Perfusion Physiology- Platelets And Coagulation

Front 1

Is the BALANCE between clotting and bleeding.

Represents a delicate balance between procoagulant and anticoagulant mechanisms allied to fibrinolysis

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Homeostasis

Front 2

body spontaneously stops bleeding and maintains blood in the fluid state within the vascular compartment

It is the property of circulation where blood is maintained within a vessel and the ability of the system to prevent excessive blood loss when injured.

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Hemostasis

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(5) major components of a balanced system

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Blood Vessels
Platelets
Coagulation Proteins ( System)
Coagulation Inhibitors
Fibrinolysis

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Major Hemostasis Systems

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Vascular System
Platelets
Coagulation System
Fibrinolytic System

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Minor Hemostasis Systems

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Kinin System
Serine Protease Inhibitors
Complement System

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Two stages of Hemostasis

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Primary and Secondary

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Primary Hemostasis

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Platelet adhesion to exposed collagen within the endothelium of the vessel wall
Platelets react with endothelium that leads to thrombus formation

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Secondary Hemostasis

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Involves the enzyme activation of the coagulation proteins to produce fibrin

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The larger the vessel … (the smaller or larger) the vessel involved

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Larger

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(3) layers of smooth endothelial lining (that is designed to facilitate blood flow and hemostasis)

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Tunica Adventitia
Tunica Media
Tunica Intima

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Tunica Adventitia

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Connective tissue

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Tunica Media

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Elastic tissue and smooth muscle, controlling vasoconstriction and sometimes vasodilation

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Tunica Intima

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Broad flat endothelial cells with underlying basement membrane supported by connective tissues, that provides a smooth non-wetable (thrombo-resistant) surface that facilitates migration of cells

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Thrombo-Resistant Actions:

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-prostacyclin ( PGI2): Synthesis and secretion of this vasodilator
-Secretion of Tissue plasminogen ( t-PA)
-Inactivation and clearance of thrombin
-Activity of co-factor thrombomodulin in the thrombin-dependent activation of protein C
-ADP and vasoactive amines: Degradation of these pro-aggregating substances

Front 15

Actions of vascular system to Prevent Bleeding

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-Contracts vessels ( vasoconstriction)
-Diversion of blood flow around damage vasculature
-Initiate contact activation of platelets
-Contact activation of coagulation system

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Normal and abnormal Platelet count

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150,000-450,000
Thrombocytopenia <150,000
Thrombocytosis >450,000
Need platelet count>50,000 for adequate hemostasis

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Platelets (2-4 um in diameter) originate where?
Circulating vs stored platelets and survival

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in the bone marrow
1 week from megakaryopoiesis to megakaryoblast to platelet
70% circulating
30% sequestered in microvasculature of spleen and , and serve as “reserves”
Survive 7-10 days in circulation and “ active” for hemostasis

Front 18

Thrombopoietin
-function
-produced where

Back 18

Major regulator of platelet production
Produce in kidney and liver
Increases number and rate of maturation of megakaryocytes.

Front 19

Platelets provide what surface membrane glycoproteins which attach to other platelets and fibrinogen?

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GPIIB and IIIa

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Platelets provide a (positive or negative) charge phospholipid surface for a __________ and ___________ activation

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Negative

Factor X and prothrombin

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(3) defined zones of Platelet Structure

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Peripheral Zone
Sol-Gel Zone
Organelle Zone

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Impairment of any of these (3) structural zones lead to...

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platelet dysfunction and abnormal hemostasis

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Peripheral Zone

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Glycocalyx
Platelet membrane
Open canalicular system ( OCS)
Sub-membranous region

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The cell membrane consists of :

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Phospholipid plasma membrane
Exterior glycoprotein coat

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Function of glycoprotein coat

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permits platelet adhesion and aggregation

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Which zone contains the cell membrane

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Peripheral Zone

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Adhesion to collagen is facilitated by...

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glycoprotein Ia

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important for attachment of platelets to von Willebrand factor

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Glycoprotein IIb/IIIa

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The cytoskelton of the platelet that consist on microtubules, microfilaments and sub-membranous filaments

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Sol-Gel Zone

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What help to maintain the discoid shape

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Microtubule

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Zone that is responsible for metabolic activity

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Organelle Zone

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(3)storage granules in Organelle Zone :

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Dense granules
Alpha α granules
Lysosomes

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Most numerous of the granules

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Alpha Granules

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Stores :
Beta –Thromboglobulin, Platelet factor 4, Platelet-Derived Growth Factor and Thrombospondin

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Alpha Granules

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Store ADP, ATP and ionic calcium, serotonin and phosphate

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Dense Granules

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Contain Neutral protease, Acid hydrolase and Bacteriocidal Enzymes

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Lysosomes

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What Granules' contents are released and secreted into the canalicular system ( OCS)?

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The Alpha and Dense

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Platelet and endothelial interaction is modulated by

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prostaglandin ( PGI2)

Front 39

PGI2 is synthesized by endothelial cells from ( a membrane phospholipid) and has an antagonistic effect in platelet adhesion and plt aggregation

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Arachidonic Acid

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Once the vessel integrity is disrupted,
plts release __________( switch inhibits heparin) to maintain normal vascular integrity

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PDGF

Front 41

5 steps to formation of platelet plug:

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Adhesion
Shape Change
Aggregation
Release/ Secretion
Stabilization of clot

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Adhesion involves (3) critical components:

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-Von Willebrand Factor
-Platelet membrane receptor GP1B
-Collagen

Front 43

VonWillebrand Factor synthesis, absorption and binding

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-synthesized by the endothelial cells
-released into the plasma
-absorbed onto the surface of the platelet
-bound to its receptor,GP1b

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The interaction of circulating agonists as ADP, collagen, thrombi and thromboxane 2 alter the and change the _______________ shape of the platelet

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cytosolic calcium

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_______ and ________bind to the membrane receptor surface and expose it to platelet membrane phospholipids which cause aggregation

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TXA2 and ADP

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Platelet to Platelet interaction is known as

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AGGREGATION

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AGGREGATION usually begins 10-2 seconds following vascular injury and platelet adhesion and Requires:

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ATP
Fibrinogen
GPIIb/IIIa complex
Ionized Calcium

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Bridges form and promote platelet aggregation from

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Calcium/Fibrinogen

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Primarily ADP, from the dense granules release:

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Serotonin
Calcium
Thromboxane A2
Von Willebrand Factor

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_____ and _______function as vasoconstrictors, Contract vascular smooth muscle, Decreases blood flow through then injured vessel.

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Serotonin and thromboxane A2

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Secreted from Alpha Granules:

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Beta Thromboglobin
Platelet Factor 4 ( PF4)
Platelet –Derived Growth Factor
Thrombospondin

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Last stage in arresting bleeding

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Stabilization

deposit of fibrin on the platelet aggregates
Fibrin interweaves through the initial platelet, compressing into place at site of injury

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Contents of platelet granules are released exponentially magnifying the accumulation of platelets and fibrin at the site of injury, creating a ______

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thrombus

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Coagulation Cascade System

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Secondary Hemostasis

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All coagulation factors are produced in the _____.

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liver

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Three CategoriesHemostatic Function

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Substrate
Cofactors
Enzymes

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Substances upon which enzymes act

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Substrate
Ex: Fibrinogen ( Factor 1)

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Accelerate enzyme reactions

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Cofactors
Ex: Labile Factor ( Factor 5)
( Anti Hemophilic Factor) Factor VIII

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Cleave the peptide bond

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Enzymes
Ex: Serine Proteases (IIa, VIIa, Ixa, Xa, XIIa, Prekallikrein)
Transaminase (Factor XIIIa)

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(2) pathways of the Coagulation Cascade

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Intrinsic
Extrinsic

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Both pathways of the Coagulation Cascade require :

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plasma proteins and phospholipids and calcium

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In the _______ Pathway, all the factors necessary for clot formation are in the vascular compartment, and are ALL found within the circulating blood

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Intrinsic

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The extrinsic system is initiated when _________, a substance NOT found in blood, enters the vascular system.

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FACTOR III (tissue thromboplastin or tissue factor)

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Following exposure to negatively charged foreign substances such as..... involving contact factors that initiates the intrinsic pathway

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collagen
sub endothelium
phospholipids
activation of factor XII

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Intrinsic Requires factors:

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VIII, IX, X, XI, XII
Prekallikrein and HMWK
Calcium and PF3

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where is factor III released from?

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From the injured vessel wall.

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Only _____, _____, and ______ are needed to activate Factor X to Xa.

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VIIa
Ca+
Factor III

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a potent platelet-aggregating agent

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Thrombin

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Thrombin promotes

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secretion of serotonin (vasoconstrictor) and thromboxane (a platelet aggregating agent)

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Thrombin provides a positive feedback mechanism to amplify the activation of cofactors

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V and VIII, which enhance thrombin formation

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What is the main physiologic inhibitor of thrombin and factors Xa, IXa, XIa and XIIa and activate protein C and kallakrein?

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Antithrombin III

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Fibrinogen/factor I is a protein produced by the _____.

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liver

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Drugs that may increase fibrinogen levels include:

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estrogen and oral contraceptives.

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Drugs that may cause decreased levels include:

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anabolic steroids, androgens, streptokinase, and valproic acid

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Thrombin cleaves a portion of each alpha and beta chain to form _______.

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fibrinopeptides

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Composed of (3) pairs of polypeptide chains....

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2 alpha
2beta
2 gamma chains
The remainder of fibrinogen is called fibrin monomer

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Thrombin hydrolyzes fibrinopeptides A and B to form ________. Fibrin Monomer links to form insoluble ______.

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monomers, fibrin polymer