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