hemostasis Flashcards
define hemostasis
cessation of bleeding from a severed blood vessel
define thrombosis
intravascular clot formation
list stages of hemostasis
- vasoconstriction
- platelet plug formation
- blood coagulation
- fibrinolysis
describe adhesion step in plug formation
- adhesion: Von Willebrand factor binds subendothelial collagen which facilitates platelet adhesion through its platelet receptors (GPIb-IX-V) which initiates tethering. collagen’s platelet receptor (GPVI) binds FcRgamma on platelet and this activates alpha2beta1 a2b3 receptors
describe activation/secretion step in platelet plug formation
- activation/secretion: receptor activation activates PIP2 –> IP3 –> Ca+ and PIP2 –> DAG –> PKC, phospholipid –> pLA2 –> arachindonic acid –> PGG2, PGH2 (via COX-1) –> thromboxane A2 (via TXA2 synthase)
these reactions cause an accumulation of thromboxane A, ADP and thrombin which stimulate GCPRs which acts as positive feedback
the granules are released due to increased cytoplasmic calcium
alpha granules of platelets
coagulants/anticoagulants: V, XI, ATIII adhesion proteins: fibrinogen, vWF integral membrane proteins: GPIIb-IIIa growth factors: EGF, TGFbeta angiogenic factors/inhibitors: VEGF, PDFG chemokines and immune mediators
dense granules of platelets
ADP
Ca2+
polyphosphate
serotonin
describe the aggregation step of platelet plug formation
after morphological changes through the inside out signlaing of platelet activation GPIIbIIIIa is able to bind fibrinogen or vWF which other platelets are bind to which allows clumping GPIIbIIIa binding to fibrinogen also causes outside in signaling which further accelerates the aggregation process
what is vWF bound to as it travels in the blood
factor VIII
which antiplatelet drug(s) block COX-1
aspirin and other NSAIDs
which antiplatelet drug(s) block ADP receptor on platelet
clopidogrel
prasurgrel
ticagrelor
cangrelor
which antiplatelet drug(s) blocks thrombin recptor (PAR-1) on platelets
vorapaxar
which antiplatelet drug(s) block fibrinogen and vWF binding to activated GPIIb/IIIa
abciximab
eptifibatide
tirofiban
prostacyclin and platelet plug formation
prostacyclin activates adenylyl cyclase –> cAMP which blocks platelet responses
factors that can activate phospholypase C
vWF, TxA, thrombin
function of phospholupase C in platelet plug formation
PIP2 –> DAG and IP3
IP3 –> Ca+
DAG –> PKC
function of Ca+ in platelet plug formation
initaite platelet responses activate PLA2 (--> aa -->TxA)
what initiates the intrinsic pathway vs the extrinsic pathway
intrinsic: contact activation pathway, everything needed is already in plasma
extrinsic: needs TF (on subendothelium)
intrinsic pathway coagulation steps
XII –> XIIa –> kalikrein/high molecular weight kininogen a –> XIIa –> XIa –> IXa –> compelx forms: IXa + VIIIa + X + Ca
when X binds this complex it becomes Xa
extrinsic pathway coagulation steps
VII + TF –> complex: VIIa, TF, X, Ca+
when X binds to complex it becomes activated
common pathway coagulation steps
complex: Xa, Va, prothrombin, Ca+ –> thrombin –> fibrin –> soft clot
thrombin –> XIIIa –> fibrin cross-linked
steps that are enhanced by thrombin
XI-->XIa VIII --> VIIIa V-->Va VII --> VIIa fibrinogen --> fibrin fibrin --> soft clot XIII-->XIIIa
TFPI
tissue factor pathway inhibitor
acts as anticoagulant in stopping early phase responses
blocks Xa and TF
antithrombin III
increased by heparin
blocks thrombin and therefore K/HMWK, XIIa, XIa, IXa, Xa
most importantly: blocks thrombin and X
thrombomodulin
changes specificity of thrombin so it cleaves protein C
protein C and protein S block VIIIa and Va
Leiden V mutation
resistant to APC (activated protein C) mediated activation so there is an increased risk of thrombosis
warfarin
competitively inhibits vitamin k epoxide reductase which reduces vitamin k-dependent gamma-carboxyglutamic acid modifications essential to biological function
reduces hepatic production of vitamin k-dependent coagulation factors: II, VII, IX, X, and the anticoagulation proteins C and S
how is VII membrane bound
Ca+ binds gamma carboxyglutamate residues on factor VII which facilitates interaction with anionic phospholipid membrane
heparin
unbranched anionic glycosaminoglycan composed of alternating variations of sulfated and or acetylated glucosamine and sulfated uronic acid
unfractionated heparin: increases antithrombin III activity to inhibit factor X and thrombin
low molecular weight heparin inhibits factor X more than thrombin
bivalirudin
competitive inhibitor which binds active site and anion binding exosite of thrombin (bivalent)
dabigatran
competitive inhibitor that binds only active site of thrombin
apixaban
competitive inhibitor for factor Xa
prothrombin time (PT) and INternationalized normalization ratio (INR)
evaluates the extrinsic and common pathways: fibrinogn, prothrombin, V, VII, and X
PT = time elapsed before clotting
INR= (PTtest/PTcontrol)^ISI
partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT)
evaluates intrinsic pathway and common pathhways
normal PTT requires: fibrinogen, prothrombin, factors V, VIII, IX,X,XI, and XII (does not require factor VII)
partial bc no tissue factor is present in assay
PTT= time elapsed before clotting
function of plasmin
in fibrinolysis: breaks down fibrin
how is plasminogen activated into plasmin
t-PA and u-PA which is released from injured endothelium
factors XIa, XIIa, and kallikrein also weakly activate
PAI-1 and PAI-2
plasminogen activator inhibitors
block t-PA and u-PA
alpha2-antiplasmin
blocks free plasmin (reduces fibrinolysis)
TAFI
thrombin activatable fibrinolysis inhibitor
inhibits fibrinolysis by removing C-terminal lysine residues of fibrin that facilitate plasminogen binding and activation
thrombolytics
plasminogen activators
ex. alteplase, reteplase, tenectaplase, urokinase, streptokinase
aminocaproic acid (amicar)
inhibits plasmin
D-dimer test
antibodies detect the neoepitope that arises upon covalently cross-linking two D domains from saparate molecules of fibrin
does not detect fibrin or fibrinogen
how do NO and prostacyclin affect hemostasis
they are secreted by healthy endothelial cells and promote vasodilation and inhibit platelet aggregation
how does thrombomodulin affect hemostasis
healthy endothelial cells express thrombomodulin which converts thrombin from pro-coagulant to anti-coagulant. thrombins specificity changes upon binding thombomodulin, leading to activation of anti-coagulant proteins such as activated protein C and TAFI
