27- Hemostasis & Clotting Cascade Flashcards
These are also called thrombocytes, and are made of cell fragments from megakaryocytes.
Platelets
What is a normal, bad, and lethal range for Platelets?
Normal = 150,000 - 450,000 ulˆ3 Bad = < 50,000 ulˆ3 Lethal = < 10,000 ulˆ3
Platelets plug small holes via a highly controlled process that includes…
Adhesion
Activation
Aggregation
The regulation of the production of platelets is controlled by ___________, which is a peptide hormone. Its N-terminus is similar to EPO and its C-terminus prolongs half-life (8-12 hrs).
Thrombopoeitin (TPO)
TPO is produced by the ________ and ________ and increases differentiation and maturation rate of hematopoietic stem cells, resulting in more megakaryocytes and platelets. It also may increase platelet function.
Kidney
Liver
TPO binds to ________ receptor, which is found on megakaryocytes and other hematopoietic cells. TPO secretion is controlled by itself and platelets themselves.
c-MPL (CD-110)
If there is a (LOW/HIGH) number of platelets, TPO is bound to the c-MPL receptor and internalized. Then it is degraded in platelets or megakaryocytes. Little TPO is free.
High
If there is a (LOW/HIGH) number of platelets, there is little TPO bound to c-MPL receptor and it is not degraded. High levels of TPO remain free.
Low
Hemostasis is composed of 4 basic steps, which are…
1) Vascular Spasm
2) Formation of platelet plug
3) Formation of blood clot
4) Repair of damage
Describe what Vasospasm does.
Damaged smooth muscle (from an injury) signals around it to constrict. This disrupts blood flow to keep blood above the spasm and avoid further blood loss.
What factors contribute to Vasospasm?
Myogenic Platelet factors (Serotonin, Thromboxane A2) Release of molecules from endothelial cells Neural reflex (not really necessary)
Platelet adhesion occurs on the cell membrane due to what?
Glycoproteins
Phospholipids
Receptors for collagen and laminin
Receptors for released signal molecules
In platelet adhesion, receptors will regulate adhesion when negative charges are exposed, ________ and ________ are exposed at the site of injury.
Collagen
Laminin
Platelets do not adhere to each other or endothelial cells. Adhesion is initiated by activation of platelet receptors such as Glycoprotein Ib/Ia. What are ligands for platelet receptors?
Von Willebrand Factor (vWF) – released from endothelial cells and platelets themselves
Collagen (Gp Ia/IIa), Fibronectin, and Laminin (Gp Ic/IIa) – underneath endothelial layer
In the formation of the platelet plug, the activation of the platelet receptors will in turn activate __________ and cause a ________ influx.
Phospholipase C
Calcium
In the formation of the platelet plug, there is a release of ATP, ADP, ________ and ________ from dense granules. There is also release of growth factors such as vWF, Factor V, and Fibrinogen from alpha granules.
Serotonin
Calcium
Platelets form finger-like filopodia extensions and there is a generation of ___________ from arachidonic acid by cyclooxygenase.
Thromboxane A2
________ is a cyclooxygenase inhibitor that inhibits clotting by reducing release of Thromboxane A2.
Aspirin
__________ (think Plavix), is an anti-platelet agent, that inhibits P2Y12 receptors, blacking further platelet activation and aggregation.
Clopidogrel
The release of ADP (which binds to ________ receptors on platelets), serotonin, and Thromboxane A2 activate additional platelets and promoting aggregation.
P2Y12
For blood clot formation, there is activation of (pro) thrombin activator and that activates _________. There is also generation of ________ as well as its polymerization and contraction of the clot, which requires Calcium.
Thrombin
Fibrin
During the repair of the vessel wall, platelets are still playing a large role. They secrete _________ ________ ________, which stimulates fibroblasts to grow into area and differentiate into smooth muscle, etc.
Platelet-derived Growth Factor
For getting rid of clots, ________ is the major player because it lyses Fibrin and Fibrinogen. Its building block, _________ is made in the liver and plasma protein and must be activated.
Plasmin
Plasminogen
Plasminogen is activated by ________ ________ _________ and is released by damaged tissue.
Tissue Plasminogen Activator (t-PA)
__________ inactivates the inhibitor of t-PA, and plasmin is responsible for the lysis of a clot.
Protein C
Chemicals that limit clotting include ________, which inhibits Thrombin.
Fibrin
This is made by injured endothelial cells and causes vasodilation. It limits platelet aggregation.
Prostacyclin (PGI2)
When bound with Thrombin, this is a coagulant.
Anti-thrombin III
This is derived from mast cells and increases anti-thrombin efficacy.
Heparin
This signal pathway is activated by external trauma and blood escapes from the vascular system. It is quick and involves Factor VII.
Extrinsic Pathway
This signal pathway is activated by trauma inside the vascular system. It is activated by platelets, exposed endothelium, chemicals, or collagen. It is slower and involves Factors XII, XI, IX, and VIII.
Intrinsic Pathway
This signal pathway meets and finishes the pathway of clot production. It involves Factors I, II, V, and X.
Common Pathway
This is the term for when platelets in the blood aggregate at the injury site and form a platelet plug to block the hole.
Primary Hemostasis
This is the term for when a platelet plug is further reinforced by a Fibrin mesh produced through proteolytic coagulation cascade.
Secondary Hemostasis
What is the key difference between Primary and Secondary Hemostasis?
Primary makes a weak platelet plug at the injury sit, while secondary makes it strong by generating a Fibrin mesh on it.
What are the major actions of Thrombin?
1) Converts Prothrombin to Thrombin
2) Activates platelets
3) Converts Factor V to Va (active)
4) Converts Factor VIII to VIIIa (active)
5) Convertes Factor XIII to XIIIa (active – cross links Fibrin)
6) Converts Fibrinogen to Fibrin
There are two types of short acting, oral anticoagulants called Hydroxycoumarins (i.e., Warfarin/Coumadin) and Indanedions. What are their method of action?
Inhibition of the action of Vitamin K
_________, also called _________ can prevent harmful blood clots from forming. Blood clots are formed through a series of Vitamin K-dependent reactions in your liver, and this medication works by decreasing the activity of Vitamin K-dependent Epoxide Reductase. This lengthens the time it takes for a clot to form.
Warfarin (Coumadin)
Vitamin K is not active until reduced from its _______ to ________ form in the liver.
Quinone
Quinol
What are the 2 steps required to activate Vitamin K?
1) Vitamin K 2,3-epoxide Reductase uses reduced NADH as a cofactor to convert Vitamin K 2,3-epoxide to its quinone form
2) Quinone Reductase reduces the quinone form of Vitamin K to the active Vitamin K quinol form
Vitamin K is a cofactor in synthesizing what clotting factors?
Factors II, VII, IX, X
Protein S
Protein C
What step of Vitamin K activation does Warfarin specifically target?
1st step – Vitamin K 2,3-epoxide Reductase
Warfares is a racemic mixture of two active enantiomers, R- and S-forms. _________ is 2-5x more potent than the other in producing an anticoagulant response.
S-Warfarin
These proteins have an important role in regulating anticoagulation. They maintain the permeability of blood vessel walls and proteolytically inactivate Factor Va and Factor VIIIa.
Protein C
Protein S
A genetic ________ deficiency causes a significantly increased risk of venous thrombosis.
Protein C
This disease is a genetic disorder caused by missing or defective Factor VIII.
Hemophilia A
- **Also called Factor VIII Deficiency
- **4 times more common than Hemophilia B
This disease is due to a Factor IX deficiency.
Hemophilia B
***Also called Factor IX Deficiency or Christmas Disease
T/F. Hemophilia A is usually caused by a spontaneous mutation. About 1/3 of cases are passed down from parents to children.
False. Hemophilia A is usually passed down from parents to children. About 1/3 of cases are caused by a spontaneous mutation.
What are the half-lives of the Vitamin K-dependent factors?
Factor II -- 60h Factor VII -- 4-6h Factor IX -- 24h Factor X -- 40-60h Protein C -- 7h Protein S -- Not defined
The ________ ________ test measures the extrinsic coagulation pathway, and evaluates the coagulation Factors I, II, V, VII, and X.
Prothrombin Time (PT)
The ________ ________ ________ test evaluates coagulation Factors XII, XI, IX, VIII, X, V, II (prothrombin), and I, as well as prekallikrein (PK) and high molecular weight kininogen (HK). This test measures the integrity of the intrinsic system and common clotting pathways.
Partial Thromboplastin Time (PTT)
By evaluating the results of the ______ and ______ together, a health practitioner can gain clues as to what bleeding or clotting disorder may be present.
PT
PTT
If the PT result is prolonged and the PTT result is normal, what is the initial think you should think is wrong?
Liver Disease
What is the normal range for PT and PTT?
PT = 12-13 seconds PTT = 30-50 seconds
