D-dimer, P-selectin, and microparticles: Novel markers to predict deep venous thrombosis
A pilot study
John E. Rectenwald
1
Departments of Surgery, Section of Vascular Surgery
,
Daniel D. Myers Jr
1
Departments of Surgery, Section of Vascular Surgery
,
Angela E. Hawley
1
Departments of Surgery, Section of Vascular Surgery
,
Christopher Longo
1
Departments of Surgery, Section of Vascular Surgery
,
Peter K. Henke
1
Departments of Surgery, Section of Vascular Surgery
,
Kenneth E. Guire
3
School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
,
Alvin H. Schmaier
2
Internal Medicine and Pathology
,
Thomas W. Wakefield
1
Departments of Surgery, Section of Vascular Surgery
› Author AffiliationsGrant support: Supported by grant HL70766 from the National Institutes of Health to T.W.W and HL52779 and HL57346 to A.H.S. Presented in part at The 46th Annual American Society of Hematology Meeting and Exposition, San Diego, CA. December 6, 2004.
Current plasma markers for diagnosis of deep venous thrombosis (DVT) allow for exclusion of the diagnosis, but lack adequate specificity to establish the diagnosis. Thus, a prospective study was performed to determine the sensitivity and specificity of plasma assays for D-dimer, soluble P-selectin (P-selectin), and total microparticles in patients with documented DVT by duplex ultrasound. Three groups of individuals were examined: 30 normals; 22 positive for DVT on duplex ultrasound (Group 2); and 21 symptomatic, but negative on duplex ultrasound for DVT (Group 3). Group 1 individuals had D-dimer values of 1.53±0.12 mg/l and P-selectin values of 0.34±0.05 ng/mg total protein. Group 2 vs. Group 3 individuals had D-dimer values of 7.57±2.03 vs. 3.19±0.79 mg/l, p=0.02; P-selectin values of 0.98±0.11 vs. 0.55±0.08 ng/mg total protein, p<0.01; and microparticle values of 129±17% vs. 99±12% of control, p=ns. Using a logistic regression model with dichotomous variables, we determined a sensitivity of 73%, specificity of 81%, and accuracy of 77% when combining D-dimer, soluble P-selectin, and total microparticles to differentiate Group 2 from Group 3 patients. Logistic regression using continuous variables yielded similar results (p=0.05).This study demonstrates that plasma markers for DVT can be developed and achieve moderate sensitivity and specificity in diagnosing DVT. However for clinical applicability, the sensitivity/specificity will need to be improved. These studies also suggest the importance of soluble P-selectin in assessing DVT in humans.
Keywords
Deep venous thrombosis -
D-dimer -
P-selectin -
microparticles -
clinical study
References
1
Stein PD,
Hull RD,
Patel KC.
et al D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004; 140: 589-602.
2
Myers DD,
Hawley AE,
Farris DM.
et al P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075-89.
3
Myers Jr. D,
Farris D,
Hawley A.
et al Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis. J Surg Res 2002; 108: 212-21.
4
Gilbert GE,
Sims PJ,
Wiedmer T.
et al Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991; 266: 17261-8.
6
Sabatier F,
Roux V,
Anfosso F.
et al Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 2002; 99: 3962-70.
7
Chou J,
Mackman N,
Merrill-Skoloff G.
et al Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 2004; 104: 3190-7.
8
Falati S,
Liu Q,
Gross P.
et al Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-98.
9
Martinez MC,
Tesse A,
Zobairi F.
et al Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 2005; 288: H1004-9.
11
Anderson DR,
Kovacs MJ,
Kovacs G.
et al Combined use of clinical assessment and d-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study). J Thromb Haemost 2003; 1: 645-51.
12
Siragusa S,
Anastasio R,
Porta C.
et al Deferment of objective assessment of deep vein thrombosis and pulmonary embolism without increased risk of thrombosis: a practical approach based on the pretest clinical model, D-dimer testing, and the use of low-molecularweight heparins. Arch Intern Med 2004; 164: 2477-82.
13
Mitchell DC,
Grasty MS,
Stebbings WS.
et al Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis. Br J Surg 1991; 78: 611-3.
14
Stevens SM,
Elliott CG,
Chan KJ.
et al Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep venous thrombosis. Ann Intern Med 2004; 140: 985-91.
28
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: 1020-5.
29
Andre P,
Spertini O,
Guia S.
et al Modification of P-selectin glycoprotein ligand-1 with a natural killer cell-restricted sulfated lactosamine creates an alternate ligand for L-selectin. Proc Natl Acad Sci U S A 2000; 97: 3400-5.
30
Palabrica T,
Lobb R,
Furie BC.
et al Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
33
Yang LC,
Wang CJ,
Lee TH.
et al Early diagnosis of deep vein thrombosis in female patients who undergo total knee arthroplasty with measurement of P-selectin activation. J Vasc Surg 2002; 35: 707-12.
34
Papalambros E,
Sigala F,
Travlou A.
et al P-selectin and antibodies against heparin-platelet factor 4 in patients with venous or arterial diseases after a 7-day heparin treatment. J Am Coll Surg 2004; 199: 69-77.
38
Biro E,
Sturk-Maquelin KN,
Vogel GM.
et al Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 2003; 1: 2561-8.
39
Jy W,
Horstman LL,
Wang F.
et al Platelet factor 3 in plasma fractions: its relation to microparticle size and thromboses. Thromb Res 1995; 80: 471-82.
40
Weerheim AM,
Kolb AM,
Sturk A.
et al Phospholipid composition of cell-derived microparticles determined by one-dimensional high-performance thinlayer chromatography. Anal Biochem 2002; 302: 191-8.
42
Steppich B,
Mattisek C,
Sobczyk D.
et al Tissue factor pathway inhibitor on circulating microparticles in acute myocardial infarction. Thromb Haemost 2005; 93: 35-9.
43
Collen D,
Hoylaearts MF.
Relationship between Inflammation and venous thrombosis as studied by microparticle assessment in plasma. J Am Coll Cardiol 2005; 45: 1472-3.
44
Chirinos JA,
Heresi GA,
Velasquez H.
et al Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45: 1467-71.
45
Inami N,
Nomura S,
Kikuchi H.
et al P-selectin and platelet derived microparticles associated with monocyte activation markers in patients with pulmonary embolism. Clin Appl Thromb Hemost 2003; 9: 309-16.
46
Bounameaux H,
Cirafici P,
de Moerloose P.
et al Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991; 337: 196-200.
47
Demers C,
Ginsberg JS,
Johnston M.
et al D-dimer and thrombin-antithrombin III complexes in patients with clinically suspected pulmonary embolism. Thromb Haemost 1992; 67: 408-12.
48
Curtin N,
Highe G,
Harris M.
et al Extensive evaluation of the instrumentation laboratory IL test D-dimer immunoturbidimetric assay on the ACL 9000 determines the D-dimer cutoff value for reliable exclusion of venous thromboembolism. Lab Hematol 2004; 10: 88-94.
50
Bates DW,
Cullen DJ,
Laird N.
et al Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. Jama 1995; 274: 29-34.
