Path XI: Hemostasis and Thrombosis

Question 1

What are the 5 players in normal hemostasis?

Answer 1

endothelium, extravascular tissue, platelets, plasma coagulation proteins, and plasma coagulation inhibitors

Question 2

What are the goals of normal hemostasis/clotting system?

Answer 2

1. trigger immediated and effectively in seconds
2. never activate when not needed
3. act strictly in local area of need
4. turn off when hemostasis is achieved

Question 3

How is speed achieved in coagulation?

Answer 3

continuous actiavtion of coagulation factors which is always occuring at a basal physiologic low level

Question 4

Many factors control normal hemostasis. What are the requirements for proceding to the next step in the plasma protein coagulation cascade?

Answer 4

plasma protein coagulation cascade that requires two activated factors AND a substrate to be present on an activated cell surface in order to activate the next protein in the cascade.
Also, there are multiple steps where inhibitors can work. Platelets must also be activated, which requires them to be exposed to subendothelial tissue.

Question 5

How does tissue factor act to control normal hemostasis?

Answer 5

Tissue factor is only present in an active form on the surface of extravascular tissues. It can therefore only be seen by coagulation factions if a vessel is breached.

Question 6

What is the role of plasma coagulation inhibitors in the control of hemostasis, and what are some of the plasma coagulation inhibitors?

Answer 6

Inhibitors can stop the coagulation cascade (duh). Examples include protein C, protein S, antithrombin, and tissue factor pathway inhibitor.

Question 7

What role do endothelial cells play in the control of the coagulation cascade?

Answer 7

they can inhibit both activation of platelets and the coagulation cascade directly.

Question 8

What is the first key event in clot formation?

Answer 8

platelet adherence and activation by exposure to subendothelial tissue containing ligands like von Willebrand factor, collagen, immobilized fibrinogen.

Question 9

What happens once platelets are activated? (clot formation step 2)

Answer 9

platelets change shape. they activate their surface adhesion receptors and secrete granule contents and other signaling molecules to get other platelets to aggregate and become activated. Signals: TxA2, serotonin, ADP.

Question 10

What happens once platelets have changed their shape and secreted their granule contents/signaling molecultes to attract and activate other platelets? (clot formation step 3)

Answer 10

tissue factor is available on subendothelial cell surfaces.
tissue factor + activated platelet surface + small amount of activated VIIa starts the coagulation cascade: thrombin is produced.

Question 11

What happens after tissue factor, activated platelet surface, and small amounts of VIIa start the coagulation cascade and produce thrombin? (clot formation step 4)

Answer 11

thrombin activates factors XI, VIII, and V. These amplify the coagulation cascade, leading to abundant thrombin production and formation of a fibrin clot (positive feedback loop). This further activates platelets.

Question 12

In what ways does thrombin participate in both positive and negative feedback loops?

Answer 12

activates factors XI, VIII, and V, which promote further thrombin production, formation of a fibrin clot, and platelet activation (factors 11, 8, 5)
also helps apply the brakes by activating protein C with the help of endothelial thrombomodulin (which MODULATES thrombin activity). Protein C and Protein S inactivate factors Va and VIIIa.

Question 13

What system limits clot spread and begins to dissolve the clot?

Answer 13

fibrinolytic system : tissue plasminogen activator-plasminogen.

Question 14

Discuss what happens, factor-wise, in terms of the clotting cascade?

Answer 14

1. tissue factor activates factor VII.
2. TF-VIIa activate factors IX and X.
3. this activates some amt of pro-thrombin (factor II).
4. IIa/thrombin activates factors XI, VIII, and V. Thrombin also activates fibrinogen to form fibrin, which forms a clot.
5. Factor Va promotes further activation of factor II.

Question 15

What are the positive regulators of clot formation?

Answer 15

As before,
tissue factor activates factor VII. factor VII activates factors IX and X. IX and X activate factor II/thrombin.
1. Factor X feedsback to help activate more factor VII. Meanwhile,
2. Thrombin activates factors XI, VIII, and V
- Factor V is a cofactor that works with factor X to continue activating prothrombin
-Factor VIII works with factor IX to activate more X (which activates more VII and therefore more thrombin).

Question 16

What are the key inhibitors of clot formation? (5)

Answer 16

1. Thrombin works with thombomodulin to activate protein C. Proteins C and S inactive factor V and VII (co-factors).
2. Xa makes TFPI, which inhibits factor VII.
3. Anti-thrombin from the liver inhibits thrombin.
4. Heparin sulfate activates anti-thrombin (indirect inactivation of thrombin).
5. Plamsinogen activated by thrombin helps break up clots.

Question 17

How does warfin work as an anticoagulant?

Answer 17

Warfan is an anti-vitamin K thing. Vitamin k is needed for the synthesis of factors 10, 9, 7 ,and 2.

Question 18

Why is DTI a dangerous drug?

Answer 18

DTI = direct thrombin inhibitor. There is no antidote, and this can severely inhibit clot formation.

Question 19

What does low molecular weight heparin do?

Answer 19

inhibits factor Xa.

Question 20

What is the deal with basal coagulation?

Answer 20

• we have low levels of basal coagulation all the time- normal ppl have some fibrinopeptides and factor VIIa floating around
• we only see coagulation when enough thrombin is made near a tissue factor bearing cell to get platelet and cofactor activation. basal coagulative factor levels are balanced by basal anticoagulant levels (low basal levels of protein C and tissue plasminogen activator.

Question 21

What properties of the endothelium oppose platelet activation?

Answer 21

PG12, NO, ecto-ATPase

Question 22

What signals from the endothelium oppose coagulation proteins?

Answer 22

activated protein C, antithrombin/cell surface heparan, TFPI (tissue factor pathway inhibitor made by VIIa/TF/Xa complex

Question 23

What is a thrombolytic factor made by the endothelium?

Answer 23

tPA, which makes plasmin, which breaks up fibrin clots

Question 24

What factors contribute to fibrinolysis?

Answer 24

plasminogen must be activated to plasmin, which breaks down fibrin clots and releases fibrin split products, which act as weak coagulants.
plasminogen is activated by tPA and uPA released by tissues. free plasmin is inactivated by circulating alpha2-antiplasmin.

Question 25

What is hemorrhage?

Answer 25

extravasation of blood due to vessel rupture. usually caused by trauma and other vascular injury.

Question 26

What is a hematoma?

Answer 26

hemorrhage enclosed within a tissue

Question 27

What are petechiae?

Answer 27

timy hemorrhages into skin, mucous membranes, or serosal surfaces. often associated with platelet dysfunction and low platelet count.

Question 28

What are purpura?

Answer 28

Larger hemorrhages into skin, mucousm or serosal surfaces that are often associated with trauma, vasculitis, vasculatr fragility, and clotting factor disorders.

Question 29

What is ecchymosis?

Answer 29

larger subcutaneous hemorrhage: color changes from purple to greenish/yellow due to conversion of hemoglobin to bilirubin and hemosiderin.

Question 30

What is hemarthrosis?

Answer 30

hemorrhage into joint spaces. typical of hemophilia

Question 31

What are three major outcomes of hemorrhage?

Answer 31

1. loss of blood volume.
2. tissue damage, esp. if in a confined space (like the cranium)
3. iron deficiency anemia if bleeding is chronic and iron stores are depleted.