Impaired contraction of blood clots as a novel prothrombotic mechanism in systemic lupus erythematosus

Abstract

The aim of this work was to examine a possible role of clot contraction/retraction in thrombotic complications of systemic lupus erythematosus (SLE). Using a novel automated method, we investigated kinetics of clot contraction in the blood of 51 SLE patients and 60 healthy donors. The functionality of platelets in the SLE patients was assessed using flow cytometry by expression of P-selectin and fibrinogen-binding capacity. The rate and degree of clot contraction were significantly reduced in SLE patients compared with healthy subjects, especially in the patients with higher blood levels of anti-dsDNA antibodies. The reduced platelet contractility correlated with partial refractoriness of platelets isolated from the blood of SLE patients to stimulation induced by the thrombin receptor activating peptide. To test if the anti-dsDNA autoantibodies cause continuous platelet activation, followed by exhaustion and dysfunction of the cells, we added purified exogenous anti-dsDNA autoantibodies from SLE patients to normal blood before clotting. In support of this hypothesis, the antibodies first enhanced clot contraction and then suppressed it in a time-dependent manner. Importantly, a direct correlation of clot contraction parameters with the disease severity suggests that the reduced compactness of intravascular clots and thrombi could be a pathogenic factor in SLE that may exaggerate the impaired blood flow at the site of thrombosis. In conclusion, autoantibodies in SLE can affect platelet contractility, resulting in reduced ability of clots and thrombi to shrink in volume, which increases vessel obstruction and may aggravate the course and outcomes of thrombotic complications in SLE.

Red blood cells: the forgotten player in hemostasis and thrombosis

“…In particular, polyhedrocytes have been observed in human arterial and especially venous thrombi, and pulmonary emboli, taken from patients . Unexpectedly, the rate and extent of clot contraction has been found to be impaired in a number of (pro)thrombotic conditions, such as ischemic stroke , deep vein thrombosis and systemic lupus erythematosus , and may be considered an underappreciated factor that increases the risk and/or exaggerates the course and outcome of thrombosis. Altogether these data suggest that the extent of clot compaction and the formation of compressed RBCs (polyhedrocytes) comprise an important pathogenic mechanism of thrombosis and could have a diagnostic and/or predictive value in (pro)thrombotic states.…”

Feeling the Force: Measurements of Platelet Contraction and Their Diagnostic Implications

“…For example, excellent work standardizing and simplifying the bulk clot contraction assay has revealed new insights into impaired whole clot contraction in patients with sickle cell disease, 40 stroke, 67 or systemic lupus erythematosus. 68 However, it is unclear whether platelet force is altered in these conditions. Other approaches that measure bulk platelet forces provide more direct evidence of impaired contractile force, although it is unclear whether the platelets themselves have impaired contractile forces or if the platelets are simply responding to a different microenvironment.…”

Blood clot contraction differentially modulates internal and external fibrinolysis

“…The expulsion of serum can also change the content of pro-and antifibrinolytic agents within the contracting clot [32]. Clot contraction is impaired in a variety of (pro)thrombotic conditions, such as ischemic stroke, deep vein thrombosis, systemic lupus erythematosus and asthma [33][34][35][36][37][38][39]. However, the effect of clot contraction on lysis has not been subject to detailed study.…”