3) Secondary hemostasis Flashcards
Intrinsic pathway
Extrinsic pathway
Common pathway
In vitro intrinsic pathway
the end product of secondary hemostasis
fibrin clot
biochemical change resulting in activated coag factors
cleavage of peptide fragments
required for the local concentration of trace plasma coag factors
examples
surface mediated interactions
in vivo: collagen, phospholipid vesicles (PF3)
in vitro: glass, ellagic acid, kaolin
a small amount of enzyme formed initially leads to a relatively enormous quantity of enzyme
biological amplification system
end stage enzyme of hemostasis
thrombin
3 parts of fibrin clot formation
extrinsic pathway
intrinsic pathway
common pathway
the ——- pathway relies on TF, which is limited, so it requires the ———- pathway for sustained coagulation to proceed
extrinsic
intrinsic
TF is the limiting factor for…
extrinsic pathway
intrinsic and extrinsic pathways converge by their action on…
X
extrinsic pathway rapidly forms thrombin within…
15 sec
(extrinsic/intrinsic) pathway starts first
extrinsic
—— acts as the enzyme converting TF to its tenase
VII
acts as a bridge in reactions of secondary hemostasis
Ca
because the extrinsic pathway’s tenase is rapidly inactivated by ————-, the intrinsic pathway is needed
tissue factor pathway inhibitor (TFPI)
2 functions of tenase
- activate X
- activate IX
2 ways intrinsic pathway can be activated
- tenase activates IX
- XI activated by thrombin, which will then activate IX
in vitro, XIIa activates —–, but this does not seem to happen in the body
XI
IXa acts as a ————- that utilizes ——– from plts to form a complex with ———-
serine protease
PF3
VIII
Xa acts as a ———— which utilizes phospholipids to form a complex with ——, called the —————
serine protease
V
prothrombinase
factor II
prothrombin
activates prothrombin
prothrombinase
thrombin acts as a ————— to convert…
serine protease
fibrinogen to fibrin
——– is activated by thrombin to crosslink “D” portions of fibrin
XIII
stages of fibrin development
- fibrinogen—D-E-D molecules with A & B peptides attached to E
- fibrin monomer—thrombin cleaves off A and B
- fibrin polymer—D-E-D molecules spontaneously attach
- stabilized fibrin polymer—XIIIa crosslinks D portions
activated factors must stay ———– so as not to cause clotting elsewhere
how?
localized
- vasoconstriction & vasodilation
- fibrin seal, active factors contained in plug
- inhibitory proteins bind activated factors
- liver clearance of factors complexed with inhibitors
examples of positive feedback in coagulation
- thrombin promotes release of plt factor Va
- thrombin activates V and VIII
- Xa activates VII and VIII
examples of negative feedback in coagulation
- thrombin inactivates Va and VIIIa at higher conc
- Xa inactivates VII
- fibrin formation limits available thrombin
- FDPs inhibit fibrin formation
functions of thrombin
- irreversible plt aggregation
- fibrinogen → fibrin
- activates V, VIII, XI, XIII
- downregulation of coagulation when bound to thrombomodulin + protein C
coagulation inhibitors
- antithrombin III
- heparin cofactor II
- protein C
- protein S
- tissue factor pathway inhibitor (TFPI)
- thrombomodulin
in vivo inhibition of thrombin and Xa
antithrombin III
directly inhibits thrombin
heparin cofactor II
inhibits Va and VIIIa
protein C
cofactor to protein C
protein S
vitamin K dependent anticoags
protein C + protein S
protein —- is synth in the liver
protein —- is synth by VECs
C
S
inhibits VIIa-TF complex and Va
TFPI
TFPI synth
VECs
binds thrombin giving it anticoagulant activity (activates protein C)
thrombomodulin
thrombomodulin location
VEC surface
adsorb onto clot when fibrin is formed
plasminogen
plasminogen activators
acts on fibrin to allow gradual dissolution
plasmin
gradual, progressive process leading to reestablishment of blood flow
fibrinolysis + tissue repair
FDPs
fibrin degradation products
produced by fibrinolysis
FDPs
FDP fate
cleared by the liver
function of plasminogen
converted to plasmin for fibrinolysis
activators of fibrinolysis in tissues & blood
tissues
- t-PA
- u-PA
blood
- plasminogen activators
- XIIa
- kallikrein
t-PA
u-PA
tissue/urokinase plasminogen activator
released by VECs and action limited to site of fibrin clot
t-PA
used in fibrinolysis & in vitro hemostasis
XII
kallikrein
exposed collagen with a negative charge provides a site for —— attachment, which mediates endogenous activation of fibrinolysis
XII
2 functions of HMWK
- prekallikrein → kallikrein
- kallikrein activation of XII
HMWK
high molecular weight kininogen
other roles of XII, PK, and HMWK
kinin system
complement system
converts single chain u-PA to double chain u-PA, increasing efficiency of plasminogen activation
kallikrein
it’s hypothesized that protein C indirectly liberates…
t-PA from VECs, initiating fibrinolysis
4 FDPs
X
Y
D
E
pathologic action of plasmin
degradation of fibrinogen, V and VIII
nonspecific test for FDPs
immunoassay
fragment X
D-E-D without small peptides from carboxyl end of alpha chains
fibrinogen degradation
fragment Y
D-E
specific FDP indicating degradation of fibrin
indicates…
D-dimer
pathologic clotting occurred
FDP detected on automated analyzer
D-dimer
inhibitors of fibrinolysis
- plasminogen activator inhibitors (PAI-1/2)
- 𝛼2 antiplasmin
- 𝛼2 macroglobulin
- thrombin activated fibrinolysis inhibitor (TAFI)
inhibit t-PA and u-PA
PAI-1/2
inhibits free plasmin, not bound to fibrin
𝛼2 antiplasmin
2nd line plasmin inhibitor (backup)
𝛼2 macroglobulin
removes binding site of plasminogen from fibrin
activated by thrombin
TAFI
PTT: ——– pathway
PT: ——— pathway
intrinsic
extrinsic
lab tests are not physiological in that excess ———— are added in both PT and PTT (not a limiting factor)
phospholipid
only PT is abnormal
problem with extrinsic system
only PTT is abnormal
problem with intrinsic system
PT and PTT are both abnormal
problem with common pathway
OR
multiple factor problems (liver disease, DIC)
