The effect of vitamin D levels on gastrointestinal bleeding in patients with warfarin therapy Upper tract gastrointestinal system (GIS) bleeding is considered as an important cause of morbidity and mortality despite modern and advanced endoscopic interventions. In patients with thrombotic state and vitamin D deficiency, vitamin D analogs and vitamin D receptor activators have been determined as adjunctive anticoagulant treatment in previous studies. However, these studies did not evaluate or reveal the possible bleeding diathesis. In this article, we evaluated the vitamin D status in patients with warfarin treatment and upper tract GIS bleeding. A total of 75 patients with a definite diagnosis of upper tract GIS bleeding who had a treatment of warfarin and current vitamin D measurement; and a total of 75 control patients without any recent or prior GIS bleeding who had a treatment of warfarin and current vitamin D measurement were enrolled to the study. GIS bleeding group had a proportionally higher vitamin D treatment (29.3 vs. 17.3%). In GIS bleeding group, the prevalence of vitamin D level less than 20 ng/ml was significantly lower (66.7 vs. 82.7%; P = 0.024) and the prevalence of vitamin D level at least 30–100 ng/ml was significantly higher (25.3 vs. 10.7%; P = 0.019). According to a subgroup analysis; in patients with a vitamin D level at least 30–100 ng/ml, major bleeding rate was significantly higher compared with other patients. There was not a significant difference regarding mortality between the groups. Our study is the first which represents the possible bleeding effect of elevated vitamin D levels and vitamin D treatment in patients with warfarin treatment. Correspondence to Ümran Keskin, MD, Internal Medicine, Health Sciences University, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey. Tel: +90 5535451454; e-mail: drumrankeskin@gmail.com Received 27 May, 2019 Revised 16 July, 2019 Accepted 27 July, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Anticoagulant activity of krait, coral snake, and cobra neurotoxic venoms with diverse proteomes are inhibited by carbon monoxide Background A phenomena of interest is the in vitro anticoagulant effects of neurotoxins found in elapid venoms that kill by paralysis. These enzymes include phospholipase A2 (PLA2), and it has recently been demonstrated that carbon monoxide inhibits the PLA2-dependent neurotoxin contained in Mojave rattlesnake type A venom. The purpose of this investigation was to assess if the anticoagulant activity of elapid venoms containing PLA2 and/or three finger toxins could be inhibited by carbon monoxide. Methods Venoms collected from Bungarus multicinctus, Micrurus fulvius, and five Naja species were exposed to carbon monoxide via carbon monoxide releasing molecule-2 prior to placement into human plasma. Coagulation kinetics were assessed via thrombelastography. Results Compared with plasma without venom addition, all venoms had significant anticoagulant effects, with a 160-fold range of concentrations having similar anticoagulant effects in a species-specific manner. Carbon monoxide significantly inhibited the anticoagulant effect of all venoms tested, but inhibition was not complete in all cases. Conclusion Given that individual neurotoxin activity often depends on intact activity that includes anticoagulant action, it may be possible that carbon monoxide inhibits neurotoxicity. Future investigation is justified to assess such carbon monoxide mediated inhibition with purified neurotoxins in vitro and in vivo. Correspondence to Vance G. Nielsen, MD, The Department of Anesthesiology, University of Arizona College of Medicine, PO Box 245114, 1501 North Campbell Avenue, Tucson, AZ 85724-5114, USA. Tel: +1 520 626 7195; fax: +1 520 626 6943; e-mail: vgnielsen333@gmail.com Received 4 June, 2019 Accepted 29 July, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Perioperative laboratory monitoring in congenital haemophilia patients with inhibitors: a systematic literature review Although the use of clotting factor concentrates is the mainstay of haemophilia care, the development of inhibitors complicates disease management. Perioperative management of patients with inhibitors is therefore a challenge. A systematic literature review was performed to identify literature reporting on the perioperative monitoring and management of haemophilia. MEDLINE, Embase and Cochrane databases were searched from database inception to 26 March 2018. Recent congress proceedings were also searched. Titles and abstracts, then full texts, were screened for relevance by two reviewers. Quality of included studies was assessed using the Critical Appraisal Skills Programme checklist. Of the 2033 individual entries identified, 86 articles met the inclusion criteria. The identified studies were screened again to find articles reporting perioperative laboratory monitoring in patients with congenital haemophilia A or B, resulting in 24 articles undergoing data extraction. Routine perioperative assay monitoring practices were the most commonly reported (n = 20/24); thrombin generation assay was the least commonly reported (n = 2/24). Other monitoring practices described were factor VII and factor VIII coagulation activity (n = 8/24, n = 5/24, respectively), and thromboelastography or rotational thromboelastometry assessments (n = 3/24). The impact of monitoring on treatment decisions was, however, rarely reported. In conclusion, many methods of perioperative monitoring of haemophilia patients with inhibitors have been identified in this review, yet there is a lack of reporting in larger scale cohort studies. More detailed reporting on the impact of monitoring outcomes on treatment decisions is also needed to share best practice, particularly as new therapeutic agents emerge. Correspondence to Daniel P. Hart, The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. E-mail: d.hart@qmul.ac.uk Received 7 March, 2019 Revised 30 May, 2019 Accepted 9 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.bloodcoagulation.com). Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Application of thrombelastography in primary total knee and total hip replacement: a prospective 87 patients study Thrombelastography (TEG) parameters and prothrombin time (PT), activated partial thromboplastin time (APTT) are compared and analysed. According to change of TEG parameters and assessment of haemostatic state of each patient, we try to explore the feasibility of individualized anticoagulant therapies. 87 people with hip or knee diseases awaiting arthroplasty were recruited. Haemoglobin levels and TEG parameters including R, K, α-angle, maximum amplitude, coagulation index were assessed in perioperative period. PT and APTT were assessed preoperatively. For 65 patients with normal TEG parameters, PT and APTT, we use tranexamic acid (TXA) to reduce blood loss during operation. As hypercoagulability group, 12 patients awaiting unilateral total knee arthroplasty with hypercoagulable state assessed by TEG parameters or risks for venous thromboembolism received daily 10-mg rivaroxaban until 24 h preoperatively and did not receive TXA during operation. All patients received intravenous administration of argatroban after 8 h postoperatively until day 3 and oral administration of rivaroxaban (10 mg) subsequently to prevent deep vein thrombosis or/and pulmonary embolism until 35 days postoperatively. TEG parameters have significant relationships with fibrinogen, platelet and APTT. The number of patients with abnormal haemostatic state assessed by TEG parameters is higher than that assessed by PT, APTT. TEG show hypercoagulability develops throughout perioperative period. There was no significant difference in haemoglobin concentration between hypercoagulability group and normal group in patients receiving unilateral total knee arthroplasty. TEG have higher sensitivity of perioperative abnormal haemostatic state than PT, APTT in primary arthroplasty. For patients with hypercoagulability, individualized anticoagulant therapies such as preoperative administration of rivaroxaban and not using TXA in operation is safe and effective. Correspondence to Guofeng Dai, Orthopaedic Department, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan 250012, China E-mail: qlwch4201@163.com Received 18 February, 2019 Revised 8 July, 2019 Accepted 9 July, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Thromboelastography testing in mice following blood collection from facial vein and cardiac puncture Blood collection is critical for mouse research studies particularly in hemostatic testing. Cardiac puncture; a standard effective method requires anesthesia and is a terminal procedure while facial vein technique allows multiple collections. Thromboelastography (TEG) is a global hemostasis test, provides a dynamic real-time picture of coagulation. However, TEG experiments in mice require large number of animals and may not allow pre/postinterventions assessment. In this study, we aimed to investigate the feasibility of facial vein sampling for TEG analysis as an alternative to cardiac puncture and examined the impact on coagulation results. Blood samples were obtained from a total of 10 C57BL/6 and CD-1 mice via cardiac puncture and a total of another eight mice of similar strains via facial vein sampling. We compared TEG parameters in both methods using descriptive statistics and the Student t test. Results show no significant difference in any of the TEG parameters between cardiac and facial vein blood indicating the two methods are comparable. Facial vein sampling provides a less costly alternative to cardiac puncture. It is a suitable blood collection method for pre/postinterventions or follow-up studies and it better addresses reduction and refinement goals in mouse studies. A larger study to evaluate the sex or strain and genetic background differences will be valuable. Correspondence to Dr Maha Othman, MD, MSc, PhD, Associate Professor, Department of Biomedical and Molecular Sciences, Queen's University, Boterell Hall, Room 513, Kingston, ON, Canada K7L 3N6. Tel: +1 613 533 6108; fax: +1 613 533 2022; e-mail: othman@queensu.ca Received 5 April, 2019 Revised 17 May, 2019 Accepted 26 June, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Prolonged activated partial thromboplastin time due to plasma prekallikrein deficiency: a case study and literature review on its clinical significance Activated partial thromboplastin time is a test assessing the intrinsic and common pathways of the coagulation cascade. We presented an asymptomatic case with isolated activated partial thromboplastin time prolongation. After excluding coagulation factor deficiency and lupus anticoagulant, the patient was diagnosed with plasma prekallikrein (PPK) deficiency. We reviewed the literature regarding effects of PPK deficiency which could have both antithrombotic and prothrombotic effects. At the moment, research supports that PPK deficiency in healthy adults rarely causes bleeding as it is not a major contributor of hemastasis; whereas in adults with multiple comorbidities or with predominant systemic inflammation, effects of PPK deficiency remain debatable. Further research is needed to clarify impacts of PPK deficiency in clinical settings. Correspondence to Kehua Zhou, MD, DPT, Catholic Health System Internal Medicine Training Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA. E-mail: kehuazho@buffalo.edu Received 20 May, 2019 Revised 23 June, 2019 Accepted 26 June, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Antithrombin concentrate during pregnancy in congenital antithrombin deficiency: a single-center experience Pregnancy carries a high risk of thromboembolic complications, especially in the postpartum period. This risk is particularly high in women with inherited thrombophilias, among these antithrombin deficiency seems to carry the highest risk. In this case, the use of low molecular weight heparin (LMWH) is recommended, while the use of antithrombin concentrate is controversial. We report our experience of seven pregnancies occurred in five women: two, with a personal and familiar history negative for venous thromboembolism, were treated with LMWH during pregnancy and antithrombin concentrate immediately before and after the delivery. The other three women had a personal and familiar history positive for venous thromboembolism and were treated with LMWH and antithrombin concentrate during all the pregnancy and the postpartum period. No thromboembolic or hemorrhagic complications were observed in both groups, demonstrating that our strategy could be safe and effective. Correspondence to Antonella Bruzzese, Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161 Rome, Italy. Tel: +39 06 857951; fax: +39 06 44241984; e-mail: bruzzese@bce.uniroma1.it Received 17 January, 2019 Revised 12 May, 2019 Accepted 4 June, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Hemostasis-related gene polymorphisms and their epistatic relationship in women with idiopathic infertility A numerous factor can cause infertility, but around one of four reproductive failure cases remain unexplained and diagnosed as idiopathic infertility. In the past few decades, analysis of gene polymorphisms takes a significant place in pathogenesis of infertility. The aim of this study was to evaluate the possible role of hemostasis-related gene polymorphisms in unexplained infertility. The study includes 117 female patients with idiopathic infertility and 130 fertile women with at least one born child. Eight polymorphisms important for hemostasis (ITGB3 1565T>C, FV 1691G>A, FII 20210G>A, MTHFR 677C>T and 1298A>C, ATIII 786G>A, PAI-14G/5G and ACE I/D) were genotyped by real-time PCR system. The frequencies of alleles and genotypes of examined polymorphisms were analyzed in SPSS statistical program, whereas gene interactions were identified using the GMDR software. Examination of etiological factors has shown that family history is a significant factor in assessing individual risk for infertility. The alleles and genotypes frequency of FV 1691G>A and FII 20210G>A polymorphisms were statistically different between control and patient group leading to a greater risk for infertility. The analysis of epistatic relationship between examined hemostasis-related gene polymorphisms identified more complex high-risk genotypes associated with infertility. Our results suggest that positive family history could be important predictive factor for fertility problems, pointing to the potential hereditary basis of this condition. Polymorphisms FVL and FII prothrombin are independent risk factors for idiopathic infertility, whereas multilocus interactions approach should be taken into consideration for the future research. Correspondence to Jelena Velickovic, PhD, Institute of Forensic Medicine, Faculty of Medicine, University of Belgrade, Deligradska 31a, 11000 Belgrade, Serbia. Tel: +381 11 3617931; fax: +381 11 3617931; e-mail: djurovic_j@yahoo.com Received 22 January, 2019 Revised 22 January, 2019 Accepted 10 June, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.bloodcoagulation.com). Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Development of an inhibitor in a child with severe hemophilia B: treatment with immunosuppression and an extended desensitization protocol Development of neutralizing alloantibodies in hemophilia B is a less common, but clinically challenging phenomenon. Novel therapeutics for hemophilia B have recently been developed and reports of clinical experience with these agents outside of clinical trials are needed. We report development of an inhibitor in a child with severe hemophilia B, and subsequent immune tolerance induction using an extended desensitization protocol with the addition of immunosuppression. This case highlights successful management of a rare complication in a rare bleeding disorder and the need for additional investigation into this infrequent and clinically challenging occurrence. Correspondence to Jonathan C. Roberts, MD, Bleeding & Clotting Disorders Institute, 9128 N Lindbergh Dr, Peoria, IL 61615, USA. Tel: +1 309 692 5337; fax: +1 309 693 3913; e-mail: jroberts@ilbcdi.org Received 4 February, 2019 Revised 17 April, 2019 Accepted 4 June, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Rare clotting factor deficiency among Sudanese children Rare clotting factor (F) deficiency is a deficiency of one or more of coagulation factors other than FVIII, FIX and vonWillebrand (FI, FII, FV, FV + FVIII, FVII, FIX, FX, FXI and FXIII) that cause bleeding disorders and are inherited as autosomal recessive. Descriptive study was conducted in Hemophilia Centre, Khartoum, Sudan. The medical files of pediatric patients presented to the center were reviewed retrospectively. Forty-seven patients (male : female ratio = 1.2 : 1) were included. The majority (93.6%) have parental history of consanguinity and around one third (31.9%) have family history of bleeding disorder. FV deficiency was the most common deficient factor (36.2%) followed by FI deficiency (23.4%) and FX111 deficiency (21.3%). Bruising (46.8%) and epistaxis (25.5%) were the most common presenting complains. FV deficiency mainly presented with cutaneous ecchymosis (47.1%). FI deficiency presented with umbilical bleeding (45.5%) and FXIII presented with cutaneous ecchymosis (50%). Rare clotting factor deficiency is an existing disease in Sudan with the male : female ratio was 1.2 : 1. FV deficiency, FI deficiency, FXIII deficiency were the common deficiency encountered. Correspondence to Ishag Adam, MD, PhD, Faculty of Medicine, University of Khartoum, PO Box 102, Khartoum, Sudan. Tel: +249 912168988; fax: +249 183771211; e-mail: ishagadam@hotmail.com Received 12 February, 2019 Revised 29 April, 2019 Accepted 4 June, 2019 Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.