Term
| What is the more technical term for the blood clot that prevents hemorrhage? |
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Definition
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Term
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Definition
| Blood clot, especially one that can lead to complication |
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Term
| Define endothelial cells and their basic role in coagulation |
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Definition
| Endothelial cells line the interior of blood vessels; when these cells are intact, inhibits coagulation, enhances clot digestion, and inactivates
platelets. |
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Term
| Define subendothelial cells and their basic role in coagulation |
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Definition
Subendothelial cells are normally not exposed to blood until injury.
When exposed by injury, platelets adhere to subendothelial cells. |
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Term
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Definition
| Platelets are small vestigial cells formed by budding from megakaryocytes in healthy bone marrow. |
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Term
| How do platelets become activated? |
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Definition
| Normally circulate in an inactive form until they bind to subendothelial cells. Upon binding, platelets activate and bind clotting factors on their phospholipid surface. |
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Term
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Definition
Soluble plasma proteins that are made in the healthy liver that circulate in inactive form.
Examples- prothrombin, fibrinogen |
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Term
| What is the function of fibrin? |
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Definition
| To aggregate platelets into a plug and glue the wound together |
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Term
| Define von Willebrand factor |
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Definition
The factor that allows a platelet receptor to recognize collagen of subendothelial cells
(Deficiency= von Willebrand disease) |
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Term
| What is the role of phosphatidyl serine in blood clotting? |
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Definition
| In a platelet cell membrane, it flip-flops to the outer surface and is essential for localizing clotting factors |
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Term
| List the steps of blot clotting, starting with clot initiation |
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Definition
1. Tissue factor (from exposed cells) turns on thrombin
2. Thrombin activates fibrin
3. Transglutaminase crosslinks fibrin
4. Clot retracts by contracting thrombosthenin |
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Term
| What is the smooth muscle protein that contracts a clot? |
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Definition
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Term
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Definition
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Term
| What allows prothrombin to bind to the activated platelet surface? |
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Definition
The addition of gamma-carboxyglutamate residues (Vitamin K-cofactor dependent carboxylation of glutamate in the liver) to prothrombin
This can bind the Ca2+ on the phosphatidylserine lipid on the activated platelet |
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Term
| What can lead to a vitamin K deficiency (and trouble blood clotting)? |
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Definition
Antibiotic treatments (gut flora make K)
A diet lacking green vegetables/eggs |
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Term
| How does prothrombin get converted to thrombin? |
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Definition
On the platelet surface, factor Xa, a serine protease, cleaves prothrombin in 2 places
Active thrombin falls off platelet (lipid binding domain cut off) and gets enmeshed in fibrinogen/fibrin network. |
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Term
| What molecules inhibit thrombin when thrombin goes too far from the clot site? |
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Definition
| Antithrombin III and heparin |
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Term
| What Factors can thrombin activate? |
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Definition
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Term
| What are the two ways to make active factor X? |
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Definition
1. Extrinsic pathway— needs tissue factor (main clot initiator)
2. Intrinsic pathway— needs negative charged surface (supportive) |
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Term
| What is the function of factor X |
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Definition
| To cleave prothrombin in two places |
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Term
| List the steps of the extrinsic pathway to form Factor X |
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Definition
| Factor VII and a subendothelial membrane protein tissue factor combine to form a complex that activates X |
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Term
What happens if the extrinsic pathway to form Factor X is lost?
What happens if the intrinsic pathway to form Factor X is lost? |
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Definition
Loss of extrinsic- death
Loss of intrinsic- hemophilia (hemorrhages, especially in tissue-factor poor areas like joints and muscles) |
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Term
| List the steps of the intrinsic pathway to form Factor X |
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Definition
1. XII binds to negative cell surface
2. XII activates kallikrein, kinogen, and XI complexes by cleavage
3. XI cleaves IX
4. IX cleaves X
(12, 11, 9, 10) |
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Term
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Definition
| Loss of factor VIII, which stimulates IX 100,000-fold to cleave X |
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Term
| Where is initiation of the coagulation cascade? Where are the final steps? |
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Definition
The initiation of the coagulation cascade is due to components of exposed subendothelial cells.
The final steps are on the lipid surface of activated platelets. |
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Term
| Describe the structure of fibrinogen |
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Definition
3 domains: DED, connected by flexible triple chain rods
Very soluble |
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Term
| List the steps of how fibrinogen domains form a clot |
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Definition
1. Platelets bind D domain and form crosslinks
2. Thrombin cleaves A and B to expose E, which activates with D domains of other fibrin molecules
3. Staggered polymerization
4. Thrombin activates transglutaminase, which forms bridges between D/D and D/E domains |
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Term
| List the steps to trim/remove a clot |
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Definition
1. Tissue plasminogen activator activates plasmin
2. Plasmin cleaves fibrin rods between D/E
3. Antiplasmin in plasma inhibits any plasmin released from the clot |
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Term
| What drugs can be given within the first hour of a heart attack to reduce the size of a clot? |
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Definition
tPA (tissue plasminogen activator)
Or streptokinase and urokinase (but these do not localize plasmin production) |
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Term
| What is the function of thrombomodulin |
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Definition
To change thrombin's proteolytic specificity so now thrombin activates protein C
Activated protein C and S degrade factors V and VIII of the clotting cascade |
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Term
| What is the function of thromboxane? |
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Definition
| To produce prostaglandin I2 that inhibits platelet activation |
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Term
| List four molecules secreted by healthy cell surfaces that prevent clotting |
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Definition
| Antithrombin III, heparin, thrombomodulin, and thromboxane |
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Term
| List possible Protein C mutations |
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Definition
1. Missense mutation of Ser270Pro that alters the ability for conformational change
2. 5 base deletion at the exon VI/intron f boundary that generates an inactive protein
Both lead to venous thrombi |
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Term
| What happens if Protein S is mutated? |
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Definition
A defective protein S will "poison" good Protein C
(about 50% of victims have venous thrombi) |
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Term
| What happens if Factor V or Factor VIII is mutated? |
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Definition
| They will be resistant to protein C and will not be inactivated, causing venous thrombi |
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Term
| List three defects that will cause venous thrombi |
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Definition
1. Protein C mutations
2. Mutant factor V or VIII
3. Mutant Protein S |
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Term
| List four types of drugs that combat clotting |
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Definition
1. Thrombolytics (ex. tPA)
2. Heparin
3. Vitamin K antagonists (ex. coumarin)
4. Aspirin |
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Term
| When using tPA (or urokinase/streptokinase) what should you have on hand? |
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Definition
| Platelets and factor VIII |
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Term
| What is disseminated intravascular coagulation? |
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Definition
| A clot that results from infection, drug complications, or acquired disease. Heparin can be used to treat DIC. |
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Term
| What is the function of heparin? |
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Definition
| The negatively charged polysaccharide brings Antithrombin III and Thrombin together |
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Term
| What is the antidote to heparin? |
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Definition
| Protamine sulfate (side effect of bloating) |
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Term
| Describe the effects of coumarin |
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Definition
Slow acting vitamin K depleters
MUST watch blood levels with vigilance, dehydration an issue |
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Term
What drug would be used for venous thrombi?
What drug would be used for arterial thrombi? |
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Definition
Venous- vitamin K antagonists
Arterial- Aspirin |
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Term
| Describe the effects of aspirin |
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Definition
Inhibits cyclooxygenase (platelets make thromboxane A2 to recruit other platelets)
Also will inhibit healthy endothelial cells from making prostaglandin I2, but these cells can regenerate (platelets can't) |
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Term
| What is "Economy Class Syndrome" |
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Definition
Sitting too long causes blood to pool in legs, which can lead to thrombophlebitis
When moving again, the embolus might dislodge and go to a critical area, leading to pulmonary embolism or stroke |
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Term
| What drug can increase clotting? What is its mechanism? |
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Definition
A competitive plasmin inhibitor, ε-aminocaproic acid (Amicar)
Inhibits plasmin, slowing down fibrin digestion
Particularly helpful in dental and neurosurgery, but extreme caution must be used |
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