Coagulation Basics

Question 1

What is hemostasis?

Answer 1

Cessation of blood loss from a damaged vessel

Question 2

Hemostasis occurs in 4 phases, what are they?

Answer 2

1. Vascular Spasm
2. Platelet plug formation (primary hemostasis)
3. Blood coagulation (Secondary hemostasis)
4. Dissolution of the fibrin clot (tertiary hemostasis)

Question 3

Following injury to the vessel wall, the initial event is what?

Answer 3

Vasoconstriction

–which is a transient, locally induced phenomenon

Question 4

Platelets, in healthy endothelium, remain in their unactivated state. What mediators are released in order to inhibit platelet aggregation?

Answer 4

Chemical mediators

• -prostacyclin and nitric oxide are release by healthy endothelium
• -inhibit platelet aggregation

Question 5

Blood vessel injury exposes what?

Answer 5

Exposes:

–collagen, Von Willebrand factor (vWF): these are components of the extra cellular matrix

Question 6

The platelet plasma membrane contains what collagen receptors?

Answer 6

GPVI and vWF receptors (GPIb)
–binding of the collagen and vWF on the extra cellular matrix to these receptors causes the platelet to adhere to the subendothelium

Question 7

Binding of the collagen and vWF to the platelet results in platelet activation, leading to the release of the contents of the cells’ granules:?

Answer 7

ADP, Ca2+, ATP, serotonin, vWF, and platelet factor 4

–all secreted from platelet granules

Question 8

What is the action of ADP?

Answer 8

Mediates platelet aggregation

• -through receptor P2Y1 which couples to Gq and mobilizes intracellular Ca2+
• -through receptor P2Y12 which couples to Gi to inhibit adenylyl cyclase

Question 9

Activated platelets synthesize and release what?

Answer 9

Thromboxane A2 (TXA2)

• -platelet aggregating agonist and vasoconstrictor
• -receptor couples to Gq and leads to mobilization of intracellular Ca2+

Question 10

Activation of platelets is enhanced by the generation of thrombin through the coagulation cascade; thrombin is an important platelet agonist. Thrombin receptors are what?

Answer 10

Protease activated G protein coupled receptors

—activation of thrombin receptors results in activation of PLC and inhibition of adenylyl cyclase

Question 11

Signaling molecules released by activated platelets activate receptors on the plasma membrane of resting platelets circulating nearby. What happens next in the cascade?

Answer 11

Previously dormant platelets become activated and start to aggregate

Question 12

Platelet aggregation is mediated primarily by what?

Answer 12

Fibrinogen
–soluble plasma glycoprotein
Binds simultaneously to GPIIB/IIIa receptors on two separate platelets
–this leads to platelet cross linking and platelet aggregation which leads to clot formation
GPIIb/IIIa does not bind fibrinogen on nonstimulated platelets
Platelet activation converts GPIIb/IIIa from a low affinity fibrinogen receptor to a high affinity receptor

Question 13

The above cards went through the formation of a platelet plus (primary hemostasis). Now secondary hemostasis is the coagulation cascade. How does blood start to coagulate after primary hemostasis?

Answer 13

Transformation of soluble fibrinogen into insoluble fibrin

Question 14

Thrombin does what?

Answer 14

Catalyzes the conversion of fibrinogen to fibrin
–which is incorporated into the plug
–this is the last step of the coagulation cascade
Cross-linking of the fibrin strands stabilize the clot and forms the hemostatic plug

Question 15

The coagulation cascade is a sequence of enzymatic events. The coagulation factors are generally serine proteases. Most plasma coagulation factors circulate as inactive proenzymes, which are synthesized by the liver. These proenzymes are proteolytically cleaved, and thereby activated, by the activated factors that precede them in the cascade

Answer 15

:)

Question 16

There are two pathways of the coagulation pathway. Describe the intrinsic pathway first

Answer 16

Activated in vitro by factor XII (Hageman factor)

Question 17

Describe the extrinsic pathway

Answer 17

In vivo is initiated by activation of clotting factor VII by the tissue factor (Thromboplastin)

Question 18

Both the intrinsic and extrinsic coagulation pathways lead to the activation of what?

Answer 18

Factor X.

• -activated factor X cleaves prothrombin (factor II) to thrombin (factor IIa)
• -thrombin converts the soluble plasma protein fibrinogen into fibrin

Question 19

Moving on to Vitamin K, what is the action of this vitamin?

Answer 19

Blood clotting factors II, VII,IX and X
–must undergo a vitamin K dependent post translational modification, which involves the gamma carboxylation of a number of glutamic acid residues

Question 20

Vitamin K is regenerated from the epoxide by what?

Answer 20

Vitamin K epoxide reductase

Question 21

Finally after vascular injury, anticoagulant factors are secreted by the endothelium:

Answer 21

Prostacyclin (PGI2) 
Antithrombin III 
Proteins C and S 
Tissue Factor Pathway Inhibitor (TFPI)
Tissue Type Plasminogen Activation (t-PA)

Question 22

How does PGI2 work as an anticoagulant factor?

Answer 22

Increases cAMP levels within platelets
–inhibit platelet activation
Also a vasodilator
–increases cAMP levels in the vascular smooth muscle cells

Question 23

How does antithrombin III work as an anticoagulant factor?

Answer 23

Inactivates thrombin and other coagulation factors

–by forming a complex with them

Question 24

How does protein C and S work as a anticoagulant agents?

Answer 24

Protein C
–vitamin K dependent serine protease that is activated by thrombin
Protein C and S
–degrade factors Va and VIIIa

Question 25

How does tissue factor pathway inhibitor (TFPI) work as an anticoagulant factor?

Answer 25

Limits the action of tissue factor (TF)

–prevents excessive TF-mediated activation of factors IX and X

Question 26

Finally how does t-PA work as an anticoagulant factor?

Answer 26

Plasmin proteolytically degrades fibrin
–plasmin is generated by cleavage of plasminogen
The cleavage is catalyzed by tissue plasminogen activator (t-PA)
–which is synthesized and secreted by the endothelium

Question 27

Finally lets touch briefly on thrombosis, what is thrombosis?

Answer 27

Pathologic extension hemostasis

–formation of a clot called a thrombus

Question 28

What are three major factors that predispose to thrombus formation?

Answer 28

Endothelial injury
Abnormal blood flow
Hypercoagulability
–this is known as Virchow’s Triad

Question 29

Venous thrombosis is usually trigged by what?

Answer 29

Blood stasis or inappropriate activation of the coagulation cascade
–clot that is rich is fibrin with fewer platelets than in arterial clots

Question 30

Arterial thrombosis most often occurs in medium sized vessels rendered thrombogenic by what?

Answer 30

Surface lesions of endothelial cells caused by atherosclerosis
–platelet rich clot