wk 11, lec 1 Flashcards
what is hemostasis
prevent blood loss in damage and also prevents excessive clot formation
3 things for hemostasis
- Vasospasm
- Platelet activation and formation of platelet plug
- Activate coagulation cascade and form fibrin
5 steps of clot formation
- Injury exposes collagen and thromboplastin
- Recruit platelets to site of injury to form temporary plug
- Platelets release 5-hydroxytryptamine (serotonin) contraction and vasoconstriction
- Activate clotting cascade (because of collagen and thromboplastin) activate thrombin which converts fibrinogen to fibrin monomers
- Fibrin monomers polymerize and cross link to form definitive clot
serotonin (5-hydroxytrypatamine) role in clot foramtion
contraction and vasoconstriction
what initiates coagulation and forms early fibrin plug vs what amplifies coagulation and forms more stable fibrin plug
i..e 1st activated and later activated
- Extrinsic system: initiate coagulation and form early fibrin plug
o Activated first - Intrinsic system: amplify coagulation and form more stable fibrin plug
o Activated later
what are the 2 things the extrinsic system depends on
factor VIIa and TF (aka TPL and thromboplastin)
what do the intrinsic and extrinsic pathway lead to and via activation of what
final common pathway via activation of thrombin
how does thrombin get activated in final common pathway
o Factor Xa + factor Va + Ca2+
thrombin role in final common pathway
activate fibrin to stabilize clot
what are antithrombotic factors (ie.. inhibit platelet binding, secretion and aggregation)
Prostacyclin (PGI2), NO, ectoADPase/CD39
what are anticoagulant factors
Heparan proteoglycans, tissue-factor pathway inhibitor (TFPI), thrombomodulin
what is a firbonlytic enzyme
plasminogen activators
how does HSPG inhibit clotting
- Heparan sulfate proteoglycan (HSPG) activates antithrombin (which inhibits IIa, IXa, Xa, XIa, XIIa)
what does thrombomodulin activate to inhibit clotting
- Thrombomodulin activates protein C via thrombin (which inhibits Va, VIIIa)
where are platelet made
- Made by megakaryocytes in bone marrow
what regulates platelets? what is this increased by
o Regulated by thrombopoietin
Increased by IL-6 inflammation and low platelet #
structure of platelets
- Anucleate cell fragments with mitochondria, cytoskeleton, secretory granules, receptors
where are platelets stored
- 1/3 stored in spleen and released into circulation during hemorrhage
platelet lifespan
7-10 days
2 types of platelet granule
dense granules and alpha granule
what are platelet granules
- Pre loaded vesicles or endosomes that are released when platelets are activated
what are in dense granules of platelets
o ADP (activate platelets), Ca2+ (co-factor to activate c.c), serotonin (vasoconstrict), polyphosphate (substrate to activate c.c)
what are the most abundant type of granules in platelets
alpha granules
what are in alpha granules
o Von Willebrand factors (vWF), factor V, fibrinogen, growth factors (FGF, VEGF, PDGF)
o Adhesive glycoproteins
what are the 3 platelet glycoproteins and what do they bind
- GP Ib/IX- binds vWF
- GP Ia/IIa- binds collagen under the endothelium
- GPIIb/IIa –once activated; binds fibrinogen or vWF (stability of platelet plug)
platelet function when in healthy body
: endothelium secretes NO, prostacyclin, ADPase to prevent platelet activation
o Also hides collagen and vWF from circulating platelet GP receptors
platelet function when endothelium injury
don’t secrete anti-platelet mediators and expose collagen and vWF
steps in platelet function when injury
- Platelet release reaction (plateRR) is triggered: GP Ib/IX and Ia/IIa binds collagen and vWF platelet adhesion to vessel wall
- PlateRR release alpha and dense granules and activate GP IIb/IIa
- GP IIb/IIa binds fibrinogen platelet aggregation
- PlateRR leads to release of mediators for hemostasis
o ADP (activates other platlets)
o Serotonin and thromboxane (vasposasm)
o Coagulation factors (increase fibrin production and aggregation)
o Ca2+ and polyphosphate release (increase fibrin)
- Platelets amplify coagulation via release of TF (tissue factor) vesicles and procoagulant microparticles
- Platelets express P-selectin to increase leukocyte recruitment
- Platelets have phospholipid surface and Ca2+ = needed for coagulation cascade
what do platelets have on surface needed for coagulation cascade
phospholipid surface and ca2+
what do platelets express to increase leukocyte recruitment
p selectin
what do platelet amplify release of for coagulation cascade
of TF (tissue factor) vesicles and procoagulant microparticles
- GP Ib/IX- binds
vWF
- GP Ia/IIa- binds
collagen under the endothelium
- GPIIb/IIa –once activated; binds
fibrinogen or vWF (stability of platelet plug)
PlateRR leads to release of what mediators
o ADP (activates other platelets)
o Serotonin and thromboxane (vasospasm)
o Coagulation factors (increase fibrin production and aggregation)
o Ca2+ and polyphosphate release (increase fibrin)
extrinsic pathway
- When injury; FVII is exposed to tissue factor (TF) binds and forms FVIIa-TF complex
- This activated FX FXa
- FXa activates prothrombin thrombin fibrinogen fibrin
intrinsic pathway
- FXII comes in contact with negatively charged surface membrane (activated by platelets, collagen) and is activated into FXIIa (slowly)
o complexed with heigh molecular weight kininogen (HMWK) -a protein expressed by activated platelets - FXIIa converts pre-kallikrein into kallikrein
o positive feedback: kallikrein makes more FXIIa from factor XIIa (helps with slow process of above conversion) - HMWK-FXIIa complex activates FXI FXIa
- FIxa complexes with FVIIIa to activate FC FXa
o Tenase= FIXa-FVIIIa-Ca2+ complex - FXa and FVa use Ca2+ to activate prothrombin thrombin
what is tense in intrinsic pathway
FIXa-FVIIIa-Ca2+ complex
positive feedback loop of kallikrein in intrinsic pathway
- FXIIa converts pre-kallikrein into kallikrein
o positive feedback: kallikrein makes more FXIIa from factor XIIa (helps with slow process of above conversion)
HMWK in what pathway
intrinsic path
what do both the extrinsic and extrinsic pathway make for cross talk coagulation
FIXa
what does thrombin activate in cross talk coagulation
o FV FVa
o FVIII FVIIIa
o FXI FXIa
o Positive feedback on self and activate prothrombin
o XIII XIIIa cross link fibrin and stabilize clots
how is FXII pro inflammatory (in intrinsic pathway)
o Activates kinin-kallikrein system release bradykinin (vasodilate, increase, permeability, pain, muscle contraction)
o Cleave C3 and C5 (complement)
o Produce thrombin and fibrin split products (chemokine, COX, and platelet activating factor production = vasodilate, permeability, leukocyte emigration)
how do platelet plugs recruit leukocytes
via p selection expression
what does p selectin expression do in platelets
recruit leukocytes to:
o Modify PG synthesis
o More thrombin generation
o Optimal defense against microbes in blood
3 things that decrease clot formation
- Downregulate platelet activation
a. Via prostacyclin, NO, and ADPase –> inhibit PlateRR - Downregulate coagulation cascade
- Fibrinolysis (destroy fibrin clots)
3 things that will downrgulate platelet activation and inhibit PlateRR
prostacyclin, NO, and ADPase
how to down regulate coagulation cascade (antithrombotic/ anticoagulation)
- antithrombin inhibits thrombin and some activated factors
- protein c (activated by thrombin)
- tissue factor pathway inhibitor (released via heparin)
antithrombin does what to dowregualrate coagulation cascade
- Antithrombin inhibits thrombin and activated factors IX, X, XI, XII
o Heparin increases antithrombin activity
protein c way to dowregualrate coagulation cascade
- Protein C is activated by thrombin
o Protein C + protein S = thrombomodulin cleaves Va and VIIIa
tissue factor pathway inhibitor can downregulate coagulation cascade by
- Tissue factor pathway inhibitor is released in presence of heparin inhibit activation of thrombin by TF and FVIIa
in healthy tissue how does fibrinolytic system (dissolve fibrin clots)
- Healthy endothelium: release tissue plasminogen activator (tPA), which activates plasminogen plasmin
o Plasmin degrades fibrin
o Crosslinked fibrins produce D-dimers (fibrin degradation products) from fibrin proteolysis
what degrades fibrin in healthy tissue
plain
how to inhibit fibrinolysis
Plasminogen activator inhibtors (PAIs) block tPA activity
o Alpha-2 antiplasmin binds to plasmin
labs for coagulation
-prothrombin time
-activated partial thromboplastin time
-thrombin time
-platelet count
thrombin time lab tests for?
o Thrombin added- test for fibrinogen activity
prothrombin time lab
what is added to blood sample
for what coagulation cascade
o International normalized ratio (INR)
o Time it takes to form clot via EXTRINSIC coagulation cascade
o Thromboplastin placed in blood sample and time to clot measured
activated partial thromboplastin time lab
what is added to blood sample
for what coagulation cascade
o Time to clot via INTRINSIC cascade
o Phospholipids placed in blood sample and tome to clot measured
which labs for intrinsic vs extrinsic cascade
- Activated partial thromboplastin time (aPTT) = intrinsic
- prothrombin time= extrinsic cascade
which hemophilia is more common
hemophilia B
hemophilia A vs hemophilia B which deficiency
- Hemophilia A is FVII deficiency
- Hemophilia B is FIX deficiency
genes in hemophilia
x linked recessive
presentation in hemophilias
defects in coagulation labs
o Severe spontaneous deep bleeds (i.e. into joints soft tissues and muscles)
o Hematuria
