Anticoagulant, Antiplatelet and Thrombolytic Drugs

Question 1

describe haemostasis - step 1

Answer 1

arrest of blood loss from damaged vessel;

1. vascular wall damage exposing collagen and tissue factor (TF, thromboplastin)

Question 2

describe haemostasis - step 2

Answer 2

2. primary haemostasis;
   local vasoconstriction
   platelet adhesion to collagen, activation and aggregation (by fibrogen) => soft plug

activated platelets then extend pseudopodia, synthesis and release thromboxane A2 (TXA2)

TXA2 binds to;
platelet GPCR TXA2 receptors causing mediator release and ADP
vascular smooth muscle TXA2 receptor causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors

Question 3

describe haemostasis - step 3

Answer 3

3. activation of blood clotting (coagulation) and the formation of a stable clot (by fibrin enmeshing platelets) => solid clot

this is done via;
ADP binds to platelet GPCR purine receptors that;
act locally to activate further platelets
aggregate platelets into a soft plug act on site of injury, TXA2 acts similarly
expose acidic phospholipids on the platelet surface that initiate coagulation of blood and solid clot formation

Question 4

describe events occurring at the platelet membrane late in the coagulation cascade important in drug action

Answer 4

production of the protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
inactive factor X is converted by tenase to active factor Xa
inactive factor II (prothrombin) is converted by prothrombinase to active factor IIa (thrombin)
fibrinogen is converted by thrombin to fibrin yielding a solid clot

Question 5

describe thrombosis

Answer 5

pathological haemostasis => blood clot 
Virchow's triad;
injury to vessel wall
abnormal blood flow
increased coagulability of blood

Question 6

describe arterial thrombus

Answer 6

white thrombus - mainly platelets in fibrin mesh
forms an embolus if detached from its site of origin, often lodges in an artery in the brain (stroke), or ther organ
primarily treated with antiplatelet drugs

Question 7

describe venous thrombus

Answer 7

red thrombus - white head, jelly like red tail, fibrin rich
if detached, forms an embolus that usually lodges in the lung (PE)
primarily treated with anticoagulants

Question 8

explain the role of vitamin K and warfarin in embolus

Answer 8

Clotting factors II (prothrombin), VII, IX and X are glycoprotein precursors of the active factors IIa (thrombin), VIIa, IXa and Xa that act as serine proteases
Precursors are post-translationally modified to produce the active factors
The carboxylase enzyme that mediates this reaction requires vitamin K in its reduced form as an essential cofactor
warfarin blocks vitamin K reductase

Question 9

describe cautions of warfarin

Answer 9

very difficult to strike balance between anticoagulant effect and haemorrhage - low therapeutic index
use complicated by delay to maximal effect and several medical and environmental influences
effect must be monitored on regular basis
overdose regulated by administration of vitamin K or concentrate of plasma clotting factors

Question 10

describe factors that potentiate warfarin action (hemorrhage increase)

Answer 10

liver disease – decreased clotting factors
high metabolic rate – increased clearance of clotting factors
drug interactions;
agents that inhibit hepatic metabolism of warfarin by CYP2C9 (consult BNF)
drugs that inhibit platelet function (e.g. aspirin, other NSAIDs)
drugs that inhibit reduction, or decrease availability, of vitamin K

Question 11

describe factors that lessen warfarin action (risk of thrombosis increased)

Answer 11

physiological state – pregnancy (increased clotting factor synthesis) – hypothyroidism (decreased degradation of clotting factors)
vitamin K consumption
drug interactions - agents that increase hepatic metabolism of warfarin (consult BNF)

Question 12

describe the role of antithrombin III

Answer 12

inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site in a 1:1
heparin binds to antithrombin III, increasing its affinity for serine protease clotting factors to increase their rate of their inactivation

Question 13

describe heparin and low molecular weight heparin

Answer 13

LMWH inhibit factor Xa but not thrombin (Ila)
heparin administered IV or SC
LMWH SC

heparin - in vitor clotting test is required to determine optimum dosage
elimination of heparin is zero order, whereas high MWH is first order
elimination of LMWH is via renal excretion, hence heparin is preferred in renal failure

Question 14

describe adverse effects of heparin and LMWH

Answer 14

haemorrhage 
rare;
osteoporosis
hypoaldosteronism
hypersensitivity reactions

Question 15

describe orally active inhibotrs

Answer 15

direct inhibitors of thrombin or factor Xa
advantages of;
convenience of administration
predictable degree of anticoagulation, but no specific agent tis available to reduce haemorrhage in overdose which is a major disadvantage

prevents venous thrombosis in patients undergoing hp and knee replacement
both agents can predictably cause bleeding but drugs of this type may be very significant advance upon warfarin which they could eventually replace

Question 16

describe anti-platelet drus

Answer 16

treatment of arterial thrombosis

e. g. aspirin
e. g clopidogrel
e. g. tirofiban

Question 17

describe aspirin

Answer 17

main anti-platelet agent
irreversibly blocks cyclooxygenase in platelets
prevents TXA2 synthesis
blocks cycloxygenase in endothelial cells inhibiting production of anti-thrombotic prostaglandin I2;
balance is shifted in favour of an antithrombotic effect because endothelial cells can synthesise new COX enzyme whereas enucleate platelets cannot. TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)

Used orally, mainly for thromboprophylaxis in patients at high cardiovascular risk
Main adverse effect is gastrointestinal bleeding and ulceration

Question 18

describe clopidogrel

Answer 18

links to P2Y12 receptor by disulphide bond producing irreversible inhibition
used in patients in tolerant to aspirin
oral administration

Question 19

describe tirofiban

Answer 19

Given IV in short term treatment to prevent myocardial infarction in high risk patients with unstable angina (with aspirin and heparin)

Question 20

describe the role of plasminogen and fibrinolytic drugs

Answer 20

fibrinolytic cascade exists endogenously which opposes the coagulation cascade (PP)
Fibrinolytics are used principally to reopen occluded arteries in acute myocardial infarction (M.I.), or stroke – less frequently life-threatening venous thrombosis or pulmonary embolism
Administered IV within as short a period as possible of the event
Percutaneous coronary intervention (PCI) is superior if available promptly
Have an additive beneficial effect with aspirin

Question 21

describe streoptokinase

Answer 21

Not an enzyme, but a protein extracted from cultures of streptococci
Reduces mortality in acute M.I. (given IV, or intracoronary) but action blocked after 4 days by the generation of antibodies. Further doses not to be given after this time
May cause allergic reactions (not be given to patients with recent streptococcal infections)

Question 22

describe alteplase and duteplase

Answer 22

Are recombinant tissue plasminogen activator (rt-PA)
Are more effective on fibrin bound plasminogen than plasma plasminogen and show selectivity for clots
Do not cause allergic reactions
Short half life, hence given by IV infusion
The major adverse effect of fibrinolytics is haemorrhage that may be controlled by oral tranexamic acid which inhibits plasminogen activation