Clotting System Flashcards
What receptors are found on a platelet
Thrombin
ADP
TXA2
Platelet aggregation mechanism
- Collagen disrupted at injury site
- Platelet release ADP and TXA2, which then further activate platelet
- ADP binds to other platelets and activates glycoprotein receptors (GPIIB/IIIA)
- Fibrinogen binds to activated GPIIB/IIIA receptors forming crosslink btw platelets
- Platelet aggregation
Clotting cascade mechanism
XII→XIIa
XI→(Ca)→XIa
IX→IXa
VIII→VIIIa OR X→(Ca)→Xa
VII→VIIa also facilitates X→(Ca)→Xa
Prothrombin (II)→(Ca)→Thrombin (IIa)→activates platelets, factors VII, VIII, XIII
Fibrinogen→(Ca)→Fibrin→Forms clot
*Fibrinogen cross links platelets*
XIII→(Ca)→XIIIa→Stabilizes clot
As we go down, the enzymes get more significant
Once a clot forms what can happen?
- Can be dissolved
- Can be stabilized
- Can be permanent fibrin seal
What class of molecules are clotting factors? Once they are activated?
Factors-circulating proteins (they are enzymes)
Activated factors-Proteolytic enzymes
What molecule is required for synth of certain clotting factor synth?
Which factors?
Vit K
Factors 7, 9, 10, and Prothrombin
Clot formation reversal
Plasminogen→Plasmin→Clot lysis
To localize clotting:
Antithrombin III→Inactivation of thrombin factors IX, X, XI, XII
Hemophilia
Inadequate clotting
Genetic disorder
More likely to bleed
More likely to get joint replacement
Too much clotting
Thrombi in arteries
Results in formation of thrombus-clot that adheres to vessel wall
White thrombi-associated w/ atherosclerotic plaque
Consists of Platelets and fibrin
Ischemic damage to tissues whose blood supply is compromised
Worst case scenario: Thromoboembolis
Piece of thrombus breaks off and travels until it can’t anymore
Clog vessel→stroke, heart attack
or cause lung damage
Too much clotting
Thrombi in veins
Results in formation of thrombus-clot that adheres to vessel wall
Red thrombi-associated w/ pooling of blood in extremities
Consists of RBC and fibrin
Ischemic damage to tissues whose blood supply is compromised
Worst case scenario: Thromoboembolis
Piece of thrombus breaks off and travels until it can’t anymore
Clog vessel→stroke, heart attack
or cause lung damage
When are anticoagulants used?
- Thromboembolic disease
- Prevent formation and extension of clot in venous system
- Thrombophlebitis-If you have deep venous thrombosis
- After surgery
- Esp. abdominal or orthopedic surgeries
- Or for traumatic injury repair
- During transfusions
- In pts w/ heart disease
- Arrythmias (AFib)
- MI
- Damaged or replaced heart valves
- Any operation on cardiovascular syst. is associated w/ increased risk of stroke
Calcium chelators
Citric acid (in blood transfusion bags(
EDTA
EGTA
Tx: Anticoagulants
Mech: Chelate Ca
Remove Ca from clotting cascade (5 steps need Ca)
We don’t give these to people b/c Ca is involed w/ lots of mechanisms
Heparin
Tx: Anticoagulant
Mech:
- Heparin activates anti-thrombin (protease inhib) and increases its affinity for clotting factors by 1000x
- Low doses: inhibits Xa
- High doses: inhibits thrombin, IXa, XIa, and XIIa
- Strong neg charge
Effects:
- Heparin inhibits clotting in vivo and in vitro
- Activates lipoprotein lipases in blood
Where we get it:
- located in mast cells
- Harvest it from cow lung and pig intestines
- Not synthetic-each batch tested individually
Pharmacokinetics: IV or subQ
- Too large to be absorbed in GI tract or pass placenta
- Immediate onset–T1/2=1 hour
- Not risk free in pregnancy though
- Degradation via heparinase
- Can bind to variety of proteins so dose response in unpredictable
_Toxicity: _
- Generally non toxic
- Major danger is bleeding
- Overdose treated w/ protamine sulfate
- Strong pos charge binds w/ strong neg of heparin
- Long term use can lead to
- Osteoporosis-act. osteoclasts
- Thrombocytopenia-loss of platelets
- HIT-heparin induced thrombocytopenia
- Fibrinogen receptor inhibitors also cause thrombocytopenia
- Hypersensitivity-rare but we are injecting animal products
Remember HAT HOT
Heparin
Anti-
Thrombin
Hypersensitivity
Osteoporosis
Thrombocytopenia
“-parin” drugs excluding heparin
Enoxaparin
Dalteparin
Tx: Anticoagulant
Low molecular wt heparins-Partially purified heparin
Activates anti-thrombin III but…
More effect on Xa than thrombin
Less osteoporosis and HIT
Longer T1/2=4 hrs
More predictable dose-response
(Smaller so don’t bind as readily to lots of proteins)
More expensive
Not readily reversed by protamine sulfate
SE: spinal hematoma in pts who have had spinal tap or anesth.
-Xabans and other -parins inhibit Xa and can cause spinal bleeding
Fondaparinux
Tx: Anticoagulant
Synthetic heparin like drug
Activates anti-thrombin III but…
Mech: only on Xa
Longest T1/2=17 hrs
Can cross placenta (heparin could not)
Can’t bind protamine
Given SubQ
Hirudin
Tx: Anticoagulant–found in leech saliva
Mech: Directly inhibits thrombin
- Enzyme inhibitor*
- Careful: *
- Hirudin inhibits thrombin*
- Heparin activates anti-thrombin*
“-rudin”s
Other than hirudin
Bivalirudin
Desirudin
Tx: Anticoagulant
Synthetic analogs of hirudin
Clinical use: when patient has HIT
Skin grafts and reattaching body parts
Route: Injection
Argatroban
Tx: Anticoagulant
Peptide from hirudin-diff structure, similar mech
Clinical use: when patient has HIT
Skin grafts and reattaching body parts
Route: Injection
Warfarin
Tx: Anticoagulant
Mech:
- Vit K analog–*Koagulation*
-
Inhibits enzyme that allows vit K to be recycled
- Leads to vit K deficiency
- Vit K is essential for factors 7, 9, 10 and prothrombin
- Works indirectly-doesn’t directly block clotting cascade
Route: Oral
Pharmacokinetics:
- Factor T1/2s (hrs)
- VII–6
- IX–24
- X–40
- II–60
- So 5-6 T1/2s for 99% to be gone
- 30-36 hrs
- So initial onset is 24+ hours–Long half life!
- Metabolism
- P450
- Lots of drug interactions
- Phenytoin/barbituates vs grapefruit juice, etc.
- Diet interactions
- Lots of Vit K in green veggies
Toxicity:
- Overdose-tx w/ Vit K
- Hemorrhage
- Can pass placenta-preg. category X
Dabigatran
Tx: Anticoagulant
Dabigatran
Mech: Direct thrombin inhibitor
Enzyme inhibitor
Route: Oral
Kinetics:
- Prodrug
- Onset w/in 1 hr
- P450 inhibitor may impact (same w/ warfarin)
SE-hemorhhage
- What else directly inhibits thrombin?*
- Hirudin*
“-xaban”s
Tx: Anticoagulant
Mech: Factor Xa inhibitor
Think -xaban=_Ban_s factor Xa
Route: Oral
Kinetics: Rapid onset
SE: Bleeding after spinal tap or spinal injury
*Spinal bleeding with -xabans and other -parins *
Vorapaxar
Tx: Anticoagulant
Mech: Platelet inhibitor
Thrombin receptor blocker on platelet
SE: Use carefully w/ pts w/ history of intracranial bleeding (like Aaron who runs into trees)
- Intracranial pressure/bleeding contraindication for vorapaxar and opiates*
- Mannitol decreases intracranial pressure*
Ticlopidine
Tx: Anticoagulant
Mech: Platelet inhibitor
ADP receptor blocker on platelet
SE:
- Neutropenia-loss of neutrophils
- Agranulocytosis
“ADP receptor blocker=_Ticl_opidinde and -grels”
_A_aron’s _D_elicious _P_enis _Tic_kles the _Girls_ (Grels)
or _A_aron’s _D_ick _P_ubes (if you prefer that image)
“-grel”s
Tx: Anticoagulant
Mech: Platelet inhibitor
ADP receptor blocker on platelet
Same as ticlopidine-diff is pharmacokinetics: rapid onset, shorter T1/2
“ADP receptor blocker=_Ticl_opidinde and -grels”
_A_aron’s _D_elicious _P_enis _Tic_kles the _Girls_ (Grels)
or _A_aron’s _D_ick _P_ubes (if you prefer that image)
Abciximab
Tx: Anticoagulant
Mech: Platelet inhibitor
Fibrinogen receptor blocker on platelet (GPIIB/IIIA receptor)
Monoclonal antibody
Clinical use: Decrease white thrombi
Used for coronary operation
Route: IV
SE: Thromobocytopenia
Heparin and the fibrinogen receptor blockers→thrombocytopenia
Tirofiban
Tx: Anticoagulant
Mech: Platelet inhibitor
Fibrinogen receptor blocker on platelet (GPIIB/IIIA receptor)
Clinical use: Decrease white thrombi
Used for coronary operation
Route: IV
SE: Thromobocytopenia
Heparin and the fibrinogen receptor blockers→thrombocytopenia
Eptifibatide
Tx: Anticoagulant
Mech: Platelet inhibitor
Fibrinogen receptor blocker on platelet (GPIIB/IIIA receptor)
Clinical use: Decrease white thrombi
Used for coronary operation
Route: IV
SE: Thromobocytopenia
Heparin and the fibrinogen receptor blockers→thrombocytopenia
Aspirin
Tx: Anticoagulant
Mech: Platelet inhibitor
COX (enzyme) inhibitor
Inhibits TXA2 synth
Decreases platelet aggregation
Cilostazol
Tx: Anticoagulant
Mech: Platelet inhibitor
Inhibits phosphodiesterase
Inh. enzyme that breaks down cAMP
Increased cAMP→Decrease platelet agg.
- Methyl xanthines also increase cAMP by inhibiting phosphodiesterase*
- Opiates decrease cAMP by binding to a receptor *
Dipryridamole
Tx: Anticoagulant
Mech: Platelet inhibitor
Inhibits phosphodiesterase
Inh. enzyme that breaks down cAMP
Increased cAMP→Decrease platelet agg.
- Methyl xanthines also increase cAMP by inhibiting phosphodiesterase*
- Opiates decrease cAMP by binding to a receptor *
Anagrelide
Tx: Anticoagulant
Mech: Platelet inhibitor
Platelet count reducer
Decreases platelet formation, maturation, and #
- Careful: This is also a -grel*
- It’s a nag that this one is also a grel*
_A_-_na__gre_lide
Contraindications for all anticoagulants
- Anyone w/ bleeding disorder
- Bleeding in GI tract
- 25% of the time this goes unoticed
- Bleeding in GI tract
- Severe hypertension
- Start sprouting leaks
- After surgery on eye, brain, or spinal cord
“-kinase”s
Streptokinase
Urokinase
Tx: Thrombolytic agent
(dissolve formed clots)
Mech:
- Urine plasminogen activator=Enzyme activator
- Plasminogen→plasmin
- Plasmin:
- hydrolyzes fibrin
- degrades fibrinogen
- degrades factors V and VII
Route: IV
SE: May prolong bleeding time
Tissue plasminogen activator (TPA)
Tx: Thrombolytic agent
(dissolve formed clots)
Mech:
- Urine plasminogen activator=Enzyme activator
- Plasminogen→plasmin
- Plasmin:
- hydrolyzes fibrin
- degrades fibrinogen
- degrades factors V and VII
Route: IV
SE: May prolong bleeding time
Aminocaproic acid
Tx: Hemostatic agent (enhance clotting)
Mech: Inhibits plasminogen activation
Enzyme inhibitor
Binds to plasminogen in plasma
Route: Oral or injection
Tranexamic acid
Tx: Hemostatic agent (enhance clotting)
Mech: Inhibits plasminogen activation
Enzyme inhibitor
Binds to plasminogen in plasma
Can we make clotting factors?
Yes
Can be synthetically made
What are the oral anticoagulants?
Warfarin (K analog–enz. inh)
-Xabans (inh Xa)
Dabigatran (direct thrombin inh)
What anticoagulants should pregnant pts avoid?
Warfarin-preg risk X
Heparin-doesn’t cross placenta but not risk free
