Hemostasis and Thrombosis Flashcards
Anti-platelet (aggregates) vs. Anti-coagulants
Anti-aggregates –> stop platelet activity, act on the primary stage of hemostasis
Anti-coagulants –> stop coagulation cascade, act on the secondary stage of hemostasis
Stages of Hemostasis
- Primary (2-5min): bleeding time, platelet count increases, anti-platelet drugs
- Secondary (8-15min): clotting time, APTT, PT, fibrinogen
- Tertiary (90-240min): fibrinolysis
Hemostasis steps
- Injury
- Vessel wall + platelets
- Activation of plasma coagulation factors
- Formation of stable fibrin clot
- Dissolution of fibrin clot
Pulmonary embolism treatment
Massive thrombus –> fibrinolytic drugs is necessary to restore normal circulation
Smaller thrombus –> anti-coagulants are necessary
Arterial vs. Venous thrombus
Arterial –> more platelets, less fibrin –> white thrombus made of thrombocytes
-use anti-aggregates
Venous –> more fibrin, less platelets –> red thrombus
First choice for Acute MI
Anti-aggregates
Anti-platelet drugs
-classes and names
- Cyclooxygenase inhibitors (COX1) – Aspirin
- ADP receptors inhibitors – Clopidogrel, Prasugrel, Ticagrelor
- Glycoprotein IIB/IIa receptor antagonists – Abciximab
ASPIRIN
- mechanism of action
- adverse effects
- COX-1 inhibitor
- IRREVERSIBLY blocks platelet
- rapidly hydrolyzed
- anti-platelet effect lasts 8-10 days
-ulcers, hepatotoxicity, asthma, rashes, renal toxicity, GI bleeding
How does thromboxane affects platelets?
Arachidonic acid (inside platelets) –> thromboxane by the action of COX
-Stimulate activation of new platelets and promote their activation
DIPYRIDAMOLE (4)
-mechanism of action
- “double effect”
- vasodilator - adenosine is inhibited
- inhibits adenosine and decreases phosphodiesterase activity = increase cAMP and cGMP
- increased cAMP levels –> decrease calcium levels –> inhibit platelet activation
ADP RECEPTOR INHIBITORS
- names
- mechanism of action
- unwanted effect
-Clopidogrel, Prasugrel, Ticagrelor
- IRREVERSIBLY block ADP receptor on platelets
- duration 7-10 days
- Clopidogrel requires activation via cytochrome P450 enzyme isoform CYP2C19
-risk of bleeding
Why is Clopidogrel usually the drug of choice?
- cheaper
- main problem: resistance
Glycoprotein IIB/IIa receptor antagonists
- name
- mechanism of action
- side effect
-Abciximab
- inhibits the final common pathway for platelet aggregation - prevents fibrinogen from binding to platelet, disrupting the cross-link
- monoclonal Ab directed against the IIb/IIIa complex
- given for a short period of time
- irreversible inhibition
- intravenous
- use in high risk patients
-bleeding
Anti-platelet drugs indications (5)
- Acute coronary syndrome
- High risk of MI
- Coronary artery bypass grafting, angioplasty or stenting
- Cerebral ischemi atack
- Arterial fibrillation
Anti-coagulants
-classes and names
- Indirect thrombin inhibitors – Heparin, Low-molecular weight Heparin (Nadroparin)
- Direct thrombin inhibitors – Dabigatran
- Oral direct Xa inhibitors – Apixaban, Rivaroxaban
- Warfarin
HEPARIN (unfractionated heparin)
- mechanism of action
- pharmacokinetics
- unwanted effects
- bind to anti-thrombin III and accelerates the inactivation of factor Xa and thrombin
- heparin molecule need to be long enough to binf both anti-thrombin and thrombin
- intravenous (immediate action) or subcutaneous
- hepatic clearance
-bleeding, osteoporosis, thrombosis, heparin-induced thrombocytopenia (HIT)
Low-molecular weight Heparin
- name
- mechanism of action
- pharmacokinetics
- Nadroparin
- more selectively increases degradation of factor Xa, less effect on thrombin
- intravenous or subcutaneous
- renal clearance
- no need to do blood tests because response is predictable
HEPARIN (unfractionated heparin)
- contraindications
- reverse action - which drug?
- HIT, hemophilia, active bleeding, thrombocytopenia, severe hypertension, intracranial hemorrhage, ulcers
- PROTAMINE
PROTAMINE (2)
- positive charged peptide combines with negative charged heparin and forms an inactive stable complex to avoid anti-coagulant activity
- mainly active against unfractionated heparin
Advantages of Low-molecular weight Heparin over Unfractionated Heparin (9)
- have equal efficacy
- higher bio-availability (for subcutaneous form too)
- less frequent dosing requirements
- decreased “heparin” resistance
- no need for laboratory monitoring
- longer 1/2 life - renal clearance is slower than hepatic
- less inhibition of platelet function - less bleeding risk
- smaller risk of osteoporosis - long term use
- less interaction with platelet factor 4 = less risk of thrombocytopenia and thrombosis
Why is monitoring of Unfractionated Heparin necessary?
Because it could bind to platelet factor 4 –> form a complex –> IgG is produced –> causes lysis of platelets
Indirect thrombin inhibitors
- names
- indications
-Heparin, Low-molecular weight Heparin (Nadroparin)
- thrombus prophylaxis
- deep vein thrombosis
- pulmonary embolism
- acute coronary syndrome
- arterial fibrillation
- clotting in extracorporeal circulation
- thrombosis of prosthetic heart valves
Direct thrombin inhibitors
- name
- mechanism of action
- Dabigatran
- inhibits thrombin preventing the conversion of fibrinogen to fibrin = increases clotting time
Advantage of Direct thrombin inhibitors over indirect thrombin inhibitors (4)
- better supression of thrombus growth
- retain activity in presence of platelet-rich thrombi
- predictable response - do not bind plasma proteins
- no risk of HIT - do not bind to platelet factor 4
Direct thrombin inhibitors
- name
- pharmacokinetics
- indications
-Dabigatran
- orally
- 1/2 life - 12h
- renal clearance
-thrombus prophylaxis, arterial fibrillation, HIT, acute coronary syndrome
Oral direct Xa inhibitors
- names
- mechanism of action
- pharmacokinetics
- indications
- Apixaban, Rivaroxaban
- bind to the active site of factor Xa preventing it from converting pro-thrombin to thrombin
- renal clearance
- thrombus prophylaxis, arterial fibrillation, deep vein thrombosis, pulmonary embolism
Oral direct Xa inhibitors
- advantages
- disadvantages
- predictable response, low interactions, rapid onset and offset, short 1/2 life, no need for monitoring, wide therapeutic window, no dietary restriction
- lack of antidote, high cost, not enough experience
WARFARIN
-mechanism of action
-block the y-carboxylation of several glutamate residues of factors II, VII, IX and X as well as the endogenous anti-coagulant protein C and S
- 8-12h delay in the action
- immediate effect of warfarin is to deplete the pro-coagulant factor VII and anti-coagulant protein C, this creates a hypercoagulable state due to first the depletion of protein C.
Warfarin and Vitamin K interaction
-prevents reductive metabolism of the inactive vitamin K epoxide back to its active form
- therefore, it will inhibit the synthesis of active clotting factors because vit. K is necessary for it.
- some clotting factors are inactive until they are carboxylated by vit. K
WARFARIN
-pharmacokinetics (7)
- 100% oral bio-availability
- small volume of distribution
- long 1/2 life - about 40h
- bound to plasma albumin
- effects starts after 12-16h and lasts 4-5 days
- hepatic clearance
- narrow therapeutic window
WARFARIN
- antidote
- unwanted effects
- contraindications
- vitamin K.
- hemorrhage, teratogenic, hepatotoxicity, necrosis of soft tissues
- high bleeding risk
- pregnancy
- not possible to do testing
WARFARIN
- advantages
- disadvantages
- high bio-availability, they have an antidote, long clinical experience, not expensive, can use in all group ages
- unpredictable pharmacokinetics, great drug-drug interactions (narrow therapeutic window), dietary restriction, slow onset and offset, long 1/2 life, skin necrosis if started without LMWH
WARFARIN
-indications (7)
- thrombus prophylaxis and treatment
- pulmonary embolism
- arterial fibrillation
- recurrent coronary syndromes
- recurrent stroke and transitory ischemic attack
- clotting in extracorporeal circulation
- prosthetic and rheumatic heart valves
Fibrinolytic Drugs (only intravenous use) -classes and names
- Non-fibrin specific agents – Streptokinase
* Fibrin – specific agents – Alteplase
The fibrinolytic system
Urokinase - converts plasminogen to active plasmin
Plasmin - it cannot be used itself because of naturally occuring inhibitors
Tissue plasminogen activator - involved in the balance between thrombolysis and thrombogenesis, binding of it + plasminogen to the fibrin surface induces a conformational change that facilitates the conversion of plasminogen to plasmin and dissolves the clot
Non-fibrin specific agents
- name
- mechanism of action
-Streptokinase
- protein synthesized by beta-hemolytic streptoccoci that combines with the pro-activator plasminogen
- catalyzed the conversion of inactive plasminogen to active plasmin
- plasmin formed inside a thrombus by these activators is protected from plasma anti-plasmins, which allows it to lyse the thrombus from within
Non-fibrin specific agents
- name
- side effects
-Streptokinase
- it often causes febrile reactions and other allergic problems
- it could also cause hypotension - dose-related
- it cannot be administered safely for a second time because it is highly antigenic and results in high levels of anti-streptoccocal Ab
Fibrin – specific agents
-name
-Alteplase
- not antigenic
- effective only at the surface of fibrin clot
- dissolve clot by directly or indirectly activating plasminogen which is then converted to plasmin (breaks fibrin links)
Fibrinolytic drugs
- unwanted effects
- contraindications
- indications
- hemorrhage
- active bleeding, invasive procedures, history of hypertension, aortic dissection, acute pericarditis, previous cerebrovascular accident
- acute MI, acute massive pulmonary embolism, acute ischemic stroke, peripheral arterial thrombi and thrombi in the proximal deep veins
Anti-fibrinolytic and hemostatic drugs
-classes and names
- Anti-fibrinolytic drugs – Tranexamic acid
- Vitamin K (Phytonadione)
- Hemostatic drugs – Etamsylate (Dycinone)
Anti-fibrinolytic drugs - Plasminogen activator inhibitors
- name
- mechanism of action
- indications
- Tranexamic acid
- stops fibrinolysis by inhibiting the binding of plasminogen to fibrin as well as conversion of plasminogen to plasmin
- adjunctive therapy in hemophilia, therapy for bleeding from fibrinolytic therapy, prophylaxis for re-bleeding from intracranial hemorrhages
Anti-fibrinolytic drugs - Plasminogen activator inhibitors
- unwanted effects
- contraindications
- intravascular thrombosis, hypotension, myopathy, abdominal discomfort, diarrhea, nasal stuffiness
- disseminated intravascular coagulation or genitourinary bleeding of the upper tract - because of potential for excessive clotting
Vitamin K (Phytonadione)
- confers biologic activity upon pro-thrombin and factors VII, IX and X
- fat-soluble
- found in leafy green vegetables
- IV or oral
- effect is complete after 24h
- onset of effect is 6h
Hemostatic drugs
- name
- mechanism of action
-Etamsylate (Dycinone)
- promotes angioprotective and pro-aggregant action
- stimulates thrombopoiesis
- activation of thromboplastin formation on damaged sites of small blood vessels and decreases protacyclin synthesis
- facilitates platelet aggregation and adhesion
