Podcast
Questions and Answers
Which of the following mechanisms prevents inappropriate primary hemostasis?
Which of the following mechanisms prevents inappropriate primary hemostasis?
- Inhibition of antithrombin III by heparin sulfate
- Secretion of nitric oxide and prostacyclin by endothelial cells (correct)
- Decreased expression of thrombomodulin on endothelial cells
- Increased production of thromboxane A2 by endothelial cells
What is the role of Factor XIIIa in the context of the intrinsic pathway?
What is the role of Factor XIIIa in the context of the intrinsic pathway?
- Initiating the cascade by binding to collagen
- Cross-linking fibrin to stabilize the clot (correct)
- Inhibiting the activation of Factor XII
- Activating Factor X to Factor Xa
Which of the following is the first factor to join the intrinsic cascade?
Which of the following is the first factor to join the intrinsic cascade?
- Factor XI
- Factor VIII
- Factor XII (correct)
- Factor IX
What is the function of von Willebrand factor (vWF) in secondary hemostasis?
What is the function of von Willebrand factor (vWF) in secondary hemostasis?
Which of the following is the result of Factor IXa interacting with Factor VIII and Platelet Factor 3 (PF3) in the intrinsic pathway?
Which of the following is the result of Factor IXa interacting with Factor VIII and Platelet Factor 3 (PF3) in the intrinsic pathway?
What is the role of Factor Xa in the conversion of fibrinogen to fibrin?
What is the role of Factor Xa in the conversion of fibrinogen to fibrin?
In the extrinsic pathway, what is the role of tissue factor (TF)?
In the extrinsic pathway, what is the role of tissue factor (TF)?
What is the role of Vitamin K in the coagulation cascade?
What is the role of Vitamin K in the coagulation cascade?
Which of the following best describes the common pathway in the coagulation cascade?
Which of the following best describes the common pathway in the coagulation cascade?
What is the significance of the prothrombinase complex in the common pathway?
What is the significance of the prothrombinase complex in the common pathway?
What role does calcium play in the coagulation cascade?
What role does calcium play in the coagulation cascade?
Which of the following is a function of thrombin?
Which of the following is a function of thrombin?
Why is Vitamin K important for coagulation?
Why is Vitamin K important for coagulation?
What are the three conditions that can make individuals susceptible to Vitamin K deficiency?
What are the three conditions that can make individuals susceptible to Vitamin K deficiency?
Which of the following is a direct thrombin inhibitor?
Which of the following is a direct thrombin inhibitor?
What role do Proteins C and S play in coagulation?
What role do Proteins C and S play in coagulation?
What happens when thrombin interacts with thrombomodulin in coagulation?
What happens when thrombin interacts with thrombomodulin in coagulation?
Which of the following is a defining characteristic of the extrinsic pathway of coagulation?
Which of the following is a defining characteristic of the extrinsic pathway of coagulation?
How does the body regulate clot formation to prevent it from becoming too extensive?
How does the body regulate clot formation to prevent it from becoming too extensive?
Deficiencies in Proteins C or S can cause which of the following?
Deficiencies in Proteins C or S can cause which of the following?
What is the role of heparin sulfate in preventing inappropriate blood clotting?
What is the role of heparin sulfate in preventing inappropriate blood clotting?
Which of the factors are vitamin k dependent serine proteases?
Which of the factors are vitamin k dependent serine proteases?
What needs to happen in order for vitamin K epoxide to keep working?
What needs to happen in order for vitamin K epoxide to keep working?
What clotting factors need Ca2+ cofactor in order to function?
What clotting factors need Ca2+ cofactor in order to function?
How are the intrinsic and extrinsic pathways linked?
How are the intrinsic and extrinsic pathways linked?
At which point does antiocoagulation occur?
At which point does antiocoagulation occur?
What is the function of Fibrinolysis?
What is the function of Fibrinolysis?
What is the definition of Factor XIII?
What is the definition of Factor XIII?
What happens to individuals who are deficient in FXIII?
What happens to individuals who are deficient in FXIII?
Flashcards
What is fibrinogen?
What is fibrinogen?
A plasma protein that is converted into fibrin by thrombin to form a stable clot.
What is Factor XIIIa?
What is Factor XIIIa?
A transamidase that crosslinks fibrin molecules to stabilize the clot.
What is the Common Pathway?
What is the Common Pathway?
The final steps in the coagulation cascade, leading to clot formation.
What are Factors Xa and IIa?
What are Factors Xa and IIa?
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What is Heparin Sulfate?
What is Heparin Sulfate?
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What is Thrombomodulin?
What is Thrombomodulin?
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What happens if you are deficient in FXIII?
What happens if you are deficient in FXIII?
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What is von Willebrand's factor (vWF)?
What is von Willebrand's factor (vWF)?
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What is Factor XIIa?
What is Factor XIIa?
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Why is has Calcium (Ca2+) needed in secondary hemostasis?
Why is has Calcium (Ca2+) needed in secondary hemostasis?
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What does Thrombin (Factor IIa) do?
What does Thrombin (Factor IIa) do?
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Why is the Extrinsic pathway extrinsic?
Why is the Extrinsic pathway extrinsic?
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Why is Calcium so vital?
Why is Calcium so vital?
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What are some facts about vitamin K?
What are some facts about vitamin K?
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What happens during absence of Vitamin K?
What happens during absence of Vitamin K?
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What does Vitamin K epoxide reductase do?
What does Vitamin K epoxide reductase do?
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What happens if there is no gamma (y)-carboxylation?
What happens if there is no gamma (y)-carboxylation?
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What is Proteins C?
What is Proteins C?
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When does anticoagulation happen?
When does anticoagulation happen?
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When does Clot retraction and Fibrinolysis?
When does Clot retraction and Fibrinolysis?
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Study Notes
Learning Objectives
- Fibrinogen is converted to fibrin by thrombin (Factor II)
- Factor XIIIa is a transamidase fibrin stabilizing factor
- The common pathway consists of the final steps in the coagulation cascade
- Vitamin K-dependent serine proteases Factors Xa and IIa must be described
Prevention of Inappropriate Primary Hemostasis
- Endothelial cells secrete nitric oxide (NO), a vasodilator, and prostacyclin (PGI2) which inhibits platelet aggregation
- Heparin Sulfate activates anti-thrombin 3 (AT III), which inactivates factors II, IX, and X and acts as an anti-coagulant
- Thrombomodulin binds thrombin (Factor II) on endothelial cells, activating Protein C, which inhibits Factors V and VIII
- Protein C stops coagulation
Secondary Hemostasis: Intrinsic Pathway
- Clotting factors are present within the blood
- Negatively charged surfaces such as activated platelets, collagen, or glass trigger it
- The liver constantly produces coagulation factors (zymogens)
- Factor XII is the first factor to join the intrinsic cascade
- Damaged cells produce von Willebrand's factor (vWF) to bind platelets and promote platelet plug formation
- Platelets also bind fibrinogen via GpIIb/IIIa
Intrinsic Pathway Cascade of Activation
- Factor XIIa activates Factor XI becoming XIa
- Factor XIa activates Factor IX becoming IXa
- Factor IXa interacts with Factor VIII and Platelet Factor 3 (PF3) and this complex needs Ca2+
- The complex activates Factor X to Xa
Thrombin Conversion of Fibrinogen to Fibrin
- Factor Xa cleaves Factor V to Factor Va, then interacts with Va and Ca2+ to form the prothrombin activator
- Factor II (prothrombin) gets activated into thrombin (Factor IIa)
- Thrombin (Factor IIa) activates fibrinogen to fibrin
- Factor XIII (fibrin stabilizing factor) crosslinks fibrins resulting in a stronger mesh
Secondary Hemostasis: Extrinsic Pathway
- The extrinsic pathway requires tissue factor, which is outside of the blood
- The extrinsic pathway is shorter and faster than the intrinsic pathway and can form a clot in ~15 seconds
- Exposure of blood to a factor found in tissues underneath the damaged endothelium (tissue factor or TF) triggers the pathway. TF is also called Factor III
- Factor VII is exposed to TF and gets activated to Factor VIIa
- Factor VIIa binds to TF and Ca2+ which forms a VIIa-TF-Ca2+ complex at the smooth muscle
- The VIIa-TF-Ca2+ complex cleaves Factor X to Factor Xa
Conversion of Fibrinogen to Fibrin and Factor XIII to Factor XIIIa
- Prothrombinase complex cleaves prothrombin (Factor II) into thrombin (or Factor IIa)
- This is the step that gets amplified
- Thrombin activates platelets and cleaves fibrinogen (Factor I, which is soluble in blood) into fibrin (Factor Ia, which is insoluble)
- Thrombin activates Factor XIII into XIIIa and 3 cofactors, Factor V of the common pathway, and Factors VIII and IX of the intrinsic pathway
- Factor XIIIa binds Ca2+ and forms crosslinks between the fibrin chains, further reinforcing the fibrin mesh
- Fibrin makes the liquid plasma become gel-like and traps formed elements
Fibrin Cross-linking Actions of Factor XIIIa
- Factor XIIIa results in the formation of a stable fibrin clot that withstands mechanical and enzymatic breakdown
- Patients deficient in FXIIIa form an initial fibrin clot, but the clot dissolves causing hemorrhage
Common Pathway
- Once Factor X is activated to Xa, the intrinsic and extrinsic pathways merge
- Factor X (Stuart-Prower factor) joins Factor Va (plus Ca2+) to form the Prothrombinase complex
- The prothrombinase complex can activate thousands of thrombin (F II) in the amplification step
- Thrombin can activate platelets and cleave fibrinogen
- Factor XIIIa stabilizes the mesh
- Factors II, VII, VIII, IX, X, XI and XIII need Ca2+ cofactor
Common Pathway Activation
- Factor X is activated by the intrinsic pathway through the Tenase Complex (VIIIa-IXa-Ca2+)
- It is activated by the extrinsic pathway through the (TF-VIIa-Ca2+) complex
- Both pathways lead to Xa-Va-Ca2+ prothrombinase complex
- The prothrombinase complex cleaves prothrombin (FII) to generate thrombin (FIIa)
- Amplification happens as thrombin activates proteins of intrinsic and common pathway
- The process releases more vWF and causes platelet activation resulting in "positive feed back"
Clot Formation
- The Intrinsic Pathway:
- Is activated by factors present in blood
- Starts with Factor XII (Hageman factor)
- Can be measured via the Partial thromboplastin time (PTT) and the normal range is between 25 and 40 seconds
- The Extrinsic Pathway:
- Is activated by muscle cell damage
- Starts with tissue factor (TF) and Factor VII
- Can be measured via the Prothrombin Time (PT) and the normal range is between 9.5 and 13 seconds
Clot formation regulation
- Anticoagulation happens during primary and secondary hemostasis, regulating clot formation
- Prevents clots from getting too big (embolus)
- The most important part of this regulation happens after production of thrombin
- Clot retraction and fibrinolysis happen after primary and secondary hemostasis reducing clot size
Calcium and Coagulation
- Ca2+ is vital for coagulation and is a component of:
- TF-FVIIa- Ca2+ complex
- Tenase complex, FVIIIa-FIXa- Ca2+
- Prothrombinase complex FXa-FVa- Ca2+
- Individual factors II, VII, IX and X (vitamin K-dependent factors) need Ca2+ as a cofactor for their activation
- Coagulation is facilitated by platelet granular release of Ca2+ and is markedly impaired in hypocalcemia
Blood clotting factors
- Most are plasma proteins synthesized in the liver
- Factor IV is calcium ions
- Vitamin K is required for synthesis of factors II, VII, IX, and X
Vitamin K-Dependent Serine Proteases, Factors Xa and IIa
- Vitamin K is a fat-soluble vitamin important for blood clot formation and bone health
- It must be ingested and metabolized in order to create mature coagulation factors
- It is used in the production of Factors II, VII, IX and X, particularly from green-leaf vegetables
- It is also synthesized by intestinal bacteria and is stable in air but decomposes in sunlight
- Absence of vitamin K leads to uncontrolled bleeding
- The ingested form of vitamin K is vitamin K quinone, which gets reduced by NADPH to vitamin K hydroquinone and acts as a cofactor to gamma-glutamyl carboxylase which converts Factors II, VII, IX and X into their functional forms
Role of Vitamin K
- Glutamate carboxylase mediates carboxylation using oxygen, carbon dioxide, water, and protons to produce ɣ-carboxyglutamate
- The extra carboxyl group allows the protein to bind calcium, helping blood clotting proteins remain at the injury site
- Vitamin K is a cofactor for glutamate carboxylase
Recycling of Vitamin K
- Carboxylation oxidizes (inactivates) vitamin K
- Inactive form of vitamin K, vitamin K Epoxide, needs to get reduced by Vitamin K epoxide reductase
- Vitamin K epoxide reductase reduces vitamin K epoxide back to vitamin K Quinone which regenerates active Vitamin K
Vitamin K Recycling Inhibition and Resulting Deficiencies
- Vitamin K epoxide reductase can be inhibited by blood thinners like warfarin or coumadin (rat poison)
- Vitamin K deficiencies lead to disordered coagulation from lack of function of Factors II, VII, IX and X, blocking both intrinsic and extrinsic pathways
- Gamma (γ)-carboxylation is important since Factors that are not carboxylated cannot bind to activating Ca2+ ions or phospholipid membranes
- Susceptibility to Vitamin K deficiency can be caused by Malabsorption (cystic fibrosis, celiac disease), broad-spectrum antibiotics or being a premature neonate
Anticoagulants
- Prothrombin time (PT) is important when using anti-coagulants and include drugs like:
- Heparins (anti-thrombin)
- Vitamin K Antagonists
- Direct Oral Anticoagulants (DOACs)
- Direct Thrombin Inhibitors
- Factor Xa Inhibitors
Hemostasis Drug Therapies
- Antiplatelets
- Anticoagulants
- Thrombolytics
- Herbal Supplements
Proteins C and S
- Protein C and S work together to prevent excessive blood clotting
- Not enough protein C or S causes increased clotting
- Protein C is a serine protease that destroys activated cofactors Va and VIIIa
- It is activated when thrombin binds to thrombomodulin (at the surface of endothelial cells)
- Protein S is a cofactor for Protein C
- Both proteins C and S are vitamin K-dependent
- Undamaged cells ensure coagulation is limited to the injured site
Deficiencies of Proteins C and S
- Not enough protein C or S may cause more clotting than needed
- Clinical relevance: hereditary or acquired deficiencies can cause thrombosis/clotting events
- Such as in deep vein thrombosis
- Treatment with warfarin can decrease protein C activity
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