Procoagulant Profile in Primary Antiphospholipid Syndrome Is Not Dependent upon Increased Inflammatory Response
Authors: Quinteiro Lais , Mazetto Bruna , Saraiva Sabrina , Colella Marina Pereira , De Paula Erich Vinicius , Appenzeller Simone , Annichino-Bizzacchi Joyce Maria , Orsi Fernanda Andrade 
Published: October 2019

Abstract
The association of systemic inflammation and thrombosis in antiphospholipid syndrome (APS) is a matter of debate. The "second hit" theory advocates that the immune-mediated activation of endothelial cells, platelets and monocytes is the stimulus which triggers the initial pathogenesis of APS, while a second stimulus would be necessary for the onset of thrombosis. According to the theory, inflammation and hypercoagulability are not necessarily correlated and the latter would be the result of other associated factors in APS. Further clinical evidences may support that theory, since patients with venous thromboembolism without antiphospholipids (VTE-non aPL) may present an inflammatory state without the aggressive and recurrent thrombotic presentation observed in APS and the presence of systemic autoimmune disease does not worsen the clinical course of thrombosis in APS. The aim of this study is to draw a parallel between the intensity of inflammatory and coagulation responses in thrombotic primary APS (t-PAPS), compared with thrombotic secondary APS (t-SAPS), spontaneous VTE-non aPL and healthy controls. Patients were consecutively selected in the outpatient unit of the Hematology and Hemotherapy Center at the University of Campinas. Clinical data were collected in medical records and interviews with the participants. The markers of inflammation: interleukin (IL)-6, IL-8, TNF-α were measured by commercial ELISA, and high-sensitive hs-CRP by BN ProSpec® Kit. The markers of hemostasis: soluble tissue factor (sTF), von Willebrand factor (vWF) and a desintegrin and metalloprotease thrombospondin motifs (ADAMTS)-13 were measured by commercial ELISA. One hundred and seventy-three patients were included, 71 had t-PAPS, 44 had t-SAPS and 58 had spontaneous VTE-non aPL; 143 patients were women, 57 were men, the median age of patients were 42 years (IQ 29-52). One hundred twenty one controls, without personal history of thrombosis, were included; 88 were women, 33 were men, their median age was 42 years old (IQ 30- 52). Serum levels of the inflammatory markers TNF-α, CRP and IL-6 were higher in the three groups of thrombotic disease (VTE-non aPL, t-PAPS and t-SAPS) compared to controls. IL-8 levels were increased only in patients with t-SAPS, compared to controls. The relative risk (RR) for elevated TNF-α values were 11.9 for VTE, 4.4 for t-PAPS and 6.0 for t-SAPS (p <0.001). RR for increased values of CRP were 1.9 for VTE, 3.5 for t-PAPS and 3.8 t-SAPS (p <0.05). RR for elevated IL-6 levels were 5.8 for VTE, 3.4 for t-PAPS and 4.1 for t-SAPS (p <0.001). Among the coagulation markers, the imbalance between VWF and ADAMTS13 was observed in patients, compared to controls, but levels of VWF and ADAMTS13 activity were similar among the three groups of patients. Compared to controls, higher levels of VWF were equally found in patients with VTE (RR = 1.015; 95% CI = 1.008-1.023), t-PAPS (RR= 1.008; 95% CI= 1.002-1.015) and t-SAPS (RR= 1.010; 95% CI= 1.003-1.018), whereas lower levels of ADAMTS-13 activity were detected in VTE (RR = 0.94; 95% CI = 0.92-0.97 and t-SAPS (RR = 0.98; 95% CI= 0.97-0.99). Patients with t-PAPS and t-SAPS presented higher levels of sTF, compared to controls and VTE (RR = 1.008; 95% CI = 1004-1012 and RR= 1.011; 95% CI= 1.007-1.015, respectively). sTF values in patients with VTE were similar to controls. The adjustment for confounders (age, sex, BMI and comorbidities such as hypertension, dyslipidemia and diabetes) did not influence the estimated relative risks. Among patients with APS, levels of sTF correlated weakly with the levels of TNF-α (r=0.308, P=0.001) and IL-6 (r=0.315, P=0.001). Other inflammatory and coagulation markers did not present any statistical correlation. In conclusion, we observed that t-PAPS patients have an exacerbated inflammatory response when compared to controls, but the level of inflammation is similar to that observed in patients with spontaneous VTE-non aPL and t-SAPS. Despite the similar levels of inflammation, the procoagulant profile in t-PAPS, detected by sTF, was higher than in non-immune thrombosis. The results suggest that inflammation in t-PAPS may not be distinct from that observed in other non-immune thrombotic disorders, whereas the exacerbation of procoagulant stimulus seems to be more evident in t-PAPS than in non-immune VTE. Furthermore, we postulate that risk factors beyond inflammation may be related to the hypercoagulability detected in t-PAPS.

Disclosures
No relevant conflicts of interest to declare.