Intravenous administration of heparin and heparin-bonded extracorporeal circuits are frequently used to mitigate the deleterious effects of blood contact with synthetic materials. The work described here utilized human blood in a micro-perfusion circuit to experimentally examine the effects of intravenous and surface-bound heparin on cellular activation. Activation markers of coagulation and of the inflammatory response were examined using flow cytometry; specifically, markers of platelet, monocyte, polymorphonuclear leukocyte (PMN), and lymphocyte activation were quantified. The results indicate that surface-bound heparin reduces the inflammatory response whereas systemically administered heparin does not. This finding has important implications for blood-contacting devices, particularly within the context of recently elucidated connections between inflammation pathways and coagulation disorders. Data presented indicate that surface-bound heparin and intravenously administered heparin play distinct, but vital roles in rendering biomaterial surfaces compatible with blood.
WendelHPScheuleAMEcksteinFS. Hemocompatibility of paediatric membrane oxygenators with heparin-coated surfaces. Perfusion1999; 14: 21–28.
2.
WeerwindPWvan der VeenFHLindhoutT. Ex vivo testing of heparin-coated extracorporeal circuits: bovine experiments. Int J Artif Organs1998; 21: 291–298.
3.
GradyRMEisenbergPRBridgesND. Rational approach to use of heparin during cardiac catheterization in children. J Am Coll Cardiol1995; 25; 325–329.
4.
WeberNWendelHP. Quality assessment of heparin coatings by their binding capacities of coagulation and complement enzymes. J Biomater Appl2000; 15: 8–22.
5.
WendelHP andZiemerG. Coating-techniques to improve the hemocompatibility of artificial devices used for extracorporeal circulation. Eur J Cardiothorac Surg1999; 342–350.
6.
PascheBKodamaKLarmO. Thrombin inactivation of surfaces with covalently bonded heparin. Thromb Res1986; 44: 739–748.
7.
AnderssonJSanchezJEkdahlKNElgueGNilssonBLarssonR. Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro. J Biomed Mater Res A2003; 67: 458–466.
8.
PascheBSwedenborgJHedinU. Thrombogenicity of the vessel wall after single and repeated injury. Thromb Res1991; 62: 531–543.
9.
KodamaKPascheBOlssonP. Antithrombin III binding to surface immobilized heparin and its relation to F Xa inhibition. Thromb Haemost1987; 58: 1064–1067.
10.
BlezerRCahalanLCahalanPT. Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation. Blood Coagul Fibrinolysis1998; 9: 435–440.
11.
Chromogenix. Antithrombin. Product Monograph 1995 version 1.1.
12.
WestRHPaulAJHibbertS. Correlation of the surface chemistries of polymer bioactive coatings, with their biological performances. J Mater Sci Mater Med1995; 6: 63–67.
13.
JohnsonGCurryBCahalanL. In vitro assessment of blood compatibility: residual and dynamic markers of cellular activation. J Biomater Appl Epub ahead of print 29Dec2011. DOI: 10.1177/0885328211428525.
14.
PassacqualeGVamadevanPPereiraL. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PLOSoneVolume 6, Issue 10 e25595. October2011.
15.
SanchezJElgueGRiesenfeldJ. Inhibition of the plasma contact activation system of immobilized heparin; relation to surface density of functional antithrombin binding sites. J Biomed Mater Res1997; 37: 37–42.
16.
BarnardMRLindenMDFrelingerALIII. Effects of platelet binding on whole blood flow cytometry assays of monocyte and neutrophil procoagulant activity. J Thromb and Haemost2005; 3: 2563–2570.
17.
ReddyMEirikisEDavisC. Comparative analysis of lymphocyte activation marker expression and cytokine secretion profile in stimulated human peripheral blood mononuclear cell cultures: an in vitro model to monitor cellular immune function. J Immunol Methods2004; 293: 127–142.
18.
SeizerPGawazMMayAE. Platelet-monocyte interactions – a dangerous liaison linking thrombosis, inflammation and atherosclerosis. Curr Med Chem2008; 15: 1976–1980.
19.
DabbaghKChambersRCLaurentGJ. From clot to collagen: coagulation peptides in interstitial lung disease. Eur Respir J1998; 11: 1002–1005.
20.
LeviM andvan der PollT. Inflammation and coagulation. Crit Care Med2010; 38: S26.
21.
AmaraURittirschDFlierlM. Interaction between the coagulation and complement system. In: LambrisJ.D. (ed.), Current topics in complement II. DOI: 10:1007/978–0–387–78952–1_6, Springer science + Business Media, LLC 2008.
22.
GorbetMBSeftonM. Biomaterial-associated thrombosis; roles of coagulation factors, complement, platelets and leukocytes. Biomaterials2004; 25: 5681–5703.
23.
HoffmanM. A cell-based model of coagulation and the role of factor VIIa. Blood Rev2003; 17: S1–S5.
ColmanRWSchmaierAH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood1997; 90: 3819–3843.
26.
FrickIMBjorckLHerwaldH. The dual role of the contact system in bacterial infectious disease. Thromb Haemost2007; 98: 497–502.
27.
OvrumEMollnesTEFosseE. High and low heparin dose with heparin-coated cardiopulmonary bypass: activation of complement and granulocytes. Ann Thorac Surg1995; 60: 1755–1761.
28.
JohnRSandhyaPHrabeJ. Activation of endothelial and coagulation systems in left ventricular assist device recipients. Ann Thorac Surg2009; 88: 1171–1179.
29.
WilhelmCRRistichJKormosRL. Monocyte tissue factor expression and ongoing complement generation in ventricular assist device patients. Ann Thorac Surg1998; 65: 1071–1076.
30.
EkdahlKNLambrisJDElwingH. Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv Drug Deliv201116; 63: 1042–1050;
SimsPJWiedmarT. Induction of cellular procoagulant activity by the membrane attack complex of complement. Semin Cell Biol1995; 6: 275–282.
33.
JyWMaoWWHorstmanLTaoJAhnYS. Platelet microparticles bind, activate and aggregate neutrophils in vitro. Blood Cells Mol Dis1995; 21: 217–231.
34.
MickelsonJKLakkisNMVillarreal-LevyGHughesBJSmithCW. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease?J Am Coll Cardiol1996; 28: 345–353.
35.
HansenJBSvenssonBOlsenREzbanMOsterudBPaulssenRH. Heparin induces synthesis and secretion of tissue factor pathway inhibitor from endothelial cells in vitro. Thromb Heamost2000; 83: 937–943.
36.
LupuCPoulsenERoquefeuilSWestmuckettADKakkarVVLupuF. Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells in culture. Arterioscler Thromb Vasc Biol1999; 19: 2251–2262.
37.
YeATakanoRHayashiK. Structural requirements of human tissue factor pathway inhibitor (TFPI) and heparin for TFPI-heparin interaction. Thromb Res1998; 89: 263–270.
38.
SmithSA. The cell-based model of coagulation. Journal of Veterinary Emergency and Critical Care2009; 19(1): 3–10.
39.
GarredPMollnesTE. Immobilized heparin inhibits the increase in leukocyte surface expression of adhesion molecules. Artif Organs1997; 21: 293–299.
40.
LappegårdKTFungMBergsethG. Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation. Ann Thorac Surg2004; 77: 932–941.
41.
SokolovAHellerudBCTennessenTI. Activation of coagulation and platelets by candidate membranes of implantable devices in a whole blood model without soluble anticoagulant. J Biomed Mater Res Part A2013; 101A: 575–581.
