Immunosuppressants accelerate microvascular thrombus formation in vivo: Role of endothelial cell activation

Püschel, Anja; Lindenblatt, Nicole; Katzfuß, J.; Vollmar, Brigitte; Klar, E.

doi:10.1016/j.surg.2011.06.026

Cited by 20 publications

(15 citation statements)

References 49 publications

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“…In our study, older and heavier heart transplant recipients appeared to be at greater risk for developing LEDVT, while the use of older donors was associated with the development of UEDVT. An additional risk factor for VTE is the need for maintenance immunosuppressive drugs that may have prothrombotic side effects . Patients who were treated with proliferation signal inhibitors at any time post‐transplant, such as everolimus and sirolimus, were significantly more likely to develop PE compared to all patients (54% vs. 29%; p = 0.01).…”

Section: Discussionmentioning

confidence: 99%

Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis

Elboudwarej¹,

Patel²,

Liou³

et al. 2015

Clinical Transplantation

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Section: Discussionmentioning

confidence: 99%

Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis

Elboudwarej¹,

Patel²,

Liou³

et al. 2015

Clinical Transplantation

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“…The use of some immunosuppressant medications has been shown to enhance systemic thrombogenicity as well as elevate levels of sP-sel. 26,27 As 15% of our study population was on some form of immunosuppression, we found it prudent to include these patients. However, in univariate analysis, there was no difference in the number of patients on immunosuppression that had a duplex-confirmed LE-DVT compared with those who did not have an LE-DVT.…”

Section: Discussionmentioning

confidence: 99%

Soluble P-selectin for the diagnosis of lower extremity deep venous thrombosis

Vandy

Stabler

Eliassen

et al. 2013

Journal of Vascular Surgery: Venous and Lymphatic Disorders

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Objective Although duplex ultrasound is the standard for the diagnosis of lower extremity deep venous thrombosis (LE-DVT), imaging is not always available. The use of D-dimer can exclude (high-sensitivity), but not rule in (low-specificity) LE-DVT. Previously, we demonstrated that soluble P-selectin (sP-sel) in combination with the Wells score, establishes the diagnosis of LE-DVT with a specificity of 96% and a positive predictive value of 100%. In order to validate our previous results, we applied the model to a separate but similar patient cohort. Additionally, we analyzed the role of biomarkers for diagnosing upper extremity DVT (UE-DVT). Methods Between April 2009 and March 2012, all patients presenting for a duplex ultrasound exam with concern of DVT were screened. Demographics, clinical data, D-dimer, sP-sel, C-reactive protein, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, and von Willebrand factor levels were prospectively collected in 279 patients (234 LE-DVT, 45 UE-DVT). Continuous and categorical variables among patients with DVT were compared with patients without DVT. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were then calculated using our previously derived cut points to rule in or exclude DVT. Results Among 234 patients evaluated for LE-DVT, 112 (48%) patients had a confirmed LE-DVT with significant differences in all biomarkers. When Wells score ≥2, sP-sel could rule in LE-DVT with a specificity of 97.5% and a positive predictive value of 91%, which was more accurate than Wells score ≥2 and D-dimer (specificity, 65%; positive predictive value, 69%). When Wells score was <2, D-dimer was superior to sP-sel for excluding the diagnosis of LE-DVT (sensitivity, 98%; negative predictive value, 95% vs sensitivity, 91%; negative predictive value, 79%). The use of additional biomarkers did not increase accuracy. Had imaging not been available, we could have correctly ruled in or ruled out LE-DVT in 29% (67/234) of patients. The use of sP-sel in UE-DVT was nondiagnostic. Conclusions We demonstrate that when Wells score ≥2, sP-sel is an excellent biomarker to rule in LE-DVT. Different from our previous study, D-dimer and a Wells score <2 was most sensitive at excluding a diagnosis of LE-DVT. Combined, Wells score, sP-sel, and D-dimer can both rule in and exclude LE-DVT in approximately one-third of patients.

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“…Prior to photochemical thrombus induction, capillary perfusion and microhemodynamics in randomly chosen venules (diameter range: 30-70 μm) were assessed by means of a ×20 objective (LUCPlanFL ×20/0.45 W, Olympus). Subsequently, photochemical thrombus formation was induced by continuous local exposure of filtered light (450-490/>520 nm excitation/emission wavelength) using a ×63 water immersion objective (Achroplanx63/0.95 W, Zeiss), as described previously by our group (26, 27). The light/dye thrombus model used is based on endothelial injury upon phototoxicity induced by exposure of FITC-dextran to excitation light.…”

Section: Methodsmentioning

confidence: 99%

Contribution of Protein Z and Protein Z-Dependent Protease Inhibitor in Generalized Shwartzman Reaction

Butschkau

Nagel²,

Grambow³

et al. 2013

Critical Care Medicine

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Objective Sepsis, a leading cause of mortality in critically ill patients, is closely linked to the excessive activation of coagulation and inflammation. Protein Z (PZ), a cofactor for the protein Z-dependent protease inhibitor (ZPI), enhances the inhibition of coagulation factor Xa and ZPI inhibits factor XIa in a PZ-independent fashion. The functions of PZ and ZPI in the inflammatory and coagulant responses to septic illness have not been evaluated. Design For induction of generalized Shwartzman reaction (GSR), dorsal skinfold chamber-equipped mice were challenged twice with lipopolysaccharide (0.05 mg/kg bw on day −1 and 5 mg/kg bw 24 h later). Time-matched control animals received equal volumes of saline. Setting University research laboratory. Subjects, Interventions and Measurements Using intravital fluorescence microscopy in ZPI-deficient (ZPI−/−) and PZ-deficient (PZ−/−) mice as well as their wild-type littermates (ZPI+/+, PZ+/+), kinetics of light/dye-induced thrombus formation and microhemodynamics were assessed in randomly chosen venules. Plasma concentrations of CXCL1, IL-6 and IL-10 were measured. Liver and lung were harvested for quantitative analysis of leukocytic tissue infiltration and thrombus formation. Main Results After induction of GSR, all mice showed significant impairment of microhemodynamics, including blood flow velocity, volumetric blood flow and functional capillary density as well as leukocytopenia and thrombocytopenia. Thrombus formation time was markedly prolonged after induction of GSR in all mice, except of ZPI−/− mice, which also had a significantly higher fraction of occluded vessels in liver sections. PZ−/− mice developed the highest concentrations of IL-6 and IL-10 in response to GSR and showed greater leukocytic tissue infiltration than their wild-type littermates. Conclusions In this murine model of GSR, ZPI deficiency enhanced the thrombotic response to vascular injury, whereas PZ deficiency increased inflammatory response.

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Immunosuppressants accelerate microvascular thrombus formation in vivo: Role of endothelial cell activation

Cited by 20 publications

References 49 publications

Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis

Risk of deep vein thrombosis and pulmonary embolism after heart transplantation: clinical outcomes comparing upper extremity deep vein thrombosis and lower extremity deep vein thrombosis

Soluble P-selectin for the diagnosis of lower extremity deep venous thrombosis

Contribution of Protein Z and Protein Z-Dependent Protease Inhibitor in Generalized Shwartzman Reaction

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