Block C - Anti platelet drugs

Question 1

how are plateletes formed ?

Answer 1

Come from a lineage of cells that are stimulated from a progenitor cell , if there is an increase in platelets there will be an increase in thrombopoietin

Question 2

what controls formation ?

Answer 2

This is a glycoprotein hormone produced by the liver and kidney which regulates the production of platelets. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that bud off the megakaryocyte and a large number of platelets are produced.

Question 3

lineage ?

Answer 3

haemocytoblast->

myeloid stem cell->

megakaryoblast->

promegakaryocyte->

megakaryocyte-> (large multi-lobed nucleus)

platelets (anucleated parts of megakaryocyte cytoplasm

Question 4

electron scanning micrograph reveal ?

Answer 4

This shows an electron scanning micrograph picture of blood cells, the RBC can be caught up in clots that form. The dots are platelets and fibres are from the mesh network formed due to activated platelets and clotting factors ultimately to due fibrinogen becoming fibrin which caches RBC to stop blood egressing from tissues.

Question 5

thrombopoeitin ?

Answer 5

Thrombopoietin is a hormone that regulates platelet production.

Question 6

life span of platelets ?

Answer 6

Lifespan approximately 7-10 days which is much less than red blood cells.

Question 7

place of formation ?

Answer 7

Place of formation is the red bone marrow

Question 8

physiological properties ?

Answer 8

Adhesion is the ability to stick to the foreign and damaged surface by engaging with cell surface receptors called epitopes. Aggregation is the ability to form a clump (cork). Agglutination is pasting of one thrombocyte to another, like glue.

Question 9

aspirin ?

Answer 9

An antiplatelet drug is what stops a platelet becoming activated for example, aspirin, which is a COX inhibitor.

Question 10

anti coagulant ?

Answer 10

An anticoagulant drug does not have a direct effect on platelets , instead they have an effect on clotting factors.

Question 11

vascular spasm ?

Answer 11

stop blood flow - vascular spasms by thromboxane (vasoconstriction at injured site)

Question 12

plug ?

Answer 12

Platelets form a plug formation by thromboxane (plugging the hole)

Question 13

coagulation ?

Answer 13

coagulation (blood clotting - complex mechanism)

Question 14

fibrin ?

Answer 14

Fibrin clot formation

Question 15

how does vascular endothelium inhibit blood clotting ?

Answer 15

Vascular endothelium will inhibit blood clotting, it releases nitric oxide and prostacyclin’s to reduce aggregation and adhesion of platelets. The surface is not conducive to clot formation. It displays membrane proteins that inhibit clotting such as heparin like molecules. Furthermore, they store von Willebrand factor granules. These are constitutively expressed and secreted into circulation or sub-endothelium. (20% made by platelets, rest endothelium). It acts as a bridging molecule at sites of vascular injury for normal platelet adhesion, and under high shear conditions, it promotes platelet aggregation

Question 16

vascular contraction ?

Answer 16

First response to vascular injury is vasoconstriction, this compression of vessel occurs to prevent escaping blood , injury “chemicals” released by injured cells and reflexes from adjacent pain receptors.

Question 17

formation of platelet plug ?

Answer 17

Platelets attach to damaged vessel wall to plug it; the platelets produce thromboxane A2 and serotonin/ histamine release enhances vascular contraction. Adenosine di phosphate (ADP) from platelets attracts and stimulates more platelets at site ,a. Cascade.

. A sharply cut vessel (clean cut with sharp razor) undergoes less spasm, i.e., bleeds longer, than a tore vessel

Question 18

prostaclyclin ?

Answer 18

Prostacyclin opposes this and inhibits aggregation and platelet activation at other sites

Question 19

platelete plug formation ?

Answer 19

Primary haemostasis, platelets aggregate to control blood loss from capillaries, arterioles, and venules. If damage is small, platelet plug can arrest bleeding completely by closing minute ruptures in vessels that occur hundreds of times a day. Exposure to collagen and other foreign substances (antigen-antibody complexes, thrombin, proteolytic enzymes, endotoxins, and viruses), platelets undergo dynamic change in appearance and begin the process of adhesion and activation. In adhesion, platelets swell, become sticky and adhere to collagen fibril on the basement membrane , this requires von Willebrand factor (vWF) adhere to collagen fibrils on the basement membrane . Activated platelets release granules containing vWF, factor V, PDGF, heparin-neutralizing protein, and ADP to attract other platelets.

Question 20

clotting factors ?

Answer 20

Clotting factors are released from platelets and injured tissue to activate platelets

Question 21

plasma proteins ?

Answer 21

Plasma proteins are synthesised in the liver and circulating in inactive forms

Question 22

central event to coagulation ?

Answer 22

Central events to coagulation are the conversion of prothrombin to thrombin and fibrinogen to fibrin which then goes on to form the mesh network.

Question 23

intrinsic coagulation pathway ?

Answer 23

intrinsic – all components are present in the blood and involved in the clotting cascade

Question 24

extrinsic coagulation pathway ?

Answer 24

Extrinsic – at least one component from tissue: injury response , need “tissue factor” (TF) for direct activation of VIIa (12a), TF and factor VIIa contact only after injury when tissue is damaged. TF-factor VIIa complex also activates factor Xia ( 11a).

Question 25

when is pathway activated ?

Answer 25

Pathway activated due to a damaged surface, this could be due to turbulent blood flow (intrinsic) or due to extrinsic cut with tissue factor.

Platelet cells activated by damage, PF3 and/or Tissue Factor produced by platelet cells, also Factor X (10) is activated. Prothrombin activator (enzyme) is produced this cuases prothrombin conversion to thrombin (another enzyme). Thrombin stimulates: fibrinogen which leads to the fibrin mesh.

Question 26

intrinsic pathway ?

Answer 26

More pro-coagulants needed and uses all the factors, (I-XIII) toward PF3 and Factor X. Allows more “scrutiny” before clotting occurs

Question 27

extrinsic pathway full ?

Answer 27

Tissue thromboplastin (Tissue Factor) is formed and skips intrinsic steps straight to PF3 and Factor X. This allows rapid response to bleeding out of vessel (clot can form in 10 to 15 seconds).

Question 28

common pathway ?

Answer 28

Factor X, PF3 (thromboplastin), Factor V, Ca++ –> prothrombin activator -> prothrombin converted -> thrombin (active enzyme) - thrombin stimulates: fibrinogen -> fibrin (meshwork) and Ca++ & thrombin -> Factor XIII (fibrin stabilizer).

Question 29

what does a decrease in blood coagulation or increase in fibrinolysis cause ?

Answer 29

A decrease in blood coagulation and/or increase in fibrinolysis RESULT IN BLEEDING

Question 30

increase in blood coagulation and decrease in fibrinolysis ?

Answer 30

An increase in blood coagulation and/or decrease in fibrinolysis RESULT IN THROMBOSIS, thromboembolism, syndrome of disseminated intravascular coagulation (DIC).

Question 31

drugs promoting haemostasis ?

Answer 31

. Drugs promoting haemostasis

  1. Pro-coagulants 
  2. Fibrinolysis inhibitors 
  3. Heparin antagonist

Question 32

drugs preventing clot formation ?

Answer 32

Drugs preventing clot formation

  1. Anticoagulants 
  2. Antiplatelet drugs

Question 33

Plasmin ?

Answer 33

Plasmin is produced in an inactive form, plasminogen, in the liver. Blue arrows denote stimulation, and red arrows inhibition. Plasmin activity is also reduced by thrombin-activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make it more resistant to the tPA-mediated plasminogen. Plasmin will break up fibrin mesh into fibrin degradation products.

Question 34

direct acting anti coagulants ?

Answer 34

Direct acting

• Heparins (Heparin, LMW heparins: Enoxaparin, Fraxiparine, Dalteparin sodium) - interfere with any of the vitamin K dependent clotting factors – clinically used
• factor Xa inhibitors (Rivaroxaban, Apixaban) - clinically used
• thrombin inhibitors (Lepirudin, Desirudin, Bivalirudin) - not used clinically

Question 35

indirect acting coagulants ?

Answer 35

2. Indirect acting

Coumarins (Warfarin)

Question 36

heparism mechanism of action ?

Answer 36

Major anticoagulant effect by inactivating thrombin and activated factor X (factor Xa) through an antithrombin (AT)-dependent mechanism. The activated AT then inactivates thrombin and factor Xa

Question 37

heparin antagonist ?

Answer 37

If too much heparin has been administered then Protamine sulfate can be given. Mechanism of action/Effect: Protamine is a strongly basic substance that combines with the strongly acidic heparin to form a stable (salt) complex. The protamine-heparin complex has no anticoagulant activity.

Question 38

Xa and IIa (thrombin) inhibitors ?

Answer 38

Parenteral drug administration means any non-oral means of administration, but is generally interpreted as relating to injecting directly into the body, bypassing the skin and mucous membranes. Fondaparinux and Low molecular weight (LMW) heparin can be given to inhibit factor 10a. Oral administration includes rivaroxaban and apixaban which also affect factor 10a in the clotting cascade.

Oral administration of dabigatran block the fibrinogen conversion to fibrin.

Question 39

Warfarin mechanism of action ?

Answer 39

Inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. it inactivates these factors and has a negative effect on the clotting process.

Question 40

Forms of warfarin ?

Answer 40

There are 2 isoforms of warfarin, an s and an R form. The S form of warfarin is 3 to 6 times more potent than the R form.

Question 41

indirect acting anticoagulants ?

Answer 41

These drugs are vitamin K antagonists!

Indirect-acting anticoagulants have no influence on coagulation factors directly in the blood. They supress the biosynthesis of coagulation proteins (Factor VII and prothrombin) in the liver as a result of antagonism with vitamin K there is a decrease in blood coagulation , an increase in fibrinolysis and a decrease in lipids concentration in blood.

Question 42

can warfarin be used in pregnancy ?

Answer 42

Warfarin is contraindicated with pregnancy as it crosses the placental barrier and is teratogenic in the first trimester & and induce intracranial hemorrhage in the baby during delivery

Question 43

what is warfarin metabolised by ?

Answer 43

Warfarin is metabolized by hepatic Cytochrome P450 enzymes with half-life of 40 hrs.

Question 44

drugs that decrease platelet aggregation

Answer 44

COX-inhibitors- Acetylsalicylic acid (aspirin)

Inhibitors of phosphodiesterase -Dipyridamole

Inhibitors of ADP-mediated aggregation

Ticlopidine

Clopidogrel

Question 45

aspirin ?

Answer 45

Aspirin blocks synthesis of thromboxane A2 by inhibiting COX1

Question 46

Dipyridamole ?

Answer 46

Dipyridamole increases cAMP concentrations in the platelets that supresses clotting associated TXA2

Question 47

Clopidogrel and ticlopidine ?

Answer 47

Clopidogrel and ticlopidine blocks ADP receptors in the platelet membrane.