Fibrinogen & Fibrinolysis

LabM 419 Clinical Coagulation Fall 2009

Cara Calvo, MS, MT(ASCP), SH(ASCP) UW, 2008.

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Learning Objectives Upon completion of required reading, after careful study, and following this lecture the student will b e able to:
1.

Define and correctly use the following keys terms anytime a discussion of fibrinogen and fibrinolysis occurs: a) fibrinogen, b) fibrin, c) fibrinolysis, d) primary fibrinolysis, e) afibrinogenemia, f) dysfibrinogenemia, g) plasminogen, h) plasmin, i) fibrin degradation products, j) D-Dimer, k) FDP, l) thrombin plasminogen activator (TPA), and m) serpins. Name the key biological and chemical substances whose activity and interactions result in the conversion of fibrinogen to fibrin monomers and the polymerization of fibrin monomers to form a stable fibrin mesh. Outline the specific events leading to the formation of a stable fibrin mesh. Discuss the activation of plasminogen to plasmin. Include the name, the source, and a brief description of the function of each key protein involved. Summarize the actions of plasmin. Contrast the hemostatic actions of thrombin and plasmin. Explain the fibrinolytic pathway in terms of its activation, products of its activity, and its role in hemostasis.

2.

3. 4. 5. 6. 7.

8.
9. 10.

Discriminate between FDPs and D-Dimer.

Name and then describe the principle underlying lab tests important in the clinical evaluation of fibrinogen and fibrinolysis. Interpret lab data, correlate lab data with patient information, and synthesize knowledge of fibrinogen and fibrinolysis to correctly respond to test questions and solve subject-matter related case studies.

REVIEW: Coagulation

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Fibrinogen Structure

Plasma Level Ref. Range 150 400 mg/dL

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Fibrinogen to Fibrin Monomer

Fibrinopeptides very negatively charged A fibrinopeptides cleaved first

Required for polymerization

B fibrinopeptides cleaved 2nd

Makes contact between monomers stronger

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Fibrin Monomer Polymerization

Exposed a & b chain ends have a strong affinity for D domain of adjacent monomers Non-covalent bonds Unstable clot

In vitro dissolves in 5 M urea

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FIBRINOLYSIS Fibrinolysis

Removing fibrin to restore normal blood flow Activation Intrinsic activators Plasma XIIa Kallikrein Extrinsic activators - Cell Injured tissue Pyrogens Exogenous activators Therapeutic
Urokinase Streptokinase

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Fibrinolysis: Key Players & Products

Go factors
Plasminogen Plasmin
Tissue plasminogen activator (TPA) Urokinase

Dont go factors - SERPINS

Plasminogen Activator inhibitor (PAI-1)
a2-antiplasmin

TAFI

Products
FDPs D-Dimer

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Plasminogen

Single peptide 5 glycosylated loops KRINGLES Help plasminogen bind fibrin lysine residues Help plasminogen bind control proteins a2-antiplasmin Free plasmin bound & inactivated by a2-antiplasmin
Otherwise - 1 Fibrinolysis

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Plasmin
Serine Protease Targets

Fibrin Fibrinogen V VIII Fibronectin

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1 - Damaged endothelia secrete TPA. 2 TPA activates plasminogen bound to fibrin clot. 3 - Free TPA circulates bound to PAI-1 and is cleared from plasma.

Plasmin systematically hydrolyzes lysine & arginine peptide bonds of the fibrin polymer. P indicates sites where plasmin cleaves the fibrin polymer.

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Fibrinolytic Mechanisms

FDPs vs D-Dimer
Activation of the Fibrinolytic System

Fibrin degradation products (FDP), also known as fibrin split products, are:
present in blood when the thrombolytic enzyme plasmin cleaves fibrin or fibrinogen

D-dimers are a type of FDP

produced when fibrin is cleaved by
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Lets See What Youve Learned!

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References

Rodak, BF, Fritsma, GA & Doig, K (2008). Hematology Clinical Principles & Applications. Saunders Elsevier. Chapters 40 & 45. McKenzie, Shirlyn B (2004). Clinical Laboratory Hematology. Pearson Prentice Hall. Chapter 35 Beckman Coulter Webinars: Fundamentals of Hemostasis at URL http://www.beckmancoulter.com/LARS/personnel/w ebinars.asp Hemostasis Basics: Programmed Learner Part I (Provided by Siemens Healthcare Diagnostics Hemostasis Technical Services at URL http://www.dadebehring.com/education/hemostasis /tutorial.htm