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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2594-2595.
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CLINICAL OBSERVATIONS
Comment on Ay et al, page 2703
Cancer and thrombosis is a sticky business
Frederick R. Rickles
THE GEORGE WASHINGTON UNIVERSITY
In this issue of Blood, Ay and colleagues demonstrate that elevated levels of soluble P-selectin are a risk factor for a first episode of venous thromboembolism in patients with all types of cancer.
It is a well-known fact that cancer cells of various types exhibit abnormal membrane surface properties, often an exaggeration of normal functions, such as vesiculation (or blebbing), shedding of microparticles (MPs), and excessive phospholipid turnover, resulting in further amplification of the adhesive characteristics of the cells. Several lines of evidence have implicated these aberrant properties in the propensity of cancer cells to induce hypercoagulability and predispose patients with cancer to venous thromboembolism (VTE). Indeed, one of those hyperactive adhesive mechanisms, selectin-ligand binding, has been postulated to be responsible for the association of Trousseau syndrome (migratory thrombophlebitis) with mucin-secreting adenocarcinomas1 (see figure). P-selectin, a member of the selectin family of cell-adhesion receptors, is localized principally in the membranes of platelet  -granules and endothelial-cell Weibel-Palade bodies. In response to various agonists, P-selectin is translocated to the cell surface, where it can function as a receptor and mediate cell adhesion via binding to several ligands; the principal ligand, or counterreceptor, is P-selectin glycoprotein ligand-1 (PSGL-1), which is a heterodimeric mucin expressed on the cell surface of the majority of leukocytes. This interaction, particularly with soluble P-selectin (sP-selectin), may play a critical role in the complex cell-cell adhesive process that results in release of procoagulant-rich (ie, tissue factor [TF] and prothrombinase) MPs from leukocytes, endothelial cells, platelets, and cancer cells.2–4 Leukocyte MPs (and presumably MPs from other sources, eg, cancer cells) can further aggravate the procoagulant state by inducing endothelial-cell TF expression.5 Elevated circulating levels of sP-selectin are clearly prothrombotic in the experimental animal4,6 and have been implicated as a risk factor for thrombosis in a number of diseases, including recurrence in patients with a first episode of unprovoked VTE—in the absence of cancer or other known risk factors,7 suggesting perhaps that patients with high levels of sP-selectin might benefit from longer duration of anticoagulation therapy.
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Proposed model for L- and P-selectin–mediated, mucin-induced activation and aggregation of platelets. Yellow circle labeled with L indicates L-selectin ligands on mucins. Blue boxes labeled with P indicate P-selectin ligands, including carcinoma mucins and PSGL-1 expressed on leukocytes. L-sel indicates L-selectin; P-sel, P-selectin. Reproduced from Wahrenbrock et al1 with permission of the publishers.
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Ay and colleagues report a similar ability to predict a first episode of VTE among patients enrolled in a large, prospective cohort study, the Vienna Cancer and Thrombosis Study. Over a 6-month period of time after the initial diagnosis of cancer, or of progression or recurrence after partial or complete remission, the cumulative probability of symptomatic VTE (documented by objective criteria), was 11.9%, or 3-fold higher in patients with an initial level of sP-selectin greater than the 75th percentile, compared with patients whose levels were below the 75th percentile (3.7%; P = .002). Ideally, the investigators would have provided the results of sequential sampling over time, in order to increase the confidence in their observations and, perhaps, the relationship of sP-selectin levels to the natural history of VTE. Similarly, a more quantitative, stepwise relationship between levels of sP-selectin and risk for VTE would have been reassuring, as would a higher degree of association between known high-risk tumors (eg, pancreatic or brain tumors, etc) and sP-selectin levels. Also missing from this study was the ability to determine the possible relationship of sP-selectin levels with other known markers for hypercoagulability, such as fibrin d-dimer levels. Regardless, this study provides the impetus to test the utility of using sP-selectin levels for stratification in trials of anticoagulant prophylaxis in cancer patients. Further in the future might come trials of inhibitors of sP-selectin function8 in the prevention of VTE in patients with cancer, selected by virtue of high levels of the circulating protein.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest. 2003;112:853–862.[CrossRef][Medline]
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- Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes. Proc Nat Acad Sci U S A. 1994;91:8767–8771.[Abstract/Free Full Text]
- Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost. 2005;3:1590–1596.[CrossRef][Medline]
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- Hrachovinova I, Cambien B, Hafezi-Moghadam A, et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003;9:1020–1025.[CrossRef][Medline]
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- Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem. 1999;274:23111–23118.[Abstract/Free Full Text]
- Andre P, Hartwell D, Hrachovinaova I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Nat Acad Sci U S A. 2000;97:13835–13840.[Abstract/Free Full Text]
- Kyrle PA, Hron G, Eichinger S, Wagner O. Circulating P-selectin and the risk of recurrent venous thrombosis. Thromb Haemost. 2007;97:880–883.[Medline]
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- Meier TR, Myers DD, Wrobleski SK, et al. Prophylactic p-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation. Thromb Haemost. 2008;99:343–351.[Medline]
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Related Article in Blood Online:
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High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS)
- Cihan Ay, Ralph Simanek, Rainer Vormittag, Daniela Dunkler, Guelay Alguel, Silvia Koder, Gabriela Kornek, Christine Marosi, Oswald Wagner, Christoph Zielinski, and Ingrid Pabinger
Blood 2008 112: 2703-2708.
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