hemostasis and thrombosis Flashcards
what are the normal steps in hemostasis?
injury to vessel => platelet activation plus => coagulation cascade/fibrin clot –> control of clote extension by antithrombotic mechanisms + fibronolysis and clot removal => healing and repair
what is the first stage of normal hemostasis?
breach in wall
vasoconstriction, neurogenic
what is the second stage of normal hemostasis?
platelets arrive, adhere, are activated, and aggregate = primary hemostasis
what is the third stage of normal hemostasis?
secondary hemostasis - coagulation cascade - CLOT
thrombrin activation, fibrin polymer produced, phospholipid complex made
what is the fourth stage of normal hemostasis?
thrombus and antithrombotic events
what is the job of endothelial cells?
maintain blood fluidity
regulate vessel tone - secrete endothelin => vasoconstriction
prevent plt aggregation and promote vasodilation - secrete prostacyclin, NO
what do anticoagulants do (ie how do they work)?
prevent interaction with adhesive proteins like collagen, VWF, tissue factor
what are the prothrombotic properties of endothelial cells?
synthesis, storage and release of VWF
storage and release of FVIII
synthesize tissue factor
what are the three A’s? what mediates them?
adhesion, activation, aggregation (actions of platelets)
adhesion mediated by vWF at site of injury
activation mediated by surface GPIIb/IIIa alteration
aggregation mediated by fibrinogen cross-links with GPIIb/IIIa => surface phospholipid exposed (coagulation matrix) and mechanical contraction
what does MLCK (myosin light chain kinase) do?
catalyzes the phosphorylation of the regulatory myosin light chain => triggers myosin-actin interaction => shortening of muscle and generation of force
how do the different forms of anti-platelet therapy work?
aspirin inhibits COX-1
ibu inhibits COX-1 (NASIDS)
clopidogrel (plavix) blocks ADP receptor
abciximab (Reopro) and tirofiban (Aggrastat) block GPIIb/IIIa
what ist the vonWillebrand factor? what stimulates its release?
from enothelium
when binds to subendothelial collagens, undergoes conformation change => binding to platelet GPIb - helps with adhesion
also helps with aggregation by binding to platelet GPIIb/IIIa
also binds to FVIII - protects FVIII from proteolytic cleavage and brings it to the site fo hemorrhage
stimulated by thrombin, fibrin, histamine, and DDAVP
which coagulation proteins are vitamin K dependent?
factors 2, 7, 9, 10
all enzymes
what are the enzymes involved in coagulation?
factors 2, 7, 9, 10, 11
protein C
tPA
plasmin
what are the cofactors involved in coagulation?
tissue factor
factors 5, 8
protein S
what are the miscellaneous proteins involved in coagulation?
fibrinogen factor 13 alpha2-antiplasmin PAI-1 antithrombin
what is the intrinsic pathway of coagulation?
7 –> 7a
7a catalyzes 11 –> 11a
11a catalyzes 9 –> 9a
8a + ca catalyzes 9a to catalyze common pathway
what is the extrinsic pathway of coagulation?
TF+ 8a catalyzes common pathway
what is the common pathway of coagulation?
either 8a + Ca (from intrinsic) or TF + 7a catalyze 10 –> 10a
5a + Ca catalyzes 2 –> 2a
2a + Ca catalyzes fibrinogen –> fibrin
8 catalyzes fibrin –> cross-linked fibrin
what does factor 8 do?
8a stabilizes the fibrin clot by crosslinking the lysine and glutamine side chains of the alpha and gamma chains of fibrin to form homopolymers
what makes up the quaternary complex?
enzyme + cofactor + phospholipid surface + calcium ions
what are possible anticoagulant therapy approaches?
vitamin K antagonists - will affect factors 2, 7, 9, 10
used heparin and derivatives or R-hirudin to inhibit action of thrombin
use fibrinolytic agents to lyse clot
how does antithrombin work?
binds to 2a => conformation change in the AT
what is von willibrand disease?
most common bleeding disorder
absent or abnormal VW multimers
S/S epistaxis, bruising, menorrhagia, GI, gingival bleeding
diagnose via BT, FVIII, VWAg, RIPA
what is bernard soulier syndrome?
deficiency of GPIB, AR
results in early childhood bruising, mucosal bleeding
diagnose based on increased bleeding time, giant platelets, thrombocytopenia, aggregation studies
treat with platelets, DDAVP
what is glanzmann’s thrombasthenia?
AR, deficiency of GPIIb/IIIa
results in early childhood bruising, bleeding
diagnose based on BT, Plt aggregation
what is the result of the factor 5 leiden mutation?
caused by an AA replacement at one of three APC cleavage sites in the factor 5a model
makes it ten times slower than normal factor 5
persists longer in the circulation => increased thrombin generation and mild hypercoagulable state
if heterozygous => slight increased risk for venous thrombosis
if homozygous => much greater risk
almost exclusively in caucasians
what is the consequence of a prothrombin 20210 mutation?
increased risk of venous thrombosis
increased prothrombin levels due to increased mRNA stability
what is heparin-induced thrombocytopenia syndrome?
generation of antibodies that bind to PF4
bind to heparin-like molecules present on platelet surface and endothelium => platelet activation or endothelial injury
prothrombotic state
what is antiphospholipid antibody syndrome?
positive antiphospholipid antibody
=> arterial or venous thrombosis, thrombocytopenia, frequent miscarriages
what will prolong prothrombin time?
deficiencies of factors 2, 5, 7, 10, or fibrinogen
inhibitors such as D-dimer, paraprotein, lupus anticoagulant
what will prolong partial thromboplastin time (PTT)?
deficiencies in factors 8, 9, 11, 12
inhibitors such as heparin, lupus anticoagulant, specific acquired factor inhibitor (esp 8)
how can PTT and PT be used?
if factor deficiency is the cause of prolongation, PTT or PT will correct when patient plasma is mixed with fresh pooled normal plasma if anticoagulant (inhibitor) is present, the PTT or PT will not correct
