F11 Gene Duplication Causes Elevated FXI Plasma Levels and Is a Risk for Venous Thrombosis

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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A Novel Chimaeric Derivative of Saruplase, rscu-PA-40kDA/Hir, Binds to Thrombin and Exerts Thrombus-specific Fibrinolysis in Arterial and Venous Thrombosis in Dogs

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656002 ◽

1997 ◽

Vol 77 (03) ◽

pp. 535-539 ◽

Cited By ~ 4

Author(s):

J Schneider ◽

R Hauser ◽

H-H Hennies ◽

J Korioth ◽

G Steffens ◽

...

Keyword(s):

Venous Thrombosis ◽

Plasma Levels ◽

Time Course ◽

Bolus Injection ◽

Specific Activity ◽

Intravenous Bolus ◽

Protease Domain ◽

Parent Molecule ◽

Significant Prolongation ◽

Inhibitory Domain

SummaryThe chimaeric molecule rscu-PA-40kDA/Hir (M23) comprises the kringle and protease domain of saruplase (rscu-PA) and a thrombin inhibitory domain fused to the C-terminus of the protease domain. The 27 amino acid long thrombin inhibitory domain contains a sequence directed to the active site of thrombin and a fragment from the C-terminal region of hirudin. 125I-radiolabelled M23 (0.03 µM) bound to thrombin that was immobilised onto CNBr-activated sepharose beads. Unlabelled M23 (0.01-10 |xM) and hirudin (0.001-10 µµM) concentra-tion-dependently displaced 125I-M23 from its binding to thrombin. Saruplase (up to 10 (iM) did not influence the thrombin binding of M23. The fibrinolytic properties of M23 and saruplase were compared in anaesthetized dogs with femoral artery and saphenous vein thrombosis. Under concomitant heparinization, the intravenous bolus injections of 1 mg/kg M23 or saruplase induced reperfusion of thrombotically occluded femoral arteries in 4 out of 5 treated animals in each case. There was one reocclusion in the M23-treated group. Time to reperfusion (23 ± 4 vs 25 ± 11 min) and maximal height of reperfusion blood flow (98 ± 21 vs 108 ± 15 % of baseline flow) did not differ significantly between the treatment groups. The time course of the lysis of incorporated 125I-fibrin radioactivity in thrombosed saphenous veins was similar after bolus injections of M23 and saruplase. The maximal dissolution of 125I-fibrin in the venous thrombosis model was 91 ± 1 % in M23-and 88 ± 5 % in saruplase-treated animals. Plasma levels of fibrinogen were not influenced and a2-antiplasmin levels were slightly reduced (-27 ± 3 %) after bolus injection of M23. In contrast, bolus injection of saruplase was accompanied by a significant decrease of fibrinogen (-55 ± 19 %) and a2-antiplasmin (-75 ±11%) plasma levels. Template bleeding times virtually did not differ before (2.8 ± 0.3 min) and 60 min after bolus injection of M23 (3.1 ± 0.3 min), whereas treatment with saruplase resulted in a significant prolongation of template bleeding time from 2.6 ± 0.2 min to 28 ± 13 min. It is concluded that the saruplase derivative M23, while inducing equieffective thrombolysis after intravenous bolus injection in dogs, causes much fewer haemostatic side effects than its parent molecule. The high thrombus-specific activity of M23 is tentatively attributed to its affinity to clot-bound thrombin.

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Association of ABO haplotypes with the risk of venous thrombosis: impact on disease risks estimation

Blood ◽

10.1182/blood.2020008997 ◽

2020 ◽

Author(s):

Louisa Goumidi ◽

Florian Thibord ◽

Kerri L. Wiggins ◽

Ruifang Li-Gao ◽

Michael R Brown ◽

...

Keyword(s):

Venous Thrombosis ◽

Blood Group ◽

Plasma Levels ◽

Odds Ratio ◽

Prediction Models ◽

Genetic Risk Score ◽

Individual Risk ◽

Abo Blood Group ◽

Increased Risk ◽

The Impact

Genetic risk score (GRS) analysis is an increasingly popular approach to derive individual risk prediction models for complex diseases. In the context of venous thrombosis (VT), any GRS shall integrate information at the ABO blood group locus, the latter being one of the major susceptibility locus for this disease. However, there is yet no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when one is interested in properly assessing the association of ABO locus with VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in up to 5,425 cases and 8,445 controls from 6 studies, we demonstrated that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal as 5% of rs8176719-delG carriers are not exposed at higher VT risk. Instead, we recommend to use 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B) and rs41302905 (O2) in any analysis aimed at assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared to O1 haplotype that can be inferred from these 4 SNPs, the A2 haplotype is associated with a modest increase in VT risk (odds ratio ~1.2), A1 and B haplotypes are associated with a ~1.8 fold increased risk while O2 tend to be slightly protective (odds ratio ~0.80). In addition, our analyses clearly showed that while the A1 an B blood group are associated with increased vWF and FVIII plasma levels only the A1 blood group is associated wih ICAM plasma levels but in an opposite direction, leaving additional avenues to be explored in order to fully understand the whole spectrum of biological effect of ABO locus on cardiovascular traits.

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Plasma levels of factor XII, prekallikrein and high molecular weight kininogen in normal blood donors and patients having suffered venous thrombosis

Thrombosis Research ◽

10.1016/j.thromres.2004.05.005 ◽

2004 ◽

Vol 114 (2) ◽

pp. 91-96 ◽

Cited By ~ 27

Author(s):

Michael J Gallimore ◽

Simon L Harris ◽

David W Jones ◽

Mark Winter

Keyword(s):

Molecular Weight ◽

Venous Thrombosis ◽

High Molecular Weight ◽

Plasma Levels ◽

Blood Donors ◽

Normal Blood ◽

Factor Xii ◽

High Molecular Weight Kininogen

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Hypercoagulability in hereditary hemorrhagic telangiectasia with epilepsy

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.158791 ◽

2015 ◽

Vol 6 (03) ◽

pp. 407-409 ◽

Cited By ~ 1

Author(s):

Josef Finsterer ◽

Ernst Sehnal

Keyword(s):

Venous Thrombosis ◽

Factor Viii ◽

Plasma Levels ◽

Coagulation Factor ◽

Coagulation Factor Viii ◽

Intestinal Bleeding ◽

Recurrent Bleeding ◽

Vein Thrombosis ◽

Increased Risk ◽

Recurrent Epistaxis

ABSTRACTRecent data indicate that in patients with hereditary hemorrhagic teleangiectasia (HHT), low iron levels due to inadequate replacement after hemorrhagic iron losses are associated with elevated factor-VIII plasma levels and consecutively increased risk of venous thrombo-embolism. Here, we report a patient with HHT, low iron levels, elevated factor-VIII, and recurrent venous thrombo-embolism. A 64-year-old multimorbid Serbian gipsy was diagnosed with HHT at age 62 years. He had a history of recurrent epistaxis, teleangiectasias on the lips, renal and pulmonary arterio-venous malformations, and a family history positive for HHT. He had experienced recurrent venous thrombosis (mesenteric vein thrombosis, portal venous thrombosis, deep venous thrombosis), insufficiently treated with phenprocoumon during 16 months and gastro-intestinal bleeding. Blood tests revealed sideropenia and elevated plasma levels of coagulation factor-VIII. His history was positive for diabetes, arterial hypertension, hyperlipidemia, smoking, cerebral abscess, recurrent ischemic stroke, recurrent ileus, peripheral arterial occluding disease, polyneuropathy, mild renal insufficiency, and epilepsy. Following recent findings, hypercoagulability was attributed to the sideropenia-induced elevation of coagulation factor-VIII. In conclusion, HHT may be associated with hypercoagulability due to elevated factor-VIII associated with low serum iron levels from recurrent bleeding. Iron substitution may prevent HHT patients from hypercoagulability.

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Plasma cholesteryl ester transfer protein and blood coagulability

Thrombosis and Haemostasis ◽

10.1160/th07-07-0451 ◽

2007 ◽

Vol 98 (12) ◽

pp. 1160-1164 ◽

Cited By ~ 10

Author(s):

Hiroshi Deguchi ◽

José Fernndez ◽

John Griffin

Keyword(s):

Venous Thrombosis ◽

Cholesteryl Ester ◽

Cholesteryl Ester Transfer Protein ◽

Plasma Levels ◽

Density Lipoprotein ◽

Factor Xa ◽

Young Male ◽

Transfer Protein ◽

Plasma Cholesteryl Ester ◽

Blood Coagulability

SummaryDyslipoproteinemia involving low levels of high density lipoprotein (HDL) is linked to venous thrombosis in young male adults and to recurrence of venous thrombosis in patients who have experienced a previous unprovoked venous thrombosis episode. Plasma cholesteryl ester transfer protein (CETP) modulates HDL metabolism and some lipoproteins can affect blood coagulation reactions with either procoagulant or anticoagulant effects. Hence, we evaluated relationships between the mass of CETP and blood coagulability in plasma samples from 39 normal healthy adults. For clotting initiated by dilute tissue factor or factor XIa,clotting times significantly correlated with CETP antigen levels. Thus,coagulation initiated by either the extrinsic or intrinsic coagulation pathway is positively correlated with CETP plasma levels. When added to plasma, a recombinant CETP preparation dose-dependently shortened factor Xa-1-stage clotting times, showing that it augmented procoagulant activity in plasma. In reaction mixtures containing purified factors Xa and Va and prothrombin, the recombinant CETP preparation dose-dependently increased prothrombin activation, suggesting it specifically enhances prothrombinase activity. Thus, our data highlight a previously unknown positive relationship between CETP plasma levels and blood coagulability that might relate to risks for thrombotic events.

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Protein Z Levels Could Help To Predict Obstetrical Complications and Arterial Thrombosis in Patients with Antiphospholipid Antibodies.

Blood ◽

10.1182/blood.v108.11.4081.4081 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4081-4081

Author(s):

Annick Ankri ◽

Isabelle Martin-Toutain ◽

Kiarach Goldar ◽

Marie-Claude Diemert ◽

Danielle Vauthier-Brouze ◽

...

Keyword(s):

Venous Thrombosis ◽

Plasma Protein ◽

Plasma Levels ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Clinical Event ◽

Protein Z ◽

Thrombotic Risk ◽

Obstetrical Complications ◽

Thrombotic Tendency

Abstract Introduction: Protein Z (PZ) is a vitamin K dependant plasma protein synthesized by the liver. The precise physiological function of PZ is still unclear: - anticoagulant, the PZ-dependant protease inhibitor complex inhibits factor Xa and acts as a naturally occurring anticoagulant; - procoagulant, PZ promote the assembly of thrombin with PL vesicles- and promote coagulation. In clinical situations, low PZ plasma levels have been associated with bleeding and thrombotic tendency while elevated PZ plasma levels have been linked with ischemic stroke. Antiphospholipid syndrome (APS) is a complex autoimmune thrombotic disorder. Despite specific clinical and laboratory criteria, diagnostic and prognostic tools in patients with APS are limited in their ability to predict adverse outcome in patients with antiphospholipid antibodies (aPLA). Therefore, we hypothesized that PZ could play a role in the thrombotic tendency. Study: to evaluate our hypothesis, we measured PZ plasma concentrations in a case control study including 61 patients with confirmed aPLA with or without APS versus 53 controls. Among the group of patients with APS, 15 had obstetrical complications (OC), 16 had arterial thrombosis (AT) and 11 venous thrombosis (VT). Nineteen patients had aPLA without APS defining the APS(−) group. Plasma PZ antigen concentrations were measured on citrated plasma using the commercial ELISA kit, Asserachrom protein Z, (Diagnostica Stago). Results: PZ plasma levels were normally distributed. Normal PZ concentrations defined as mean ±2 SD were contained between 0.4 and 2.6 μg/mL. No difference was found in mean+ SD between male and female. Two per cents of controls and 18% of patients with venous thrombosis had PZ under 0.4 μg/mL. Forty per cents of patients with OC, 25% with AT and 18% with VT had PZ above 2.6 μg/mL. Plasma protein Z levels measured at least 6 month after any clinical event were significantly higher in APS patients than in controls and APS(−) patients [mean ± SD μg/mL, 2.0 ± 0.9 vs 1.5 ± 0.5 and 1.3 ± 0.5 respectively). According to the clinical complications, PZ concentrations were significantly greater in the group with OC (2.4+0.6 μg/mL) and AT (2.05+0.8 μg/mL) than in controls (1.5+0.5 μg/mL), VT(1.3+0.9 μg/mL) and APS(−) (1.3+0.5 μg/mL) patients [OC vs Controls: p<0.0001; AT vs Controls: p= 0.0047; OC vs AT: p= NS; OC vs APS(−):p< 0.0001; OC vs VT: p= 0.0016, APS(−) vs controls: NS; APS(−) vs VT: NS; VT vs Controls: NS; APS(−) vs AT: p=0.0034; AT vs VT: p= 0.05]. We found an increased relative risk of OC and AT with increasing PZ levels with odds ratios of 7.1 [95% CI: 2.1–23.7] for OC and 2.4 [95% CI: 1.1–5.4] for AT. Conclusion: our study retrospective on a small size sample, indicates that high protein Z plasma could be a high risk for obstetrical complications and a lower risk for arterial thrombosis in aPLA patients. Measure of PZ could help to evaluate obstetrical and thrombotic risk of patients with aPLA. Further prospective studies are needed to confirm our results.

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In prothrombin G20210A carriers the genetic mutation and the history of Venous Thrombosis contribute both to thrombin generation independently of factor II plasma levels

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2010.03773.x ◽

2010 ◽

Author(s):

G. Lavigne-Lissalde ◽

C. Sanchez ◽

C. Castelli ◽

S. Alonso ◽

E. Mazoyer ◽

...

Keyword(s):

Venous Thrombosis ◽

Plasma Levels ◽

Thrombin Generation ◽

Genetic Mutation ◽

Prothrombin G20210a ◽

Factor Ii ◽

History Of

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C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S–independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

Blood ◽

10.1182/blood-2010-01-263038 ◽

2010 ◽

Vol 115 (23) ◽

pp. 4644-4650 ◽

Cited By ~ 40

Author(s):

Alfonso Buil ◽

David-Alexandre Trégouët ◽

Juan Carlos Souto ◽

Noémie Saut ◽

Marine Germain ◽

...

Keyword(s):

Venous Thrombosis ◽

Association Study ◽

Plasma Levels ◽

Protein S ◽

Case Control ◽

Genome Wide Association ◽

Susceptibility Locus ◽

Case Control Studies ◽

Genome Wide ◽

Independent Mechanism

AbstractThrough its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, α7β1, α6β1, and α7β0, we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with α7β0 levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased α7β0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.

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