Observational studies have shown that inflammatory cells accumulate within the thrombus and surrounding vein wall during the natural history of venous thrombosis. More recent studies have begun to unravel the mechanisms that regulate this interaction and have confirmed that thrombosis and inflammation are intimately linked. This review outlines our current knowledge of the complex relationship between inflammatory cell activity and venous thrombosis and highlights new areas of research in this field. A better understanding of this relationship could lead to the development of novel therapeutic targets that inhibit thrombus formation or promote its resolution.

Background: Radiation exposure during fluoroscopically guided interventions such as endovascular aortic repair (EVAR) is a growing concern for operators. This study aimed to measure DNA damage/repair markers in operators perfoming EVAR. Methods: Expression of the DNA damage/repair marker, γ-H2AX and DNA damage response marker, phosphorylated ataxia telangiectasia mutated (pATM), were quantified in circulating lymphocytes in operators during the peri-operative period of endovascular (infrarenal, branched, and fenestrated) and open aortic repair using flow cytometry. These markers were separately measured in the same operators but this time wearing leg lead shielding in addition to upper body protection and compared with those operating with unprotected legs. Susceptibility to radiation damage was determined by irradiating operators’ blood in vitro. Results: γ-H2AX and pATM levels increased significantly in operators immediately after branched endovascular aortic repair/fenestrated endovascular aortic repair ( P <0.0003 for both). Only pATM levels increased after infrarenal endovascular aortic repair ( P <0.04). Expression of both markers fell to baseline in operators after 24 hours ( P <0.003 for both). There was no change in γ-H2AX or pATM expression after open repair. Leg protection abrogated γ-H2AX and pATM response after branched endovascular aortic repair/fenestrated endovascular aortic repair. The expression of γ-H2AX varied significantly when operators’ blood was exposed to the same radiation dose in vitro ( P <0.0001). Conclusions: This is the first study to detect an acute DNA damage response in operators performing fluoroscopically guided aortic procedures and highlights the protective effect of leg shielding. Defining the relationship between this response and cancer risk may better inform safe levels of chronic low-dose radiation exposure.

A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2‐expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10‐fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two‐fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2‐negative monocytes in vitro . Using a mouse model of hindlimb ischemia, lentiviral‐based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients. →See accompanying articles 10.1002/emmm.201302695 and 10.1002/emmm.201302794

Background—: The magnetic resonance longitudinal relaxation time (T ₁ ) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T ₁ signal in venous thrombi and whether changes in T ₁ relaxation time are informative of the susceptibility to lysis. Methods and Results—: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T ₁ relaxation time correlated with thrombus composition. The mean T ₁ relaxation time of thrombus was shortest at 7days following thrombus induction and returned to that of blood as the thrombus resolved. T ₁ relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase ( iNOS ^−/− )–deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis–derived iron to paramagnetic Fe ³⁺ , which causes thrombus T ₁ relaxation time shortening. Studies using chemokine receptor-2–deficient mice ( Ccr2 ^−/− ) revealed that the return of the T ₁ signal to that of blood is regulated by removal of Fe ³⁺ by macrophages that accumulate in the thrombus during its resolution. Quantification of T ₁ relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. Conclusions—: The source of the T ₁ signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe ³⁺ form. Quantification of T ₁ relaxation time appears to be a good predictor of the success of thrombolysis.

Significance: During an inflammatory response, L-selectin, an immune cell-specific adhesion molecule, guides monocytes from the bloodstream toward the surrounding extravascular environment (termed “transmigration”). We show, under conditions that mimic blood flow, that L-selectin is proteolytically cleaved (or shed) exclusively within leading migratory fronts (pseudopods) of actively transmigrating monocytes. Calmodulin/L-selectin interaction, which acts to block shedding, is lost through Ser phosphorylation of the L-selectin cytoplasmic tail, occurring specifically within transmigrating pseudopods. Blocking L-selectin shedding specifically during transmigration increases pseudopod numbers, leading to defective front/back polarity that is essential for migration. These findings are the first to report, to our knowledge, an extended role for L-selectin in regulating morphological changes in leukocytes that are required for migration.