Thrombosis→ Flashcards
Definition of Thrombosis
Blood Clot in the Blood Vessel
→ decreased Blood Flow
→decreased Blood Supply to Organs and Peripheral Tissues
leading to Angina, Myocardial Infarction
Stroke
Pulmonary Embolus
Deep Vein Thrombosis
Formation of Thrombin
Activated clotting factors acts on prothrombin → thrombin (also acts on platelets ) which acts on soluble fibrinogen →insoluble fibrin and form thrombus with platelets
Drugs Used in Coagulation Disorders
Antiplatelet Drugs
- decreased activation/aggregation of platelet s
Anticoagulants [Blood Thinners]
-decreased formation of fibrin
Fibrinolytic Agents
- increased degradation of fibrin
Platelet Reaction
PGi2 from endothelial cells (inhibit) and TXA,ADP and 5-HT from platelets lead to adhesion of platelets → activation of platelet → aggregation of platelet
Mechanism, Effect and Adverse effect of Aspirin
Mechanism of Action
- irreversibly inhibits the activity of c yclooxygenase
→ decreased synthesis of thromboxane A 2 (TXA 2 by the platelets
→ decreased platelet aggregation
Very Potent as an Antiplatelet Drug
→ low doses are needed
Adverse Effects
gastrointestinal disturbances and risk of gastric damage in chronic users
[→ haemorrhage and ulceration]
→contraindicated in patients with gastric ulcer
prolonged bleeding
- due to inhibition of prostaglandins production in the gastrointestinal tract
decreased gastric mucus secretion and increased gastric acid secretion
- due to inhibition of thromboxane A 2 production in the platelets
Name, Mechanism, Effect and Adverse effect of ADP Receptor Inhibitors
clopidogrel , ticlopidine and ticagrelor
Mechanism of Action
- block adenosine diphosphate (ADP) receptors on platelets
→inhibit ADP pathway in platelets
→→inhibit the expression of fibrinogen receptors
→→→prevent linkage of platelets by fibrinogen
→→→→decreased platelet aggregation
Can be Used in Patients Who Cannot Tolerate Aspirin
Adverse Effects
- gastrointestinal disturbances
- haemorrhage
- thrombotic thrombocytopenic purpura→ monitor platelet count
- leukopenia → monitor white blood cell count
thrombotic thrombocytopenia purpura and leukopenia → rare with clopidogrel
→→ clopidogrel preferred over ticlopidine
Name, Mechanism, Effect and Adverse effect of Glycoprotein
IIb IIIa Inhibitors
e.g. abciximab , eptifibatide
Mechanism of Action
-block glycoprotein IIb IIIa (receptors for fibrinogen) in platelets
→inhibit linkage of adjacent platelets by fibrinogen
→→decreased platelet aggregation
•Used Intravenously for Short Term Treatment
Adverse Effects
- bleeding
- thrombocytopenia
Name, Mechanism, Characteristics and Adverse effect of Thrombin Receptor Antagonists
vorapaxar
Mechanism of Action
-binds to the proteinase-activation receptor 1 (PAR1;
thrombin receptors) in platelets
→→ compete with and prevent the activation of the receptor
by the “tethered ligand” (which is exposed following
the cleavage of the extracellular domain by thrombin)
→ decreased platelet activation and aggregation
Characteristics
-metabolized by hepatic cytochrome enzymes CYP3A4 and CYP2J2 → drug interactions
Adverse Effects
- bleeding →contraindicated in patients with a history of stroke, transient ischemic attack, or intracranial
haemorrhage
Mechanism and effect of Dipyridamole
mechanisms of actions
-inhibits adenosine uptake into cells
→adenosine remains in extracellular
space to activate A 2 receptors
-inhibits phosphodiesterase
→ decreased breakdown of cyclic nucleotides
- both increases cAMP level→ decreased platelet aggregation
- vasodilatoin
Limited therapeutic usage
-ineffective on its own
used in combination with aspirin or warfarin
Mechanism and effect of Cilostazol
mechanism of actions
- inhibits phosphodiesterase → increased cAMP level
→→decresed platelet aggregation
→→vasodilation
Limited therapeutic usage
- used primarily to treat intermittent claudication
Coagulation Process
Non-functional Prothrombin
→ functional prothrombin by (reduced form of vitamin K to the oxidized form of vitamin K)
Non-functional clotting factors
→functional clotting factors (by reduced form of vitamin K to oxidized form of vitamin K)
→→Activated clotting factors
→→→form with functional prothrombin to thrombin
Effects of Anticoagulant Drugs
Increased Inactivation of Clotting Factors
- indirect thrombin inhibitors
- direct thrombin inhibitors
- oral direct factor Xa inhibitors
Decreased Formation of Functional Clotting Factors
-vitamin K antagonists
Mechanism, Characteristics of Vitamin K Antagonists
e.g. warfarin
Mechanism of Action - inhibit the action of vitamin K epoxide reductase →inhibit conversion of inactive vitamin K epoxide (oxidized form) to active hydroquinone form (reduced form) →→ decreased formation of functional clotting factors/prothrombin →→→ decreased thrombin formation
Characteristics
- oral anticoagulant
- protein bound → long half life in plasma
- metabolized by hepatic mixed P 450 enzymes →interaction with food and drugs
- delayed onset of action [by 8 12 hours the time required for the degradation of the clotting
factors]
- onset time can be reduced by using large initial doses
- narrow therapeutic index
Adverse effect and complication of Vitamin K Antagonists
e.g. warfarin
haemorrhage
→this risk can be reduced by
→→starting with a low dose and with careful dose adjustment
over a week [because of late onset of anticoagulant action of warfarin]
→→monitoring anticoagulant effect by Prothrombin
time (PT) ratio International
normalized ratio (INR)
- reversed by stopping warfarin therapy and/or administration
of vitamin K 1 ( fresh frozen plasma or
prothrombin
complex concentrates
-birth defects [because warfarin readily cross the placenta]
→avoided in pregnancy
-skin necrosis (rare) characterized by thrombosis of microvasculature
Complications
- anticoagulant actions affected by
- genetic variation
- concurrent diseases
- drug interactions
Name , mechanism, characteristics of Indirect Thrombin Inhibitors
e.g. heparin
Mechanism of Action -bind to antithrombin →increased the activity of antithrombin →→ increased the rate of inactivation of clotting factors IIa (thrombin) IXa and Xa →→→ decreased formation of fibrin
Characteristics
only for intravenous or subcutaneous administration
→because they are large and charged molecules
→→cannot be absorbed from the stomach
drugs for anticoagulation during pregnancy
- because they do not cross the placenta
- because their use are not associated with fetal malformations
Heparin and Its Derivatives (I)
Unfractionated Heparin (UFH) molecular weight range 5000 30000 Da -repeating sulfated disaccharide units of D glucosamine L-iduronic acid and D- glucosamine-D-glucuronic acid
High Molecular Weight (HMW) Fractions
- long chain with molecular weight 5400 Da (at least 18
saccharide units)
→ simultaneously bind to antithrombin and thrombin
- high affinity for antithrombin
Unpredictable pharmacokinetics →bind to plasma proteins →degraded mainly by reticuloendothelial system →→need to monitor plasma levels
Name of Heparin and Its Derivatives (II)
Low Molecular Weight (LMW) Fractions
eg enoxaparin, dalteparin tinzaparin
- mean molecular weight 5000 Da 17 saccharide units)
- less effective than UFH in inactivating thrombin
-equal anticoagulant efficacy as UFH
Synthetic Form e g fondaparinux
- pentasaccharide molecule
- high affinity for antithrombin
- not effective in inactivating thrombin
advantages over UFH →decreased binding to plasma proteins →increased bioavailability →decreased drug resistance long biological half life →decreased dosing frequency
mainly renal clearance →predictable pharmacokinetics decreased need to monitor plasma levels] contraindicated in patients with renal impairment
Adverse Effects of Heparin and Its Derivatives
Haemorrhage
risk reduced by
- careful patient selection [contraindicated in patients with active bleeding, haemophilia or active
hepatic disease cautious in high risk patients such as elderly women and patients with renal failure]
- careful control of dosage with close monitoring by
- activated partial thromboplastin time aPTT or PTT 2 3 x normal value)
- protamine titration
- anti Xa activity
reversed by stopping heparin therapy and/or intravenous
administration of the heparin antagonist, protamine sulfate
[fondaparinux effect cannot be reversed by protamine]
Adverse Effects of Heparin and Its Derivatives
Allergic Response to Heparin of Animal Origin
Increased Loss of Hair and Reversible Alopecia
Thrombocytopenia
→ thrombosis in severe case (→ monitor the platelet counts
- treated by stopping heparin therapy or by administration of a direct thrombin inhibitor
Mechanism of Direct Thrombin Inhibitors (I)
Mechanism of Action
directly bind to the active site of thrombin
→inhibit its effects
anticoagulant action is independent of antithrombin
→inactivate fibrin bound thrombin in thrombi
Name. Type and characteristics of Direct Thrombin Inhibitors (II)
Parenteral Direct Thrombin Inhibitors
Hirudin, Lepirudin
- bivalent inhibitor of thrombin
- bind at both active and substrate recognition sites of thrombin
- usage needs to be closely monitored by aPTT
- excreted by kidneys → cautious in patients with renal insufficiency
Bivalirudin
bivalent inhibitor of thrombin that also inhibits platelet activation
useful in percutaneous coronary angioplasty
Argatroban
small molecule binding only at thrombin active site eg argatroban
clearance depended on liver function → cautious in patients with liver diseases
Name. Type and characteristics of Direct Thrombin Inhibitors (III)
Oral Direct Thrombin Inhibitors e.g dabigatran
-competitively and reversibly blocks the active site of free and
clot bound thrombin
Advantages over parenteral anticoagulant drugs and warfarin
-predictable pharmacokinetics and bioavailability
→ allow for fixed dosing
→ decreased need for routine monitoring
- rapid onset
- no interaction with P 450 interacting drugs
-renal clearance
→dosage reduction is required in patients with severe renal impairment
- adverse effect bleeding
→→can be reversed by idarucizumab a humanized monoclonal antibody fragment that binds to dabigatran
Name, Mechanism of Action, advantages, Adverse effect, and Precautions of Oral Direct Factor
Xa Inhibitors
e.g. rivaroxaban , apixaban
Mechanism of Action
-directly bind to free and clot bound factor Xa
→inhibit conversion of prothrombin to thrombin
Advantages
- fixed dosage no need for monitoring
- rapid onset of action
Adverse Effects
- risk of bleeding
- can be reversed by andexanet alfa, a recombinant analogue of factor Xa
Precautions
- prolonged action in elderly patients or patients with renal impairment
- interact with drugs that inhibit or induce P-glycoprotein or CYP3A4
Mechanism of Fibrinolysis
Plasminogen to Plasmin
- act on fibrinogen to fibrinogen degradation process
- act on insoluble fibrin to fibrin degradation products
Name, Mechanism of Action, Adverse effect, Therapeutic use of Fibrinolytic Drugs
e.g. streptokinase, urokinase , alteplase , tenecteplase
Mechanism of Action
increased formation of plasmin from plasminogen
→increased degradation of insoluble fibrin
[drugs with selectivity on fibrin bound plasminogen e.g alteplase, tenecteplase
→→confine fibrinolysis to the formed thrombus (“clot selective”)
Intravenous or Intra Arterial Administration
Therapeutic Use
- acute myocardial infarction → reopen occluded coronary artery
- multiple pulmonary emboli, central deep venous thrombosis
Adverse Effects
- bleeding → gastrointestinal haemorrhage stroke]
- reversed by administration of antifibrinolytic agent aminocaproic acid, fresh
frozen plasma or coagulation factors
→→contraindicated in patients with internal bleeding, peptic ulcer, pregnancy and concurrent use of
anticoagulants
Name Effect and Adverse effect of Drugs Used in Bleeding Disorders
Vitamin K 1 ( Phytonadione)[essential for the formation of bioactive clotting factors]
- for treatment of excess warfarin or vitamin K deficiency
Plasma Fractions Concentrated with Clotting (Coagulation) Factors
- treated with heat and/or extracted with solvents and detergents
→ decreased risk of the transmission of viral diseases eg hepatitis B, hepatitis C and HIV
[risk of other transmissible diseases such as prions→ recombinant clotting factor preparations preferred]
- for treatment of clotting factor deficiency e g haemophilia
Fibrinolytic Inhibitors (Antifibrinolytic Drugs)
- bind to plasminogen and plasmin → block their interaction with fibrin
eg aminocaproic acid, tranexamic acid
- for treatment of conditions of bleeding or risk of bleeding
eg adjunct therapy in haemophilia, prevention of bleeding from intracranial aneurysms
- excreted by kidneys → dose reductions in patients with renal impairment
Adverse effects
- intravascular thrombosis
- hypotension, myopathy, abdominal discomfort
