bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparin-Induced Thrombocytopenia in Patients with Coronary Artery Disease: A Common but Underdiagnosed Syndrome.
Authors: Kim Min Ju , Park Se Hoon , Ahn Tae Hoon , Shin Eak Kyun , Bang Soo-Mee , Cho Eun Kyung , Shin Dong Bok , Lee Jae-Hoon 
Published: October 2019

Abstract
Heparin-induced thrombocytopenia (HIT) is occurring in a relatively low frequency but is sometimes problematic clinically. The aims of this study were to know the epidemiology of HIT in Korean population and to gain some insight of the physicians’ awareness of this syndrome. We obtained the records of all patients treated with unfractionated heparin (UFH) for their acute coronary syndrome at the Gachon Medical School Gil Heart Center during 2002–2003. Eligible patients were required to have checked complete blood counts at least twice in their hospital courses and to have normal baseline platelet count. Patients who had unexplained (absence of all common causes) thrombocytopenia were considered to have clinical HIT. We also reviewed the medical record of all patients with thrombocytopenia to determine whether the treating-physicians have thought and/or ordered any laboratory evaluation for immune-mediated HIT. Among 874 consecutive patients treated with UFH, 272 (31.1%) had never followed their platelet count after admission and 58 (6.6%) had baseline thrombocytopenia. Thus, 554 patients had protocol-compliant data and were included in the study. Median duration of UFH administration was 6 days (range 1 to 41) and 62 (11.1%) patients developed thrombocytopenia. Among the 442 patients who received UFH for > 96 hours, 51 (11.5%) developed thrombocytopenia. In these patients with prolonged UFH administration, 16 had a hematology consult, 30 had suspected to have clinical HIT, and only one had a diagnosis of HIT in their medical records. In 21 patients, possible other causes for thrombocytopenia were evident. Even though this is a tertiary academic hospital, serologic tests for HIT was never ordered. Keeping in mind the limitations of retrospective analyses, the present study shows that thrombocytopenia is common in patients treated with UFH and that physician’s awareness of this syndrome is limited.
The Polymorphism of Platelet Membrane Integrin α2 β1(α2807TT) Is Associated with Premature Onset of Fetal Loss.
Authors: Gerhardt Andrea , Scharf Rudiger E. , Mikat-Drozdzynski Barbara , Krüssel Jan S. , Bender Hans G. , Zotz Rainer B. 
Published: October 2019

Abstract
Inherited thrombophilia could increase susceptibility to adverse pregnancy outcomes such as fetal loss. We determined the G1691A mutation of the factor V gene (FVL), the G20210A mutation of the prothrombin gene, the C677T polymorphism of the methylentetrahydrofolate-reductase (MTHFR) gene, the HPA-1 polymorphism of the b subunit of the platelet integrin αIIbβ3 and the C807T polymorphism of the α subunit of integrin α2β1 in 104 women with fetal loss and 277 normal women. In a subgroup analysis of women with recurrent early fetal loss (n=34), the prevalence of the genetic markers did not differ significantly between the women with early fetal loss and the normal women. However, in this subgroup of patients, the onset of fetal loss was significantly earlier in women with the α2807TT genotype (7.1 ± 1.9 vs. 8.8 ± 1.5 weeks, p=0.001). No such significant difference was observed in carriers of the other genetic markers. In the subgroup analysis of women with late fetal loss (n=70), only the prevalence of heterozygous FVL was significantly associated with late fetal loss (odds ratio 3.2, p=0.002). There was no significant association of any genetic risk factor with premature fetal loss in the subgroup analysis of women with at least one late miscarriage. This study demonstrates a significant association of the α2807TT genotype of the platelet membrane integrin α2β1 with premature onset of early fetal loss. Based on our results it appears that this risk factor does not induce the pathomechanism but modulates the course of fetal loss. Furthermore, our study confirms the association of FVL with late fetal loss.
Localization of Protein Z (PZ) In Situ in Human Neoplastic Tissues.
Authors: Sierko Ewa , Tokajuk Piotr , Ramlau Rodryg , Zimnoch Lech , Kisiel Walter , Wojtukiewicz Marek 
Published: October 2019

Abstract
Tumor cells synthesize and release procoagulants that lead to multi-factorial activation of factor X and subsequent thrombin generation and fibrin formation that in turn contribute to tumor growth and metastatic spread. The activity of factor Xa is inhibited by TFPI (tissue factor pathway inhibitor). Another mechanism of direct inhibition of factor Xa involves protein Z (PZ). Protein Z is a 62-kD, vitamin K-dependent plasma nonpeptidase glycoprotein, which, in complex with PZ-dependent protease inhibitor (ZPI), inhibits factor Xa in the presence of Ca2+ and phospholipids. However, data on the presence of the PZ in tumor malignant tissue are lacking. Results obtained from randomized clinical trials indicate that inhibition of blood coagulation may improve the results of anticancer therapy in selected tumor types. The purpose of the study was to evaluate the localization of PZ in situ in colon, breast, gastric, laryngeal, pancreatic, renal, endometrial cancer, non-small cell lung cancer (NSCLC), malignant melanoma and glial neoplasms. Studies were performed on tumor fragments obtained at surgical treatment of proviously untreated patients. Immunohistochemical procedures using the ABC method employed a specific polyclonal antibody directed against human PZ antigen. Protein Z was localized in cancer cell bodies in all types of malignant tumors examined. Staining intensity was more pronounced in less differentiated cancer cells of anaplastic gliomas. In contrast, more differentiated cancer cells of gastric cancer revealed stronger staining than more malignant ones. Cancer cell bodies of NSCLC and renal cancer were characterized by weak intensity of staining for PZ. In the case of pancreatic and renal cancer, as well as malignant melanoma, the intensity of staining for PZ in cancer cell bodies was irregular: both high and low expression of PZ was observed independent of the degree of malignancy. The expression of PZ was also revealed in association with tumor infiltrating macrophages in colon cancer, NSCLC and malignant melanoma. Furthermore, PZ was localized in small blood vessels of colon, renal, endometrial, gastric cancer, NSCLC, malignant melanoma and glial neoplasms. The observed localization of PZ, particularly in association with cancer cells of all malignant tumors examined, suggests that this protein may exert regulatory effects on tumor growth and metastatic dissemination.
Experimental Study of Fibrinolytic Factors and Its Inhibitors in Rabbits’ Tissues Extract.
Authors: Xu Xiaohua , Huang Liansheng , Lu Xingguo , Xu Genbo , Zhao Xiaoying 
Published: October 2019

Abstract
Objective: To study the expression character of fibrinolytic factors and its inhibitors in rabbits’ tissues extract.
Methods: Tissue plasminogen activator ( tPA ), Plasminogen activator inhibitor-1 ( PAI-1 ), Plasminogen ( Plg ), Plasmin ( Pl ) and α2 Plasmin inhibitor ( α2PI ) were measured by colorimetric assay.
Results: The tissues extract in renal, small intestine, lung, brain and spleen showed strong fibrinolytic function, and expressed markedly high activity levels of tPA, Plg and Pl. But striped muscle, tongue and stomach expressed markedly high activity levels of PAI-1 and α2PI, and showed low fibrinolytic character. There were linear correlation between levels of tPA and PAI-1 ( r=−0.8076, P<0.01 ), Pl and αPI ( r=−0.3278, P<0.05 ), Plg and Pl ( r=0.6811, P<0.01 ) in tissues extract fibrinolytic targets. In relative tissues, renal cortex and renal marrow were significantly high level of tPA and low level of PAI-1, but levels of Plg and Pl in cortex renalis were higher than in renal marrow, the α 2PI level in renal marrow were higher than in renal cortex ( P<0.05~0.01 ). The levels of tPA, Plg and Pl in small intestine were higher than tin large intestine ( P<0.05~0.01 ), but the levels of PAI-1 and α 2PI in small intestine were markedly lower than in large intestine ( P<0.01 ). These indicated that fibrinolytic function in small intestine was stronger than in large intestine. Although the fibrinolytic function in muscle tissue was low, but the levels of tPA, Plg, and Pl in cardiac muscle were obviously higher than in striped muscles, and the levels of PAI-1 and α 2PI were obviously lower than in striped muscle ( P<0.05~0.01 ). These indicated that the fibrinolytic function in cardiac muscle were stronger than in the striped muscle.
Conclusion: The fibrinolytic character existed significant difference in tissues, it has profound significance in the function of heamostasis and thrombosis and physiologic function in tissues.
A Quantitative Trait Locus for Cholesterol/Low Density Lipoprotein within the Promoter of the Factor IX Gene.
Authors: Viel Kevin R. , Khachidze Manana , Buil Alfonso , Soria José Manuel , Souto Juan Carlos , Fontcuberta Jordi , Blanco-Vaca Francisco , Ordoñez-Llanos Jordi , Almasy Laura , Tom Howard 
Published: October 2019

Abstract
The correlation between vitamin K-dependent coagulation factors (CF) and lipids has been previously established, with Factor VII notably receiving attention in the investigation of atherosclerosis. Current evidence suggests that plasma phospholipids (PL) may enhance the procoagulant reactions and may increase the availability of fat soluble vitamin K. PL may also affect the clearance of CF. There appears to be a concomitant decrease in CF as the result of lipid lowering therapies. While investigating single nucleotide polymorphisms (SNP) of the Factor IX (fIX) gene as potential quantitative trait loci (QTL) for fIX activity level (fIX:C) in the GAIT study, we observed an apparent relationship between two SNPs, G-793A and C-698T, with plasma cholesterol concentration. As expected, a similar relationship existed with low density lipoprotein (LDL) concentrations. In the current study, we examine these fIX promoter SNPs, which exhibit near perfect linkage disequilibrium (ρ=0.998, p<0.0001), as a possible QTL for cholesterol and LDL. We performed variance components analyses using Solar. We observed significant (p<0.05) marginal associations between LDL and factor VIII activity level (fVIII:C), fIX:C, cholesterol, VLDL, triglycerides, and BMI. We observed significant marginal associations between cholesterol and fVIII:C, fIX:C, LDL, VLDL, triglycerides, lipoprotein A (Lp(a)), and BMI. There was no association for smoking status or contraceptive use. For LDL, the most parsimonious model included age, age2, sex, age2 by sex, fIX:C, and the SNP covariate (coded −1,0,1). C(−698)T was significantly associated with LDL levels (nominal p=0.0262) and these covariates accounted for 33% of the total variance of LDL, with a similar result for G(−793)A. For cholesterol, the most parsimonious model included age, age2, fIX:C, Lp(a), and the SNP covariate. C(−698)T was significantly associated with LDL levels (nominal p=9.54 X 10−3) and these covariates accounted for 40% of the total variance of cholesterol, with a similar result for G(−793)A. Interestingly, these SNPs showed no association with fIX:C. Even though an increase in fIX:C results in an increase in cholesterol in this study, it is the same unit increase regardless of which allele is present, i.e. there is no interaction. The results of a linkage analysis for markers on the X chromosome were insignificant. Though this finding is intriguing and interesting with regard to the correlation between the vitamin K-dependent coagulations factors and lipids, it is entirely possible that it is by chance alone. These findings and the correlation between lipids and the vitamin K-dependent coagulation factors merit verification in an independent study population.
Quantitative Evaluation of Factor VIII in Factor VIII Products.
Authors: Butenas Saulius , Parhami-Seren Behnaz , Gissel Matthew T. , Gomperts Edward D. , Mann Kenneth G. 
Published: October 2019

Abstract
Several factor VIII products, recombinant and natural, have been used for hemophilia A treatment worldwide. Typically, two activity-based assays (factor Xase and aPTT) are used for the assessment of factor VIII concentration in these products. Frequently, the results are dependent upon the assay and its modifications in different laboratories. In this study, we evaluated five pharmacologic factor VIII products (three lots of each) in three activity-based assays and in two immunoassays for the concentration and activity of factor VIII protein. Two factor VIII products were plasma-derived (Immunate and Hemofil M) and three were recombinant; two of these contained full-length factor VIII (Recombinate and Kogenate) and one was B-domainless (ReFacto). Albumin-free full-length recombinant factor VIII was used as a standard in all assays. In the factor Xase assay, all recombinant factor VIII products and Immunate at 1U/ml (indicated by manufacturer) showed activity similar to that of 0.7nM (1U/ml) standard, whereas activity of Hemofil M was 64–68% of the standard. In the aPTT assay both full-length recombinant products and Hemofil M displayed activity similar to the standard, whereas Immunate had increased (142% of standard) and ReFacto decreased (83% of standard) activity. In synthetic plasma, all three recombinant products had standard-like activity, whereas Hemofil M and Immunate were slightly more active than standard. The ELISA immunoassay revealed that the factor VIII protein content in Recombinate, Kogenate and Hemofil M corresponded to the units assigned by manufacturers (1.4–1.6x1012U/mol vs1.4x1012U/mol calculated for standard), whereas the specific activity of Immunate was 50% of that expected (0.7x1012U/mol). In contrast, the specific activity of ReFacto was almost 3-fold that of full-length factor VIII (4.0x1012U/mol). The data of this study indicate that: 1) factor VIII activity estimated in different assays gives dissimilar results; 2) the specific activity of factor VIII in various factor VIII products is different and, as a consequence, administration of an equal factor VIII activity in U/ml means the administration of different amounts of factor VIII protein.
Von Willebrand Factor Levels Do Not Increase with Age in Patients with Type 1 Von Willebrand Disease.
Authors: Tarng Hong I. , Taylor Lynne , Konkle Barbara A. 
Published: October 2019

Abstract
A number of inherited and acquired factors modulate von Willebrand factor antigen (VWF:Ag) levels, including blood type, race, activity and stress level, thyroid hormone status, and, in women, time in menstrual cycle. In reported studies a positive correlation between VWF:Ag and/or factor VIII levels and age has been demonstrated, with an increase of 5 – 6 IU/dL per decade (Conlan MG et al, 1993; Kamphuisen PW et al, 1998). Those studies have primarily assessed VWF and factor VIII as risk factors for ischemic heart disease, cerebrovascular disease, and venous thromboembolism. None of the subjects had von Willebrand disease (VWD). Their VWF:Ag levels were in the higher normal or elevated range. The purpose of this study was to determine whether there is a relationship between age and VWF:Ag level in patients with Type 1 VWD. We collected the data from 36 patients who were diagnosed with type 1 VWD and followed at the Penn Comprehensive Hemophilia and Thrombosis Program up to a period of 13 years (See Table 1 below). For each patient, date of birth, VWF:Ag levels with corresponding test dates were collected by reviewing the medical histories and the lab results. Test results obtained during pregnancy, DDAVP testing, or during prophylaxis or therapy for bleeding control were excluded. One year was set as the observation period, so the adjacent VWF:Ag levels that were tested less than one year were excluded from the dataset. When two test results were available on a patient within a one-year period, the lower test result was used.
To investigate whether there was a relationship between VWF:Ag levels and age, cross-sectional analyses (across each visit) and longitudinal analyses were performed using scatter plots, Spearman and Pearson correlations, and regression analysis. No significant increase in VWF:Ag levels with age was demonstrated. The fact that we did not find an increase in VWF:Ag levels over time in our patients could be due to the relatively small number of patients studied or could reflect a subtype of VWD, due to our selection criteria. Only patients with abnormal values were included. Some patients have a prior diagnosis of VWD and bleeding symptoms, but have normal values when tested. Since these patients are adults, this may be due, at least in part, to an age-related increase. Type 1 VWD may occur secondary to decreased VWF synthesis and/or clearance. It is possible that age-related effects on VWF levels will differ depending on the underlying factor(s) resulting in a lower VWF level. Further studies correlating a patient’s values longitudinally with the underlying pathophysiology of their disease would aid in our understanding of their bleeding risks over time.
Patient # Age at Last Visit, range (mean) Females (%) Race % (Cauc/AA/Other) VWF:Ag mean 36 17–70 (34) 89 78/19/3 49%
Effectiveness of DDAVP in Von Willebrand’s Disease.
Authors: Balasubramanian Lakshmi , Boggio Lisa N. , Foiles Nancy , Green David 
Published: October 2019

Abstract
Objective: Of the inherited bleeding disorders von Willebrand’s disease (VWD) is the most common, with a prevalence of one in 10,000. Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and a variety of plasma-derived concentrates of Factor VIII (FVIII) and von Willebrand factor (VWF) have been used to treat VWD. A prospective multicenter European study recently reported the effectiveness of DDAVP to be 27% in type 1 VWD and 18% in all type 2, which suggests that DDAVP is less effective than previously thought. Here we report our experience in a retrospective analysis of patients with known VWD challenged with DDAVP.
Methods: Intranasal DDAVP was administered to 20 patients with known VWD who were studied before and 2 hours after dosing. A response to DDAVP was defined by a 2-fold increase in both FVIII concentration and ristocetin cofactor activity (VWF:RCo) as well as attainment of a level of at least 30 IU/dL. In addition, 6 subjects had bleeding time (BT) tests performed. Statistical analysis was performed using one-tailed multivariate Student’s t-test.
Results: Three of the 20 patients were excluded from the study: 2 had acquired VWD and 1 inadequate data. Of the 17 evaluable patients, 13 were type 1 and four type 2 (confirmed by multimer analyses). Overall response in the 17 patients was 59% (p<0.001); 13 subjects had FVIII levels that increased to more than 80 IU/dl, and 9 subjects had VWF:RCo levels of more than 50 IU/dl. Responses were observed in 8 of the 13 (62%, p<0.001) subjects with type 1 disorder and 2 of the 4 with type 2. The BT was >10 min prior to DDAVP and decreased significantly, to ≤7.5 min, in 5 of the 6 patients after DDAVP. Even when more stringent requirements for defining a response were used (a 3 fold increase and a level of at least 30 IU/dL of both FVIII and VWF:RCo activity, as used by the European multicenter study), 5 of 13 (39%, p=0.01) of the type 1 patients had a response. The average increase in responders in VWF:RCo was 3.33 fold and FVIII, 4.43 fold.
Conclusions: The majority of patients with VWD have a significant biological response to intranasal DDAVP; a challenge test with intranasal drug identifies responders who should be considered for treatment with this agent.
The Prevalence and Clinical Significance of Inherited Thrombophilic Risk Factors in Patients with Antiphospholipid Syndrome.
Authors: Diz-Kucukkaya Reyhan , Inanc Murat , Pekcelen Yuksel 
Published: October 2019

Abstract
Antiphospholipid syndrome (APS) is defined as the occurrence of thrombosis and/or recurrent fetal losses in association with the presence of antiphospholipid antibodies (APLA). Although it has been suggested that APLA have a pathogenic role in the thrombotic complications of APS, pathogenicity of APLA has not been conclusively proven. It has been speculated that other inherited or acquired thrombogenic risk factors might influence the development of thrombosis in patients with APS. In the present study, we examined the effect of well known inherited thrombophilic risk factors (inherited protein C (PC), protein S (PS) and antithrombin (AT) deficiencies; factor V Leiden (FVL) G1691A mutation, and prothrombin G20210A mutation) in the development of thrombosis in APS patients. Seventy-three definite APS patients with arterial and venous thrombosis (group 1: APS patients with thrombosis), 29 antiphospholipid antibody-positive patients with first trimester abortus and/or thrombocytopenia and no history of thrombosis (group 2: APLA-positive patients without thrombosis), and 126 healthy controls (group 3) were included into the study. PC, PS, and AT deficiencies were screened with functional assays; the presence of FVL mutation and prothrombin mutation were detected by polymerase chain reaction. PS and AT activities were found to be normal in all groups. Only a single APS patient with thrombosis had been found to have PC deficiency, PC activities were normal in both APLA-positive patients without thrombosis and healthy controls. The frequencies of FVL A allele for APS patients with thrombosis, APLA-positive patients without thrombosis, and healthy controls were 10.4%, 6.8%, and 4.9%, respectively. The frequency of FVL A allele was significantly higher in APS patients with thrombosis compared with healthy controls (10.4% vs 4.9%, p= 0.02 with chi-square test). The frequencies of prothrombin A allele for APS patients with thrombosis, APLA-positive patients without thrombosis and healthy controls were 3.4%, 0%, and 1.3%, respectively. Although the frequency of A allele was higher in APS patients with thrombosis compared with both APLA-positive patients without thrombosis and healthy controls, it was not statistically significant. Our results showed that inherited PC, PS, AT deficiencies, and prothrombin G20210A mutation are not common in patients with APS. FVL G1691A mutation may contribute to the development of thrombosis in a small group of APS patients. This study suggests that the known inherited thrombophilic risk factors are not responsible for the development of thrombosis in the majority of APS patients. Further prospective studies in larger cohorts of patients are needed to delineate the exact role of thrombophilic mutations in the development of thrombosis in APS.