Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis

Downing, L.; Wakefield, Thomas W.; Strieter, Robert M.; Prince, Martin R.; Londy, Frank J.; Fowlkes, J. Brian; Hulin, Marc S.; Kadell, Amy M.; Wilke, Carol A.; Brown, Sandra L.; Wrobleski, Shirley K.; Burdick, Marie D.; Anderson, Donald C.; Greenfield, Lazar J.

doi:10.1016/s0741-5214(97)70211-8

Cited by 111 publications

(96 citation statements)

References 22 publications

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“…Moreover, elevated levels of sP-sel might be involved in the recurrent thrombotic process of angina (45) and in restenosis (46). Our findings support and provide an explanation for the promising results of antithrombotic therapies directed against P-selectin in various thrombotic models such as stroke (47), or deep vein thrombosis (48). A reduction in numbers of circu- TF-induced Xa activity was determined on the corresponding fraction of microparticles.…”

Section: Discussionsupporting

confidence: 73%

Pro-coagulant state resulting from high levels of soluble P-selectin in blood

André

Hartwell

Hrachovinová

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

296

251

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The plasma concentration of soluble adhesion receptors is increased under pathological circumstances, but their function remains enigmatic. Soluble P-selectin (sP-sel) is shed from activated platelets and endothelial cells. Mice genetically engineered to express P-selectin without the cytoplasmic tail (⌬CT) constitutively show a 3-to 4-fold increase of sP-sel in plasma. We observed that the ⌬CT mice formed fibrin very readily. In an ex vivo perfusion chamber, there was more fibrin deposited at the site of platelet thrombus formation than in wild type (WT), whereas no fibrin deposits were detected using P-selectin-deficient blood during the same interval. Similarly, in vivo, the hemorrhage produced by local Shwartzman reaction was smaller in the ⌬CT mice than in WT. In contrast, we previously showed hemorrhage to be more prominent in P-selectin knock-out mice. Infusion of mouse P-sel-Ig chimera produced the same protective effect in WT mice as seen in the ⌬CT mice, indicating that the effect was due to increased levels of sP-sel. Mice infused with P-sel-Ig showed significantly more fibrin deposited on the luminal face of the injured vessels than control mice. Plasma from ⌬CT mice or mice infused with P-sel-Ig contained higher concentration of pro-coagulant microparticles and clotted one minute faster than WT. This pro-coagulant phenotype of ⌬CT mice could be reversed by a 4-day treatment with PSGL-Ig, a P-selectin inhibitor. We propose that sP-sel should no longer be considered only as a marker of inflammation or platelet activation, but also as a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases. P-selectin is a member of the selectin family localized in the membranes of ␣-granules of platelets and the Weibel-Palade bodies of endothelial cells (1). A soluble form of P-selectin can be found in the plasma as a circulating protein (2). In vivo, two main physiological roles are attributed to the integral membrane form of P-selectin. First, in inflammation, P-selectin is redistributed onto the surface of activated endothelial cells where it mediates the rolling of leukocytes (3). Second, in thrombosis, P-selectin expressed on activated platelets present in a thrombus supports the recruitment of leukocytes (4). Soluble P-selectin (sP-sel) of healthy individuals has been suggested to originate from the alternatively spliced form found in endothelial cells and platelets (5). Alternatively, elevated levels of sP-sel may reflect platelet activation (6) because P-selectin is proteolytically shed from the plasma membrane in vivo shortly after activation (7,8). Therefore, plasma levels of sP-sel have been considered a useful tool to predict thrombotic consumptive platelet disorders (9-12), but they can also reflect endothelial cell activation (13,14). Although the circulating form of P-selectin is potentially active because only the lectin and epidermal growth factor (EGF) domains are required to bind its receptor, P-selectin glycoprotein ligand-1 (PSGL-1) (15), the biological role of ...

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Section: Discussionsupporting

confidence: 73%

Pro-coagulant state resulting from high levels of soluble P-selectin in blood

André

Hartwell

Hrachovinová

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

296

251

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“…Platelets play critical roles in both hemostasis and inflammation. Studies have shown that platelet surface glycoprotein (GP) Ib-VI 31 and p-selectin 32 or ADP, 33 released from activated platelets, may provide receptors or signal for recruiting neutrophils and monocytes. The accumulation and activation/degranulation of neutrophils may result in the massive release of granular contents, including neutrophil extracellular traps (NETs) 20 and HNP1-3 34 at the sites of vascular injury.…”

Section: Discussionmentioning

confidence: 99%

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

et al. 2016

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A cquired thrombotic thrombocytopenic purpura is primarily caused by the deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease, but the underlying mechanisms are not fully understood. Herein, 52 patients with acquired autoimmune thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study. The plasma levels of human neutrophil peptides 1-3 and complement activation fragments (i.e. Bb, iC3b, C4d, and sC5b-9) were determined by enzyme-linked immunosorbent assays. Univariate analyses were performed to determine the correlation between each biomarker and clinical outcomes. We found that the plasma levels of human neutrophil peptides 1-3 and Bb in patients with acute thrombotic thrombocytopenic purpura were significantly higher than those in the control (P<0.0001). The plasma levels of HNP1-3 correlated with the levels of plasma complement fragment Bb (rho=0.48, P=0.0004) and serum lactate dehydrogenase (rho=0.28, P=0.04); in addition, the plasma levels of Bb correlated with iC3b (rho=0.55, P<0.0001), sC5b-9 (rho=0.63, P<0.0001), serum creatinine (rho=0.42, p=0.0011), and lactate dehydrogenase (rho=0.40, P=0.0034), respectively. Moreover, the plasma levels of iC3b and sC5b-9 were correlated (rho=0.72, P<0.0001), despite no statistically significant difference of the two markers between thrombotic thrombocytopenic purpura patients and the control. We conclude that innate immunity, i.e. neutrophil and complement activation via the alternative pathway, may play a role in the pathogenesis of acute autoimmune thrombotic thrombocytopenic purpura, and a therapy targeted at these pathways may be considered in a subset of these patients.

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“…One consequence is the inhibition of the interaction between P-selectin and its receptor, which occurs on different cell types, including platelets and leukocytes. Inhibiting the interaction between P-selectin and PSGL-1 with P-selectin antagonists (recombinant soluble PSGL-immunoglobulin), intravenously administered soluble ligands, or an orally administered nonprotein inhibitor (PSI-697) markedly attenuated the prothrombotic effect in a mouse model (13)(14)(15)(16)(17). Statin medication has recently been reported to reduce sP-selectin concentrations significantly (38 -40 ), and sP-selectin concentration was inversely correlated with the progression of coronary heart disease (38 ).…”

Section: /97mentioning

confidence: 99%

High Concentrations of Soluble P-Selectin Are Associated with Risk of Venous Thromboembolism and the P-Selectin Thr715 Variant

Ay¹,

Jungbauer²,

Sailer³

et al. 2007

Clinical Chemistry

116

109

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Background:The cell adhesion molecule P-selectin has an important role in the pathophysiology of thrombosis. The effect on venous thromboembolism (VTE) of increased circulating concentrations of soluble P-selectin (sP-selectin) and their association with the P-selectin variant Thr715Pro is still uncertain. Methods: This study was a case-control study of 116 patients with confirmed recurrent VTE and at least 1 event of unprovoked deep venous thrombosis or pulmonary embolism, and 129 age-and sex-matched healthy individuals. We measured sP-selectin by ELISA and P-selectin gene (SELP) variation by genotyping and sampled blood after a mean interval of 2.55 years after the most recent VTE event. Results: The mean (SD) sP-selectin concentration was higher in patients than in controls: 47.3 (15.0) g/L vs 36.8 (11.0) g/L, P <0.001. The unadjusted odds ratio (OR) for sP-selectin >55.1 g/L, representing the 95th percentile for controls, was 8.5 (95% CI, 3.7-23.3; P <0.001) and increased after adjustment for factor V Leiden, the prothrombin G20210A variant, increased factor VIII, and hyperhomocysteinemia (OR, 10.6; 95% CI, 4.1-31.2; P <0.001). Pro715 carriers were more prevalent among controls than patients (21.7% vs 14.7%).

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Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis

Abstract: Anti-P-selectin antibody decreases vein wall inflammation and thrombus formation. Inhibition of P-selectin may be useful in venous thrombosis prophylaxis.

Cited by 111 publications

References 22 publications

Pro-coagulant state resulting from high levels of soluble P-selectin in blood

Pro-coagulant state resulting from high levels of soluble P-selectin in blood

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

High Concentrations of Soluble P-Selectin Are Associated with Risk of Venous Thromboembolism and the P-Selectin Thr715 Variant

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