9C Hemostasis
Which pathway is revealed to be the most important pathway to coagulation? Extrinsic, intrinsic, or common pathway?
Extrinsic pathway is how coagulation cascade is activated compared to intrinsic and common pathways
What degrades Fibrin? How is the degradation of fibrin modulated? How is the degradation of fibrin inactivated (decrease in coagulation)?
Fibrin is degraded by Plasmin Plasmin is created by the activation of plasminogen Plasminogen is converted to Plasmin by Plasminogen activators (t-PA, and u-PA) Plasminogen activators are turned off by PAI-1 (Plasmin activator inhibitor) this decreases coagulation Turning off Plasmin by alpha2-antiplasmin
What are fibrin split products?
Fibrin split products - when fibrin is broken down and can be measured using D-Dimer Clots are in the process of breaking down which create these fibrin split products
Which are the Vitamin K - dependent factors?
Factors 2, 7, 9, 10 (Factors II, VII, IX, X) require vitamin K
Why are PT and PTT assessed together? What if both PT and PTT are prolonged?
PT and PTT together are good to assess a patient's coagulation If both are prolonged, theres something wrong with the common pathway
Describe the steps of the Prothrombin Time test. What part of the coagulation cascade does this reflect?
PT: Prothrombin Time Take blood from patient Add Citrate, remove cells and extract plasma Add Thromboplastin and Calcium Take the time for clot to form Reflects the extrinsic pathway (Factor 7, 10)
Describe the steps of the Partial Thromboplastin Time test. What part of the coagulation cascade does this reflect?
PTT: Partial Thromboplastin Time Take blood from patient Add Citrate, removes cells and extract plasma Add Cephalin and Kaolin, and Calcium Take the time it takes to form a clot Reflects the intrinsic pathway (Factor 12, 11, 9, 8, 10)
Which factors use Vitamin K to undergo carboxylation on the carboxyl group to create two carboxyl groups? Why does this occur?
Precursor factors 2, 7, 9, 10 use vitamin K and undergoes carboxylation on the carboxyl residue to create a double negative charge, to make it more efficient to bind Calcium. This enhances the ability to bind a factor to make it procoagulant.
What substances activate Factor XII of the intrinsic pathway?
Prekallikrein, high-molecular-weight kininogen, Ca2+,
What do serine proteases do?
Serine proteases - break down proteins, active site has a Serine, they activate and digest proteins, cleave to activate proteins
How is the coagulation cascade shut down? 1) Tissue Factor Pathway Inhibitor shuts down _____ and _______ 2) Antithrombin shuts down _____ and _____ 3) Activated Protein C shuts down ______ and ______. Activated Protein C is a product of ________________ and ________________ catalyzed by _________________.
Shutting down the coagulation cascade: Tissue Factor Pathway Inhibitor (TFPI) shuts down Factor 7 (FVIIa), and Factor 10 (FXa) on the extrinsic pathway Antithrombin shuts down Factor 10 (FXa) and Factor 2 (Thrombin) (FIIa) Activated Protein C shuts down Factor 8 (FVIIIa) and Factor 5 (FVa). Activated Protein C is a product of Protein C and Thrombomodulin catalyzed by Protein S.
What is the most important thing that Thrombin (FIIa) converts? What four other substances does Thrombin activate?
Thrombin (FIIa) converts Fibrinogen (FI) --> Fibrin (FIa) Thrombin also helps activate: Factor 13 (FXIII--> FXIIIa) Thrombomodulin Factor 8 (FVIII-->FVIIIa) Factor 5 (FV-->FVa)
After Fibrin (Factor 1) is made, what needs to be done? What does this?
After Fibrin is made, it needs to be crosslinked - Transglutaminase (Factor XIII)
How can Vitamin K be reduced in persons taking antibiotics?
Beta-Lactam antibiotics are broad-spectrum antibiotics that can knock out Vitamin K-producing bacteria (normal gut flora) - leading to bleeding disorder that prolongs both PT and PTT
What are the cofactors of the clotting cascade? What do they do?
Cofactors Factors 5 and 8 (factors V and VIII) localize reaction of clotting
What is Disseminated Intravascular Coagulation (DIC)? How does this present in lab findings?
Disseminated Intravascular Coagulation (DIC) - the formation of microclots throughout the body which uses a lot of the clotting factors and platelets. This presents as lab values having: -low platelets -prolonged PT PTT -lower coagulation factors
What is Factor V Leiden?
Factor 5 Leiden thrombophilia is a genetic disorder affecting blood clotting where Factor 5 Leiden is a variant form of Factor 5 that causes an increase in blood clotting (hypercoagulability). The Leiden variant can not be inactivated by the anticoagulant protein - Activated Protein C, so coagulation is favored. Factor 5 Leiden is the most common hereditary hypercoagulability disorder among ethnic Europeans.
Factor ____ deficiency is on the ___ chromosome and is called ___________________ Mom is carrier - sons get it Factor ____ deficiency is also on ___ chromosome and has the same inheritance pattern, clinical presentation, indistinguishable from Factor ____ deficiency
Factor VIII deficiency is on X chromosome and is called Hemophilia A Factor IX deficiency is also on X chromosome and has the same inheritance pattern, clinical presentation, indistinguishable from Factor VIII deficiency
What happens when Factor XIII is activated?
Factor XIII is activated, then it converts Fibrin --> crosslinked Fibrin
How do you treat extreme bleeding via reintroduction of coagulation factors?
Give fresh frozen plasma in cases of extreme bleeding. The FFP has coagulation factors.
What is important to know about the half lives of clotting factors?
Half lives of factors are different - when trying to coagulate a patient, it will be difficult because the half-lives of different factors are not the same.
Deep tissue bleeding into muscles and joints, rebleeding after surgical procedures
Hemophilia A
How does Heparin work? What does it work on?
Heparin works by increasing the action of Antithrombin, increases the affinity of Antithrombin for Factor 10 (FXa) and Factor 2 (Thrombin) (FIIa)
What is an INR?
INR = International Normalized Ratio INR allows for standardization
If both PT and PTT are prolonged, what two effects could this represent?
If both PT and PTT are both prolonged, there may be two defects, or two defective clotting factors involved, or deficiency in Vitamin K Vitamin K is needed to activate Factors 2,7 9, 10 (Factors II, VII, IX, X)
Explain the first step of the extrinsic pathway involving the initiator factor, Ca2+, and Factor VII which result in the activation of Factor X. How else can Factor VII (extrinsic pathway) activate Factor X?
Initiator molecule: Factor III, Ca2+ and Factor VII --> complexes into a complex Activator VII complex --> activates Factor X on the phospholipid... can also do this indirectly through Factor IX pathway Activator VII complex can also activate Factor IV --> Factor IV creates its own complex with Factor VIII, Ca2+, and phospholipid ---> activates Factor X on the phospholipid Phospholipid = platelet surface
Where in the body are coagulation proteins made?
Most coagulation proteins are made in liver.
Once Factor 10 is activated, what does it complex with? What does this complex do? How does Vitamin K affect Factor II?
Now with activated Factor X, you create another complex: Activated Factor X complexes with Activated Factor V, along with Ca2+, and phospholipid --> converts Prothrombin (factor II) to Thrombin (factor IIa) Vitamin K is important for Prothrombin (factor II) through the carboxylase reaction
What factor is the substrate (product) of the clotting cascade? What is the initiator of the clotting cascade called? Name the six serine proteases of the clotting cascade Name the two cofactors of the clotting cascade Name the Transglutaminase of the clotting cascade
Substrate - Fibrinogen/Fibrin (factor I) Initiator - Tissue factor (factor III) Serine proteases - 2,7,9,11,12 (factors II, VII, IX, X, XI, XII) Cofactors - Factors V and VIII Transglutaminase - Factors XIII
What does Thrombomodulin do? How is Thrombomodulin activated? How does Thombomodulin work? What Factors does Thrombomodulin ultimately work on?
Thrombomodulin modulates the action of Thrombin Thrombin binds to Thrombomodulin. Thrombomodulin binds with Protein C, catalyzed by Protein S, creates Activated Protein C. Activated Protein C shuts down FVa and FVIIIa (cofactors)
Why does Tissue Factor (Factor III) cause the initiation of clotting?
Tissue factor (factor III) usually does not exist in blood - causes initiation of clotting. Factor III is usually in tissues.
How does Warfarin work to decrease coagulation?
Warfarin is a drug that blocks the recycling of Vitamin K in the liver. Reduced Vitamin K interferes with the carboxylation of precursor FIX to procoagulant FIX
PT and PTT are both normal = still a coagulation effect?
Yes PT and PTT do not assess Factor XIII (crosslinking) PT and PTT only look at forming a clot.
