bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Associations and Significance of Biphasic aPTT Transmittance Waveforms.
Authors: Stoffman Jayson M. , Israels Sara J. 
Published: October 2019

Many modern automated coagulometers determine coagulation parameters such as the PT and aPTT using optical endpoints. One instrument (MDA-180, BioMerieux, Durham, NC) continuously monitors changes in optical transmittance through the specimen over the course of clot formation, and is able to analyze measurements derived from the resulting waveform. The waveform is typically sigmoid, with a sharp drop in transmittance at the time of clot formation. In some specimens, a biphasic waveform (BPW) pattern has been observed, in which the normally flat pre-coagulation segment has a negative slope prior to the sharp drop in transmittance associated with clot formation. The BPW pattern has been associated with sepsis, DIC, and increased mortality in adult patients.
The Special Haemostasis Laboratory of the Health Sciences Centre in Winnipeg, Canada uses the MDA-180 for all automated coagulation assays. Over a two-year period (August, 2002 to July, 2004), a BPW was identified in 21 adult and 12 pediatric patients. Hospital records of these patients were reviewed for details of their clinical condition, and coagulation test results were examined for presence of hemostatic abnormalities.
Sepsis was a common diagnosis at the time of detection of the BPW, seen in 57% of the adults and 42% of the children. However, 4 adults (19%) and 4 children (33%) were identified during routine investigations for clinical bleeding or thrombophilia. In contrast to previously reported studies, DIC was less prevalent, seen in only 7 (33%) of the adults and 3 (25%) of the children. The presence of lupus anticoagulants, alone or in conjunction with other coagulation abnormalities, was observed in 8 adults (38%) and 9 children (75%). This association has not previously been reported. Nine adults (43%) and four children (33%) died, all from complications of sepsis.
Despite the small sample size, this study questions the clinical utility and specificity of the BPW as an indicator of sepsis and DIC. The association with DIC seems particularly weak in the pediatric population, in which the BPW has not been previously evaluated. Further study is required to determine the strength of the association between the BPW and DIC, and to identify other clinical and laboratory conditions, such as lupus anticoagulants, which may confound this association.
Factor V Leiden Mutation Enhances Thrombin Formation in Healthy Newborn Infants.
Authors: Hyytiäinen Satu , Ulander Veli-Matti , Wartiovaara-Kautto Ulla , Kaaja Risto , Heikinheimo Markku , Petäjä Jari 
Published: October 2019

Abstract
Background: At birth, the coagulation system is activated resulting in thrombin formation in the newborn. In sick newborns, the coagulopathy may lead to bleeding or thrombotic complications. Known genetic prothrombotic defects are risk factors for thrombosis in adults but their potential influence on perinatal coagulopathy remains unknown. Accordingly, we prospectively studied the influence of genetic thrombophilia on thrombin formation during the first two weeks of life.
Methods: Newborns from 22 pregnant women with thrombophilia (Factor V Leiden (FVL), n=16; anticardiolipin antibodies, n= 3; lupus anticoagulant, n=1; protein C deficiency, n=1; prothrombin G20210A mutation, n=1) were enrolled into the study. All women were treated with low-molecular-weight heparin during pregnancy and all the infants were born at term. Blood samples were collected from the umbilical cord, and on postnatal days 1 and 14. Newborns were screened for FVL and prothrombin G20210A mutation. Eight FVL heterozygotes were found. No infant tested positive for anticardiolipin antibodies or lupus anticoagulant. Thrombin formation was assessed by measuring prothrombin fragment F1+2. For samples on day 1, a previous cohort of 32 newborns (mean gestational age 33.6 weeks, unknown FVL status) treated in our neonatal intensive care unit (NICU) was used as an additional control.
Results: Relative to known normal range in adults, enhanced thrombin formation (F1+2>1.1 nM) was detected in cord blood and on day 1 in all newborns followed by near normalization on day 14. The median level of F1+2 from umbilical cord sample to day 1, and to day 14 in FVL negative newborns was 2.4 nM (n=13) − 2.0 nM (n=10) − 2.0 nM (n=12), and in FVL heterozygotes 4.8 nM (n=7) − 5.8 nM (n=5) − 1.7 nM (n=8). In FVL heterozygotes but not in FVL negative newborns the F1+2 decrease from umbilical cord sample to day 14 was significant (Wilcoxon p=0.02). On day 1, the FVL heterozygotes showed elevated F1+2 levels when compared with a cohort of 32 newborns in NICU (median F1+2 2.3 nM in NICU group vs 5.8 nM in FVL heterozygotes; p=0.06).
Conclusions: Factor V heterozygosity was associated with transiently enhanced thrombin formation in healthy newborns during the first days of life.
Murine Reagents and Analytical Tools to Enhance the Utility of Mouse Models for the Study of Human Thrombotic Disorders and Disease States.
Authors: Marcotuillo Michelle , Johnson Vicki , Jenny Richard J. , Dorfman Ryan H. 
Published: October 2019

Abstract
The mechanisms that govern blood coagulation and fibrinolysis have been studied extensively by employing a variety of experimental techniques and in-vivo model systems. Murine models are a valuable resource to test new strategies in the areas of thrombosis and haemostasis. Because both normal and genetically altered mice are available, the murine models are ideal for this application. Murine models are in prevalent use and there exists a limited number of reagents available to assist the researcher. Development of murine reagents and analytical tools will enhance the utility of murine coagulation models by allowing researchers to acquire appropriate standards for characterization, validation, and screening of murine model systems. Recently, we have purified and characterized a group of nine mouse plasma proteins including the enzymatic forms of many of these proteins. A total of eight new polyclonal antibodies to murine antigens were generated including sheep a-mouse plasminogen and sheep anti-mouse factor X. Here we report on the development of two competitive based ELISA’s for the quantitation of mouse plasminogen and mouse factor X. The assay format utilizes purified antigen (plasminogen and factor X) standard. A standard curve is generated based upon the competition between fluid-phase antigen and an antigen-biotin conjugate for an immobilized affinity purified polyclonal antibody (sheep a-mouse plasminogen and sheep anti-mouse factor X). Solid-phase antibody/biotinyl-antigen complexes are detected using avidin-peroxidase. A colormetric signal, which is inversely proportional to the amount of antigen in the fluid-phase, is obtained following the addition of chromogenic substrate. Calibration curves are generated for an immobilized antibody ELISA by plotting the absorbance at 490 nm versus the concentration of non-biotin labeled antigen standard. Biotinylated-antigens were used at single concentrations of 50 ng/ml and 10 ng/ml for factor X and plasminogen respectively. In both cases, immobilized antibodies were adsorbed to microtiter plates at 5ug/ ml. Linearity of the factor X assay extends from approximately 10 ng/ml to 1000 ng/ml. The intra-assay coefficient of variation (CV) is ≤1.1 %, while the inter-assay CV is ≤5 %. Linearity of the plasminogen assay extends from approximately 0.1 μg/ml to 10 μg/ml. The intra-assay coefficient of variation (CV) is ≤2.0 %, while the inter-assay CV is ≤6.3 %. Preliminary studies have demonstrated the feasibility of these assays. With further testing and analysis these assays may prove useful to the researcher attempting to quantitate mouse plasma concentrations of these analytes.
Relationship between Uteroplacental Blood Flow snd Thrombophilia in Women eith Late Complicated Pregnancies.
Authors: Pranger Delphine , Deneys Veronique , Hubinont Corinne , Bernard Pierre , Debieve Frederic , Biard Jean-Marc , Ferrant Augustin , Hermans Cedric 
Published: October 2019

Abstract
There is a growing body of evidence that thrombophilia is linked to several obstetrical complications, most likely through uteroplacental vascular insufficiency. Very few studies have however evaluated whether alterations of the uteroplacental blood flow, as assessed functionally by Doppler ultrasound analysis, are associated with thrombophilic abnormalities in women with late pregnancy complications. Forty-nine non-smoking women followed during their whole pregnancy in the High Risk Pregnancy Clinic of the Cliniques Universitaires Saint-Luc, Brussels, in 2003 were enrolled in this retrospective study. They all had an unexplained late pregnancy complication (intrauterine growth retardation (IUGR) (n=34), intrauterine fetal death (IUFD) (n=4), preeclampsia (n=11)). They were not treated with anti-thrombotic agents. They all had a complete thrombophilic work-up (functional antithrombin, protein C and S assays, homocystein level, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), activated protein C resistance, G20210A prothrombin gene mutation). Doppler evaluation of the uterine arteries (assessed by the presence of bilateral notches after 26 weeks) and umbilical arteries (assessed by resistance index above 90th percentile) was performed. Thrombophilic abnormalities were identified in 8 of 49 (16%) women (factor V Leiden (FVL) (n=4), G20210A prothrombin gene mutation (n=2) and isolated anticardiolipin antibodies (n=2)). Of the 49 women, 20 had an abnormal Doppler (uterine (n=5) and umbilical (n=15)) including IUGR (n=13), IUFD (n=2) and preeclampsia (n=5). Four women with thrombophilia were found to have Doppler abnormalities (4/20; 20%) while most women with Doppler alterations had no thrombophilia. In conclusion, abnormal uteroplacental Doppler findings are frequently found in women with late pregnancy complications. They do not seem to be correlated with the presence of thrombophilic abnormalities even if thrombophilia seems to be more frequent in obstetrical complications.
Thrombophilic Disorders and the Risk of Thromboembolic Events in Women on Oral Contraceptives and Hormone Replacement Therapy.
Authors: De Sancho Maria Teresa , Barauskas Tanya M. , Rand Jacob H. 
Published: October 2019

Abstract
Objective: To evaluate the frequency and distribution of thrombophilic conditions in women with thromboembolic events (TEE) while on oral contraceptives (OC) or hormone replacement therapy (HRT). To assess the contribution of the duration of hormone use and a positive family history for TEE in predicting thrombosis.
Methods: Retrospective analysis of all case records of women who developed a TEE while on OC or HRT and who were referred for hypercoagulable evaluation to the Thrombosis and Hemostasis Section at a teaching hospital from 1999–2002.
Results: 65 women who were taking OC or HRT and developed a TEE were identified with one or more hypercoagulable disorders. 23 women tested positive for two or more hypercoagulable disorders: 16 had Factor V Leiden 3 of them were homozygous and 13 heterozygous, 5 were heterozygous for the prothrombin gene g20210a polymorphism, 26 had positive antiphospholipid antibody tests, 10 had elevated homocysteine levels, 4 had protein C deficiency and 7 had protein S deficiency. There were 65 thromboembolic events: 16 pulmonary emboli, 17 cerebrovascular events, 11 intra-abdominal vascular thromboses, 13 extremity deep venous thrombosis (DVTs), 5 superficial thrombophlebitis, and 2 retinal vein thromboses. Of the 65 women, 37% of patients had a positive family history of thrombosis. 52% had additional risk factors for thrombosis including smoking or obesity. 51% had been taking OC or HRT for > 1 year.
Conclusions: In this population, thrombophilic conditions contribute in most cases to TEE in women on OC and HRT. Approximately 50% of TEE occurred in women on OC or HRT for > 1 year. The burden of thrombosis associated with hypercoagulability in women on OC and HRT has been underestimated in prior studies by including only DVT/PE. Family and personal history of thrombosis must be thoroughly explored before initiating or continuing OC or HRT and a positive history of thrombosis may warrant a hypercoagulable evaluation.
The Hemostatic State in Cancer Patients: The Relationship between Hypercoagulable Markers and Cancer Prognostic Markers.
Authors: Mousa Shaker A. , Alizadeh Hussain , Al-Tajer Shaikhah 
Published: October 2019

Abstract
Background: The most common abnormalities described in cancer patients are the elevation of the clotting factors V, VIII, IX, and XI; increased fibrinogen/fibrin degradation products; hyperfibrinogenemia; and thrombocytosis. We performed a prospective study to evaluate the relationship between changes in hemostatic parameters and cancer prognostic markers.
Methods: We enrolled patients who were diagnosed as having different types of nonhematological, solid organ tumor. The most important natural inhibitors of abnormal coagulation (protein C, protein S, and antithrombin) and D-dimer and prothrombin activation peptide F 1 + 2 as markers of the status of coagulation system were studied in these groups of patients prior to any form of therapy. These markers were repeatedly measured with each treatment course and their results were correlated with other markers of tumor prognosis. These parameters were also studied before and after any surgical intervention for the tumor. The main aim of the study was to assess the changes in hemostatic parameters and to see if these changes can be used as markers for tumor prognosis.
Results: Fifty-two patients were enrolled in this study. Two patients had esophageal adenocarcinoma, 6 had gastric cancer, 16 had colorectal cancer, 4 had exocrine pancreatic carcinoma, 2 had adenocarcinoma of gallbladder, 6 had adenocarcinomatous type of non-small cell lung cancer, 2 had small cell lung cancer, 12 had infiltrating breast carcinoma, and 2 had ovarian cancer. In all cases, the elevation of the levels of hypercoaguable markers was directly correlated with tumor stage, tumor markers, and radiological findings of cancer state. Additionally, the level of naturally occurring coagulation inhibitors were all decreased with progression of tumor. These hypercoaguable parameters were also raised after surgical resection of these tumors.
Conclusions: Based on our findings, determination of D-dimer, F1 + 2, protein C, protein S, and antithrombin levels can be used as markers to assess the tumor prognosis.
D-Dimer Assay during Menstrual Period.
Authors: Chan Howard H. , Johnson Judith A. , Panju A. , Bradley Christine A. 
Published: October 2019

Abstract
Introduction:
Fibrin D-dimer is the degradation products from cross-linked fibrin. It is a marker of intravascular thrombogenesis. Menstruation is associated with activation of coagulation and fibrinolytic pathways. To investigate the changes of plasma fibrin D-dimer level during menstruation cycle, we measure the D-dimer level on day 1, 3, 5, and 21 of the menstruation period for 5 consecutive female volunteers. MDA D-dimer assay is used because it is one of the most sensitive laboratory methods for quantitative measurement of D-dimer level.
Methods:
Normal female volunteers with normal regular menstruation cycle are recruited. To avoid other confronting factors, subjects with recent history of thromboembolic diseases; ischemic heart disease; pregnancy or child birth; active malignancy; active inflammatory or infectious disease; surgery or trauma; and/or use of birth control pills are excluded. All volunteers have the menstruating period identified. Day 1 of menstruating period is defined as the first day when menstruating flow occurs. On Day 1, 3, 5 and 21 of menstruating cycle, blood samples are collected in tubes precoated with 3.2% trisodium citrate-dihydrate. Specimens are centrifuged at 2500 g for 15 minutes. The MDA D-dimer assay is performed using a commercial kit as per manufacturer’s instructions. Plasma fibrin MDA D-dimer level is expressed in F.E.U./ml (normal range is <0.50 F.E.U./ml). ANOVA statistical analysis for single factor is used to compare the differences among the D-dimer levels on day 1, 3, 5 and 21 of the menstruation cycle. The study has been reviewed and approved by the committee for ethics for research.
Results:
The results are summarized in table 1 and figure 1. There is no significant variation of D-dimer level measured on day 1, 3, 5, and 21 of menstruation cycle. (p = 0.382)
Conclusion:
The MDA D-dimer level does not have significant change during the menstruation period. The clotting process during menstruation may mainly be extravascular and, therefore, not affect the D-dimer level. Clinically, D-dimer test can still be used to rule out venous thromboembolism in a menstruating woman.
D-dimer levels (F.E.U./ml) on various days of menstruation cycle for 5 volunteers
Figure Figure Subject Number 2 3 4 5 6 Day 1 0.12 0.21 0.31 0.34 0.44 Day 3 0.10 0.18 0.23 0.13 0.31 Day 5 0.11 0.17 0.16 0.27 0.22 Day 21 0.21 0.10 0.17 0.39 0.29
Sticky Platelet Syndrome (SPS) as a Cause of Unexplained Thrombosis.
Authors: Kubisz Peter , Musial Jan 
Published: October 2019

Abstract
Background: Sticky platelet syndrome (SPS) was first described in 1983 by Holliday. The results of recent studies suggest SPS to be a common cause of arterial and venous thrombosis. With respect to otherwise unexplained venous thrombosis, the prevalence of SPS approximates that of activated protein C resistance (APC-R). It has been found that SPS accounted for about 21% of otherwise unexplained arterial events (acute myocardial infarction, cerebrovascular thrombosis, transient cerebral ischemic attacks, retinal thrombosis, and peripheral arterial thrombosis) and accounted for about 13,2% of otherwise unexplained venous events (deep vein thrombosis, with or without pulmonary embolus).
SPS is an autosomal dominant platelet disorder associated with arterial and venous thromboembolic events, frequently recurrent under oral anticoagulant therapy. It is characterized by hyperaggregability of platelets in platelet-rich plasma with adenosine diphosphate (ADP) and epinephrine (type I), epinephrine alone (type II), or ADP alone (type III). Combination of SPS with other congenital thrombophilic defects have been described. Low-dose aspirin treatment (80–100 mg) ameliorates the clinical symptoms and normalizes hyperaggregability. The precise etiology of this defect is at present not known, but receptors on the platelet surface may be involved.
Patients and methods: We examined fifty patients with otherwise unexplained arterial or venous thrombosis. SPS evaluations were performed according to the method of Mammen. The equipment used was PACKS-4 aggregometer.
Results: SPS was detected in eight patients. Clinically SPS resulted as an arterial thrombosis in five patients (2 coronary thrombosis, 2 cerebral ischemic attacks, 1 peripheral arterial thrombosis), two individuals showed deep venous thrombosis (DVT) and one patient passed recurrent abortions. SPS was classified as type I in 2 cases, 5 patients had type II and only 1 patient was diagnosed as type III, respectively (4 of them showed a glycoprotein IIIa abnormality).
Conclusion: Because treatment with heparin or warfarin will not alleviate the thrombotic tendency of SPS, but simple aspirin therapy almost always will correct the defect and protect the individual from second event, it is particularly important to define the presence of this defect.
Synthetic Anti-Xa Drugs Can Be Used for Parenteral Anticoagulation but Not Fondaparinux.
Authors: Iqbal Omer , Hoppensteadt Debra , Fareed Daniel , Fareed Jawed 
Published: October 2019

Abstract
Targeting at the level of factor Xa and/or prothrombinase complex by synthetic anti-Xa agents such as JTV-803 (Akros Pharma, Princeton, NJ), DX-9065a (Daiichi Pharmaceuticals, Tokyo, Japan), and Fondaparinux (Sanofi-Synthelabo, Toulouse, France) represents an important approach in anticoagulant therapy. Factor Xa is an essential component of the prothrombinase complex and leads to the generation of thrombin. Synthetic heparin pentasaccharide, Fondaparinux (Arixtra®) has been approved by the United States Food and Drug Administration for the prophylaxis of deep vein thrombosis in patients undergoing hip and knee replacement surgeries. There is a rapid stride in the development of newer synthetic inhibitors of factor Xa such as DX-9065a, and JTV-803 in various thrombotic indications. In order to evaluate the parenteral anticoagulant potential of these synthetic factor Xa inhibitors, we used the Hemochron (celite) activated clotting time (ACT) assay. DX-9065a at a final concentration of 5 and 10 μg/ml increased the ACTs to 250 and 300 seconds, respectively. Similar anticoagulant potential was noticed with JTV-803. These findings suggest that these agents may be useful as parenteral anticoagulants during interventional cardiologic procedures, surgical anticoagulation and for the prevention of vascular access occlusion. Fondaparinux requiring antithrombin (AT) for its anticoagulant effect does not increase the celite ACT to the extent as other synthetic factor Xa inhibitors. Fondaparinux even at a final concentration of 100 μg/ml increase the ACT to about 200 seconds and hence are not suitable to be used as parenteral anticoagulants. The concentrations of JTV-803, DX-9065a and fondaparinux required to increase the ACT to near 250 seconds are 6.2, 5 and 125 μg/ml, respectively. While fondaparinux is AT-dependent, the synthetic anti-Xa agents are AT-independent in their actions. The antithrombin sparing effect of direct anti-Xa agents may contribute to an additional anticoagulant effect as reflected by increased ACT levels. Furthermore, there are some other advantages of direct anti-Xa agents when compared to fondaparinux. While direct anti-Xa agents may be used for patients with AT deficiency, fondaparinux being AT-dependent, may not. The inhibition of the clot-bound and prothrombinase-bound factor Xa are additional advantages of direct Xa inhibitors when compared to fondaparinux. Fondaparinux being AT-dependent and upon complexation with AT is not capable of inhibiting the clot-bound factor Xa. Oral Xa inhibitors are being developed and when available patients may have an ideal transition from a parenteral anti-Xa agent to an oral Xa inhibitor. The results clearly suggest that synthetic factor Xa inhibitors except fondaparinux may be used as parenteral anticoagulants. Large-scale clinical studies are warranted to evaluate these findings.