Download - Hemostasis, platelets and Blood management Julie Wegner, PhD, CP Midwestern University Glendale, AZ
Hemostasis, platelets and Blood management
Julie Wegner, PhD, CP
Midwestern University
Glendale, AZ
None
Why do patients bleed?
• Macrovascular• Microvascular
– Inability to generate thrombin• Insufficient clotting surface (platelets)• Insufficient substrates (clotting factors)• Inhibitors (anticoagulants, antithrombotic agents)
– Clot not strong enough• Insufficient thrombin generation• Weak fibrin-platelet mesh (platelets, fibrinogen)
– Clot vulnerable to lysis
Hemostatic components
Clot location
Substrates for: thrombin generation fibrin formation
Generating environmentProvide substrateProvide protection
Clot formation requirements
PlateletsEndotheliumWBCRBC
Procoagulant factors Intrinsic ExtrinsicAnticoagulant factorsAntithrombotic factors
EndotheliumSubendothelium
Cell-based model
Platelet contributionInitiation and propagation
Serial samplesCancer patients
Correlations: platelet count vs. MA r=0.7 vs. R r=-0.7 vs. r=0.8
Roeloffzen WWH et al. Thrombocytopenia affects plasmatic coagulation as measured bythromboelastography. Blood Coag Fibrinolysis 2010 (in press).
http://www.integrilin.com/popups/platelet2.html
Platelet cascade
Adhesion
Thrombin generation and
hemostasis
Insufficient clotting surface
Insufficient substrates
Presence of inhibitors
Central role of thrombin
From: Crawley JTB et al. The central role of thrombin. J Thromb Haemost. 2007; 5(Suppl 1): 95-101.
Thrombin generationkinetics
T1 = lag phaseT2 = maximum rate of TGT3 = Peak [thrombin]T4 = Total free thrombin (AUC)
Fibrin cross linkingLateral aggregation
TG = thrombin generation, AUC = area under the curve = endogenous thrombin potential (ETP)
from: Wolberg AS. Blood Rev. 2007.
From: Vanschoonbeek K, Feijge MAH, van Kampen RJW et al. Initiating and potentiating role of platelets in tissuefactor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogramcharacteristics. J Thromb Haemost. 2004; 2:478-484.
Thrombin generating surfaceThrombin generation and platelet #
Bollinger D et al. Br J Anaesthesiol 2009; 102:793
TG and [substrate]
PPP
(50%)
1. No change in lag time2. Slight decrease rate TG3. Decrease peak TG
1. Decrease coagulation factors• FV and FVII ~ 28% Dilution• FII and FX ~ 44% Dilution + consumption
2. Thrombin potential – [FX] and [FII]-dependent3. Blood loss vs. thrombin potential (r = -0.75*)
Post-op bleeding:Hemodilution vs. consumption?
• Hemodilution global (cells and factors)
• Consumption → global?– Importance of adequate anticoagulation
• ACT @ 480 sec: clots vs consumption?
Heparin and thrombin generation
From: Tanaka KA, Katori N, Szlam F, Sato N, Kelly AB, Levy JH. Effects of tirofiban on haemostatic activation in vitro. Br J Anaesth.2004; 93:263-269.
Peak thrombin Max. rate thrombin generation Lag time
Reversing heparin effectIs more protamine always good?
• Fine tuning protamine– ‘excess’ protamine:
TG– ‘excess’ protamine:
• Increased time to clot• Decreased clot strength • Enhanced vulnerability
to fibrinolysis
Ni Ainle F et al. Blood 2009; 114:1658
TF
Celite
Nielsen VG. Ann Thorac Surg 2006; 81:1720
Weak clots
Insufficient thrombin generation
Insufficient substrate (fibrinogen)
Weak fibrin-platelet mesh (platelets)
Clot quality and [thrombin]
Wolberg, AS. Thrombin generation and fibrin clot structure. Blood Review 2007; 21: 131- 142
Fiber thickness
Fiber weave
Thick Thin
Loose Tight
Clot strengthLow High
Anesth Analg. 2010 In press
Plateau effect1 g/L
120 x 109/L
Bleeding• Depends on clot strength (MA)
• fibrinogen levels• platelet function
100
Clot strengthFibrinogen vs. platelets
Lang T et al. Anesth Analg 2009; 108:751
Velik-Salchner C et al. JTH 2007; 5:1019
Clot vulnerability to lysis
Importance of clot strength in hemostasis
http://www.setma.com/article.cfm?ID=330 Holly, J. Cardiometabolic Risk Syndrome Part V: Fibrinolytic Dysfunction
Fibrinolysis
endothelium
contact activation
TAFI Thrombin
I
Clot quality:Clot structure and local [thrombin]
Wolberg, AS. Thrombin generation and fibrin clot structure. Blood Review 2007; 21: 131- 142
Clot strengthLow High
Fibrinolysis vulnerabilityHigh Low
Colloid solutions (HES) do not activate fibrinolysis, but they do makeclots more vulnerable to fibrinolysis
Summary
• Variability in hemostasis– One size fits all?– Monitoring
• Thrombin generation – Multiple roles– Rate and peak vs. total thrombin
• Clot structure– Thrombin– Platelets– Fibrinogen
• Clot structure and fibrinolysis