Hemostatic risk factors for pregnancy-related venous thrombosis
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AbstractBackground: Limited data exist on thrombophilia and the risk of pregnancy-related venous thrombosis (VT), and there are no information on differential risk factors for pregnancy-related pulmonary embolism (PE) and deep vein thrombosis (DVT).
Objectives: To investigate whether hemostatic parameters known to be risk factors for VT in the general population were associated with pregnancy-related VT and whether these risk factors were differentially associated with the risk of PE and DVT.
Methods: Blood samples were collected from a total of 313 cases with objectively verified first time VT and 353 controls with no history of VT originating from a source population of 613,232 pregnancies.
Results: Factor (f)VIII, normalized endogenous thrombin potential (n-ETP) and D-dimer values >90th percentiles were independent risk factors for pregnancy-related VT; adjusted ORs (aORs) 1.7 (95% confidence interval (CI) 1.1-2.8), 1.8 (95% CI 1.1-3.0) and 2.1 (95% CI 1.3-3.3), respectively. Reduced sensitivity to activated protein C (aPC), expressed as elevated normalized aPC sensitivity ratio (n-aPC-sr), was a risk factor for pregnancy-related VT in non-carriers of F5 rs6025 polymorphism (commonly known as factor V Leiden), aORs for VT for n-aPC-sr in the 4th quartile as compared with n-aPC-sr ≤ the 4th quartile was 2.6 (95% CI 1.7-4.0). Analysing only carriers of factor V Leiden the risk of VT increased, although not statistical significant, with higher n-aPC-sr, indicating a relation between an aPC resistance phenotype and risk of VT. The risk for PE as compared with controls was more than doubled in women with fIX >90th percentile; aOR 2.4 (95% CI 1.1-5.0) and three times increased in women with free protein S (PS) antigen ≤ 65%; aOR 3.1 (95% CI 1.3-7.2). Carriers of factor V Leiden, and non-carriers of factor V Leiden with n-aPC-sr in the 4th quartile had increased risk of DVT as compared with controls; OR 7.7 (95% CI 4.7-12.7) and aOR 3.3 (95% CI 2.1-5.2), respectively. 9 cases and none controls were positive for at least two antiphosholipid antibodies (APAs) (multi-positive). Excluding women with IgM antibodies, 7 cases were still APA multi-positive.
Conclusions: Elevated levels of fVIII, n-ETP, D-dimer and reduced sensitivity to aPC in absence of factor V Leiden were independent risk factors for pregnancy-related VT. APA multi-positivity was strongly associated with pregnancy-related VT. High levels of fIX and low levels of free PS antigen was associated with increased risk of PE, and the risk of DVT was increased in women with reduced sensitivity to aPC in absence of factor V Leiden, and in carriers of factor V Leiden. Our data substantiate the hypothesis of differential pathophysiology between DVT and PE.
List of papers. The papers are removed from the thesis due to publisher restrictions.
Paper I: Bergrem A, Dahm AE, Jacobsen AF, Sandvik L, Sandset PM. Differential risk factors for pregnancy related deep vein thrombosis and pulmonary embolism - A populationbased case-control study. Thrombosis and Hemostasis 2012; 108: 1165-71. doi:10.1160/TH12-05-0350
Paper II: Bergrem A, Dahm AE, Jacobsen AF, Mowinckel MC, Sandvik L, Sandset PM. Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism. British Journal of Haematology 2011; 157: 241-47. doi:10.1111/j.1365-2141.2011.08712.x
Paper III: Bergrem A, Jacobsen EM, Skjeldestad FE, Jacobsen AF, Skogstad M, Sandset PM. The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis – a population-based case-control study. Thrombosis Research 2010; 125: e222-7. doi:10.1016/j.thromres.2009.12.006