Accelerated Spatial Fibrin Growth and Impaired Contraction of Blood Clots in Patients with Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease associated with thrombotic complications. To elucidate pathogenic mechanisms, hemostatic disorders in RA were correlated with other laboratory and clinical manifestations. Hemostasis was assessed using relatively new complementary tests, the spatial growth of a plasma clot (Thrombodynamics assay), and contraction of whole blood clots. Platelet functionality was assessed with flow cytometry that quantified the expression of P-selectin and the fibrinogen-binding capacity of platelets before and after activation with a thrombin receptor-activating peptide. Parameters of fibrin clot growth and the kinetics of contraction of blood clots were significantly altered in patients with RA compared to the control group. In Thrombodynamics measurements, an increase in the clot growth rate, size, and optical density of plasma clots altogether indicated chronic hypercoagulability. The rate and extent of blood clot contraction in patients with RA was significantly reduced and associated with platelet dysfunction revealed by an impaired response to activation. Changes in the parameters of clot growth and contraction correlated with the laboratory signs of systemic inflammation, including hyperfibrinogenemia. These results confirm the pathogenic role of hemostatic disorders in RA and support the validity of fibrin clot growth and the blood clot contraction assay as indicators of a (pro)thrombotic state.

Extent of intravital contraction of arterial and venous thrombi and pulmonary emboli

“…Question 5: How can the apparent contradiction between impaired clot contraction in patients with thrombotic diseases and the predominance of compressed RBCs indicating clot contraction in thrombi be resolved? There is now evidence that clot contraction is diminished in patients with many (pro)thrombotic conditions: ischemic stroke, 5 venous thromboembolism, 6 systemic lupus erythematosus, 8 sickle cell disease, 38 high risk of pregnancy loss, 9 rheumatoid arthritis, 10 postoperative thrombosis, 12 hyperhomocysteinemia, 11 and COVID-19. 39 At the same time, quantitative determination of the composition of venous and arterial thrombi and pulmonary emboli has revealed that these structures contain few biconcave RBCs, and they are almost entirely polyhedrocytes or intermediate forms of RBCs.…”

“…Formation of blood clots is followed by their volumetric shrinkage known as contraction or retraction 1,2 driven by forces generated by the platelet cytoskeleton that are transmitted to fibrin fibers 3 . The contraction of blood clots and thrombi can occur not only in vitro, but also in vivo as a pathophysiologic process that improves hemostasis 4 , increases blood flow past otherwise obstructive thrombi 5 , prevents thrombotic embolization 6 , and alters clot susceptibility to fibrinolysis 7 , and other clinical implications 5,6,[8][9][10][11][12] .…”

Chronic Immune Platelet Activation Is Followed by Platelet Refractoriness and Impaired Contractility

“…The impaired platelet contractility as a potential prothrombotic mechanism is less apparent, although the inability of platelets to cause full clot contraction has been observed earlier in a number of (pro)thrombotic states of various origins [32,[55][56][57]. The reduced ability of blood clots and thrombi to shrink can promote thrombosis via several pathogenic mechanisms that include increased obstructiveness of thrombi [56][57][58][59], reduced susceptibility to fibrinolysis [60], and increased embologenicity or reduced resistance to rupture [56,61]. Therefore, the secondary platelet dysfunction following platelet activation is a novel hemostatic mechanism in SLE and probably in other autoimmune disorders.…”

Platelet Mechanobiology Inspired Microdevices: From Hematological Function Tests to Disease and Drug Screening

“…At the molecular scale, increasing evidences suggest that platelets can undergo mechanosensing upon receiving these hemodynamic stimuli. Key players in such mechanosensing processes include von Willebrand factors (VWF) ( Savage et al, 1996 ; Fu et al, 2017 ), fibrinogen ( Butera and Hogg, 2020 ; Peshkova et al, 2020 ), mechanoreceptors including glycoprotein Ib (GPIb) ( Chen et al, 2016 ; Ju et al, 2016 ) and glycoprotein IIb/IIIa (GPIIb/IIIa or integrin α IIb β 3 ) ( Nesbitt et al, 2009 ; Chen Y et al, 2019 ), and mechanosensitive ion channels ( Abbonante et al, 2017 ; Ilkan et al, 2017 ; Liu et al, 2021 ). Further, activated platelets generate contractile forces to stabilize and consolidate the thrombus ( Osdoit and Rosa, 2001 ; Ono et al, 2008 ; Hansen et al, 2018 ).…”