Coagulation activation in sickle cell trait: an exploratory study

Amin, Chirag; Adam, Soheir; Mooberry, Micah J.; Kutlar, Abdullah; Kutlar, Ferdane; Esserman, Denise; Brittain, Julia E.; Ataga, Kenneth I.; Chang, Jen Yea; Wolberg, Alisa S.; Key, Nigel S.

doi:10.1111/bjh.13641

Cited by 29 publications

(22 citation statements)

References 55 publications

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“…5 While sickle cell disease is a hypercoagulable state, few prior studies have examined hemostatic measures in HBB rs334 heterozygotes. 5, 30, 31, 33 We did not find any association between HBB rs334 and other hemostasis biomarkers, though our analysis may be limited by sample size. The mechanism responsible for higher D-dimer in sickle cell mutation carriers is unknown.…”

Section: Discussioncontrasting

confidence: 57%

D-Dimer in African Americans

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Zakai

Duan

et al. 2017

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Objective Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared to those of European ancestry and higher among women compared to men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident CVD. Approach and Results We measured baseline D-dimer in 4,163 AAs aged 21–93 years from the prospective Jackson Heart Study (JHS) cohort and assessed association with incident CVD events. In participants with whole genome sequencing data (n=2,980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20–30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β= 0.284, p=3.24 × 10−11). The rs2022030 effect size was nearly three times larger among women (β= 0.373, p= 9.06 × 10−13) than men (β= 0.135, p= 0.06, p-interaction= 0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10,808 multi-ethnic men and women (p-interaction=0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (β= 0.507, p=1.41 × 10−14), and this association was successfully replicated in 1,933 AAs (p= 2.3 × 10−5). Conclusion These results highlight D-dimer as an important predictor of CVD risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

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Section: Discussioncontrasting

confidence: 57%

D-Dimer in African Americans

Raffield

Zakai

Duan

et al. 2017

ATVB

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“…Thrombin generation assays (TGA) reliably assess an individual’s rate and potential to generate thrombin ex vivo in plasma and possibly in whole blood, following a calibrated trigger of coagulation (27,28). Although multiple studies are published (29–32), the results of ex vivo TGA in SCD patients at “steady state” compared with age-matched controls or with patients during acute painful episodes are inconsistent. This inconsistency may be due to heterogeneity in the genotypes and treatments of enrolled subjects, lack of race-matched controls in some studies, variability in the timing of blood collection, sample preparation and/or the analytical conditions of the assays (Table 1).…”

Section: Hemostatic Alterations Of Scdmentioning

confidence: 99%

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

2016

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Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis “steady state.” Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia-reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted.

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“…Two small case-control studies have shown an association of SCT to D-dimer, but these analyses were limited by sample size and lack of adjustment for confounders. 15,16 A recent, larger prospective study by Folsom et al evaluating the relationship of D-dimer with future VTE noted higher D-dimer levels among SCT carriers, but this association was not further quantified. 21 That study also found that D-dimer elevations conferred a stepwise increase in risk of future VTE, but that the presence of SCT did not fully modify or explain the association of D-dimer with VTE.…”

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confidence: 99%