Section 6: Anti-Thrombotic Therapy Flashcards
Thrombosis versus embolus
Thrombosis: clot forms where it shouldn’t and stays there in the vessel
Embolus: clot dislodges and travels somewhere else
Thrombosis consequences
- obstruct flow in critical vessels
- obliterate valves and other structures that are essential to normal hemodynamic function
List principle clinical syndromes that result from thrombosis
- AMI
- DVT
- PE
- acute ischemic stroke
- acute peripheral arterial occlusion
- occlusion of indwelling catheters
part of purpose to issue anti-thromboticc therapy
to avoid DIC
Causes of DIC
- septicemia
- obstetric complication
- severe burns
- trauma
- casting of legs
- snake venoms
- APL (acute promyelocytic leukemia)
Describe DIC process
- Extensive endothelial damage or release of tissue thromboplastin
- Start out-of-control clotting process, which uses up clotting factors and formation of many thrombi/platelet aggregates everywhere in the body
- Platelet aggregation contributes to thrombocytopenia and excessive clot formation results in ischemia and multiple infarctions -> organ failure from lack of oxygen
- Overwhelming clotting leads to excessive fibrinolysis, coupled with reduced serum fibrinogen -> excessive bleeding and hemorrhage
- Simultaneous excessive clotting and bleeding at same time (it’s a mess)
List obstetric complications that can lead to DIC
- Dead fetus syndrome (dies in utero without removal from mom -> release TF3)
- Amniotic fluid embolus
- Abruptio placentae (placenta pulls from uterine wall)
- Preeclampsia, eclampsia, HELLP
- Increase in FVII, VIII, IX, XII, and I (increase at end of term)
- Decrease Protein S
- Abortion
Clinical signs of DIC
- Oozing
- Bleeding from multiple sites due to using up clotting factors (GIT, UR tract, IV sites, nose…etc)
- Organ damage from fibrin deposition
Purpose of anti-thrombotics (“not blood thinners””
- Limit or prevent clotting by suppressing synthesis/function of various hemostatic constituents
- Prevent thrombosis without causing hemorrhage
List 3 categories of anti-thrombotics and what they do
- anti-platelets (inhibit aggregation)
- anti-coagulants (inhibit cascade)
- thrombolytics (dissolve clot)
Warfarin (Coumadin/Jantoven)
- Oral anti-coagulant
- Arrests vit K in storage form and makes it unavailable to add second carboxyl group to produce complete factors II, VII, IX, and X
How to monitor Warfarin and interfering factors
- Monitor by PT and INR monthly
- Vit K rich foods interfere (green tea, bananas)
How are patients with venous thrombosis usually treated?
- Unfractionated heparin (UFH) and then Warfarin
- Low MW heparin (LMWH) getting popular bc difficulties monitoring UFH/Warfarin
UFH or standard heparin drug mechanism
- Heparin causes conformational change in the anti-thrombin (AT) molecule, thus increasing AT’s inhibitory effect
- AT forms an irreversible complex with factors IIa, IXa, Xa, XIa, XIIa, and plasmin
- Heparin not consumed, so dissociates and serves as cofactor for more AT molecules
- Also inhibits factor Xa
Heparan sulfate
Heparin-like substances made by endothelial cells
How can heparin cause thrombosis, even tho it’s meant to prevent it?
- Heparin therapy leads to decreased circulating AT -> less thrombin inhibition
- Lower AT levels and prematurely stopping heparin before its fully effective can lead to recurrent thrombosis
Describe the following for heparin UFH or standard
-administration
-drug that reverses heparin effects
-how therapy is monitored
-what heparin may cause
- IV but may be administered subcutaneously
- protamine sulfate binds heparin and reverses its anti-coag effects
- monitored by APTT or anti-Xa assay
- may cause HIT
LMWH
- doesn’t inhibit thrombin as much as heparin
- prepared from UFH by depolymerization, which produces heparins of more uniform molecular mass
- inhibitory effect more limited to factor Xa
Describe the following for LMWH
-administration
-how it’s monitored
-what it causes
- administered subcutaneously and does not require therapeutic monitoring
- monitored by chromogenic anti-Xa heparin assay bc APTT is insensitive to LMWH
- does NOT cause HIT, but can cross-react with HIT Ab
Fondaparinux (Arixtra) drug mechanism
Binds AT and increases its affinity for Factor Xa, thus inhibiting Factor Xa
What is Fondaparinux?
Synthetic form of the active pentasaccharide sequence of UFH and LMWH
How to monitor Fondaparinux
Anti-Xa assay
Direct Factor Xa inhibitors
- Do not require AT to express anti-coag activity
- Inhibition is Factor Xa-specific
- Administered orally - replacing coumadin
Direct Factor Xa inhibitor clearance
Cleared by kidney, so monitor renal function
Direct Factor Xa inhibitor monitoring
- Drug-specific version of anti-Xa assay
- Interferes with PT and APTT results
- Factor assays assoc w false decrease
- Immunoassays unaffected
- Proteins C and S, AT, and Lupus anticoag false increase
Direct Thrombin inhibitors
- neutralize thrombin by binding to active site
- action extends to fibrin-bound thrombin increasing their effectiveness
- Substitute for heparin esp in HIT/HITTS
- APTT monitoring
anti-platelet agents
- Reduce platelet activation and function by several drug mechanisms
- monitored with PFA-100 platelet function analyzer
Aspirin/NSAIDs drug mechanism
- anti-platelet agents
- inhibit cyclooxygenase to reduce TXA2 production, thus inhibiting plt aggregation -> no primary hemostatic clot formation
When to administer anti-platelet agents?
- Thrombosis clogging arteries
- cerebrovascular disease, CAD, peripheral arterial disease
When to administer anti-coagulants?
- Thrombosis affecting veins
- pulmonary embolism, atrial fibrillation, DVT
What to do if a thrombus or embolus already formed?
Thrombolytic therapy to break apart the clot
What are thrombolytic agents?
Serine proteases that work by converting plasminogen to the natural fibrinolytic agent plasmin
What does plasmin do?
It lyses the clot by breaking down fibrinogen and fibrin contained in a clot
Can PTT/APTT detect fibrinolysis?
No
Streptokinase and urokinase
Agents that directly convert plasminogen to plasmin
How to monitor direct agents and health consequences
- Euglobulin Clot Lysis test
- Cause hypofibrinogenemia in nearly all patients
Tissue plasminogen activator (tPA)
- High fibrin specificity/affinity
- tPA and plasminogen both bind to fibrin surface and induce conformational change that help plasminogen convert to plasmin and dissolve the clot
- No routine labs done. Monitor neuro function, BP, CT scan
- Could monitor fibrinogen level
Mechanical thrombectomy
Surgeons insert 3-ft wire thru groin and feed stent up artery to blockage in brain -> expand wire mesh to enclose clot and pull out to restore blood flow
