Download This is more prevalent in vascular grafts

BLOOD-DEVICE INTERACTIONS
Thrombosis and Complement
Thrombosis
CARDIAC VALVES AND VASCULAR GRAFTS
Taxol stent thrombosis
(late stage thrombosis related to Tissue
Factor 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.
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 stentgraft (arrowheads). (c) Axial helical CT scan
obtained at the level of the graft limbs shows
complete thrombosis of the left graft limb (arrow).
Tillich M et al. Radiographics 1999;19:1573-1583
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
This is more prevalent in vascular
grafts
HMW-Kininogen activated by binding to material
This is more prevalent in early dialysis membranes (and ECMO)
INCREASED ACTIVATION OF FACTOR XII
FACTOR XIIA ACTIVATES FACTOR XI
This is directly related to the thrombogenicity of the vascular graft material
Theory I
http://www.hopkinsmedicine.org/hematology/coagula
tion.swf
Relationships between inflammation and coagulation?
Theory II
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.
CONTROL POINTS
• Calcium
• Calcium chelators
• Thrombin
• Key in common pathway and
feedback loops
• Platelets
• Adherence to biomaterials
CONTROL OF COAGULATION
FIBRINOLYSIS AND ANTICOAGULANTS
tpa-tissue plasminogen activator
The Intersection Between Coagulation and Complement Activation
Complement Activation
DIALYSIS MEMBRANES/ECMO
COMPLEMENT ACTIVATION
HTTP://HIGHERED.MCGRAWHILL.COM/SITES/0072507470/STUDENT_VIEW0/CHAPTER22/ANIMATION__ACT IVATION_OF_COMPLEME
NT.HTML
XII/Thrombin binding and
COMPLEMENT ACTIVATION AND RENAL Factor
proteolysis of C3 followed by C3b
binding
DIALYSIS/ECMO (THEORY 1)
O-C3b/C5
C5a
Generation of arachidonic acid
metabolites and cytokines
Pulmonary hypertension
Neutrophil activation
Neutropenia
Increased conc. Of
degradative enzymes
Reactive oxygen species
Complement regulatory proteins in glomerular diseases
Masaomi Nangaku
Fibrinogen and C4b2a binding to material (along with albumin) activate
conversion of C3 into C3a and C3b
Theory 2
Regenerated
Cellulose
(Cuprophan)
Rapid activation of the complement system by cuprophane depends on complement component C4
Karl Lhotta, Reinhard Würzner, Florian Kronenberg, Martin Oppermann and Paul König
Thrombosis and Complement:Crosstalk
Cleavage of C3 results in formation of C3a and C3b resulting in amplification of C3
activation 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
PLATELET/LEUKOCYTE AGGREGATES
•
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
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 membrane
Bradykinin system activated
by Factor XII (clotting cascade)
Vasodilation
Anaphylaxis
POST-PERFUSION SYNDROME
CONTACT PHASE ACTIVATION
BRADYKININ GENERATION
POTENTIATION BY ACE INHIBITORS
Systemic inflammatory
response
Acute lung failure
Sepsis
Multi-organ failure