the AT protein was analyzed with bioinformatics software.</p><p><b>RESULTS</b>The AT:Ag of pedigree 1 was normal, but its AT:A has reduced to 30%. A heterozygous c.235C>T mutation in exon 2 causing p.Arg47Cys, in addition with two single nucleotide polymorphisms (c.981G>A, c.1011G>A) in exon 5 were identified in the patient. His four children, except for the elder daughter, were heterozygous for the mutations. The plasma levels of AT:A and AT:Ag in proband 2 have decreased to 39% and 103 mg/L, respectively. A heterozygous deletion (g.5890-5892delCTT) leading to loss of p.Phe121 was also detected in his father. Bioinformatic analysis suggested that the missense mutation Arg47Cys can affect the functions of AT protein. Meanwhile, lacking of Phe121 will result in loss of hydrogen bonds with Ala124, Lys125 and the cation π interactions with Lys125, Arg47, which may jepordize the stability of the protein.</p><p><b>CONCLUSION</b>The proband 1 had type II AT deficiency, while proband 2 had type I AT deficiency. The p.Arg47Cys and g.5890-5892delCTT mutations of the AT gene are significantly correlated with the levels of AT in the two probands, respectively.</p>

Etiologic characteristics and index pregnancy outcomes of recurrent pregnancy losses in Korean women

OBJECTIVE: The goal of this study was to evaluate the etiologies and clinical outcomes of Korean recurrent pregnancy loss (RPL) patients. And also, we investigated the differences between primary and secondary RPL patients, between two and three or more pregnancy losses. METHODS: One hundred seventy eight women diagnosed as RPL were enrolled. We performed chromosomal analysis, thyroid stimulating hormone, prolactin, blood glucose, plasminogen activator inhibitor-1, natural killer cell proportion, anticardiolipin antibodies, antiphospholipid antibodies, lupus anticoagulant, anti-β2glycoprotein-1 antibodies, antinuclear antibody, protein C, protein S, antithrombin III, homocysteine, MTFHR gene, factor V Leiden mutation, and hysterosalphingography/hysteroscopic evaluation. RESULTS: The mean age was 34.03±4.30 years, and mean number of miscarriages was 2.69±1.11 (range, 2 to 11). Anatomical cause (13.5%), chromosomal abnormalities (5.6%), and endocrine disorders (34.3%) were observed in RPL women. Elevated natural killer cell and antiphospholipid antibodies were observed in 43.3% and 7.3% each. Among of 178 women, 77 women were pregnant. After management of those women, live birth rate was 84.4% and mean gestational weeks was 37.63±5.12. Women with three or more RPL compared with women with two RPL had more common anatomical cause such as intrauterine adhesions and lower rates of spontaneous pregnancy. Compare with secondary RPL women, immunological abnormalities were more common in primary RPL. However, miscarriage rates were not different. CONCLUSION: Immunological factor including autoimmune and alloimmune disorders was most common etiology of RPL. Inherited thrombophilia showed different patterns with other ethnic countries. Miscarriage rates were not different between primary and secondary RPL, or between two and three or more miscarriages group.

Etiologic characteristics and index pregnancy outcomes of recurrent pregnancy losses in Korean women

OBJECTIVE: The goal of this study was to evaluate the etiologies and clinical outcomes of Korean recurrent pregnancy loss (RPL) patients. And also, we investigated the differences between primary and secondary RPL patients, between two and three or more pregnancy losses. METHODS: One hundred seventy eight women diagnosed as RPL were enrolled. We performed chromosomal analysis, thyroid stimulating hormone, prolactin, blood glucose, plasminogen activator inhibitor-1, natural killer cell proportion, anticardiolipin antibodies, antiphospholipid antibodies, lupus anticoagulant, anti-β2glycoprotein-1 antibodies, antinuclear antibody, protein C, protein S, antithrombin III, homocysteine, MTFHR gene, factor V Leiden mutation, and hysterosalphingography/hysteroscopic evaluation. RESULTS: The mean age was 34.03±4.30 years, and mean number of miscarriages was 2.69±1.11 (range, 2 to 11). Anatomical cause (13.5%), chromosomal abnormalities (5.6%), and endocrine disorders (34.3%) were observed in RPL women. Elevated natural killer cell and antiphospholipid antibodies were observed in 43.3% and 7.3% each. Among of 178 women, 77 women were pregnant. After management of those women, live birth rate was 84.4% and mean gestational weeks was 37.63±5.12. Women with three or more RPL compared with women with two RPL had more common anatomical cause such as intrauterine adhesions and lower rates of spontaneous pregnancy. Compare with secondary RPL women, immunological abnormalities were more common in primary RPL. However, miscarriage rates were not different. CONCLUSION: Immunological factor including autoimmune and alloimmune disorders was most common etiology of RPL. Inherited thrombophilia showed different patterns with other ethnic countries. Miscarriage rates were not different between primary and secondary RPL, or between two and three or more miscarriages group.

Antitrombina III / Antithrombin III

Antitrombina III Antithrombin IIICódigo SCPC (Sociedad Colombiana de Patología Clínica): 10700. Código CUPS (CodificaciónÚnica de Procedimientos en salud): 902007. Sección: Hematología. Nivel de complejidad:alto. Metodología: colorimetría. Sinónimos: actividad de antitrombina.DefiniciónLa prueba de antitrombina III, un inhibidor natural de la coagulación, es útil para el diagnóstico del riesgo de trombosis o bien para definir la etiología en pacientes con episodios previos de tromboembolismo venoso. La actividad de la antitrombina se determina mediante un método colorimétrico a partir de muestras de plasma citratado.Espectro clínico de aplicaciónLa antitrombina es una glicoproteína dependiente de vitamina K, sintetizada en el hígado, que actúa como un inhibidor natural de la coagulación mediante la unión irreversible a la trombina y al factor Xa y, en menor medida, a los factores Ixa, XIa, XIIa, plasmina y calicreína. De esta forma, la antitrombina inhibe múltiples puntos la cascada de la coagulación y, debido a esto, su deficiencia funcional o cuantitativa predispone a la trombosis.En la población general la deficiencia de antitrombina es variable, afectando alrededor de una por cada 500-5.000 personas. La deficiencia de antitrombina puede corresponder a una deficienciaen la concentración, la actividad o ambas; a su vez, puede ser hereditaria, congénita o adquirida. Existen varios tipos de deficiencia congénita y hereditaria que se resumen en la tabla 1. Por su parte, la deficiencia adquirida de antitrombina se puede presentar en pacientes con enfermedades hepáticas, coagulación intravascular diseminada, síndrome nefrótico, bypass cardiopulmonar, sepsis o con historia de nacimiento prematuro.

A Case of Streptococcus pneumoniae associated Hemolytic Uremic Syndrome with DIC

Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is one of the causes of atypical hemolytic uremic syndrome, and increasingly reported. They are more severe and leave more long-term sequelae than more prevalent, typical hemolytic uremic syndrome. But it is not so easy to diagnose SpHUS for several reasons (below), and there was no diagnostic criteria of consensus. A 18 month-old-girl with sudden onset of oliguria and generalized edema was admitted through the emergency room. She had pneumonia with pleural effusion and laboratory findings of HUS, DIC, and positive direct Coombs' test. As DIC or SpHUS was suspected, we started to treat her with broad spectrum antibiotics, transfusion of washed RBC and replacement of antithrombin III. On the 3rd day, due to severe hyperkalemia and metabolic acidosis, continuous renal replacement therapy (CRRT) was started. She showed gradual improvement in 4 days on CRRT and discharged in 16 days of hospital care. At the follow up to one year, she has maintained normal renal function without proteinuria and hypertension. We report this case with review of articles including recently suggested diagnostic criteria of SpHUS.

A Case of Streptococcus pneumoniae associated Hemolytic Uremic Syndrome with DIC

Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is one of the causes of atypical hemolytic uremic syndrome, and increasingly reported. They are more severe and leave more long-term sequelae than more prevalent, typical hemolytic uremic syndrome. But it is not so easy to diagnose SpHUS for several reasons (below), and there was no diagnostic criteria of consensus. A 18 month-old-girl with sudden onset of oliguria and generalized edema was admitted through the emergency room. She had pneumonia with pleural effusion and laboratory findings of HUS, DIC, and positive direct Coombs' test. As DIC or SpHUS was suspected, we started to treat her with broad spectrum antibiotics, transfusion of washed RBC and replacement of antithrombin III. On the 3rd day, due to severe hyperkalemia and metabolic acidosis, continuous renal replacement therapy (CRRT) was started. She showed gradual improvement in 4 days on CRRT and discharged in 16 days of hospital care. At the follow up to one year, she has maintained normal renal function without proteinuria and hypertension. We report this case with review of articles including recently suggested diagnostic criteria of SpHUS.

Inherited thrombophilia profile in patients with recurrent miscarriages: Experience from a tertiary care center in north India

The cause of recurrent miscarriage (RM) remains unexplained in approximately 30% to 50% cases. The association of inherited thrombotic factors and RM patients has not been documented from the northern part of India. A total of 40 patients had been investigated for inherited thrombophilia workup (protein C, protein S [PS], antithrombin III, and factor V Leiden [FVL] mutation) over a period of 10 years (2005 to 2014). RM patients were divided in to three groups. Group I (only 1st trimester loss), group II (only 2nd and 3rd trimester), and group III (mixed). Each group comprised of the following numbers of patients respectively: I, 24; II, 2; III, 14. Heterozygous FVL mutation was found in 10% (4/40) cases. PS deficiency was detected in 2.7% (1/37) cases. In the present study FVL and PS were seems to be associated with a subset of patients however further studies with larger numbers of patients are recommended for better evaluation.

Proteomic Profiling of Serum from Patients with Tuberculosis

BACKGROUND: Effective treatment and monitoring of tuberculosis (TB) requires biomarkers that can be easily evaluated in blood samples. The aim of this study was to analyze the serum proteome of patients with TB and to identify protein biomarkers for TB. METHODS: Serum samples from 26 TB patients and 31 controls were analyzed by using nano-flow ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry in data-independent mode, and protein and peptide amounts were calculated by using a label-free quantitative approach. The generated data were analyzed by using principal component analysis and partial least squares discriminant analysis, a multivariate statistical method. RESULTS: Of more than 500 proteins identified, alpha-1-antitrypsin was the most discriminative, which was 4.4 times higher in TB patients than in controls. Peptides from alpha-1-antitrypsin and antithrombin III increased in TB patients and showed a high variable importance in the projection scores and coefficient in partial least square discriminant analysis. CONCLUSIONS: Sera from patients with TB had higher alpha-1-antitrypsin levels than sera from control participants. Alpha-1-antitrypsin levels may aid in the diagnosis of TB.