Unit 05: Thromboembolic Disease

Question 2

What are thombembolic diseases?

Answer 2

• encompasses two interrelated conditions from similar pathologies
• involves thrombus (formation of a blood clot) and emboli formation (detached travelling intravascular mass

*thrombeombolism = blood clot that pbstructs a blood vessel and later beomes disloged and migrates in the body

Question 3

what is the difference between a red and white thrombus

Answer 3

red = fibrin rich, containing a large number of RBCs and typically occurs in venous vessels

• White = platelet rich and usually found in arterial vessels

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Question 4

descirbe the pathogenesis of thrombosis

Answer 4

• requires the presence of various prothrombic factors
• can be released due to local vessel injury, circulatory stasis or altered blood coagulability - namely hyperactivity of hemostatic mechanisms (hypercoagulability) or hyperactivity of fibrinolytic mechansims

Question 5

what are the main classes of drugs for treatment of thromboembolic disease

Answer 5

anticoagulants, antithrombotic drugs and fibrinolytic drugs

Question 6

what are systemic anticoagulants?

Answer 6

• ideally should prevent pathologic thrombosis, limit reperfusion injury, allow for a normal response to vascular injury and limit bleeding

Question 7

what is Heparin

Answer 7

• mixture of sulfonated mucopolysaccharides (or glycosaminoglycans = long unbrached polysaccharides)
• widely used anticoagulant
• isolated from mast cells in bovine lung or procine GI mucosa - usually stored in secretory granules

Question 8

how does heparin work?

Answer 8

• enhances or accelerates (approx 100x fold) the action of antithrombin III (AT-III) which forms a heparin AT III complex
• AT III inhibits activated clotting factors, especially thrombin (IIa) and factor Xa by means fo irreversible binding

Question 9

onset of action of heparin and averse effects

Answer 9

heparin has rapid onset - usefula cute anticoagulant

• oral version usually taken concurrently

*keparin will only prevent new thrombus formation will not lyse an eisiting thrombus

• adverse effects = increase bleeding tendencies and possible thrombocytopenia

Question 10

what can be ued for overdose from heparin

Answer 10

protamine sulfate

Question 11

how should patients taking haparin be monitored?

Answer 11

• activated partial thromboplastin time (aPTT)
• measures the anticoagulant effect

Question 12

what is heparin used to treat?

Answer 12

• primarily for initial treatment of thrombosis and thromboemolic disease

can also be used for venous thrombosis, pulmonary embolism, unstable angina, atrial fibrillation, acute myocardial infarction and various cardiovascular surgeries

Question 13

what is enoxaparin

Answer 13

aka lovenox

• low mol weight heparin that is fractioned from standard unfractionated heparin
• anticoagulant no used more commonly due to advantages over unfractionated heparin
• fewer bleeding tendencies, less risk of thrombocytopenia and imporved pharmacokinetics like longer 1/2 life

Question 14

what is warfarin

Answer 14

aka coumadin

• oral anticoagulant (injectible formulas also available
• antagonises the actions of vitamkin K to reduce clotting factors (II, VII, IX and X)
• used as chronic preventative anticoagulant therapy
• dosing usually begins w/ heparin administration

Question 15

how are indiivduals on warfarin monitored?

Answer 15

• using international normalized ratio (INR) as opposed to a PTT (used for those on heparin)
• tests for patients prothombin (PT) measured over average PT for the lab

Question 16

what toxicities are associated with warfarin

Answer 16

• bleeding tendencies which cna be combated with vitamin K1
• series bleeding however requires fresh blood and plasma transfusion

*warfarin crosses the placenta therefore it should nto be taken during pregnancy- heparin does not cross so should be taken instead

Question 17

what are antithombotic drugs

Answer 17

target platelet activators -> reduce formation of blood clots

• can act on platelt membrane or produced within granules and act on the membrane once they are released
• can also be produced and act within platelet itself

Question 18

what is collagen

Answer 18

• antithrombotic drug
• agents outside of the platelet that act on the platelet membrane

Question 19

what is thrombin

Answer 19

• antithrombotic drug
• agents outside of the platelet that act on the platelet membrane

Question 20

what is ADP, 5-HT and Tx A2

Answer 20

produced within the granules and act on the platelet membrane once they are released

Question 21

what are cyclooxygenase cAMP, cGMP and calcium ions used for

Answer 21

antithrombotic drugs

-produced in the platelet and act within the platelet itself

Question 22

what is aspirin

Answer 22

cyclooxygenase inhibitor

• coomonly used as an antiplatelet drug
• irreversibly binds and acetylates cyclooxygenase-1 which prevents TxA2 production in platelets and reduces platelet aggregation
• *other NSAIDs can also inhibits cyclooxygenase-1 but are not irrevesible and therefore have a shorter duration of action
• prevents thrombus formation as re-thrombosis formation which can contribute to myocardial infarcts, stroke and peripheral vascular disease

Question 23

adverse effects of aspirin

Answer 23

gastrointestinal ulceration, renal damage and bleeding tendencies

Question 24

what is clopidogrel

Answer 24

• ADP inhibitor to treat thrombosis
• reduced paltelet aggregation by inhibiting ADP pathways
• act as P2Y12 (found on surface ofpaltelets) receptor antagonists and prevent bindign of ADP to receptors
• actions might also be synergistic with aspirin as they work through different mechanisms of aciton

*prodrug needs to be acivated by CYP 250

*ADP inhibits are indicated to reudce or prevent the recurrence of strokes, myocardial infracts in affetced individuals

*considered safe

Question 25

what is ticlopidine

Answer 25

aka ticlid

• ADP inhibitor to treat thrombosis
• reduced paltelet aggregation by inhibiting ADP pathways
• act as P2Y12 (found on surface ofpaltelets) receptor antagonists and prevent bindign of ADP to receptors
• actions might also be synergistic with aspirin as they work through different mechanisms of aciton

*prodrug needs to be acivated by CYP 250

*ADP inhibits are indicated to reudce or prevent the recurrence of strokes, myocardial infracts in affetced individuals

*considered safe

Question 26

what is glycoprotein IIb/IIa

Answer 26

• platlet surface integrin receptor for fibrinogen and von willebran factor
• PLA2 (activated by TxA2) and platelet glycoprotein VI (GPVI: activated by collagen)
• subsequently activate this integrin receptor which binds and anchors paltelets to each other via fibrinogen and to exposed vessel matric via con vollebran factor
• inhibtsi the receptor so used as antithrombotic drug

Question 27

what is Abciximab

Answer 27

aka ReoPro

• Glycoprotein Iib/Iia receptor antagonist that acts as platelet aggregation inhibitro
• Indicated in percuraneous angioplasty that is associated with coronary thrombosis
• Similar to toher antithrombotic drugs the major toxicity = bleeding tendencies

Question 28

what are fibrinolytic drugs

Answer 28

rapidly lyse thrombi by activating plasmin from plasminogen

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Question 29

what is tissue plasminogen activator

Answer 29

aka t-PA (Alteplase)

• serine protease invovled in the breakdown of a clot
• bidns fibrin and preferentially activates clot-bound plasminogen and limits activation of systemic plasmin
• T-PA has fairly short half-life which necessitates delivery via constant infusion
• can be used to treat coronary thrombosis in actue mycardial infraction, deep venous thrombosis, stroke and pulmonar embolism
• toxicites are also bleeding tendencies