Thrombosis and Complement

BLOOD-DEVICE INTERACTIONS

CARDIAC VALVES AND VASCULAR GRAFTSThrombosis

Taxol stent thrombosis(late stage thrombosis related to TissueFactor generation-see later slide)

CLINICAL MANIFESTATIONS• Thrombotic events can range between 2% and 10% depending upon the device

• Sudden and complete obstruction within weeks

• Sub-acute thrombotic occlusion

• Long-term “chronic” thrombosis

• Embolism

THROMBOSIS-WHY?

• Vascular grafts• Midgraft thrombosis

• Lack of endothelium

• Intimal narrowing at anastamosis

• Surgical trauma

• Variations in flow

• Low flow-augmentation of anastomotic intimal hyperplasia

• Shear stress

• Diameter mismatches

Figure 11b.  Stent-graft thrombosis after therapy with a bifurcated graft.

Tillich M et al. Radiographics 1999;19:1573-1583

Figure 11b.  Stent-graft thrombosis after therapy with a bifurcated graft. (a) Axial helical CT scan of the midgraft region obtained 5 months after therapy shows a crescent-shaped, parietal thrombus adjacent to the left wall of the stent-graft (arrowheads) extending distally into the left graft limb. (b) Photograph of the surgical specimen shows the thrombus adjacent to the left wall of the stent-graft (arrowheads). (c) Axial helical CT scan obtained at the level of the graft limbs shows complete thrombosis of the left graft limb (arrow).

Small diameter vascular grafts are most prone to coagulation and occlusion

THROMBOSIS-WHY?

• Cardiac Valves• Intimal narrowing at anastamosis

• Surgical trauma

• Lack of endothelium

• Variations in flow and turbulence

• Shear stress

• Diameter mismatches

Mechanical mitral valve with pannus obstructing the leaflet.

Imran U H et al. BMJ Case Reports 2011;2011:bcr.03.2011.3969

©2011 by BMJ Publishing Group Ltd

Heart 2009;95:430-436 doi:10.1136/hrt.2007.134726

THE INITIAL STEPS…(PLATELET ACTIVATION)

• Exposure of biomaterial surface or platelet trauma

• Initiation of the clotting cascade automatically initiates wound healing (soft tissue lecture)

• Binding of Factor XII

• Activation of platelets and release of phospholipids and platelet factor 3

• Activation of Factor X

• Culimination in common pathway

• Fibrin clot formed from bound and circulating fibrinogen

Contact phase proteins

Factor XII activated by binding to material

HMW-Kininogen activated by binding to material

This is more prevalent in early dialysis membranes (and ECMO)

This is more prevalent in vasculargrafts

INCREASED ACTIVATION OF FACTOR XIIFACTOR XIIA ACTIVATES FACTOR XI

This is directly related to the thrombogenicity of the vascular graft material

Theory I

http://www.hopkinsmedicine.org/hematology/coagulation.swf

Activation of blood monocytes resulting from device –related inflammation may result in the release of TF. TF release may then lead to coagulation along the extrinsic pathway.

Relationships between inflammation and coagulation?

Theory II

CONTROL POINTS

• Calcium• Calcium chelators

• Thrombin• Key in common pathway and

feedback loops

• Platelets• Adherence to biomaterials

CONTROL OF COAGULATIONFIBRINOLYSIS AND ANTICOAGULANTS

tpa-tissue plasminogen activator

The Intersection Between Coagulation and Complement Activation

DIALYSIS MEMBRANES/ECMOComplement Activation

COMPLEMENT ACTIVATIONHTTP://HIGHERED.MCGRAW-HILL.COM/SITES/0072507470/STUDENT_VIEW0/CHAPTER22/ANIMATION__ACTIVATION_OF_COMPLEMENT.HTML

COMPLEMENT ACTIVATION AND RENAL DIALYSIS/ECMO (THEORY 1)

Complement regulatory proteins in glomerular diseasesMasaomi Nangaku

Neutrophil activationNeutropeniaIncreased conc. Ofdegradative enzymesReactive oxygen species

Generation of arachidonic acidmetabolites and cytokinesPulmonary hypertension

O-C3b/C5 C5a

Factor XII/Thrombin binding and proteolysis of C3 followed by C3bbinding

Rapid activation of the complement system by cuprophane depends on complement component C4Karl Lhotta, Reinhard Würzner, Florian Kronenberg, Martin Oppermann and Paul König

RegeneratedCellulose(Cuprophan)

Theory 2

Fibrinogen and C4b2a binding to material (along with albumin) activateconversion of C3 into C3a and C3b

Thrombosis and Complement: Crosstalk

Cleavage of C3 results in formation of C3a and C3b resulting in amplification of C3activation and also C5 conversion to C5a and C5b

THE HOST’S RESPONSE• Protein deposition on membrane

• Boundary layer/secondary layer

• Cellular Activation

• Platelet/leukocyte aggregates

• Immune stimulation

• Complement

• Hypersensitivity reactions

• Residual ETO

• Hemodynamic Effects• Contact phase formation of bradykinin

PROTEIN DEPOSITION• Deposition of protein occurs instantaneously

• A protein layer forms on the surface of the membrane as the levels of solution phase proteins increase

• Composition of adsorbed proteins depends upon membrane type

• Hydrophobic membranes tend to adsorb more proteins

• Proteins adsorb and then detach until permanent adsorption and denaturing occurs

• This may result in the formation of a boundary layer

• Protein adsorption determines cellular responses

• Protein adsorption may serve as a way to successfully remove unwanted proteins from patients or may negatively effect the diffusivity of the membrane

• Low MW-interleukins, inflammatory cytokines

• High MW-albumin, fibrinogen, IgG

• Platelets aggregate on membrane surface resulting in further aggregation of leukocytes

• Aggregation causes activation of the platelets as well as the leukocytes and can result in release of platelet-derived factors and cytokines

• Results: superoxide release, cytokine release and leukopenia

• Superoxide release resulting from chronic dialysis has been implicated in atherosclerosis

• Cytokine release and leukopenia can result in general feeling of malaise

PLATELET/LEUKOCYTE AGGREGATES

UPenn

HYPERSENSITIVITY AND HEMODYNAMICS“First use syndrome”-Inflammation and Hypersensitivity

Toxins-ETO (sterilization) residuals

Plasticizers-Membrane mfg

Leachables-Membrane mfg

Post-perfusion syndrome (neucleophiles)Contact phase activation

Bradykinin is formed due to contact with the membraneBradykinin system activated by Factor XII (clotting cascade)

VasodilationAnaphylaxis

POST-PERFUSION SYNDROMECONTACT PHASE ACTIVATION

BRADYKININ GENERATIONPOTENTIATION BY ACE INHIBITORS

Systemic inflammatory responseAcute lung failureSepsisMulti-organ failure