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Biomaterials Tutorial

Blood Compatibility

Mª Cristina L. Martins
Instituto de Engenharia Biomédica (INEB), Porto, Portugal

Blood compatibility is often referred to as haemocompatibility and is one aspect of biocompatibility.  Blood compatibility relates to the specific interactions between biomaterials and circulating blood. Biocompatibility is defined as the ability of a material to perform with an appropriate response related to a specific application [1].

The human body is equipped with interrelated regulation systems. These systems’ purpose is to heal wounds and to protect against intrusion by foreign organisms. This overall regulation is termed “homeostasis” [2]. When a biomaterial is brought into contact with blood, the first event that occurs is a rapid, almost immediate, adsorption of proteins onto its surface. The performance of the biomaterial is influenced by this film of adsorbed proteins.  It can elicit adverse host responses, such activation of plasma enzyme cascades (coagulation, fibrinolytic, kinin and complement systems) and adhesion and activation of platelets and leukocytes [3-6]. These systems coordinate together in order to eliminate the biomaterial by isolation (fibrin) or degradation (phagocytosis combined with liberation of enzymes and reactive radicals) [4].

Contact Activation

Generally, the first proteins to be adsorbed are the relatively abundant plasma proteins, such as albumin, fibrinogen, immunoglobulin G and fibronectin.  These are soon replaced by trace proteins, including factor XII (Hageman factor) and high molecular weight kininogen (HMWK). This hierarchical adsorption process is called the “Vroman effect” [7-11]. The small amount of activated factor XII (XIIa) is the key enzyme in initiating the coagulation, fibrinolysis and kinin cascades. Activated factor XII and its fragments (XIIf) can potentially induce activation of the classical pathway of complement system [5, 6]     (Figure 1).

Figure 1. Simplified schematic represents contact activation on biomaterials surface. The initial event is the adsorption of factor XII to the biomaterial where it is activated to form factor XIIa. Abbreviations for the following clotting factors are: prekallikrein (PK); kallikrein (K); high molecular weight kininogen (HMWK); factor XII (XII); activated factor XII (XIIa); factor XII fragment (XIIf); factor XI (XI); activated factor XI (XIa). Adapted from Spatnekar and Anderson [6].

 

Coagulation System

Blood coagulation is a local cascade process whereby soluble plasma proteins become activated in response to vascular injury, leading to the formation of a fibrin clot that arrests blood flow [2, 12]. In the process, thrombin production leads to platelet activation.  Platelet aggregates are part of the final clot. 

Coagulation can be triggered either by surface-mediated reactions (intrinsic pathway), or  by exposure to factors derived from damaged tissue (extrinsic pathway). The two  processes join into a common path leading to the formation of an insoluble fibrin gel (Fig. 2) [2, 5, 6, 12].

Figure 2. Simplified schematic represents coagulation by activation of factor XII (intrinsic pathway) and factor VII / tissue factor (extrinsic pathway). Adapted from Spatnekar and Anderson [6].

Fibrinolytic System

The fibrinolytic system is designed to degrade unneeded blood clots by the action of plasmin, a specific protease which cleaves the fibrin networks that were formed during coagulation (Figure 3) [5, 6, 12].

Figure 3. Simplified schematic represents the fibrinolytic system. Adapted from Hanson and Harker [5].

Kinin System

The plasma kinin system is an enzymatic system that is triggered by activated factor XII.

The activation of prekallikrein into kallikrein by the activated factor XII occurs on the surface of biomaterials and in the fluid phase (Figure 4).

Figure 4. Simplified schematic represents kinin system.

The major function of kallikrein is to amplify the activation of coagulation and the fibrinolytic systems. Kallikrein also cleaves HMWK to produce bradykinin, a potent inflammatory mediator that produces vasodilation during the recruitment of leukocytes [6].

References:

  1. Williams DF. The Williams dictionary of biomaterials. Liverpool University Press, 1999.
  2. van Wynsberghe D, Noback CR, Carola R. Human anatomy and physiology, 3rd edition. WCB/McGraw-Hill, 1995.
  3. Eberhart RC, Huo H, Nelson K. Cardiovascular materials. MRS Bulletin 1991; 50-54.
  4. Dawids S. Haemocompatibility, What does it mean? In: Kluwer DS, editor.  Test procedures for the blood compatibility of biomaterials. The Netherlands: Academic Publisher; 1993. p 3-11.
  5. Hanson SR and Harker LA. Blood coagulation and blood-materials interactions. In: Ratner BD, Hoffman AS, Schoen FJ, Lemons JL, editors. Biomaterials science: An introduction to materials in medicine. San Diego, CA: Academic Press Inc.; 1996.
  6. Sapatnekar S, Anderson JM. Hemocompatibility: Effects on humoral elements. In: von Recum AF. Handbook of biomaterials evaluation: Scientific, technical and clinical testing of implant materials, 2nd edition. Philadelphia, PA : Taylor & Francis: 1999. p. 353-365.
  7. Vroman L, Adams AL, Fischer GC, Munoz PC. Interaction of high molecular weight kininogen, factor XII and fibrinogen in plasma at interfaces. Blood 1980; 55: 156-159.
  8. Horbett TA. Mass action effects on competitive adsorption of fibrinogen from hemoglobin solutions and from plasma. Thromb Haemost 1984; 51:174-181.
  9. Brash JL, Hove P. Effect of plasma dilution on adsorption of fibrinogen to solid surfaces. Thromb Haemost 1984; 51: 326-330.
  10. Andrade JD, Hlady V. Vroman effects, techniques, and philosophies. J Biomater Sci Polymer Edn 1991; 2: 161-172.
  11. Brash JL. Studies of protein adsorption relevant to blood compatible materials.  In: Missirlis YF, Lemm W, editors. Modern aspects of protein adsorption on biomaterials.  The Netherlands: Kluwer Academic Publishers; 1991. p. 38-47.
  12. Dailey JF. Blood,  2nd edition. Ipswich, MA: Medical Consulting Group, 1998.
 
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