Thrombosis Flashcards
antiplatelet effects?
prostacyclin, NO - impede platelet adhesion
ADPase: degrades ADP
anticoagulant effects?
heparin like molecule: enhances inactivation of thrombin by antithrombin
thrombomodulin: needs protein C, and S - ginds thrmbin and converts it into an anticoagulant
tissue factor pathway inhibitor: binds and inhibits factor VIIa
fibrinolytic effects?
tissue plasminogen activator –> cleaves plasminogen to plasmin –> plasmin cleaves fibrin and degrades thrombin
- results in fibrin split products
- XIIa pathway: converts plasminogen to plasmin via coagulation cascade
- Clinically administered plasminogen activators: tPA, urokinase, streptokinase: all will produce high plasmin levels to induce rapid clot dissolution
whats blocked by warfarin?
need vitamin K
- Factors: VII, IX, X, II, Protein C, Protein S
blocked by heparin?
activates antithrombin III:
- IIa,, IXa, X, XI, XIIa, (VIIa and VIIIa)
Antithrombin = Antithrombin III
• neutralizes activated serine proteases and inhibits coagulation via thrombin (II, IX, X, XI, XII)
• antithrombin’s binding reaction is amplified 1000x by heparin
LMWH blocks?
only deactivates Xa
factor 12 defic?
Factor XII does not doe much- deficiency only results in problems with thrombosis as it is important in lysis and activation of plasmin → prothrombotic state
How does clotting occur in vivo?
- in real life, tissue factor + Ca2+ VIIa à IXa à Xa à IIaà Ia
- the rest is amplification via Thrombin, IIa
- all of these factors require Vitamin K and Ca2+
fibrinolysis
- Plasmin cleaves cross-linked fibrin into Fibrin split products
- Positive D dimer = if adjacent, positive D-Dimers, then you have clotting and fibrinolysis occurring somewhere in the body
- Fibrin split products = if positive, then you have fibrin is being broken down and there is clotting somewhere in body
hemorrhage
due to anti-coagulation = Fibrinogen is not converted to fibrin (very little fibrin) • low thrombin • high plasmin • too few/nonfunctional platelets
thrombosis
\: due to hypercoagulation = Fibrinogen is converted into lots of fibrin • high thrombin • low plasmin • too many platelets
thrombus
= clot that has grown larger than required for its physiologic role and is now serving as a hemostatic plug
• Arterial thrombus: see diminished (ischemia) or occluded (infarction) blood flow to distal thrombus location
• Venous thrombus: see vascular congestion and edema proximal to the obstruction of blood flow
• Fates of thrombosis:
o propagation: clot continues to grow
o embolization: clot dislodges and travels to another site
o dissolution: fibrinolysis
o organization and recanalization in older thrombi, often resulting in scarring
Note: heparin and Coumadin stop the propagation of the clot, but don’t break down the clot. To break down the clot you must use tPA
Virchows triad
these three things lead to thrombosis
Endothelial injury:
o hypercholesterolemia
o inflammation
Abnormal blood flow:
o stasis: prolonged immobilization, MI, atrial fibrillation, atrial dilation
o aortic aneurysm with no re-entry
o non-contractile myocardium
o hyperviscosity syndromes: polycythemia, hypergammaglobulinemia
o turbulence: atherosclerotic plaques, aortic aneurysm w/ re-entry
Hypercoagulability:
o Inherited: antithrombin deficiency, protein C/S deficiency, Factor V Leiden mutation
o Acquired: Lupus inhibitor, malignancy, nephrotic syndrome, heparin therapy, hyperlipidemia, TTP
Factor V Leiden Mutations
“activated Protein C resistance” - heterozygous genetic
• mutant V converts to Va and is fully functional in its coagulant role
• mutant has decreased affinity to activated Protein C and is thus not deactivated
= hypercoagulable state
Prothrombin G20210 A mutation
• causes increased prothrombin levels which are converted into working thrombin
= hypercoagulable syndrome
genetic hypercoagulable states?
Hyperhomocysteinemia, heterozygous 5 - 15
Factor V Leiden, heterozygous 2 - 15
Prothrombin G20210A mutation 1-2
Protein S deficiency 0.7
Protein C deficiency 0.5
Antithrombin deficiency 0.2
Heparin- Induced Thrombocytopenia Syndrome (HIT), type II
acquired hypercoagulable state
• unfractionated heparin administered over time induces autoantibodies to a molecular complex with platelet factor 4
o results in body recognizing factor 4 as something foreign and Abs are developed against this complex → patients develop coagulative state and tend to thrombose
• develops in 1-5% of patients with repeated use of heparin
• patients have thrombocytopenia and disseminated clots
• autoantibody-heparin-platelet complexes cause endothelial injury → prothrombotic state
Antiphospholipid autoantibody syndrome:
aquired coagulable state
• phospholipids on platelet surface have affinity for coagulation factors
• detected clinically:
o lupus anticoagulant detected during aPTT testing
o false positive VDRL (syphillis) test (Anticardiolipin antibody)
• see recurrent venous or arterial thrombosis and fetal loss
• patients may have SLE or other AI diseases
Hyperhomocysteinemia:
most common genetic cause of hypercoagulable state
- homocysteine is a molecule that contributes to arterial and venous thrombosis and atherosclerosis
- homocystinuria: see marked elevations of homozygous deficiency of cystathione Beta synthetase (CBS)
- heterozygous CBS result in moderate homocysteine elevations
- reducing homocysteine levels does not decrease ASCVD risk
embolus
detached intravascular solid, liquid, or gaseous mass that is carried by blood to a site distant from its origin
• the number one cause is due to DVT – 60-80% of pulmonary emboli are clinically silent
• Types of embli: fat, bone marrow, tumor, air, nitrogen, talc/metal oxides, bullets, amniotic fluid
- Thromboembolus: when thrombotic fragment moves through the venous system
infarcts:
- pale infarcts: due to one way blood supply, i.e. kidneys
- hemorrhagic infarcts: due to dual blood supply, or infarcrion then reperfusion
• i.e. lungs due to dual circulation
• i.e. if pt. was given tPA following ischemic infarct in heart then it would show as hemorrhagic
- Distributive Shock
– vasodilation
a. septic shock (gram + bacteria), neurogenic shock, anaphylactic shock
b. see peripheral vasodilation and pooling of blood, endothelial activation, leukocyte induced damage, DIC and activation of cytokine cascade
cardiogenic shock
– cardiac pump failure
a. MI
b. ventricular rupture
c. arrhythmia
d. cardiac tamponade
e. pulmonary embolism
hypovolemic shock
– intravascular volume loss
a. hemorrhagic shock, vomiting, diarrhea, burns, trauma
