Microparticles from Patients with Multiple Organ Dysfunction Syndrome and Sepsis Support Coagulation through Multiple Mechanisms

Karin Joop; René J. Berckmans; Rienk Nieuwland; Johanna Berkhout; Fred P. H. T. M. Romijn; C. Erik Hack; Augueste Sturk

doi:10.1055/s-0037-1615753

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 85(05): 810-820
DOI: 10.1055/s-0037-1615753

Review Article

Schattauer GmbH

Microparticles from Patients with Multiple Organ Dysfunction Syndrome and Sepsis Support Coagulation through Multiple Mechanisms

Karin Joop

¹Departments of Clinical Chemistry

,

René J. Berckmans

¹Departments of Clinical Chemistry

,

Rienk Nieuwland

¹Departments of Clinical Chemistry

,

Johanna Berkhout

²Medical Microbiology and Infectious Diseases of the Leiden University Medical Center, Leiden, The Netherlands

,

Fred P. H. T. M. Romijn

¹Departments of Clinical Chemistry

,

C. Erik Hack

³Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands

,

Augueste Sturk

¹Departments of Clinical Chemistry

› Author Affiliations

Abstract

Summary

Aim. We investigated the occurrence and thrombin generating mechanisms of circulating microparticles (MP) in patients with multiple organ dysfunction syndrome (MODS) and sepsis.

Methods. MP, isolated from blood of patients (n = 9) and healthy controls (n = 14), were stained with cell-specific monoclonal antibodies (MoAbs) or anti-tissue factor (anti-TF) MoAb and annexin V, and analyzed by flow cytometry. To assess their thrombin-generating capacity, MP were reconstituted in normal plasma. The coagulation activation status in vivo was quantified by plasma prothrombin fragment F₁₊₂- and thrombin-antithrombin (TAT) measurements.

Results. Annexin V-positive MP in the patients originated predominantly from platelets (PMP), and to a lesser extent from erythrocytes, endothelial cells (EMP) and granulocytes (GMP). Compared to healthy controls, the numbers of annexin V-positive PMP and TF-exposing MP were decreased (p = <0.001 for both), EMP were decreased (E-selectin, p = 0.003) or found equal (CD144, p = 0.063), erythrocyte-derived MP were equal (p = 0.726), and GMP were increased (p = 0.008). GMP numbers correlated with plasma concentrations of elastase (r = 0.70, p = 0.036), but not with C-reactive-protein or interleukin-6 concentrations. Patient samples also contained reduced numbers of annexin V-negative PMP, and increased numbers of erythrocyte-derived MP and GMP (p = 0.005, p = 0.021 and p <0.001, respectively). Patient MP triggered thrombin formation, which was reduced compared to the healthy controls (p = 0.008) and strongly inhibited by an anti-factor XII MoAb (two patients), by anti-factor XI MoAb (eight patients) or by anti-TF MoAb (four patients). Concentrations of F₁₊₂ and TAT were elevated (p = 0.005 and p = 0.001, respectively) and correlated inversely with the number of circulating MP (and r = –0.51, p = 0.013, and r = –0.65, p = 0.001, respectively) and their thrombin generation capacity (F₁₊₂: r = –0.62, p = 0.013).

Conclusions. In patients with MODS and sepsis relatively low numbers of MP are present that differ from controls in their cellular origin, numbers and coagulation activation mechanisms.

Keywords

Microparticles - coagulation - factor XI - factor XII - tissue factor - sepsis

Full Text

References

References
1 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988; 263: 18205-12.
2 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989; 264: 17049-57.
3 Hoffman M, Monroe DM, Roberts HR. Coagulation factor IXa binding to activated platelets and platelet-derived microparticles: a flow cytometric study. Thromb Haemost 1992; 68: 74-8.
4 Gilbert GE, Sims PJ, Wiedmer T, Furie B, Furie BC, Shattil SJ. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991; 266: 17261-8.
5 Satta N, Toti F, Feugeas O, Bohbot A, Dachary-Prigent J, Eschwege V, Hedman H, Freyssinet JM. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol 1994; 153: 3245-55.
6 Kagawa H, Komiyama Y, Nakamura S, Miyaka T, Miyazaki Y. Expression of functional tissue factor on small vesicles of lipopolysaccharide-stimulated human vascular endothelial cells. Thromb Res 1998; 91: 297-304.
7 Allan D, Thomas P, Limbrick AR. The isolation and characterization of 60 nm vesicles (“nanovesicles”) produced during ionophore A23187-induced budding of human erythrocytes. Biochem J 1980; 188: 881-7.
8 Nomura S, Shouzu A, Omoto S, Hayakawa T, Kagawa H, Nishikawa M, Inada M, Fujimura Y, Ikeda Y, Fukuhara S. Effect of cilostazol on soluble adhesion molecules and platelet-derived microparticles in patients with diabetes. Thromb Haemost 1998; 80: 388-92.
9 Nomura S, Suzuki M, Katsura K, Xie GL, Miyazaki Y, Miyake T, Kido H, Kagawa HFS. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 1995; 116: 235-40.
10 George JN, Pickett EB, Saucerman S, McEver RP, Kunicki TJ, Kieffer N, Newman PJ. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects and observations in patiens during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 1986; 78: 340-8.
11 Katopodis JN, Kolodny L, Jy W, Horstman LL, De Marchena EJ, Tao JG, Haynes DH, Ahn YS. Platelet microparticles and calcium homeostasis in acute coronary ischemias. Am J Hematol 1997; 54: 95-101.
12 Warkentin TE, Hayward CPM, Boshkov LK, Santos AV, Sheppard JAI, Bode AP, Kelton JG. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 1994; 84: 3691-9.
13 Lee YJ, Jy W, Horstman LL, Janania J, Reyes Y, Kelley RE, Ahn YS. Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multiinfarct dementias. Thromb Res 1993; 72: 295-304.
14 Nomura S, Shouzu A, Nishikawa M, Kokawa T, Yasunaga K. Significance of platelet-derived microparticles in uremia. Nephron 1993; 63: 485.
15 Jy W, Horstman LL, Arce M, Ahn YS. Platelet microparticles in ITP. J Lab Clin Med 1992; 119: 334-5.
16 Holme PA, Solum NO, Brosstad F. Clinical significance of platelet-derived microvesicles: demonstration of their presence in patients suffering from disseminated intravascular coagulation (DIC). Thromb Haemost. 1993 69. (Suppl 01), Ref Type: Abstract.
17 Nieuwland R, Berckmans RJ, McGregor S, Böing AN, Romijn FPHTM, Westendorp RGJ, Hack CE, Sturk A. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-5.
18 Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, Maquelin KN, Roozendaal KJ, Jansen PGM, ten Have K, Eijsman L, Hack CE, Sturk A. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534-41.
19 Berckmans RJ, Nieuwland R, Böing AN, Romijn F, Hack CE, Sturk A. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85: 639-46.
20 Combes V, Simon A-C, Grau G-E, Arnoux D, Camoin L, Sabatier F, Mutin M, Sanmarco M, Sampol J, Dignat-George F. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104: 93-102.
21 Bone RC. The sepsis syndrome. Clinics in Chest Medicine 1996; 17: 175-81.
22 Dors DM, Nuijens JH, Huijbregts CCM, Hack CE. A novel sensitive assay for functional factor XII based on the generation of kallikrein-C1-inhibitor complexes in factor XII-deficient plasma by glass-bound factor XII. Thromb Haemost 1992; 67: 644-8.
23 Beguin S, Lindhout T, Hemker HC. The effect of trace amounts of tissue factor on thrombin generation in platelet rich plasma, its inhibition by heparin. Thromb Haemost 1989; 61: 25-9.
24 Siljander P, Carpen O, Lassila R. Platelet-derived microparticles associate with fibrin during thrombosis. Blood 1996; 87: 4651-63.
25 Nemerson Y. Tissue factor: then and now. Thromb Haemost 1995; 74: 180-4.
26 Pixley RA, De La Cadena R, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor Jr FB, Colman RW. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest 1993; 91: 61-8.
27 Taylor Jr FB, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS. Lethal E coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-34.
28 Lämmle B, Wuillemin WA, Huber I, Krauskopf M, Zürcher C, Pflugshaupt R, Furman MI. Thromboembolism and bleeding tendency in congenital factor XII deficiency: a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65: 117-21.
29 von Känel R, Wuillemin WA, Furlan M, Lämmle B. Factor XII clotting activity and antigen levels in patients with thromboembolic disease. Blood Coag Fibrinol 1992; 3: 555-61.
30 Gillis S, Furie BC, Furie B. Interactions of neutrophils and coagulation proteins. Sem Haemath 1998; 34: 336-42.
31 Henderson LM, Figueroa CD, Muller-Esterl W, Bhoola KD. Assembly of contact-phase factors on the surface of the human neutrophil membrane. Blood 1998; 84: 474-82.
32 Seligsohn U. Factor XI deficiency. Thromb Haemost 1993; 70: 68-71.
33 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-12.
34 von dem Borne PAKr, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-42.
35 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999; 19: 170-7.
36 Hsu TC, Shore SK, Seshsmma T, Bagasra O, Walsh PN. Molecular cloning of platelet factor XI, an alternative splicing product of the plasma factor XI gene. J Biol Chem 1998; 273: 13787-93.
37 Hu C, Baglia FA, Mills DCB, Konkle BA, Walsh PN. Tissue-specific expression of functional platelet factor XI is independent of plasma factor XI expression. Blood 1998; 91: 3800-7.
38 Levi M, ten Cate H. Disseminated intravascular coagulation. N Eng J Med 1999; 341: 586-92.
39 Holme PA, Solum NO, Brosstad F, Pederson T, Kveine M. Microvesicles bind soluble fibrinogen, adhere to immobilized fibrinogen and coaggregate with platelets. Thromb Haemost 1998; 79: 389-94.
40 Nasser TK, Wilensky RL, Mehdi K, March KL. Microparticle deposition in periarterial microvasculature and intramural dissections after porous balloon delivery into atherosclerotic vessels: quantitation and localization by confocal scanning laser microcopy. Am Heart J 1996; 131: 892-8.
41 Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human athero-sclerotic plaques. Circulation 1999; 99: 348-53.
42 von Segesser LK, Turina M. Cardiopulmonary bypass without systemic heparinization. Performance of heparin-coated oxygenators in comparison with classic membrane and bubble oxygenators. J Thorac Cardiovasc Surg 1989; 98: 386-96.
43 von dem Borne PAKr, Mosnier LO, Tans G, Meijers JCM, Bouma BN. Factor XI activation by meizothrombin: stimulation by phospholipid vesicles containing both phosphatidylserine and phosphatidylethanolamine. Thromb Haemost 1997; 78: 834-9.
44 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: 23111-8.
45 Barry OP, Kazanietz MG, Praticò D, Fitzgerald GA. Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway. J Biol Chem 1999; 274: 7545-56.