Hemostasis and Thrombosis Flashcards

1
Q

Anti-platelet (aggregates) vs. Anti-coagulants

A

Anti-aggregates –> stop platelet activity, act on the primary stage of hemostasis

Anti-coagulants –> stop coagulation cascade, act on the secondary stage of hemostasis

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2
Q

Stages of Hemostasis

A
  1. Primary (2-5min): bleeding time, platelet count increases, anti-platelet drugs
  2. Secondary (8-15min): clotting time, APTT, PT, fibrinogen
  3. Tertiary (90-240min): fibrinolysis
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3
Q

Hemostasis steps

A
  1. Injury
  2. Vessel wall + platelets
  3. Activation of plasma coagulation factors
  4. Formation of stable fibrin clot
  5. Dissolution of fibrin clot
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4
Q

Pulmonary embolism treatment

A

Massive thrombus –> fibrinolytic drugs is necessary to restore normal circulation

Smaller thrombus –> anti-coagulants are necessary

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5
Q

Arterial vs. Venous thrombus

A

Arterial –> more platelets, less fibrin –> white thrombus made of thrombocytes
-use anti-aggregates

Venous –> more fibrin, less platelets –> red thrombus

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6
Q

First choice for Acute MI

A

Anti-aggregates

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7
Q

Anti-platelet drugs

-classes and names

A
  • Cyclooxygenase inhibitors (COX1) – Aspirin
  • ADP receptors inhibitors – Clopidogrel, Prasugrel, Ticagrelor
  • Glycoprotein IIB/IIa receptor antagonists – Abciximab
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8
Q

ASPIRIN

  • mechanism of action
  • adverse effects
A
  • COX-1 inhibitor
  • IRREVERSIBLY blocks platelet
  • rapidly hydrolyzed
  • anti-platelet effect lasts 8-10 days

-ulcers, hepatotoxicity, asthma, rashes, renal toxicity, GI bleeding

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9
Q

How does thromboxane affects platelets?

A

Arachidonic acid (inside platelets) –> thromboxane by the action of COX

-Stimulate activation of new platelets and promote their activation

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10
Q

DIPYRIDAMOLE (4)

-mechanism of action

A
  • “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
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11
Q

ADP RECEPTOR INHIBITORS

  • names
  • mechanism of action
  • unwanted effect
A

-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

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12
Q

Why is Clopidogrel usually the drug of choice?

A
  • cheaper

- main problem: resistance

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13
Q

Glycoprotein IIB/IIa receptor antagonists

  • name
  • mechanism of action
  • side effect
A

-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

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14
Q

Anti-platelet drugs indications (5)

A
  • Acute coronary syndrome
  • High risk of MI
  • Coronary artery bypass grafting, angioplasty or stenting
  • Cerebral ischemi atack
  • Arterial fibrillation
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15
Q

Anti-coagulants

-classes and names

A
  • Indirect thrombin inhibitors – Heparin, Low-molecular weight Heparin (Nadroparin)
  • Direct thrombin inhibitors – Dabigatran
  • Oral direct Xa inhibitors – Apixaban, Rivaroxaban
  • Warfarin
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16
Q

HEPARIN (unfractionated heparin)

  • mechanism of action
  • pharmacokinetics
  • unwanted effects
A
  • 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)

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17
Q

Low-molecular weight Heparin

  • name
  • mechanism of action
  • pharmacokinetics
A
  • 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
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18
Q

HEPARIN (unfractionated heparin)

  • contraindications
  • reverse action - which drug?
A
  • HIT, hemophilia, active bleeding, thrombocytopenia, severe hypertension, intracranial hemorrhage, ulcers
  • PROTAMINE
19
Q

PROTAMINE (2)

A
  • positive charged peptide combines with negative charged heparin and forms an inactive stable complex to avoid anti-coagulant activity
  • mainly active against unfractionated heparin
20
Q

Advantages of Low-molecular weight Heparin over Unfractionated Heparin (9)

A
  • 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
21
Q

Why is monitoring of Unfractionated Heparin necessary?

A

Because it could bind to platelet factor 4 –> form a complex –> IgG is produced –> causes lysis of platelets

22
Q

Indirect thrombin inhibitors

  • names
  • indications
A

-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
23
Q

Direct thrombin inhibitors

  • name
  • mechanism of action
A
  • Dabigatran

- inhibits thrombin preventing the conversion of fibrinogen to fibrin = increases clotting time

24
Q

Advantage of Direct thrombin inhibitors over indirect thrombin inhibitors (4)

A
  • 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
25
Q

Direct thrombin inhibitors

  • name
  • pharmacokinetics
  • indications
A

-Dabigatran

  • orally
  • 1/2 life - 12h
  • renal clearance

-thrombus prophylaxis, arterial fibrillation, HIT, acute coronary syndrome

26
Q

Oral direct Xa inhibitors

  • names
  • mechanism of action
  • pharmacokinetics
  • indications
A
  • 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
27
Q

Oral direct Xa inhibitors

  • advantages
  • disadvantages
A
  • 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
28
Q

WARFARIN

-mechanism of action

A

-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.
29
Q

Warfarin and Vitamin K interaction

A

-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
30
Q

WARFARIN

-pharmacokinetics (7)

A
  • 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
31
Q

WARFARIN

  • antidote
  • unwanted effects
  • contraindications
A
  • vitamin K.
  • hemorrhage, teratogenic, hepatotoxicity, necrosis of soft tissues
  • high bleeding risk
  • pregnancy
  • not possible to do testing
32
Q

WARFARIN

  • advantages
  • disadvantages
A
  • 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
33
Q

WARFARIN

-indications (7)

A
  • 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
34
Q
Fibrinolytic Drugs (only intravenous use)
-classes and names
A
  • Non-fibrin specific agents – Streptokinase

* Fibrin – specific agents – Alteplase

35
Q

The fibrinolytic system

A

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

36
Q

Non-fibrin specific agents

  • name
  • mechanism of action
A

-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
37
Q

Non-fibrin specific agents

  • name
  • side effects
A

-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
38
Q

Fibrin – specific agents

-name

A

-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)
39
Q

Fibrinolytic drugs

  • unwanted effects
  • contraindications
  • indications
A
  • 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
40
Q

Anti-fibrinolytic and hemostatic drugs

-classes and names

A
  • Anti-fibrinolytic drugs – Tranexamic acid
  • Vitamin K (Phytonadione)
  • Hemostatic drugs – Etamsylate (Dycinone)
41
Q

Anti-fibrinolytic drugs - Plasminogen activator inhibitors

  • name
  • mechanism of action
  • indications
A
  • 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
42
Q

Anti-fibrinolytic drugs - Plasminogen activator inhibitors

  • unwanted effects
  • contraindications
A
  • 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
43
Q

Vitamin K (Phytonadione)

A
  • 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
44
Q

Hemostatic drugs

  • name
  • mechanism of action
A

-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