Angela robinson PE Flashcards
Describe the mechanisms by which the body prevents inappropriate thrombus formation
This is achieved through various mechanisms carried out by the endothelium of vessels
(1) Anti-platelet effects
-Prostacyclin (PGI2) release prevents platelet activation and aggregation
-Nitric oxide release causes vasodilation and prevents platelet adhesion
-Adenosine diphsophatase production breaks down ADP which is used by platelets to bind to a growing platelet plug via P2Y12 receptors.
(2) Anti-coagulant effects
(i) - Thrombomodulin receptor expressed by endothelial cells can bind to thrombin and prevent it from activating platelets, fibrinogen (to fibrin) and clotting factors V, VIII and IX
-Instead, Protein C is cleaved and activated which, along with protein S, can degrade clotting factors Va and VIIIa.
(ii) Heparin like molecules on the surface of endothelial cells can bind to and activate anti-thrombin III which can then inactivate factors 9a->12a.
(iii) laminar flow dilutes clotting factors by maintaining normal flow
(3) Fibrinolytic effects
- Endothelial cells can synthesise tissue-plasminogen activator (t-PA) which can then activate thrombin-bound plasminogen to plasmin to initiate fibrinolysis and clot dissolution.
Describe how endothelial dysfunction/injury promotes thrombosis
Endothelial damage/dysfunction can result in a shift towards a prothrombotic state which facilitates thrombus formation.
- Direct endothelial injury can expose underlying subendothelial collagen which allows for the binding of vWF and subsequently platelets
- Inflammatory responses due to cytokine release or bacterial endotoxins result in the production of Tissue Factor by endothelial cells -> activates extrinsic pathway of coagulation.
- Downregulation of thrombomodulin results in sustained thrombin activity -> clotting factor and platelet activation.
- Downregulation of endogenous anticoagulant production; protein C and S.
- Reduced fibrinolytic effects due to secretion of plasminogen-activator-inhibitor (PAIs) which downregulate tPA + fibrinolysis -> favours thrombus formation.
- Reduced production of prostacyclin + nitric oxide release
- Increased adhesion molecules, and endothelin
4 contraindications to thrombolysis
- Active bleeding
- Recent sx/trauma/head injury in last 3 weeks
- hx of intracranial haemorrhage
- Ischemic stroke in last 6 months
- GI bleed in last month
- CNS neoplasm
- Severe uncontrolled HTN
name the 3 antibodies associated with anti-phospholipid syndrome
what is it associated with?
- Anti-cardiolipin antibody
- Lupus anticoagulant
- Anti-beta 2 glycoprotein antibody
Associated with:
-Recurrent venous and arterial thrombosis
-Recurrent fetal loss- particularly >3 consecutive fetal losses before 3 weeks.
list 5 indications that may prompt a hypercoagulable work up on a patient
What tests are available to run>
Indications
- Unprovoked DVT or PE
- Stroke/MI if young <40 years
- Thrombosis at an unsual site e.g. hepatic or portal veins.
- Recurrent or late miscarriages
- Warfarin induced skin necrosis.
- family hx of thrombophilia
Tests to run
- Antithrombin level
- Protein C and S levels
- Factor V leiden gene mutation
- Prothrombin gene mutation
- Antiphospholipid antibodies
- Cancer screen
Why might you choose a direct thrombin inhibitor over a direct Xa inhibitor or vice versa as an anticoagulant?
Direct thrombin inhibitors e.g. Dabigatron
-may be preferred in cases of heparin induced thrombocytopenia as they do not interact with platelets.
-There is a reversal agent/antidote for anticoagulant reversal in emergencies: idarucizumab.
Direct Xa inhibitors: Apixiban, rivaroxiban, edoxaban.
-Have lower bleeding risk
-more predictable pharmacokinetically allowing for more fixed dosing.
list 4 ADRs of heparin
- Haemorrhage
- Osteoporosis
- Thrombosis
- Thrombocytopenia
- Hypoaldosteronism -> hyperkalemia
Explain the pathogenesis of heparin induced thrombocytopenia and thrombosis
HIT
- Heparin binds to platelet activator 4 (a platelet derived chemokine), forming a complex.
-This complex can then be targeted and bound by antibodies IgG or IgM
-The heparin-PA4-antibody complex can then bind to circulating platelets -> thrombocytopenia.
thrombosis
-Heparin can target PA4 associated with the endothelial cells of vessel walls leading to endothelial injury and thrombus formation.
what drug reverses the effects of heparin?
Protamine sulphate - binds to and inactivates heparin
When is warfarin most teratogenic?
How does it cause bone deformities?
6-12 weeks.
Causes bone deformities by inhibiting normal function of the vitamin-k dependent protein osteocalcin. This results in impaired cartilage and bone development. Most notably nasal bridge hypoplasia, absent nasal septum, microcephaly.
Name 4 drugs that increase and decrease warfarins anticoagulant effects
Increase warfarin effects
CYP450 inhibitors
-“Azole” antifungals e.g. Fluconazole
-Macrolides
-Quinolones e.g. ciprofloxacin
-Amiodarone (Anti-arrythmic)
Decrease warfarin effects
CYP450 inducers
-Phenytoin
-Phenobarbitol
-Carbemezepine
-Rifampicin
Describe the Extrinsic pathway of the coagulation cascade
- The extrinsic pathway is activated following direct endothelial injury (i.e. skin tissue).
- Tissue factor is exposed to the blood stream as a result of endothelial injury.
- Tissue factor becomes bound by calcium (factor IV), its cofactor.
- Factor VII is activated when bound to this complex –> VIIa
- The TF-VIIa-calcium-membrane phospholipid complex can then activate factor X –> Xa which can then enter to common pathway –> prothrombinase complex activates prothrombin to thrombin –>cleaves fibrinogen to fibrin.
Describe the Intrinsic pathway of coagulation
- The intrinsic pathway can be activated by surface contact, when damage to the vascular endothelium leads to exposure of clotting factors to negatively charged subendothelial surfaces, mediated by the molecule Kallikrein.
- Factor XII is exposed to collagen, kallikrein and kininogen and is activated -> XIIa
- XIIa activates factor XI -> XIa
- XIa + Calcium then activate factor IX -> IXa
- Complex: IXa-calcium-VIIIa -membrane phospholipid activates X -> Xa
Describe the common pathway of coagulation
- Factor Xa combines with calcium, Va + membrane phospholipids to form the prothrombinase complex.
- Prothrombinase complex cleaves prothrombin to form thrombin.
- Thrombin then:
o Cleaves fibrinogen to form fibrin -> fibrin deposits in clot
o Cleaves stabilizing factor XIII -> XIIIa - XIIIa + Ca2+ can then act to cross-link fibrin strands -> stable fibrin clot formed.
Describe the process of primary hemostasis (platelet plug)
- Damage to endothelium results in transient vasoconstriction due to endothelin release and neural reflexes.
- von-willebrand factor, found in alpha granules of platelets and weibel palade bodies of endothelial cells, binds to exposed collagen at site of injury.
- Platelets then use vWF as anchorage, binding to it via GPLB receptors.
- Activated platelets release TXA2, serotonin, vWF, ADP and Ca2+ to enchance activity of other platelets.
- More platelets bind to ADP using P2Y12 receptors which stimulates expression of GIIb/IIIa on platelets surface. Fibriogen can then bind to these glycoproteins and become activated to fibrin via Thrombin.
- Fibrin can then cross link the platelets, forming a meshwork which traps platelets and red blood cells thereby forming a fibrous plug/growing thrombus.
