Hemostasis Flashcards
Hemostasis
process by which blood clots form at sites of vascular injury
results in arrest of bleeding
What’s involved?
- endothelium
- platelets (primary)
- coagulation cascade (secondary)
- fibrinolysis
Healthy Endothelium
hemostasis
maintains anticoagulant env. to maintain smooth + easy path for blood
1) platelets don’t readily adhere to intact endothelium
- prostaglandin-I2 inhibits platelet adhesion + activation
- NO keeps endothelium relaxed + inhibits platelet aggregation
- ADP-ase breaks down ADP
- etc.
2) thrombomodulin inhibits thrombin from activating fibrin
Endothelium in Disease
procoagulant effects of endothelium activated upon vascular injury
1) vasoconstriction
- reflex neurogenic mechanism -> immediate but transient
- markedly reduces blood flow to injured area
- brings platelets in contact with endothelium
2) exposure of subendothelial collagen
- site at which platelets can assemble
- sets stage for subsequent steps
Platelets
responsible for initial plug formed during primary hemostasis
cytoplasmic fragments which originate from cytoplasm of megakaryocytes
- platelets normally circulate in health
Cytoplasm:
1) several types of granules w/ procoagulant factors
- Ca2+, ADP, vWF, Factor V
2) open cannicular system
- allows for transport of substances + signaling mol. into platelets
- pathway for release of platelet granule products
Membrane Receptors:
- Gp-Ib
- GpIIB-IIIa complex
megakaryocytes
originate from bone marrow in most species
large cells which divide via endomitosis when mature
- nuclear division without cell division
pseudopodial extensions called proplatelets reach into bone marrow sinusoids
- fragments which break off of proplatelets become circulating platelets
Adhesion
Platelet Function
Gp-Ib on platelet binds vWF expressed on subendothelial collagen
requires vascular injury
- subendothelial collagen is inaccessible if endothelium is intact
Activation
Platelet Function
once adhered, platelets change shape + become activated
1) conformational changes in membrane GpIIb/IIIa receptor increases affinity for fibrinogen
2) phosphatidylserine (-) translocates to cell surface to allow for Ca2+ binding
3) secretion of granule contents promotes platelet aggreggations
- ADP activates nearby platelets
- Thromboxane A2 induces aggregation
Aggregation
Platelet function
conformation change in GpIIb/IIIa allows platelets to bind fibrinogen (+/- vWF)
- forms bridges between adjacent platelets leading to aggregation
- initially reversible, becomes permanent once thrombin formed through coagulation cascade
resulting platelet plug initially patches area of endothelial injury
- completes process of primary hemostasis
- sets stage for secondary hemostasis
Thrombocytopenia v Thrombocytopathy
Thrombocytopenia = decreased platelet conc.
v
Thrombocytopathy = abnormal plateley function
Coagulation Cascade (Secondary Hemostasis)
series of steps which result in formation of fibrin
classic/lab model consists of 3 major pathways:
- intrinsic
- extrinsic
- common
cell-based model better reflects in vivo cascade
Coagulation Factors
majority are proteins produced in liver
- circulate as inactive proteins in steady state
named as Factor I - XIII
- active forms have subscript = a
Vitamin K dependent Factors = II, VII, IX, X
cascade of factor activation to form fibrin
- active forms of each factor activate next factor in pathway
Intrinsic Pathway
Coagulation
Exposure of collagen stimulates platelet adhesion + aggregation
negatively charged surface of platelets activates Factor XII to XIIa to start cascade
Factor VIIIa activated seperately by forming complex with vWF
Extrinsic Pathway
Coagulation
stimulated by release of Tissue Factor (FIII) from damaged endothelium
Factor VII has short 1/2 life of all factors
in vivo = factor VIIa also activate Factor IX via intrinsic
Common Pathway
Coagulation
activation of factor X via extrincsic +/or intrinsic pathway
conversion of prothrombin (II) to thrombin (IIa)
thrombin responsible for converting fibrinogen to fibrin -> stabilizes platelet plug
factor VIII activated by thrombin to crosslink fibrin + stabilize clot
Full Coagulation Cascade
Fibrinolysis
breakdown of clot following endothelial repair
plasmin major protein involved in breakdown of fibrin
1) normally present as inactive plasminogen
2) multiple activators = t-Pa on healthy endo, Factor XIIa in vivo, kallikrein, urokinase
Fibrin Degradation Products (FDPs) generated from fibrin breakdown
- can be measured clinically
Thrombus + Thrombosis
thrombus = aggregate of platelets, fibrin, other components of blood formed on vascular wall
- may be physiologic
- pathologic forms as result of 1+ = abnormal blood flow, hypercoagulabilit, endothelial injury
thrombosis = refers to blood clot inside vessel which disrupts blood flow to tissue often resulting in ischemic necrosis + damage/death of tissue
Altered blood flow
Thrombosis
turbulent blood flow causes endothelium damage + activation
disruption of laminar flow allows platelets to interact with endothelium more readily
abnormal influx of blood prevents dilution of activated coagulation factors + inflow of clotting factor inhibitors
- check + balance system disrupted in favor of clot formation
Fate of Thrombus
Propagation
- thrombus continues to grow + more platelets + fibrin
Dissolution
- fibrinolysis kicks in + major clot shrinkage occurs
Emobolization
- chunks of thrombus break off + travel to other locations
Organization + Recanalization
