Blood Clotting

Front 1

Hemostasis

Back 1

stop bleeding from damaged blood vessels

Rapid constriction of vessel, aggregation of platelets to form plug, clotting

Front 2

Clotting

Back 2

web forms consisting of fibrin polymers

traps platelets and RBCs

contracts to squeeze out fluid

generates seal

Front 3

Platelets

Back 3

produced by splitting off from megakaryocytes, no nucleus or protein synthesis

replaced after 10 days

circulate in blood in inactive state

Front 4

Aggregation of Platelets

Back 4

injury to blood vessel wall exposes ECM components that bind to receptors on platelets to initiate activation

platelet forms projections, dump secretory granules, contents of granules activates additional platelets

activated platelets adhere strongly to ECM and to each other

Front 5

Von Willebrandt facto (vWf)

Back 5

present in blood plasma

important for associating platelets w/ECM

binds collagen and receptors on platelets (integrins and other receptor complexes)

Front 6

Glycoprotein IIb/IIIa

Back 6

type of integrins

receptors for fibrinogen

forms a complex by crosslinking w/fibrinogen and other proteins

Front 7

GPIIb/IIIa Inhibitors

Back 7

inhibit platelet aggregation

used during angioplasty and for acute coronary syndromes

Front 8

Signaling Pathways in Platelet Activation

Back 8

activation of many signaling pathways: one important one involves formation of prostaglandins and thromboxanes

1. Phospholipase A2 cleaves membrane phospholipids to form arachidonic acid

2. Cyclooxygenase converts arachidonic acid to a prostaglandin (PGG2)

3. In platelets, PGG2 converted to thromboxane A2 (TxA2)

4. In endothelial cells, PGG2 converted PGI2 (prostacyclin) which activates adenylate cylcase and inhibits platelet aggregation

Front 9

Phospholipase A

Back 9

produces arachidonic from cleavage of membrane phospholipids

Front 10

Cyclooxygenase

Back 10

converts arachidonic acid to a prostaglandin (PGG2)

Front 11

Prostaglandin (PGG2)

Back 11

produced by cyclooxygenase from arachidonic acid

coverted to thromboxane A2 in platelets

converted to PGI2 in endothelial cells

Front 12

PGI2

Back 12

prostacyclin

released and enters platelets

inhibits platelet aggregation by activating adenylate cyclase

inactivates platelets that leave damaged area

Front 13

Thromboxane A2

Back 13

acts both within the cell and released to neighboring cell

causes Ca2+ release in cytosol which promotes dumping of secretory granules, platelet aggregation, and vasoconstiction

inhibits adenylate cyclase which prevents platelets in damaged area from being inactivated

Front 14

Aspirin

Back 14

thromboxane A2 can be bad for the elderly b/c platelet aggregation can interfere w/blood flow

aspirin is a cyclooxygenase inhitbitor

inhibits platelet aggregation by lowering thromboxane A2 levels

also lowers PGI2 levels, but not dramatically

Front 15

Fibrinogen

Back 15

major blood plasma protein

soluble

coverted to insoluble fibrin by proteolytic cleavage by thrombin

composed of 6 polypeptide chains: two each of alpha, beta, and gamma chains

three stranded coiled-coil interaction of alpha, beta, and gamma chains

2 alphabetagamma complexes linked by disulfide bonds

Front 16

Thrombin

Back 16

cleaves off 4 small peptides at N-terminus of each alpha and beta chain - fibrinopeptides A and B

contains peptides designated A and B linked through disulfide bonds

Front 17

Fibrinopeptides A and B

Back 17

cleaved off of N-terminus of alpha and beta chain

Front 18

Fibrin Monomer

Back 18

resulting structure after thrombin cleaves off fibrinopeptides

associate as half-staggered arrays to form fibers

Front 19

Soft Clot

Back 19

half-staggered arrays of fibrin monomers that form fibers

unstable

Front 20

Hard Clot

Back 20

stable

formed by cross-linking monomers

transamidation reaction forms isopeptide bonds btwn side chains at C-termini of alpha chains

Front 21

Factor XIII

Back 21

catalyzes cross-linking of fibrin monomers in soft clot to form a hard clot

Front 22

Cascade of Proteases

Back 22

proteases present in blood plasma as inactive precursors prior to cleavage

most synthesized in the liver

each protease cleaves the next protease in the pathway, activating it

results in amplification of signal

Front 23

Intrinsic Pathway for Fibrinogen Cleavage

Back 23

everything needed for pathway contained in blood

stimulated by contact of blood w/negatively charged surface (glass tube or surface exposed from ruptured vessel)

end step is cleavage of factor X to activate it

Front 24

Extrinsic Pathway for Fibrinogen Cleavage

Back 24

requires componentfrom surrounding tissue to stimulate

need tissue factor (thromboplastin) that is normally buried below endothelium

exposed by injury

activates factor VII and cleaves factor X to activate it

Front 25

Thromboplastin

Back 25

tissue factor needed in extrinsic pathway

Front 26

Common Pathway

Back 26

activated factor X cleaves inactive prothrombin to generate active thrombin which then cleaves fibrinogen

Front 27

Factor X

Back 27

cleaved at end of intrinsic and extrinsic pathways to become active

cleaves inactive prothrombin at 2 sites releasing the N-terminal peptide

Front 28

Vitamin K and Clotting

Back 28

cofactor for enzyme that produces Gla modification on prothrombin so that it can be cleaved

Front 29

Gla

Back 29

gamma-carboxyglutamate

modification to clotting factors where carboxyl group is added to glutamic acid

prothrombin has 10 at N-terminal region

cannot be cleaved when Gla unmodified

Front 30

Dicoumarol

Back 30

found in spoiled sweet clover

interferes w/ vitamin K cycle and inhibits clotting

can be used as blood thinner durg

Front 31

Warfarin

Back 31

used as rat poison

intereferes w/vitamin K cycle and inhibits clotting

can be used as blood thinner drug

Front 32

Gla Residues in Prothrombin Cleavage

Back 32

prothrombin must associate w/negatively charged phospholipid membrane to be cleaved by Factor X - occurs at site vessel injury

prothrombin-membrane association requires calcium which forms bridges linking Gla residues to phospholipids

higher negative charge from Gla modification provides stronger attraction for calcium

calcium chelating agents prevent clotting of blood samples

Front 33

Hemophilia A

Back 33

inherited deficiency of factor VIII

x-linked

Front 34

von Willebrandt Disease

Back 34

inherited deficiency of vWf

platelet adhesion depends on vWf

factor VIII forms complex w/vWf which increases stability of factor VIII

lose of vWf decreases stability of factor VIII

Front 35

Protein C - Protein S

Back 35

1. excess thrombin binds to endothelial cell receptor (thrombomodulin)

2. thrombin bound to thrombomodulin activates protein C, forming complex w/protein S (APC)

3. APC anchored by protein S to platelet surface at clot by calcium brigdges

4.APC destroys activated factor V and VIII by proteolysis

Front 36

Activated Protein C Complex

Back 36

protein c and protein s complex after thrombin uses thrombomodulin to activate protein C

Front 37

Venous Thromboembolism

Back 37

increased risk w/inherited deficiency of protein c or protein S or point mutation in APC cleavage site of factor V

Front 38

Antithrombin

Back 38

protein present in blood that inhibits clotting by inhibiting most proteases of clotting system

weak activity strongly enhanced by binding GAG,heparin

Front 39

Heparin

Back 39

secreted by mast cells that line blood vessels in response to injury

limit spread of clot

useful as blood thinner drug

Front 40

Plasmin

Back 40

protease that cleaves fibrin to dissolve blood clots

plasminogen present in blood and cleaved to active plasmin by various proteases known as plasminogen activators

Front 41

Plasminogen Activators

Back 41

proteases that cleave plasminogen present in blood into active plasmin

Front 42

Tissue-type Plasminogen activator

Back 42

released from endothelial cells

useful drug for dissolving blood clots in stroke and