Sg1E2: Vocab: Coagulation Cascade And Fibrinolytic Cascade

Front 1

coagulation cascade:

Back 1

1. the proteins and the series of their enzymatic reactions that is the third arm of hemostasis in addition to endothelium and platelets.

Front 2

Hemophilia A and hemophilia B
type of deficiencies?
type of disorders?

Back 2

1. hemophilia A: (factor VIII deficiency)
2. hemophilia B (factor IX deficiency)
*X-linked disorders

Front 3

Hemophilia C

Back 3

1. factor XI deficiency
2. an autosomal genetic disorder (i.e. not X-linked).
3. Not completely recessive; heterozygous individuals also show increased bleeding.

Front 4

thrombin:

Back 4

1.Crucial component of hemostasis because it has roles in the coagulation cascade and affects the hemostatic roles of endothelium and platelets.
2. Thrombin has both prothrombotic and antithrombotic effects.

Front 5

vitamin K:

Back 5

1. cofactor for the gamma-carboxylation of glutamate side chain in coagulation cascade factors II, VII, IX, and X and in anticoagulant proteins protein C and protein S.

Front 6

Why is gamma-carboxylation of glutamate side chain important? (2)

Back 6

1) to form calcium-carboxylate networks that stabilize Gla-containing domains in proteins
2) to express the phospholipid binding site in vitamin K-dependent proteins of blood coagulation.

Front 7

coumadin (Warfarin®):
*used clinically
*taken orally

Back 7

1. inhibitor of gamma-glutamyl carboxylase
2. without it, coagulation factors show reduced activity
3. effect on protein C and protein S is not as prominent and the anticoagulant effect dominates
4. Ultimately: reduced activity in the coagulation cascade, reduced clotting, and an increased tendency toward bleeding

Front 8

gaama-glutamyl carboxylase

Back 8

the enzyme that carries out the gamma-carboxylation of glutamate side chain in factors II, VII, IX, and X and in anticoagulant proteins protein C and protein S

Front 9

extrinsic and intrinsic pathways

Back 9

two different enzymatic pathways of the coagulation cascade that converge on prothrombinase

Front 10

The extrinsic pathway

Back 10

the most physiologically relevant pathway for coagulation occurring when vascular damage has occurred
2. it is activated by tissue factor (also known as thromboplastin or factor III), a membrane-bound lipoprotein expressed at sites of injury.

Front 11

prothrombin time (PT), partial thromboplastic time (PTT):

Back 11

two clinically-used assays of the function of the coagulation cascade.
The PT assay assesses the function of the proteins in the extrinsic pathway (factors VII, X, II, V, and fibrinogen).

Front 12

protease-activated receptor (PAR):

Back 12

1. member of a protein family that is activated by thrombin and leads to an effect that depends on the receptor and cell host

Front 13

where are PARs exposed?

Back 13

endothelium, monocytes, dendritic cells, T lymphocytes, and other cell types.

Front 14

How is PAR activated?

Back 14

1. Receptor activation is initiated by cleavage by thrombin of the extracellular end of the PAR.
2. This generates a tethered peptide that binds to the "clipped" receptor, causing a conformational change that triggers signaling.

Front 15

what are the 5 molecules that counteract coagulation by interfering with factors of the coagulation cascade

Back 15

1. endogenous anticoagulants
2. antithrombin
3. protein C
4. protein S
5. Tissue factor pathway inhibitor

Front 16

Why must the coagulation cascade be restricted to the site of vascular injury?

Back 16

injury to prevent runaway clotting of the entire vascular tree

Front 17

Besides restricting factor activation to sites of exposed phospholipids, what three categories of endogenous anticoagulants also control clotting?

Back 17

1. antithrombins
2. proteins C and S
3. TFPI

Front 18

antithrombins
i.e. antithrombin III
why is it restricted to minimize thrombosis?

Back 18

1. inhibit the activity of thrombin and other serine proteases, including factors IXa, Xa, XIa, and XIIa.
2. Antithrombin III is activated by binding to heparin-like molecules on endothelial cells
3. hence the clinical usefulness of administering heparin to minimize thrombosis

Front 19

Proteins C and S as endogenous anticoagulants

Back 19

They are vitamin K-dependent proteins that act in a complex that proteolytically inactivates factors Va and VIIIa

Front 20

TFPI as an anticoagulant

Back 20

a protein produced by endothelium (and other cell types) that inactivates tissue factor-factor VIIa complexes

Front 21

fibrinolytic cascade

Back 21

mechanism that opposes the coagulation cascade

Front 22

what does activation of the coagulation cascade also set in motion?

Back 22

fibrinolytic cascade that moderates the size of the ultimate clot

Front 23

How is fibrinolysis largely accomplished?

Back 23

through the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization

Front 24

fibrin split products

Back 24

1. fibrin degradation products: can also act as weak anticoagulants.
2. products of fibrinolysis

Front 25

Elevated levels of FSPs
(most notably fibrin-derived D-dimers)

Back 25

can be used in diagnosing abnormal thrombotic states including disseminated intravascular coagulation (DIC), deep venous thrombosis, or pulmonary embolism

Front 26

Plasmin

Back 26

1. generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII-dependent pathway or by plasminogen activators

Front 27

when is t-PA (the most important part of PA) most active?

Back 27

1. it is synthesized principally by endothelium and is most active when bound to fibrin.

Front 28

why is t-PA a useful therapeutic agent?

Back 28

1. affinity for fibrin
2. largely confines fibrinolytic activity to sites of recent thrombosis

Front 29

Urokinase-like PA (u-PA)

Back 29

is another PA present in plasma and in various tissues; it can activate plasmin in the fluid phase

Front 30

plasminogen

Back 30

1. can be cleaved to plasmin by the bacterial enzyme streptokinase, an activity that may be clinically significant in certain bacterial infections
2. As with any potent regulator, plasmin activity is tightly restricted.

Front 31

How is excess plasmin kept from lysing thrombi indiscriminately elsewhere?

Back 31

free plasmin is rapidly inactivated by α2-plasmin inhibitor.

Front 32

D-dimer:

Back 32

1. A D-dimer is a specific FSP that is formed only by plasmin degradation of fibrin, and not by plasmin degradation of intact fibrinogen.
2. Thus, the presence of D-dimers indicates that fibrin has been formed and degraded.

Front 33

what does a positive FSP assay indicate?

Back 33

that fibrin and/or fibrinogen is being degraded by plasmin because the FSP assay detects fibrin degradation products, including D-dimers, and fibrinogen degradation products.