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Article ; Online: Monitoring heparin anticoagulation in the acute phase response.

Uprichard, James / Manning, Richard A / Laffan, Michael A

2010 Volume 149, Issue 4, Page(s) 613–619

Abstract: The anticoagulant effect of unfractionated heparin (UFH) is monitored using the activated partial thromboplastin time (APTT). An APTT of 1.5-2.5 times the control is usually taken as the therapeutic range and assumed to reflect an anti-activated factor X ...

Abstract	The anticoagulant effect of unfractionated heparin (UFH) is monitored using the activated partial thromboplastin time (APTT). An APTT of 1.5-2.5 times the control is usually taken as the therapeutic range and assumed to reflect an anti-activated factor X (anti-Xa) level of 0.35-0.7 u/ml. However, in some cases, despite administration of sufficient heparin to achieve a therapeutic anti-Xa assay level, the APTT remains sub-therapeutic. This 'apparent heparin resistance' is commonly due to high levels of factor VIII (FVIII). In these situations, the anti-Xa is usually preferred for monitoring in order to avoid, what might be, dangerously high levels of heparin. We hypothesized that at high FVIII levels, the heparin resistance encountered may be genuine rather than apparent and that higher doses of heparin may indeed be needed for an equivalent anticoagulant effect. The relationship between heparin level, APTT and anticoagulant effect at different FVIII concentrations was determined using thrombelastography and the thrombin generation assay. Thromboelastographic and thrombin generation parameters concurred with APTT, demonstrating a genuine heparin resistance in the presence of high FVIII levels. This suggests that APTT may be a more accurate measure of anticoagulant effect in vivo than anti-Xa.
MeSH term(s)	Acute-Phase Reaction/blood ; Anticoagulants/administration & dosage ; Anticoagulants/therapeutic use ; Blood Coagulation Tests/methods ; Dose-Response Relationship, Drug ; Drug Monitoring/methods ; Drug Resistance ; Factor VIII/metabolism ; Factor Xa Inhibitors ; Heparin/administration & dosage ; Heparin/therapeutic use ; Humans ; Male ; Partial Thromboplastin Time ; Thrombelastography/methods ; Thrombin/biosynthesis
Chemical Substances	Anticoagulants ; Factor Xa Inhibitors ; Factor VIII (9001-27-8) ; Heparin (9005-49-6) ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2010-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/j.1365-2141.2010.08129.x
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Article: Beta-adrenergic receptor polymorphisms in patients with elevated factor VIII levels with venous thrombosis.

O'Donnell, James / Manning, Richard A / Laffan, Michael A

British journal of haematology

2003 Volume 123, Issue 1, Page(s) 139–141

Abstract: Beta-blockers significantly reduce elevated factor VIII (FVIII) levels in patients with venous thromboembolism (VTE). To determine whether beta-adrenergic receptors are important in the aetiology of high FVIII levels, we investigated four coding ... ...

Abstract	Beta-blockers significantly reduce elevated factor VIII (FVIII) levels in patients with venous thromboembolism (VTE). To determine whether beta-adrenergic receptors are important in the aetiology of high FVIII levels, we investigated four coding polymorphisms of the beta1- and beta2-receptor genes in 64 patients with high FVIII and VTE and 100 healthy controls. Genotypic and allelic frequencies were not significantly different between the patient and control groups. However, a significant dosage effect of the beta2 E27 allele on plasma FVIII coagulant activity levels was observed in normal group O individuals.
MeSH term(s)	Adolescent ; Adult ; Aged ; Alleles ; Blood Coagulation/genetics ; Case-Control Studies ; Chi-Square Distribution ; Factor VIII/analysis ; Female ; Gene Frequency ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Pulmonary Embolism/blood ; Pulmonary Embolism/genetics ; Receptors, Adrenergic, beta/genetics ; Venous Thrombosis/blood ; Venous Thrombosis/genetics
Chemical Substances	Receptors, Adrenergic, beta ; Factor VIII (9001-27-8)
Language	English
Publishing date	2003-05-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1046/j.1365-2141.2003.04571.x
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Article ; Online: Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia.

Livesey, John A / Manning, Richard A / Meek, John H / Jackson, James E / Kulinskaya, Elena / Laffan, Michael A / Shovlin, Claire L

Thorax

2012 Volume 67, Issue 4, Page(s) 328–333

Abstract: Background: Elevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses.: Objectives: To identify reversible biomarkers associated with high factor VIII and assess potential significance ... ...

Abstract	Background: Elevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses. Objectives: To identify reversible biomarkers associated with high factor VIII and assess potential significance in a specific at-risk population. Patients/methods: 609 patients with hereditary haemorrhagic telangiectasia were recruited prospectively in two separate series at a single centre. Associations between log-transformed factor VIII measured 6 months from any known thrombosis/illness, and patient-specific variables including markers of inflammation and iron deficiency, were assessed in stepwise multiple regression analyses. Age-specific incidence rates of radiologically proven pulmonary emboli/deep venous thromboses were calculated, and logistic regression analyses performed. Results: In each series, there was an inverse association between factor VIII and serum iron that persisted after adjustment for age, inflammation and/or von Willebrand factor. Iron response elements within untranslated regions of factor VIII transcripts provide potential mechanisms for the association. Low serum iron levels were also associated with venous thromboemboli (VTE): the age-adjusted OR of 0.91 (95% CI 0.86 to 0.97) per 1 μmol/litre increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 μmol/litre compared with the mid-normal range (17 μmol/litre). The association appeared to depend on factor VIII, as once adjusted for factor VIII, the association between VTE and iron was no longer evident. Conclusions: In this population, low serum iron levels attributed to inadequate replacement of haemorrhagic iron losses are associated with elevated plasma levels of coagulation factor VIII and venous thromboembolic risk. Potential implications for other clinical populations are discussed.
MeSH term(s)	Biomarkers/blood ; Cohort Studies ; Diagnostic Imaging ; Factor VIII/analysis ; Female ; Humans ; Iron/blood ; Male ; Plasma/chemistry ; Prospective Studies ; Pulmonary Embolism/blood ; Pulmonary Embolism/diagnosis ; Regression Analysis ; Risk Factors ; Serum/chemistry ; Telangiectasia, Hereditary Hemorrhagic/blood ; Venous Thrombosis/blood ; Venous Thrombosis/diagnosis ; von Willebrand Factor/analysis
Chemical Substances	Biomarkers ; von Willebrand Factor ; Factor VIII (9001-27-8) ; Iron (E1UOL152H7)
Language	English
Publishing date	2012-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204353-1
ISSN	1468-3296 ; 0040-6376
ISSN (online)	1468-3296
ISSN	0040-6376
DOI	10.1136/thoraxjnl-2011-201076
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Article ; Online: Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia.

Shapiro, Susan E / Phillips, Emma / Manning, Richard A / Morse, Colin V / Murden, Sherina L / Laffan, Michael A / Mumford, Andrew D

British journal of haematology

2012 Volume 160, Issue 2, Page(s) 220–227

Abstract: Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) ... ...

Abstract	Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic. Amongst subjects with bleeding, symptoms were typically mild, at one anatomical site and seldom occurred after invasive procedures. All subject showed dry clot weight within or above laboratory reference interval (median 3·2 g/l; range 1·9-5·1), reduced Clauss fibrinogen (median 0·52 g/l; range 0·21-1·3), and prolonged thrombin (median 30·7 s; range 21·3-45·7) and reptilase (median 42·0 s; range 20·0-68·0) times. In all subjects, the prothrombin time ratio (PTR), determined by Sysmex CA-1500 coagulometer and Innovin activator, was abnormal (median 1·42; range 1·22-1·61). The activated partial thromboplastin time ratio and PTR with other coagulometers and activators were comparatively insensitive to HD. All subjects with HD harboured heterozygous candidate nucleotide variations within known hotspots in the FGN genes. The HD variants identified in this cross-sectional study seldom have significant clinical manifestations and show similar laboratory features irrespective of genotype. Selection of coagulometer and PT activator may markedly affect the detection of new HD cases using coagulation screening tests.
MeSH term(s)	Adolescent ; Adult ; Afibrinogenemia/blood ; Afibrinogenemia/epidemiology ; Afibrinogenemia/genetics ; Aged ; Alleles ; Blood Coagulation Tests/instrumentation ; Blood Coagulation Tests/methods ; Child ; Cross-Sectional Studies ; DNA Mutational Analysis ; England/epidemiology ; Female ; Fibrinogens, Abnormal/genetics ; Gene Frequency ; Genotype ; Hemorrhage/epidemiology ; Hemorrhage/etiology ; Humans ; Male ; Mass Screening ; Middle Aged ; Phenotype ; Point Mutation ; Polymorphism, Single Nucleotide ; Reproducibility of Results ; Young Adult
Chemical Substances	Fibrinogens, Abnormal
Language	English
Publishing date	2012-10-15
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.12085
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Article: Low-density lipoprotein receptor-related protein polymorphisms in patients with elevated factor VIII coagulant activity and venous thrombosis.

Cunningham, Nicholas / Laffan, Michael A / Manning, Richard A / O'Donnell, James S

Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis

2005 Volume 16, Issue 7, Page(s) 465–468

Abstract: Elevated factor VIII coagulant activity (FVIII:C) levels (>150 IU/dl) represent a prevalent independent risk factor for venous thromboembolism (VTE). Low-density lipoprotein receptor-related protein (LRP) is involved in factor VIII clearance in vivo, and ...

Abstract	Elevated factor VIII coagulant activity (FVIII:C) levels (>150 IU/dl) represent a prevalent independent risk factor for venous thromboembolism (VTE). Low-density lipoprotein receptor-related protein (LRP) is involved in factor VIII clearance in vivo, and elevated FVIII:C was a feature of the LRP knockout mouse model. Three coding polymorphisms of LRP1 (exon 3, C766T; exon 14, A217V; and exon 39, D2080N), together with an insertion/deletion polymorphism within the first intron of lipoprotein receptor-associated protein (LRPAP1), have been identified. In addition, LRP1 2080D was recently reported to be associated with increased plasma FVIII:C levels in normal individuals. In this study, we investigated the role of these four polymorphisms in patients with objectively confirmed VTE and elevated FVIII:C levels. In our control group, genotype distributions were consistent with previous reports. Neither the allele frequencies nor genotype distributions at LRP1 A217V, LRP1 D2080N and LRPAP1 intron 1 were significantly different between the elevated FVIII:C and control groups. In contrast to previous reports, we found no effect of LRP1 D2080N genotype on plasma FVIII:C levels in normal individuals. More importantly, prevalence of the LRP1 2080D allele was not increased in the group of patients with high FVIII:C and VTE. We conclude that LRP1 and LRPAP1 polymorphisms are not responsible for high FVIII:C levels in patients with VTE.
MeSH term(s)	Adult ; Case-Control Studies ; Factor VIII/metabolism ; Female ; Humans ; Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Venous Thrombosis/blood
Chemical Substances	Low Density Lipoprotein Receptor-Related Protein-1 ; Factor VIII (9001-27-8)
Language	English
Publishing date	2005-08-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1033551-1
ISSN	0957-5235
ISSN	0957-5235
DOI	10.1097/01.mbc.0000178831.45049.aa
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Zs.A 2920: Show issues

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Article ; Online: Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2.

Jones, Matthew L / Murden, Sherina L / Brooks, Claire / Maloney, Viv / Manning, Richard A / Gilmour, Kimberly C / Bharadwaj, Vandana / de la Fuente, Josu / Chakravorty, Subarna / Mumford, Andrew D

BMC medical genetics

2013 Volume 14, Page(s) 42

Abstract: Background: Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic ... ...

Abstract	Background: Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic characteristics include reduced pigmentation, absent platelet dense granule secretion, neutropenia and reduced cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function. To date HPS2 has been associated with non-synonymous, stop-gain or deletion-insertion nucleotide variations within the coding region of AP3B1. Case presentation: We describe a consanguineous female infant with reduced pigmentation, neutropenia and recurrent infections. Platelets displayed reduced aggregation and absent ATP secretion in response to collagen and ADP, indicating a platelet dense granule defect. There was increased basal surface expression of CD107a (lysosome-associated membrane protein 1(LAMP-1)) on NK cells and CTLs from the study subject and a smaller increase in the percentage of CD107a positive cells after stimulation compared to most healthy controls. Immunoblotting of protein extracts from EBV-transformed lymphoblasts from the index case showed absent expression of full-length AP-3 β3A subunit protein, confirming a phenotypic diagnosis of HPS2.The index case displayed a homozygous pericentric inv(5)(p15.1q14.1), which was also detected as a heterozygous defect in both parents of the index case. No loss of genetic material was demonstrated by microarray comparative genome hybridisation at 60kb resolution. Fluorescence in-situ hybridisation using the 189.6kb probe RP11-422I12, which maps to 5q14.1, demonstrated dual hybridisation to both 5q14.1 and 5p15.1 regions of the inverted Chr5. The RP11-422I12 probe maps from intron 1 to intron 16 of AP3B1, thus localising the 5q inversion breakpoint to within AP3B1. The probe RP11-211K15, which corresponds to an intergenic region on 5p also showed dual hybridisation, enabling localisation of the 5p inversion breakpoint. Conclusion: This case report extends the phenotypic description of the very rare disorder HPS2. Our demonstration of a homozygous Chr5 inversion predicted to disrupt AP3B1 gene provides a novel pathogenic mechanism for this disorder.
MeSH term(s)	Adaptor Protein Complex 3/genetics ; Adaptor Protein Complex 3/metabolism ; Adaptor Protein Complex beta Subunits/genetics ; Adaptor Protein Complex beta Subunits/metabolism ; Blood Platelets/metabolism ; Blood Platelets/ultrastructure ; Chromosome Inversion ; Chromosomes, Human, Pair 5/genetics ; Female ; Genes ; Hermanski-Pudlak Syndrome/genetics ; Hermanski-Pudlak Syndrome/pathology ; Homozygote ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Infant ; Killer Cells, Natural/metabolism ; Lysosomal-Associated Membrane Protein 1/genetics ; Lysosomal-Associated Membrane Protein 1/metabolism ; Lysosomal Membrane Proteins/genetics ; Lysosomal Membrane Proteins/metabolism ; Phenotype ; Pigmentation/genetics ; Protein Subunits/metabolism ; T-Lymphocytes, Cytotoxic/metabolism
Chemical Substances	AP3B1 protein, human ; Adaptor Protein Complex 3 ; Adaptor Protein Complex beta Subunits ; LAMP1 protein, human ; Lysosomal-Associated Membrane Protein 1 ; Lysosomal Membrane Proteins ; Protein Subunits
Language	English
Publishing date	2013-04-04
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041359-2
ISSN	1471-2350 ; 1471-2350
ISSN (online)	1471-2350
ISSN	1471-2350
DOI	10.1186/1471-2350-14-42
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Article ; Online: Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels.

O'Donnell, James / Boulton, Frank E / Manning, Richard A / Laffan, Michael A

Arteriosclerosis, thrombosis, and vascular biology

2002 Volume 22, Issue 2, Page(s) 335–341

Abstract: To investigate whether the effect of ABO blood group on plasma von Willebrand factor (vWF) levels is mediated by the ABH antigenic determinants carried on N-linked glycans of vWF, we studied 158 group A and group O healthy volunteers. vWF antigen (vWF:Ag) ...

Abstract	To investigate whether the effect of ABO blood group on plasma von Willebrand factor (vWF) levels is mediated by the ABH antigenic determinants carried on N-linked glycans of vWF, we studied 158 group A and group O healthy volunteers. vWF antigen (vWF:Ag) and factor VIII antigen (FVIII:Ag) levels were highest in A(1)A(1) individuals and higher in A(1)O(1) than in A(2)O(1) or O(1)O(1) individuals. Plasma A transferase activity and the amount of A antigen expressed per unit vWF (AvWF) were significantly higher in A(1)A(1) than in A(1)O(1) individuals and higher in A(1)O(1) than in A(2)O(1) individuals. AvWF was correlated strongly with plasma levels of A transferase activity. Thus, we have clearly demonstrated a direct relationship between ABO genotype, A transferase expression, and the amount of A antigen expressed on circulating vWF. H antigen expression per unit vWF (HvWF) was highest in group O individuals. Among group A individuals, the pattern of HvWF expression was A(2)O(1)>A(1)O(1)>A(1)A(1). In group O and group A(2)O(1) individuals, HvWF was inversely correlated with plasma vWF levels. In contrast, among group A(1)A(1) and A(1)O(1) individuals, there was no relationship between AvWF and plasma vWF levels. These findings suggest that it is H antigen expression that mediates the ABO effect on plasma vWF concentration.
MeSH term(s)	ABO Blood-Group System/genetics ; ABO Blood-Group System/immunology ; Antigens/blood ; Antigens, Bacterial/blood ; Coenzyme A-Transferases/metabolism ; Factor VIII/immunology ; Female ; Genotype ; Glycosyltransferases/metabolism ; Humans ; Male ; Reference Values ; von Willebrand Factor/metabolism
Chemical Substances	ABO Blood-Group System ; Antigens ; Antigens, Bacterial ; H antigen ; Von Willebrand antigen ; von Willebrand Factor ; Factor VIII (9001-27-8) ; Glycosyltransferases (EC 2.4.-) ; Coenzyme A-Transferases (EC 2.8.3.-)
Language	English
Publishing date	2002-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/hq0202.103997
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Zs.A 1705: Show issues

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Article ; Online: Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension.

Shovlin, Claire L / Angus, Gillian / Manning, Richard A / Okoli, Grace N / Govani, Fatima S / Elderfield, Kay / Birdsey, Graeme M / Mollet, Inês G / Laffan, Michael A / Mauri, Francesco A

PloS one

2010 Volume 5, Issue 2, Page(s) e9154

Abstract: Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. ... ...

Abstract	Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. Methodology/principal findings: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by RT-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab-reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5' exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms. Conclusions/significance: The pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future research on the regulation and perturbation of FVIII synthesis, and of potential relevance to haemophilia, thromboses, and pulmonary hypertensive states.
MeSH term(s)	Alternative Splicing ; Base Sequence ; Blood Coagulation ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Enzyme-Linked Immunosorbent Assay ; Exons/genetics ; Factor VIII/genetics ; Factor VIII/metabolism ; Flow Cytometry ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Immunohistochemistry ; Lung/blood supply ; Lung/cytology ; Lung/metabolism ; Microscopy, Confocal ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Pulmonary Artery/cytology ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Transcription Initiation Site ; Transcription, Genetic/genetics ; von Willebrand Factor/metabolism
Chemical Substances	Protein Isoforms ; von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2010-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0009154
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Article: Genotype at the secretor blood group locus is a determinant of plasma von Willebrand factor level.

O'Donnell, James / Boulton, Frank E / Manning, Richard A / Laffan, Michael A

British journal of haematology

1999 Volume 116, Issue 2, Page(s) 350–356

Abstract: Previous reports on the effect of Secretor and Lewis blood groups on plasma factor VIII-von Willebrand factor (FVIII-VWF) levels have produced conflicting findings. To determine whether either or both loci can influence plasma FVIII-VWF complex levels, ... ...

Abstract	Previous reports on the effect of Secretor and Lewis blood groups on plasma factor VIII-von Willebrand factor (FVIII-VWF) levels have produced conflicting findings. To determine whether either or both loci can influence plasma FVIII-VWF complex levels, we studied the relationship between Secretor and Lewis genotypes, determined definitively using polymerase chain reaction-restriction fragment length polymorphism analysis, and plasma FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) levels in 136 healthy volunteers. Overall, significantly higher VWF:Ag levels were found in those individuals homozygous for the Se allele (genotype SeSe) than in those heterozygous for the Se allele (P < 0.001). To minimize any confounding influence of ABO genotype/phenotype, we investigated the relationship between Secretor genotype and plasma FVIII-VWF levels within individuals of the same ABO blood group genotype. In the subgroup analysis of group O1O1 individuals alone, VWF:Ag levels were again significantly higher in those individuals with Secretor genotype SeSe than in those either heterozygous or homozygous for the se null allele. Among A1O1 subjects, homozygous Secretors also had significantly higher VWF:Ag levels. In contrast, we found no relationship between Lewis genotype and either VWF:Ag or FVIII:C levels. This study is the first based on genotypic rather than serological analysis, and resolves the previously confounding effects of the Lewis and Secretor loci on plasma FVIII-VWF complex levels.
MeSH term(s)	ABO Blood-Group System ; Adolescent ; Adult ; Aged ; Blood Group Antigens/genetics ; Enzyme-Linked Immunosorbent Assay/methods ; Factor VIII/metabolism ; Genotype ; Homozygote ; Humans ; Lewis Blood-Group System ; Middle Aged ; Polymorphism, Restriction Fragment Length ; von Willebrand Factor/analysis
Chemical Substances	ABO Blood-Group System ; Blood Group Antigens ; Lewis Blood-Group System ; von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	1999-08-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1046/j.1365-2141.2002.03270.x
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Article: Elevation of FVIII: C in Venous Thromboembolism Is Persistent and Independent of the Acute Phase Response

O’Donnell, James / Mumford, Andrew D. / Manning, Richard A. / Laffan, Michael

Thrombosis and Haemostasis

2000 Volume 83, Issue 01, Page(s) 10–13

Abstract: Recent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to determine whether the increased FVIII:C precedes the ... ...

Abstract	Recent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to determine whether the increased FVIII:C precedes the thrombosis or represents a secondary reactive phenomenon. In an attempt to address this question, we followed 35 patients with confirmed VTED, raised FVIII:C level (>1.5 iu/ml) and no other thrombotic tendency. Serial measurements of FVIII:C, vWF:Ag, C-reactive protein and fibrinogen were performed. We hypothesized that a persistent increase in FVIII:C in the absence of any other measures of ongoing acute phase response, would support the idea that elevation of FVIII:C is a constitutional phenomenon. Of this initial group, 94% continued to have an elevated FVIII:C level throughout the period of follow up (median 8 months; range 3 to 39 months), with no significant difference between the FVIII:C levels determined at first estimation and those obtained during follow up (p = 0.58). Conversely, only 18% had evidence of an acute phase reaction when first assessed, and nonparametric ranking analysis demonstrated no correlation between FVIII:C and either C-reactive protein or fibrinogen (p = 0.315 and 0.425 respectively).We conclude that increased FVIII:C levels following VTED are persistent, independent of the acute phase reaction, and thus may represent a constitutional risk factor for VTED.
Keywords	FVIII:C ; venous thromboembolism ; acute phase
Language	English
Publishing date	2000-01-01
Publisher	Schattauer GmbH
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0037-1613748
Database	Thieme publisher's database

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