Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Abstract

Key Points• Platelets, neutrophils, and coagulation factor XII are implicated as important players in experimental venous thrombosis pathophysiology.• We demonstrate that platelets, but not neutrophils, are critical in spontaneous venous thrombosis, whereas low factor XII aggravates thrombosis.Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNAmediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology. (Blood. 2016;127(21):2630-2637

The biology of the platelet with special reference to inflammation wound healing and immunity

“…A TF-dependent coagulant state promotes fibrin formation in large vessels in DVT (see 150). Despite much evidence that neutrophils play important roles in venous thrombosis, the role of platelets and FXII has been recently emphasized (151). Neutrophils kill and remove bacteria and viruses at sites of infection and the NETs consisting of scaffolds of histone-containing chromatin fibers, serine proteases and released reactive oxygen species allow this to be done on a large scale.…”

Plasma contact factors as therapeutic targets

“…A model of spontaneous venous thrombosis in mice was developed using siRNA-mediated reductions of the coagulation regulatory proteins antithrombin and protein C [126]. When an siRNA that reduces FXII was studied in this model, surprisingly, there was an acceleration of thrombosis [127]. This suggests that FXII may serve a previously unrecognized regulatory (antithrombotic) function.…”

The role of leukocytes in thrombosis

“…22,103 In contrast, a model of spontaneous venous thrombosis using small interfering RNA knockdown of protein C and antithrombin, showed that although neutrophils were associated with venous thrombi, neutrophil depletion did not diminish thrombus formation. 104 Interestingly, protein arginine deiminase 4 (PAD4) and neutrophil elastase, which regulate chromatin decondensation and NETosis, have contradictory influence on DVT induction. Although PAD4 deficiency was associated with impaired thrombus formation in the IVC stenosis model, 105 an electrolytic injury model reported no influence of PAD4 deficiency on DVT.…”