Quiz #3 (10/21-10/26)

Question 1

Hemostasis

Answer 1

The ability of the body to control the flow of blood following vascular injury.

1. Vascular constriction: limits the flow of blood to area of injury
2. Platelet aggregation: blood platelets clump when binding to collagen that becomes exposed following rupture of the endothelial lining of vessels. Blood platelets become activated and aggregate at the site of injury. Upon activation, platelets release ADP and TXA2 which activates additional platelets
3. Stable clot formation: to insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug.
4. fibrinolysis: the clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin.

Question 2

Formation of platelets from megakaryocytes

Answer 2

hematopoietic stem cell –> promegakaryoctye –> megakaryocyte –> platelet.

Megakaryocytes are large bone marrow cells with lobulated nucleus that are responsible for the production of thrombocytes or platelets.

Question 3

Clopidogrel (Plavix)

Answer 3

• ADP antagonist

Question 4

Ticlopidine (Ticlid)

Answer 4

• ADP antagonist

Question 5

Prasugrel (Ticagrelor)

Answer 5

• ADP antagonist

Question 6

Dipyridamole (Aggrenox)

Answer 6

• PDE inhibitor/adensoine uptake inhibitor

Question 7

Abciximab (Reopro)

Answer 7

• Platelet surface protein binder

Question 8

Tirofiban (Aggrastat)

Answer 8

• Platelet surface binder

Question 9

Eptifibatide (Integrelin)

Answer 9

• Platelet surface binder

Question 10

Aspirin

Answer 10

• irreversible COX inhibitor

Question 11

Overview of platelet clot formation

Answer 11

1. vessel damage –> platelets activate. Signal through collagen via a GPCR
2. Platelet activation –> platelet adhesion. Platelet activation also stimulates platelet recruitment and more platelets are released to form platelet aggregation.
3. platelet adhesion –> platelet aggregation. And releases ADP, TBxA2, which causes positive feedback on platelet adhesion.
4. Platelet aggregation – > soft clot –> stable clot
5. Second pathway: vessel damage –> coagulation reactions –> thrombin –> fibrin –> soft clot –> stable clot. Thrombin causes positive feedback regulation on platelet adhesion through cAMP and IP3/Ca++
6. What stops the feed forward control: healthy endothelium produces EDRF, PGI2, tPA and heparin that negatively feedbacks on platelet aggregation.

Question 12

Thrombin

Answer 12

Factor IIa. GPCR “tethered ligand” mechanism of thrombin receptor activation.

Receptor is PAR1 (protease activated receptor 1) and is 7 transmembrane GPCR. Thrombin cleaves the N-terminal of the extracellular tail of the receptor. This exposes the “tethered ligand” which can activate the receptor. Signal stops by internalization of the receptor, which is irreversible.

Question 13

Platelet Adhesion/Aggregation factors

Answer 13

1. Broken epithelial cell stimulates collagen.
2. Gp Ia, the platelet receptor for collagen binds to collagen allowing platelets to bind.
3. Gp Ib is the receptor on platelets for the VWF. VWF is the von willebrand factor.
4. Gp IIb-IIIa is an integrin that binds fibrin and is expressed on platelets. Fibrin binds to these receptors.
5. Antagonists to GpIIb/IIIa prevent binding to fibrin and include abciximab (Reopro), Tirofiban (RGD) and Eptifibatide (Integrillin). Eptifibatide is the C-terminal of fibrinogen which will prevent polymerization to fibrin but not binding to fibrin.

Question 14

Arachadonic Acid Pathway

Answer 14

1. Phospholipids produce arachidonic acid through phospholipase A.
2. Arachidonic forms endoperoxides (PGG2 + PGH) through cycloxygenase enzymes COX-1 and COX-2
3. Endoperoxides produce prostaglandins (PGE2), thromboxane and prostacyclin (PGI2).
4. Prostaglandins: cause fever, sensitize nociceptors and increase local blood flow
5. Thromboxane: produced in platelets and leads to increased platelet aggregation
6. Prostacyclin: produced in the endothelial cells and leads to decreased platelet aggregation. Also, sensitizes nociceptors, increases local blood flow.

Question 15

Aspirin

Answer 15

Aspirin is an irreversible inhibitor of COX and inhibits the synthesis of thromboxane and prostacyclin. Note that thromboxane synthesis cannot begin again until the platelets are fully recycled and new COX enzymes are incorporated, because platelets do not have nuclei. However, prostacyclin production can be recovered because endothelial cells have nuclei and can produce new proteins.

Question 16

NSAIDS

Answer 16

Other NSAIDs: non-selective inhibitors of COX-1 and and COX-2 but are reversible and thus do not have the same anti-clotting effects as aspirin.

Question 17

Ticlid and Plavix (Thienopyridines)

Answer 17

ADP receptor antagonists used for prevention of recurrent stroke, DVT and intermittent claudication.

Block the ADP receptor from being activated by ADP thus blocking platelet adhesion.

Covalent and irreversible

Question 18

New ADP receptor antagonists

Answer 18

Prasugrel (Effient): requires enzymatic activation. Noncompetitive antagonist at the P2Y12 purinergic receptor on platelets.

Ticagrelor (Brilinta). reversible allosteric antagonist.

Question 19

Dipyridamole

Answer 19

1. PDE3 inhibitor which inhibits breakdown of cAMP. Probably is more than just a PDE3 inhibitor, and maybe acts on more than just platelets.
2. Intermittent claudication
3. Cilostazol
4. Aggrenox: extended release tablet (tartaric acid) with aspirin added into the middle.

Question 20

common cascade major factors

Answer 20

Factors IXa and VIIa activate factor X to form Xa

Xa: converts prothrombin (II) to thrombin (IIa)

IIa: thrombin, converts fibrinogen to fibrin

XIIIa: converted to active form through trans-glutaminase. Converts soluble fibrin to insoluble fibrin.

Question 21

Indirect effectors of the clotting cascade

Answer 21

warfarin, vitamin K analog. Prevents formation of active prothrombin through inhibition of recycling of the active hydroquinone cofactor

Question 22

Direct effectors of the clotting cascade

Answer 22

New oral anticoagulants, and do not require the cofactor antithrombin III (ATIII).

Dabigatran: inhibits thrombin (IIa)
Rivaroxan: Xarelto, inhibit factor Xa
Apixaban: inhibit factor Xa

Question 23

Heparin

Answer 23

directly affects the clotting cascade

endogenous. Forms a complex with ATIII to quickly inhibit the actions of factors Xa and IIa (thrombin).

LMWHs are more specific toward factor X (aren’t long enough to bridge from ATIII to thrombin) and are the drug of choice. Longer forms of heparin are needed for full inhibition of thrombin (IIa)

Question 24

Lepirudin

Answer 24

recombinant form of hirudin from the leach, that functions as a direct thrombin inhibitor. It was discontinued in May 2012 due to bleeding side effects.

Question 25

Limiting Coagulation

Answer 25

1. Endothelial health: healthy endothelium releases PGI2, EDRF etc that limit coagulation 2. Plasma protease inhibitors: excess ATIII (endothelium makes heparin) for example 3. Protein C/thrombomodulin: Thrombomodulin receptor located in healthy endothelium and when bound by thrombin activates protein C. Two effects of protein C A. Through Protein S it inactivates Va and VIIIa stopping the coagulation cascade B. Inactivates tissue plasminogen activator inhibitor which increases tissue plasminogen activator activity which acts to cause fibrinolytic action.

Question 26

Mechanism of clot removal

Answer 26

t-Pa (tissue plasminogen activator) activates plasminogen to plasmin plasmin in an active protease with catalyzes the stable fibrin clot to change to soluble peptides

Question 27

Fibrinolytic agents

Answer 27

1. Streptokinase (SK): direct binding activator. purified from bacteria. Binds to plasminogen and the complex activates a second plasminogen molecule to plasmin. High incidence of allergic reactions 2. Urokinase (UK): protease. Purified from urine initially, but the recombinant form now available. Proteolytically activates plasminogen directly 3. Tissue plasminogen activator (t-PA): protease. Made by endothelial cells and increases affinity for fibrin-bound plasminogen. Have to treat within 3 hours to show statistically significant mortality reduction.

Question 28

Lipids: Background

Answer 28

high levels of total cholesterol and particularly LDL are associated with increased risk of CAD and death. Interventions include diet, smoking cessation, drugs to reduce plasma cholesterol, control of blood pressure, control of diabetes and regular moderate exercise

Question 29

Chylomicrons

Answer 29

Deliver triglycerides derived from dietary fats to non-hepatic tissues. Mainly composed of lipids. Main apolipoprotein is B-48. Carries triacylglycerols and cholesteryl esters in core

Question 30

Lipids: VLDL

Answer 30

deliver triglycerides derived from liver synthesis to non-hepatic tissues. Mainly composed of lipids. Main apolipoprotein is B-100, which acts as a ligand for the LDL receptor. Also has C and E proteins on its surface...function unknown.

Question 31

Lipids: LDL

Answer 31

Derived from VLDL and delivers cholesterol from liver synthesis to various non-hepatic tissues. Main apolipoprotein is B-100 which acts as a ligand for the LDL receptor

Question 32

Lipids: HDL

Answer 32

collects/scavenges cholesterol from non-hepatic tissues and delivers it to the liver. Different types depending on what ApoA proteins are present on the surface (i.e. ApoAI or ApoAII). Also has a ApoC protein present on the surface which plays a structural role and is a cofactor for lipoprotein lipase which breaks down triglycerides.

Question 33

Lipids: Lp(A)

Answer 33

atherogenic form of lipoprotein, determined by genetics. More disposed to be taken up by foam cells because of a mutated B-100 molecule that doesn't allow binding and internalization into the cell by the LDL receptor.

Question 34

VLDL conversions

Answer 34

VLDL is excreted from the liver and combines with HDL. At this point VLDL is primarily TG content, and B-100 apolipoprotein. As it moves along, it binds to LPL on endothelial cells, this binding releases HDL and lowers the proportion of TG:CE. Subsequent bindings on endothelial cells lowers the ratio of TG:CE until only CE is left which is now called LDL. If B-100 is oxidized it can no longer bind to LDL receptor and is taken up by the SR-B1 scavenger receptor or is added to a plaque.

Question 35

HDL Transport

Answer 35

Selective reuptake pathway. Through LCAT HDL takes up free cholesterol that is released from peripheral tissue. The HDL can either transfer the FC to plasma proteins through CTEP or it is taken up in the liver or steroidogenic tissues by the SR-B1 receptor.

Question 36

HDL goal levels

Answer 36

TC:HDL ratio goal 40. Not all forms of HDL are helpful, may want HDL3.