| 11. |
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| 12. |
- Kunz, G, et al.
(author)
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Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function
- 2002
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In: Blood. - 1528-0020. ; 99:10, s. 3646-3653
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Journal article (peer-reviewed)abstract
- Sporadic mutations in the thrombomodulin (TM) gene occur in patients with both arterial and venous thrombosis, but the effects of these mutations on expression and function are largely unexplored. Full-length wild-type TM complementary DNA (cDNA) was incorporated into vector pcDNA6 for transfection into COS-7 cells for transient expression. Mutagenesis was performed to create 7 TM mutants with natural mutations either previously identified (Ala25Thr, Gly6lAla, Asp468Tyr, Pro477Ser, Pro483Leu) or reported here (an 11-base pair [bp] deletion, del791-801, leading to STOP306, and a missense mutation, Arg385Ser). Four mutations were found to detrimentally affect the level of expression of the TM protein. Of the missense mutations, 3 had reduced expression compared to wild-type TM (100%), Arg385Ser (50.2% +/- 5%, P < .001), Pro477Ser (76.8% +/-11%, P <.001), Pro483Leu (82.1% +/- 8%, P < .007). No TM protein expression could be detected on the cell surface for mutation del791-801. The cofactor activity of TM in protein C activation was also evaluated. The Michaelis constant (K,) for wild-type thrombin-TM complex was 634 +/- 6 nmol/L. Two mutants, with Arg385Ser and Pro477Ser, had Increased (P < .0001) K, 2967 +/- 283 nM, and 2342 +/- 219 nM, respectively, demonstrating impaired function of the thrombin-TM complex. This work presents biochemical evidence that certain (but not all) natural mutations In the TM gene reduce expression and impair function of the protein on the cell surface, and helps clarify the suggested contribution that these mutations might make to the risk of thromboembolic disease.
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| 13. |
- Lind, Marcus, et al.
(author)
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Thrombomodulin as a marker for bleeding complications during warfarin treatment
- 2009
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In: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 169:13, s. 1210-1215
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Journal article (peer-reviewed)abstract
- BACKGROUND: The major adverse effect of warfarin treatment is hemorrhage. Several risk factors for bleeding complications are also risk factors for thromboembolic events, making the clinical decision to initiate or withhold anticoagulant treatment difficult. Specific markers that solely identify patients at high risk of bleeding would have great clinical impact. This study aimed to test if thrombomodulin (TM) concentrations were associated with bleeding complications, cardiovascular events, or mortality in long-term anticoagulant-treated patients. METHODS: In a longitudinal cohort study we followed up 719 patients receiving warfarin treatment for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified. Soluble TM antigen (sTM) concentration in plasma was measured with an enzyme-linked immunosorbent assay method. RESULTS: During the follow-up time, 113 clinically relevant bleeding events and 73 major bleeding events occurred. Increased concentration of sTM was associated with both clinically relevant bleeding and major bleeding events after adjustment for age. In the multivariable models, hazard ratios for the highest tertiles compared with the lowest were 2.29 (95% confidence interval, 1.35-3.89) and 2.33 (95% confidence interval, 1.21-4.48), respectively. No association between sTM concentration and nonfatal ischemic cardiovascular events or all-cause mortality was found. CONCLUSIONS: Increased levels of sTM are associated with bleeding complications during warfarin treatment but not with cardiovascular events or all-cause mortality. Soluble TM antigen concentration has potential as a new specific marker to identify patients at high risk of bleeding during warfarin treatment.
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| 14. |
- Norlund, Lena, et al.
(author)
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A common thrombomodulin amino acid dimorphism is associated with myocardial infarction
- 1997
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In: Thrombosis and Haemostasis. - 0340-6245. ; 77:2, s. 51-248
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Journal article (peer-reviewed)abstract
- Endothelial dysfunction and haemostatic imbalance are believed to be important aetiological factors in the development of acute coronary syndromes. Thrombomodulin (TM) is an integral membrane protein crucial for normal endothelial function and activation of the protein C anticoagulant pathway. We have investigated the importance of a common C/T dimorphism in the TM gene (nucleotide 1418) for development of premature myocardial infarction (MI). The C/T dimorphism predicts an Ala455 to Val replacement in the sixth EGF-like domain of TM. The dimorphism was investigated in 97 MI survivors and 159 healthy controls. The C allele was significantly more frequent among patients than controls (p = 0.035). The allele frequency for the C allele was 0.82 in the patients and 0.72 in the control group. The plasma concentration of TM was investigated among healthy controls but was not related to the C/T dimorphism. In conclusion, the association of the C allele with premature MI, suggests that the TM gene and the C/T dimorphism may be aetiological factors involved in the pathogenesis of MI. Possibly, the Ala455 to Val replacement may affect the function of the TM molecule and the activation of the protein C anticoagulant pathway.
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| 15. |
- Norlund, Lena, et al.
(author)
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A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis
- 1997
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In: Thrombosis and Haemostasis. - 0340-6245. ; 78:4, s. 1164-1166
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Journal article (peer-reviewed)abstract
- Thrombomodulin is an endothelial cell membrane glycoprotein that promotes protein C activation. It has been clearly demonstrated that the anticoagulant functions of the protein C system are important in the prevention of thromboembolic disease. Patients with protein C or protein S deficiency and/or resistance to activated protein C (APC resistance) are at higher risk for developing thromboembolic disease. The first mutation in the thrombomodulin gene was discovered in an American patient suffering from pulmonary embolism at the age of 45 (Ohlin and Marlar 1995). Here we report a case of sagittal sinus thrombosis in a 42-year-old Swedish woman. She was found to carry a heterozygous point mutation changing G127 to A, predicting an Ala25 to a Thr change in the mature thrombomodulin protein. This mutation was also found in her 16-year-old daughter, who so far has not suffered from any thrombotic events. The patient had no other detectable prothrombotic genetic defects associated with the coagulation system. This case supports the hypothesis of an association between mutations in the thrombomodulin gene and venous thrombosis.
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| 16. |
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| 17. |
- Przybyla, Beata, et al.
(author)
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Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD – A longitudinal study
- 2017
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Journal article (peer-reviewed)abstract
- Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6–8 time points over three months. Results Overall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64–0.82, p<0.001) and between PC and AT (r = 0.62–0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation. Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
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