Biochemistry of Hemostasis Flashcards
Why is the coagulation cascade often compared to a staged waterfall?
The coagulation cascade operates in stages, where each stage depends on the function of the previous stage, similar to a waterfall with cascading stages.
How does the extrinsic pathway differ from the intrinsic pathway in the coagulation cascade?
The extrinsic pathway depends on tissue factor and factor 7, while the intrinsic pathway involves factors 8, 9, 11, and 12. Both pathways contribute to thrombin production.
What is the purpose of anti-thrombotic factors in the coagulation cascade?
Anti-thrombotic factors help control the coagulation cascade and maintain a balance in the blood clotting process.
How is a blood clot ultimately destroyed in the coagulation cascade?
Plasmin, a protein, is produced to degrade fibrin, leading to the dissolution of the blood clot.
What factors in the coagulation cascade are vitamin K dependent?
Factors 2, 7, 9, and 10 are vitamin K dependent.
How do you describe the coagulation cascade in a summarized manner?
The coagulation cascade is a staged process, initiated by tissue factor and involving extrinsic and intrinsic pathways. Thrombin production, amplification, and fibrin formation lead to stable blood clot formation. Anti-thrombotic factors provide control, and plasmin destroys clots.
What is the definition of hemostasis?
the collection of processes that stops bleeding by keeping blood within a damaged blood vessel.
Why is hemostasis important, and what must it achieve?
it prevents blood loss after an injury. It must be fast, localized, and reversible to maintain the balance between coagulation and anti-coagulation factors.
What are the consequences of an imbalance in hemostasis?
An imbalance can lead to thrombosis (clot in the wrong place) or hemorrhage (uncontrolled bleeding), both of which can be life-threatening.
What factors can influence the balance in hemostasis?
The balance can be influenced by inherited conditions, environmental factors, and drugs.
What are the key phases of hemostasis, and what are their main goals?
The phases include vessel constriction, platelet activation (formation of a platelet plug), the coagulation cascade (producing fibrin), and fibrinolysis (clot dissolution).
What substances are secreted by endothelial cells and what role do they play in hemostasis?
Endothelial cells secrete prostacyclin, nitric oxide, heparan sulfate, tissue factor pathway inhibitor, and thrombomodulin. These substances inhibit thrombus formation and maintain normal vessel function.
How is hemostasis initiated, and what processes are triggered by vessel injury?
Vessel injury exposes collagen and tissue factor, initiating two parallel processes: platelet activation and the coagulation cascade.
What is the goal of platelet activation, and what substances are crucial for it?
Platelet activation aims to form a platelet plug. Important substances include von Willebrand factor and fibrinogen.
What is the objective of the coagulation cascade, and what is the role of thrombin in this process?
The coagulation cascade aims to produce thrombin. Thrombin is a serine protease that converts fibrinogen into fibrin, which forms a stable clot.
What is fibrinolysis, and how is it activated?
Fibrinolysis is the process of dissolving a blood clot. Plasmin is a key player in this process, and it reverses clot formation.
What are platelets?
small, disc-shaped blood cells that play a crucial role in blood clotting and wound healing.
Platelets arise from
megakaryocytes, found in bone marrow
What is the function of von Willebrand Factor (vWF) in hemostasis?
mediates platelet adhesion by bridging GpIb on platelets and collagen, playing a crucial role in blood clot formation.
Where is von Willebrand Factor (vWF) normally found in the body?
circulating in the blood and is secreted constitutively by endothelial cells, megakaryocytes, and connective tissue.
How do platelets release von Willebrand Factor (vWF)?
upon degranulation, contributing to the formation of platelet plugs in response to vascular injury.
Besides platelet adhesion, what other roles does von Willebrand Factor (vWF) play in hemostasis?
platelet aggregation and the coagulation cascade, contributing to the overall process of blood clot formation.
Adhesion to collagen triggers
platelet activation
Platelet activation includes:
- Shape change
- Degranulation
- GpIIbIIIa activation and aggregation
Activation of fibrinogen
(GPIIb-IIIa) receptors facilitates
platelet aggregation (interaction between multiple platelets)
Collagen, thrombin, ADP, and
TXA2 all activate
platelets
Endothelial cells secrete substances that inhibit
thrombus formation
platelets support hemostasis by
- Adhering to endothelial surface
- Secreting platelet-activating substances and
vasoconstrictors - Aggregating
- Providing a surface that facilitates formation of a fibrin network and stabilizes the clot
Which clotting factors, when bound to calcium, adopt a conformation that binds the phospholipid surface of platelets?
Factors II (prothrombin), VII, IX, and X.
Why is the binding of these clotting factors to the phospholipid surface of platelets important in hemostasis?
This binding concentrates clotting factors at the site of injury, promoting localized fibrin formation, and facilitating blood clot formation.
How are platelets localized to the site of injury, where these clotting factors are concentrated?
Platelets are localized to the site of injury via collagen, and they are joined by fibrinogen, contributing to the formation of a stable blood clot.
What triggers the cascade of enzymatic reactions in hemostasis?
The cascade of enzymatic reactions is triggered by blood vessel injury.
What is the key role of thrombin in this cascade?
Thrombin plays a key role by converting fibrinogen to fibrin.
How does fibrin contribute to hemostasis and the formation of a stable blood clot?
Fibrin aggregates and crosslinks to form a network, stabilizing the platelet plug.
Which clotting factors rely on vitamin K for their activity?
Factors II, VII, IX, and X require vitamin K for their activity.
How is the cascade of enzymatic reactions in hemostasis regulated?
It is highly regulated by natural inhibitors.
What are PT and aPTT, and how are they used in medical monitoring?
PT and aPTT are laboratory tests used to monitor drug dosage and diagnose diseases related to hemostasis. PT/INR is more sensitive for assessing warfarin, while aPTT is more sensitive for assessing heparin.
John Cena, a 46 year old pro-wrestler
accidentally drops his ice cream cone and
slips on it. He falls down and scrapes his
knee. Which hemostatic response will be the
quickest to activate?
a. Extrinsic pathway
b. Intrinsic pathway
c. Vasoconstriction
d. Common Pathway
c. Vasoconstriction happens immediately upon vascular injury and is the first line of defense against bleeding
Tirofiban, a GpIIbIIIa antagonist is given to
a patient who is to undergo a PCI procedure
following a STEMI. Based on its drug class,
explain how you think its MOA will prevent
clot formation
As a GpIIbIIIa antagonist, tirofiban prevents
both fibrinogen and vWF from binding to
GpIIbIIIa receptors. This will inhibit platelet
crosslinking, which will stop platelet
aggregation from happening. Without platelet
aggregation, clots cannot form!
A mysterious drug, RICEKRISPIES, was trialed for anticoagulant treatment and was designed to only inhibit activation of clotting factor VIII (part of the intrinsic pathway). Would this make an effective anticoagulant?
Most likely no, because inhibiting only factor VIII will not optimally inhibit thrombin production, as there will still be a bit of thrombin production from the extrinsic pathway. Since thrombin is directly responsible for clot formations (which is what we do not want), anticoagulants should aim to either inhibit thrombin formation (e.g. common pathway inhibitors) or inhibit thrombin itself (e.g. direct thrombin inhibitors).
One day after giving a STEP session, a student
asks: ‘If the extrinsic pathway responds much faster than the intrinsic pathway, what’s so significant about the intrinsic pathway?’ How would you
explain?
While the extrinsic pathway does induce a much quicker response to injury, the intrinsic pathway is responsible for majority of the thrombin surge that is needed for clot formation, as the enzyme intrinsic ten-ase
(IXa/VIIIa) activates factor X at a rate ~50x-100x faster than extrinsic tenase (VIIa/TF)
What is the role of calcium in clotting?
Calcium binds to factors II (prothrombin), VII, IX, and X to help them adhere to the surface of platelets. This localizes the coagulation cascade
What is the role of vitamin K?
It modifies factors II, VII, IX, and X (1972), allowing them to bind to calcium. Also, modifies Protein C and S.
What do Protein C and S do?
Protein C (with Protein S as a cofactor) inactivate factors Va and VIIIa, thus, inhibiting coagulation
What is the MOA of warfarin?
Warfarin inhibits vitamin-k epoxide reductase, an enzyme needed to activate Vitamin K. It depletes functional vitamin K reserves, thus, reducing synthesis of clotting factors which require modification.
Endothelial cells secrete substances that inhibit
thrombus formation
Prostacyclin + Nitric oxide
- Vasodilates
- Inhibit platelet activation
Heparin sulfate
Activates Antithrombin III (ATIII) (which inhibits factors Xa, IXa, VIIa, IIa)
Tissue Factor Pathway
Inhibitor
Inhibit TF, Xa, VIIa
ADP Phosphatase
Breakdown ADP
J.T. (he/him) is rushed into the emergency room. Upon encounter, the patient is alert and stable, face is drooping, and speech is slurred. CT Scan is performed and J.T. is diagnosed with ischemic stroke (due to blood clot forming in the brain). What do you recommend administering and its mechanism of action?
tPA should be recommended. It converts plasminogen into active plasmin, which breaks down fibrin/ the clot
After successfully treating J.T., your preceptor asks you to counsel him on his discharge medication - Warfarin. J.T. mentions that his friend gets frequent labs, since he is also taking warfarin. Which test is J.T. referring to?
PT/INR: it is more sensitive to and used to assess warfarin
5 days later, J.T. returns due to excessive bleeding that won’t stop and has an elevated INR. What should be administered?
IV Vitamin K -to promote clotting
H.F. (she/her) is admitted to the hospital with acute liver failure. She has an elevated INR, but is not on any anticoagulant. Why is her INR elevated?
The liver produces the majority of coagulation proteins needed in the blood clotting cascade. Severe liver injury leads to reduced liver synthesis of clotting factors, resulting in a prolonged PT or increased INR.
