Blood Coagulation & Fibrinolysis

Thromboelastometry in critically ill patients with disseminated intravascular coagulation Coagulopathy has a high incidence in critically ill patients and is often caused by disseminated intravascular coagulation (DIC). Although the clinical picture of DIC ranges from a prothrombotic state to severe consumption coagulopathy with an increased bleeding tendency, there are no clinical tests that reflect of in-vivo hemostatic profile. Rotational thromboelastometry (ROTEM) may be able to indicate whether a patient has a hypocoagulable or hypercoagulable profile and possibly be able to discriminate patients with and without DIC. The aim of this article was to study the diagnostic ability of thromboelastometry to detect DIC. A predefined subgroup analysis of a clinical trial in critically ill patients with a coagulopathy was done. ROTEM and markers of coagulation and levels of natural anticoagulants were measured in patients with and without DIC. Twenty-three patients were included, 13 fulfilled criteria for overt DIC. Patients with DIC had lower platelet count, lower levels of fibrinogen, factors II, VII and VIII compared with those without DIC. Antithrombin, protein C and S were also reduced in DIC patients. Receiver operator characteristic analyses showed that EXTEM CFT, alpha angle and MCF were capable of discriminating patients with and without DIC. Combination of ROTEM values with protein C or antithrombin further improved discriminatory ability. In patients with DIC, thromboelastometry profiles were more hypocoagulable compared with those without DIC. ROTEM correlates well with ISTH DIC score, diagnostic strength improves when ROTEM values are combined with antithrombin or protein C levels. Thereby, ROTEM may be a useful tool in diagnosing DIC in the critically ill.

Pulmonary embolism location is associated with the co-existence of the deep venous thrombosis Multiple studies have shown that in approximately half of individuals with pulmonary embolism (PE), the deep venous thrombosis (DVT) is not evident at the moment of PE diagnosis. The underlying factors and the origin of PE in these patients are not completely understood: missed DVT, embolization of DVT in its entirety, or de-novo PE being possible explanations. The aim of this study was to evaluate the differences in PE patient with or without co-existing DVT. Sixty-three consecutive PE patients were included. Whole leg bilateral Doppler compression ultrasound was performed to all patients. The PE location and extension, C-reactive protein, platelet count, hemostatic markers FV, FVIII, FXIIIa, Fibrinogen, von Willebrand factor antigen, thrombomodulin were assessed. Thorough clinical assessment including echocardiography and pulmonary function tests were performed upon arrival and seven months later. The mean age of the patients was 57 years (SD 17.3) and 33 (52%) were women. Thirty-one patients (49.2%) had co-existing DVT. The presence of DVT was associated with the proximal location of the PE (100%), whereas none of the patients (n = 10) with exclusively peripheral PE had co-existing DVT. The PE extension, the measured hemostatic and inflammatory markers or the patient characteristics did not statistically differ between patients with isolated PE and PE with co-existing DVT. In roughly half of the PE patients no DVT could be detected. The location of the PE was associated with the presence of co-existing DVT. There were no differences in the PE extension, hemostatic markers or in the patient characteristic between patients with isolated PE or PE with co-existing DVT.

A series of 10 Polish patients with thromboembolic events and antithrombin deficiency: two new c.1154-1 G>C and c.1219-534 A>G: SERPINC1: gene splicing mutations Inherited antithrombin (AT) deficiency, with prevalence in the general population ranging 0.02–0.17%, is an autosomal dominant disorder associated with a high risk of venous thromboembolism. In most cases, deficiency is caused by mutations in the AT-coding gene (SERPINC1). Only 24 splicing defects have been described causing AT deficiency, all affecting exon flanking regions. The aim of the current study was to characterize the mutations underlying AT deficiency in 10 venous thromboembolism Polish patients aged 42.9 (14–63) years. Whole SERPINC1 gene sequencing was done by next generation sequencing methods. Eight cases had mutations previously described. However, we identified two new intronic mutations that might affect the correct splicing of exon 6 according to in-silico predictions: c.1154-1 G>C, which strongly disturbs the acceptor sequence and c.1219-534 A>G, a deep intronic mutation that might generate a cryptic donor sequence; both might compete with the wild-type donor sequence and explain the associated moderate AT deficiency of carriers. In conclusion, we show the molecular base of AT deficiency in 10 new Polish patients, including two novel SERPINC1 gene mutations potentially affecting splicing.

Point-of-care hemostasis in children with congenital heart disease, the POCHEMO study: baseline reference values of thromboelastometry and impedance aggregometry Viscoelastic tests and impedance aggregometry allow coagulation evaluation at the bedside, but reference values are scarce in pediatrics. The aim of this study was to establish reference values of thromboelastometry and impedance aggregometry for this population and compare it between age groups. This prospective, single-center, observational study evaluates viscoelastic tests and impedance aggregometry in children with congenital heart disease. A total of 204 children were included with a median age of 3.6 years old. We provide references values for this population with median, percentile 2.5 and percentile 97.5. Infants demonstrate for extrinsic activity a shorter coagulation time (52 [49–55] vs. 56 [51–62] s, P = 0.007) and clot formation time (90 [71–118] vs. 113 [93–146] s, P < 0.0001) so as for intrinsic activity a shorter clot formation time (53 [44–69] vs. 75 [59–92] s, P < 0.0001). The maximal clot firmness was significantly stronger in infants for extrinsic (65 [61–69] vs. 59 [54–63] mm, P < 0.0001), intrinsic (68 [64–70] vs. 61 [57–65] mm, P < 0.0001), and fibrinogen (12 [9–16] vs. 10 [8–13] mm, P = 0.02) activities. Platelet aggregation was significantly higher in infants with an amplitude at 6 min of 28 [23–34] vs. 22 [15–27] Ω, P less than 0.0001, a maximum speed of 11 [9–13] vs. 7 [5–10] Ω/min, P less than 0.0001, and an area under the curve of 120 [92–135] vs. 86 [59–112] Ω min, P less than 0.0001. We provided the first reference values for impedance aggregometry and thromboelastometry in children with congenital heart disease. We showed that these infants tend to have accelerated coagulation and stronger clot firmness compared with older children, but this finding may have only minimal relevance when treating a bleeding child. Trial registration number: ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT02387944).

Serum metabolomics reveals the progression of coronary artery stenosis in patients with hypercholesterolemia: a pilot study The current study explores potential characteristic metabolic signatures associated with the high cholesterol (CHO), and the progression of coronary artery stenosis (CAS) in high-CHO patients. A metabolomics strategy based on ultra high-performance liquid chromatography/MS-MS and multivariate statistics has been implemented to identify potential biomarkers in high-CHO patients with different levels of CAS. The current study included 57 individuals, comprising 17 healthy paticipants, and 40 high-CHO patients. The high CHO patients were subgrouped based on the computed tomography angiography results, that is, CHO+ no ART (n = 10), CHO+ ART less than 50% (n = 13), CHO+ ART 50–75% (n = 11), and CHO+ ART more than 75% (n = 6). After metabolomics study, 16 discriminating metabolites in positive ion mode and 17 discriminating metabolites in negative ion mode were regarded as possible biomarker candidates to reflect metabolic traits differences between patients with healthy subjects and CHO. A total of six metabolites were tentatively identified as potential biomarkers for the progression diagnosis of CAS: three lysophosphatidylcholines (Lyso-phosphocholine, lysoPC and Lysopersicon esculentum, lysoPE), proline betaine and tryptophan, and prasterone sulfate. The results demonstrated that tryptophan and proline betaine could differentiate the patients with or without high CHO. Tryptophan, prasterone sulfate, LysoPE (0 : 0/18 : 2) or LysoPE (18 : 2/0 : 0), and LysoPE (0 : 0/18 : 1) or LysoPE (18 : 1/0 : 0) could differentiate the patients with severe stenosis (ART > 70%) from the healthy or mild stenosis ones. Proline betaine and significant decrease of LysoPC (17 : 0) could also be a promising biomarker for the mild stenosis (ART < 50%).

The platelet surface glycosylation caused by glycosidase has a strong impact on platelet function Platelet surface glycosylation defects has been reported to be significantly associated with many diseases. Our previous study found that platelet surface glycosylation is altered in coronary heart disease. In this study, we further investigated whether altered glycosylation affects platelet function. Platelets were obtained from ten healthy volunteers. The platelet surface terminal sialic acid was removed by neuraminidase A, and N-linked oligosaccharides was removed by PNGase F. The function of the enzyme-treated platelet was measured. The activation and platelet adhesion to von Willebrand factor (vWF) was measured by flow cytometry. Platelet aggregation induced by ADP, arachidonic acid and collagen was detected through light transmission aggregometry, and platelet-leukocyte aggregates (PLAs) was detected by flow cytometry. Neuraminidase A treatment caused sialic acid level decrease and β-galactose level increase significantly on platelet surface. Activation marker CD62P did not change. Platelet adhesion to vWF was increased significantly (P < 0.05). ADP-induced platelet aggregation was significantly reduced (P < 0.05). Platelet-granulocytes aggregates and platelet-monocytes aggregates increased (P < 0.05). Platelet surface sialic acid was increased after PNGase F treatment. Platelet aggregation by all agonists were significantly reduced (P < 0.05). There is no difference in the binding of vWF and PLAs for PNGase F treated platelet. We demonstrated that asialoglycosylation enhances platelet binding to vWF and forming PLAs, suggest that it may be associated with high platelet reactivity and the increased risk of thrombosis.

First description of the molecular and clinical characterization of hereditary factor V deficiency in Saudi Arabia: report of four novel mutations Coagulation factor V plays a significant role in the blood coagulation cascade as part of the prothrombinase complex. Factor V deficiency (FVD) is a rare autosomal recessive bleeding disorder with a variable phenotypic expression which varies from being asymptomatic-to-severe bleeding episodes. The aim of this study was to perform molecular and clinical characterization of FVD in patients originating from Saudi Arabia. Eleven patients (two males and nine females) with confirmed FVD were recruited in the study with ages ranging between 5 and 53 years. A next-generation sequencing-based hematology panel encompassing 393 known genes was used. A total of six sequence variations in F5 gene were identified, including four missense mutations (p.Pro189Leu, p.Trp2004Arg, p.Met2148Thr, p. Arg2202Cys), a deletion (p.Arg872Lysfs*12) and a splicing variant (c.1118+5G>T). Four variants were identified for the first time in this study. Three patients were homozygous for their respective mutations and seven patients were heterozygous. We were not able to identify a pathogenic variant in one patient of the cohort. In-silico and three-dimensional structural analyses were performed to predict the possible impact and functional consequences of the identified variants. To our knowledge, this is the first study addressing factor V mutations in patients with Arab ancestry. Results have helped in providing a definitive diagnosis to the patients and carrier detection in extended family members. Overall, the hematology panel assay was an efficient platform, demonstrating a formidable approach for the molecular diagnosis of other suspected bleeding disorders.

Phenotypic and genetic analysis of hypofibrinogenemia because of a novel missense mutation in the FGB: Leu121Arg In this study, we found a novel missense gene mutation of fibrinogen (FIB) and it will help us to understand the pathogenesis of this type of disease. The FIB activity (FIB:C) and FIB antigen (FIB:Ag) were detected using matched commercially available kits. To identify the novel missense mutation, the fibrinogen gene sequencing was carried out. Bioinformatics and model analysis were used to study the harm of the mutation. The FIB:C and FIB:Ag of the proband were 0.82 and 1.19 g/l, respectively. Sequencing analysis detected a heterozygous c.425T>G in exon three of FGB gene resulting in p.Leu121Arg. The Leu121Arg mutation was responsible for the decrease of FIB:C, and it was the first report of such a mutation in the world.

Acquired von Willebrand syndrome in a patient with small lymphocytic lymphoma and Sjögren's syndrome: which associated condition should be prioritized? Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic condition that poses both a diagnostic and a therapeutic challenge. Here we report a singular case of AVWS with two associated conditions, small lymphocytic lymphoma (SLL) and Sjögren's syndrome. The patient presented with recurrent and severe digestive bleeding that forced us to raise a curative attempt of AVWS. A first immunosuppressive therapy with immunoglobulins was unsuccessful and it was later decided to treat lymphoproliferative entity with bendamustine and rituximab effectively achieving SLL and AVWS remission. On the basis of our case and through literature review, we discuss potential strategies to achieve AVWS remission when it appears in the setting of several causative associated conditions.

Gastrointestinal angiodysplasia in two patients with type 3 von Willebrand disease Angiodysplastic (AD) lesion is the most common cause of recurrent gastrointestinal (GI) bleeding in inherited Von Willebrand disease (VWD) patients lacking high-molecular-weight multimers. Defect or dysfunction of von Willebrand factor (VWF) may lead to enhanced endothelial cell proliferation followed by the development of neoangiogenesis and vascular malformation, which result in severe bleeding. Recurrent bleeding causing by GI AD is a challenging complication of VWD. The management of VWD could be difficult due to frequent recurrence and severity of bleeding episodes. The primary aim of management is not only to stop but also to prevent bleeding. We present two patients of type 3 VWD associated with AD and severe GI bleeding, which were successfully treated by endoscopic coagulation and prophylactic therapy with different regimens of plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate to maintain a trough level in the patient unresponsive to standard treatment. ORIGINAL ARTICLES Thromboelastometry in critically ill patients with disseminated intravascular coagulation Müller, Marcella C.A.; Meijers, Joost C.; van Meenen, David M.; More Blood Coagulation & Fibrinolysis. 30(5):181-187, July 2019. Abstract Favorites  PDF  Get Content & Permissions Coagulopathy has a high incidence in critically ill patients and is often caused by disseminated intravascular coagulation (DIC). Although the clinical picture of DIC ranges from a prothrombotic state to severe consumption coagulopathy with an increased bleeding tendency, there are no clinical tests that reflect of in-vivo hemostatic profile. Rotational thromboelastometry (ROTEM) may be able to indicate whether a patient has a hypocoagulable or hypercoagulable profile and possibly be able to discriminate patients with and without DIC. The aim of this article was to study the diagnostic ability of thromboelastometry to detect DIC. A predefined subgroup analysis of a clinical trial in critically ill patients with a coagulopathy was done. ROTEM and markers of coagulation and levels of natural anticoagulants were measured in patients with and without DIC. Twenty-three patients were included, 13 fulfilled criteria for overt DIC. Patients with DIC had lower platelet count, lower levels of fibrinogen, factors II, VII and VIII compared with those without DIC. Antithrombin, protein C and S were also reduced in DIC patients. Receiver operator characteristic analyses showed that EXTEM CFT, alpha angle and MCF were capable of discriminating patients with and without DIC. Combination of ROTEM values with protein C or antithrombin further improved discriminatory ability. In patients with DIC, thromboelastometry profiles were more hypocoagulable compared with those without DIC. ROTEM correlates well with ISTH DIC score, diagnostic strength improves when ROTEM values are combined with antithrombin or protein C levels. Thereby, ROTEM may be a useful tool in diagnosing DIC in the critically ill. BUY Pulmonary embolism location is associated with the co-existence of the deep venous thrombosis Sane, Markus A.; Laukkanen, Jari A.; Granér, Marit A.; Piirilä, Päivi L.; Harjola, Veli-Pekka; Mustonen, Pirjo E. Less Blood Coagulation & Fibrinolysis. 30(5):188-192, July 2019. Abstract Favorites  PDF  Get Content & Permissions Multiple studies have shown that in approximately half of individuals with pulmonary embolism (PE), the deep venous thrombosis (DVT) is not evident at the moment of PE diagnosis. The underlying factors and the origin of PE in these patients are not completely understood: missed DVT, embolization of DVT in its entirety, or de-novo PE being possible explanations. The aim of this study was to evaluate the differences in PE patient with or without co-existing DVT. Sixty-three consecutive PE patients were included. Whole leg bilateral Doppler compression ultrasound was performed to all patients. The PE location and extension, C-reactive protein, platelet count, hemostatic markers FV, FVIII, FXIIIa, Fibrinogen, von Willebrand factor antigen, thrombomodulin were assessed. Thorough clinical assessment including echocardiography and pulmonary function tests were performed upon arrival and seven months later. The mean age of the patients was 57 years (SD 17.3) and 33 (52%) were women. Thirty-one patients (49.2%) had co-existing DVT. The presence of DVT was associated with the proximal location of the PE (100%), whereas none of the patients ( n  = 10) with exclusively peripheral PE had co-existing DVT. The PE extension, the measured hemostatic and inflammatory markers or the patient characteristics did not statistically differ between patients with isolated PE and PE with co-existing DVT. In roughly half of the PE patients no DVT could be detected. The location of the PE was associated with the presence of co-existing DVT. There were no differences in the PE extension, hemostatic markers or in the patient characteristic between patients with isolated PE or PE with co-existing DVT. BUY A series of 10 Polish patients with thromboembolic events and antithrombin deficiency two new c.1154-1 G>C and c.1219-534 A>G SERPINC1 gene splicing mutations Wójcik, Magdalena; de la Morena-Barrio, María E.; Michalik, Justyna; More Blood Coagulation & Fibrinolysis. 30(5):193-198, July 2019. Abstract Favorites  PDF  Get Content & Permissions Inherited antithrombin (AT) deficiency, with prevalence in the general population ranging 0.02–0.17%, is an autosomal dominant disorder associated with a high risk of venous thromboembolism. In most cases, deficiency is caused by mutations in the AT-coding gene ( SERPINC1 ). Only 24 splicing defects have been described causing AT deficiency, all affecting exon flanking regions. The aim of the current study was to characterize the mutations underlying AT deficiency in 10 venous thromboembolism Polish patients aged 42.9 (14–63) years. Whole SERPINC1 gene sequencing was done by next generation sequencing methods. Eight cases had mutations previously described. However, we identified two new intronic mutations that might affect the correct splicing of exon 6 according to in-silico predictions: c.1154-1 G>C, which strongly disturbs the acceptor sequence and c.1219-534 A>G, a deep intronic mutation that might generate a cryptic donor sequence; both might compete with the wild-type donor sequence and explain the associated moderate AT deficiency of carriers. In conclusion, we show the molecular base of AT deficiency in 10 new Polish patients, including two novel SERPINC1 gene mutations potentially affecting splicing. BUY Point-of-care hemostasis in children with congenital heart disease, the POCHEMO study baseline reference values of thromboelastometry and impedance aggregometry Longchamp, David; Perez, Marie-Hélène; Natterer, Julia; Amiet, Vivianne; Ferry, Thomas; Boegli, Yann; Mauron, Sylvain; Dolci, Mirko; Plaza Wuthrich, Sonia; Di Bernardo, Stefano Less Blood Coagulation & Fibrinolysis. 30(5):199-204, July 2019. Abstract Favorites  PDF  Get Content & Permissions Viscoelastic tests and impedance aggregometry allow coagulation evaluation at the bedside, but reference values are scarce in pediatrics. The aim of this study was to establish reference values of thromboelastometry and impedance aggregometry for this population and compare it between age groups. This prospective, single-center, observational study evaluates viscoelastic tests and impedance aggregometry in children with congenital heart disease. A total of 204 children were included with a median age of 3.6 years old. We provide references values for this population with median, percentile 2.5 and percentile 97.5. Infants demonstrate for extrinsic activity a shorter coagulation time (52 [49–55] vs. 56 [51–62] s, P  = 0.007) and clot formation time (90 [71–118] vs. 113 [93–146] s, P  < 0.0001) so as for intrinsic activity a shorter clot formation time (53 [44–69] vs. 75 [59–92] s, P  < 0.0001). The maximal clot firmness was significantly stronger in infants for extrinsic (65 [61–69] vs. 59 [54–63] mm, P  < 0.0001), intrinsic (68 [64–70] vs. 61 [57–65] mm, P  < 0.0001), and fibrinogen (12 [9–16] vs. 10 [8–13] mm, P  = 0.02) activities. Platelet aggregation was significantly higher in infants with an amplitude at 6 min of 28 [23–34] vs. 22 [15–27] Ω, P less than 0.0001, a maximum speed of 11 [9–13] vs. 7 [5–10] Ω/min, P less than 0.0001, and an area under the curve of 120 [92–135] vs. 86 [59–112] Ω min, P less than 0.0001. We provided the first reference values for impedance aggregometry and thromboelastometry in children with congenital heart disease. We showed that these infants tend to have accelerated coagulation and stronger clot firmness compared with older children, but this finding may have only minimal relevance when treating a bleeding child. Trial registration number: ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT02387944). BUY Serum metabolomics reveals the progression of coronary artery stenosis in patients with hypercholesterolemia a pilot study Qiu, Qi; Wang, Yong; Jing, Shan; Chen, Yanhua; Cao, Jinglin; Pan, Yu; Ye, Ming; Lin, Yang Less Blood Coagulation & Fibrinolysis. 30(5):205-216, July 2019. Abstract Favorites  PDF  Get Content & Permissions The current study explores potential characteristic metabolic signatures associated with the high cholesterol (CHO), and the progression of coronary artery stenosis (CAS) in high-CHO patients. A metabolomics strategy based on ultra high-performance liquid chromatography/MS-MS and multivariate statistics has been implemented to identify potential biomarkers in high-CHO patients with different levels of CAS. The current study included 57 individuals, comprising 17 healthy paticipants, and 40 high-CHO patients. The high CHO patients were subgrouped based on the computed tomography angiography results, that is, CHO+ no ART ( n  = 10), CHO+ ART less than 50% ( n  = 13), CHO+ ART 50–75% ( n  = 11), and CHO+ ART more than 75% ( n  = 6). After metabolomics study, 16 discriminating metabolites in positive ion mode and 17 discriminating metabolites in negative ion mode were regarded as possible biomarker candidates to reflect metabolic traits differences between patients with healthy subjects and CHO. A total of six metabolites were tentatively identified as potential biomarkers for the progression diagnosis of CAS: three lysophosphatidylcholines (Lyso-phosphocholine, lysoPC and Lysopersicon esculentum, lysoPE), proline betaine and tryptophan, and prasterone sulfate. The results demonstrated that tryptophan and proline betaine could differentiate the patients with or without high CHO. Tryptophan, prasterone sulfate, LysoPE (0 : 0/18 : 2) or LysoPE (18 : 2/0 : 0), and LysoPE (0 : 0/18 : 1) or LysoPE (18 : 1/0 : 0) could differentiate the patients with severe stenosis (ART > 70%) from the healthy or mild stenosis ones. Proline betaine and significant decrease of LysoPC (17 : 0) could also be a promising biomarker for the mild stenosis (ART < 50%). BUY The platelet surface glycosylation caused by glycosidase has a strong impact on platelet function Li, Liping; Qu, Chenxue; Lu, Yao; More Blood Coagulation & Fibrinolysis. 30(5):217-223, July 2019. Abstract Favorites  PDF  Get Content & Permissions Platelet surface glycosylation defects has been reported to be significantly associated with many diseases. Our previous study found that platelet surface glycosylation is altered in coronary heart disease. In this study, we further investigated whether altered glycosylation affects platelet function. Platelets were obtained from ten healthy volunteers. The platelet surface terminal sialic acid was removed by neuraminidase A, and N-linked oligosaccharides was removed by PNGase F. The function of the enzyme-treated platelet was measured. The activation and platelet adhesion to von Willebrand factor (vWF) was measured by flow cytometry. Platelet aggregation induced by ADP, arachidonic acid and collagen was detected through light transmission aggregometry, and platelet-leukocyte aggregates (PLAs) was detected by flow cytometry. Neuraminidase A treatment caused sialic acid level decrease and β-galactose level increase significantly on platelet surface. Activation marker CD62P did not change. Platelet adhesion to vWF was increased significantly ( P  < 0.05). ADP-induced platelet aggregation was significantly reduced ( P  < 0.05). Platelet-granulocytes aggregates and platelet-monocytes aggregates increased ( P  < 0.05). Platelet surface sialic acid was increased after PNGase F treatment. Platelet aggregation by all agonists were significantly reduced ( P  < 0.05). There is no difference in the binding of vWF and PLAs for PNGase F treated platelet. We demonstrated that asialoglycosylation enhances platelet binding to vWF and forming PLAs, suggest that it may be associated with high platelet reactivity and the increased risk of thrombosis. BUY First description of the molecular and clinical characterization of hereditary factor V deficiency in Saudi Arabia report of four novel mutations Al-Numair, Nouf S.; Ramzan, Khushnooda; Saleh, Mahasen; More Blood Coagulation & Fibrinolysis. 30(5):224-232, July 2019. Abstract Favorites  PDF  Get Content & Permissions Coagulation factor V plays a significant role in the blood coagulation cascade as part of the prothrombinase complex. Factor V deficiency (FVD) is a rare autosomal recessive bleeding disorder with a variable phenotypic expression which varies from being asymptomatic-to-severe bleeding episodes. The aim of this study was to perform molecular and clinical characterization of FVD in patients originating from Saudi Arabia. Eleven patients (two males and nine females) with confirmed FVD were recruited in the study with ages ranging between 5 and 53 years. A next-generation sequencing-based hematology panel encompassing 393 known genes was used. A total of six sequence variations in F5 gene were identified, including four missense mutations (p.Pro189Leu, p.Trp2004Arg, p.Met2148Thr, p. Arg2202Cys), a deletion (p.Arg872Lysfs*12) and a splicing variant (c.1118+5G>T). Four variants were identified for the first time in this study. Three patients were homozygous for their respective mutations and seven patients were heterozygous. We were not able to identify a pathogenic variant in one patient of the cohort. In-silico and three-dimensional structural analyses were performed to predict the possible impact and functional consequences of the identified variants. To our knowledge, this is the first study addressing factor V mutations in patients with Arab ancestry. Results have helped in providing a definitive diagnosis to the patients and carrier detection in extended family members. Overall, the hematology panel assay was an efficient platform, demonstrating a formidable approach for the molecular diagnosis of other suspected bleeding disorders. BUY SDC Table of Contents Outline | Back to Top  Collapse Box MUTATION REPORT Phenotypic and genetic analysis of hypofibrinogenemia because of a novel missense mutation in the FGBLeu121Arg Zhang, Haiyue; Luo, Shasha; Fang, Weiwei; More Blood Coagulation & Fibrinolysis. 30(5):233-238, July 2019. Abstract Favorites  PDF  Get Content & Permissions In this study, we found a novel missense gene mutation of fibrinogen (FIB) and it will help us to understand the pathogenesis of this type of disease. The FIB activity (FIB:C) and FIB antigen (FIB:Ag) were detected using matched commercially available kits. To identify the novel missense mutation, the fibrinogen gene sequencing was carried out. Bioinformatics and model analysis were used to study the harm of the mutation. The FIB:C and FIB:Ag of the proband were 0.82 and 1.19 g/l, respectively. Sequencing analysis detected a heterozygous c.425T>G in exon three of FGB gene resulting in p.Leu121Arg. The Leu121Arg mutation was responsible for the decrease of FIB:C, and it was the first report of such a mutation in the world. BUY Table of Contents Outline | Back to Top  Collapse Box CASE REPORTS Acquired von Willebrand syndrome in a patient with small lymphocytic lymphoma and Sjögren's syndrome which associated condition should be prioritized? Pardos-Gea, José; Martínez, Fernanda; Abrisqueta, Pau; Santamaría, Amparo; Bosch, Francesc Less Blood Coagulation & Fibrinolysis. 30(5):239-242, July 2019. Abstract Favorites  PDF  Get Content & Permissions Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic condition that poses both a diagnostic and a therapeutic challenge. Here we report a singular case of AVWS with two associated conditions, small lymphocytic lymphoma (SLL) and Sjögren's syndrome. The patient presented with recurrent and severe digestive bleeding that forced us to raise a curative attempt of AVWS. A first immunosuppressive therapy with immunoglobulins was unsuccessful and it was later decided to treat lymphoproliferative entity with bendamustine and rituximab effectively achieving SLL and AVWS remission. On the basis of our case and through literature review, we discuss potential strategies to achieve AVWS remission when it appears in the setting of several causative associated conditions. BUY Gastrointestinal angiodysplasia in two patients with type 3 von Willebrand disease Liao, Li-Chin; Liao, Szu-Chia; Chang, Chung-Hsin; More Blood Coagulation & Fibrinolysis. 30(5):243-245, July 2019. Abstract Favorites  PDF  Get Content & Permissions Angiodysplastic (AD) lesion is the most common cause of recurrent gastrointestinal (GI) bleeding in inherited Von Willebrand disease (VWD) patients lacking high-molecular-weight multimers. Defect or dysfunction of von Willebrand factor (VWF) may lead to enhanced endothelial cell proliferation followed by the development of neoangiogenesis and vascular malformation, which result in severe bleeding. Recurrent bleeding causing by GI AD is a challenging complication of VWD. The management of VWD could be difficult due to frequent recurrence and severity of bleeding episodes. The primary aim of management is not only to stop but also to prevent bleeding. We present two patients of type 3 VWD associated with AD and severe GI bleeding, which were successfully treated by endoscopic coagulation and prophylactic therapy with different regimens of plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate to maintain a trough level in the patient unresponsive to standard treatment. BUY Imatinib-induced platelet dysfunction and hypofibrinogenemia in chronic myeloid leukemia Nair, Ragesh R.; Chauhan, Richa; Harankhedkar, Shivangi; Mahapatra, Manoranjan; Saxena, Renu Less Blood Coagulation & Fibrinolysis. 30(5):246-248, July 2019. Abstract Favorites  PDF  Get Content & Permissions We aim to present a case of chronic myeloid leukemia (CML) in chronic phase, in major molecular response for 5 years of treatment with imatinib 400 mg OD. He presented with recurrent melena for one and a half years, requiring 11 U of packed red cell transfusion since then. Various causes of bleeding in CML, such as thrombocytopenia, disease progression related to accelerated phase/blast crisis or imatinib-induced cytopenia were ruled out. His investigations revealed reduced plasma fibrinogen (150 mg/ml; range 200–450 mg/ml). The platelet count, prothrombin time, activated partial thromboplastin time and thrombin time were 314 × 10 6 /l, 13 s (control 13 s), 31 s (control 30 s) and 16 s (control 16 s), respectively. Platelet aggregometry revealed normal platelet aggregation with adenine-di-phosphate, epinephrine and ristocetin, and reduced response with arachidonic acid (30%). Bleeding subsided with transfusion of fresh frozen plasma. Moreover, his medication was changed to nilotinib 300 mg BD. Thereafter, his subsequent repeat investigations were normal. Platelet function defects in CML both pretherapy and on tyrosine kinase inhibitors has been described in the literature. However, concomitant hypofibrinogenemia has rarely been reported. BUY Table of Contents Outline | Back to Top  Collapse Box SHORT COMMUNICATION Evolving paradigm in thrombophilia screening Ashraf, Noman; Visweshwar, Nathan; Jaglal, Michael; Sokol, Lubomir; Laber, Damian Less Blood Coagulation & Fibrinolysis. 30(5):249-252, July 2019. Abstract Favorites PDF  Get Content & Permissions The role of genetic thrombophilia screening for identifying a hypercoagulable state in the management of venous thromboembolism. We searched MEDLINE and EMBASE from 1995 to 2017, the websites of the professional bodies including American Society of Hematology, British Society of Hematology, International Society of Thrombosis and Hemostasis, College of American Pathologists, American College of Medical Genetics, and American Society of obstetrics and gynecology for their clinical practice guidelines. We used search strategy terms – venous thromboembolism, inherited, thrombophilia, and hypercoagulable state. Thrombophilia screening does not alter management in pregnancy, infertility, recurrent miscarriages, in primary occlusive arterial syndromes, and for primary prevention in relatives of venous thromboembolism patients considering hormonal manipulation including oral contraceptives. Routine thrombophilia screening for identifying a hypercoagulable state is not indicated in venous thromboembolism, as it is only useful in a select group of patients. There is no difference in the treatment of venous thromboembolism in patients with or without an inherited hypercoagulable state.