Recap 2 Flashcards
What molecules can pass through continuous capillaries?
H2O, O2, CO2 and ions
Composition of post-capillary venules
Low resistance for return of blood, high distensibility = store large amounts of blood (65% of total blood volume is in systemic veins)
What does endothelial activation produce?
Activation by oxidative stress, hypoxia, inflammation, infectious agents and tissue injury -> produce and release numerous substances locally
What is the body water distribution?
Water = 60% body weight
2/3 = IC
1/3 = EC = 80% interstitium 20% plasma
What can water move through?
Water and polar molecules move through internedothelial pores = large enough for water, small nutrients (ions, glucose, amino acids), waste products but not cells or large proteins
Actions of histamine, bradykinin, leukotrienes, substance P
Endothelial contraction and widening of interendothelial gaps = immediate increase in permeability
What is the consequence of exposition of platelet phospholipids during platelet aggregation?
+++ phosphatidylserine, phosphatidylethanolamine = biologic surface to localize and concentrate activated coagulation factors
Vitamin K dependent coag factors
2, 7, 9, 10
Highly labile fibrinogen group of coag factors
1, 5, 8, 13
How are coagulation factors activated
Activated by hydrolysis or arginine or lysine-containing peptides to convert enzymatically active serine proteases (except XIII = has cysteine-rich active sites)
Action of Nitric oxide (anticoag)
Maintains vascular relaxation
Inhibit platelet aggregation
Acts synergically with protC pathway and antithrombin III (ATIII) to suppress thrombin production
Role of protein S
Cofactor in protC pathway
Independently inhibits activation of factors 5 et 8
Role of Tissue factor pathway inhibitor-1 (TFPI-1)
A cell-surface protein that directly inhibits the factor TF : 7a complex and factor Xa
When is VwF released?
After endothelial exposure to substance such as thrombin, histamine and fibrin
substance causing vasoD
Nitric oxide
PGI2
Endothelial derived hyperpolarizing factor
C-type peptide
Substance causing vasoC
ROS
Angiotensin II
TxA
More efficient adhesion of platelets (how)
Occurs when vWf (released by activated endothelium or cleavage by fVIII) coats subendothelial collagen to form a Sp bridge between collagen and GPIb
Where is the tissue factor (TF) expressed?
Perivascular cells (fibroblasts), microparticals derived from activated endothelium, platelets, monocytes, apoptotic cells
Actions of circulating factor 7 or 7a (extrinsic pathway)
Forms a Ca2+ dependent TF:VII complex on the surface of injured area expressing TF and is activated
Activators : 12a, 10a, 9a, thrombin, plasmin, factor VII-activating protease
TF:VIIa (extrinsic tenase complex) directly activates factor 10 and 9 (component of intrinsic tenase complex IXa/VIIIa)
Action of thrombin
Amount insufficient to convert significant amount of fibrinogen into fibrin but activates platelets bound to vWf or collagen at site of injury -> activates factors 11, 8, 5, 13 (amplification phase)
How does the bound plasmin restricts the size of the platelet-fibrin aggregate
By degrading both cross-linked (insoluble) fibrin and fibrinogen so that additional fibrin formation is inhibited
Dissolution of insoluble fibrin by plasmin results in formation of fibrin degradation products (FDP) = can impair homeostase = inhibit thrombin, interfere with fibrin polymerization and can coat platelet membranes to inhibit their aggregation
Functions of prot C et prot S, activation
VitaminK dependent glycoproteins that (when complexed together on phospholipid surfaces) potently inhibit coagulation by destroying factor 5a et 8a
Activation at low concentration but increase in efficiency after binding of thrombin to the endothelial-R thrombomodulin
Further enhanced by presence of protC-R on the surface of endo cells
ProtC-S complex can also enhance fibrinolysis by neutralizing plasminogen activator inhibitors
To what is endothelial heparan sulfate bound
AT and TFPI
Role of heparin
Major role = bind and enhance activity of AT
Inhibits coag by enhancing the release of TFPI from endo cells and interfering with binding of platelet-R to vWf
What is AT, role?
AT = most potent and clinically significant = circulating serine protease produced by endothelium and hepatocytes
Degrades to some extent virtually all activated coag factors (+++ 2,7,9,10,11,12) but most recognized for inhibition of thrombin and factor 10a
Inhibits fibrinolysis (inactive plasmin and kallikrein), kinin formation, complement activation (inactive C1)
Role of plasminogen activator inhibitor 1 (PAI1)
Inhibits tPA and urokinase = inhibe fibrinolysis and promotes fibrin stabilisation
Inactive active protC, plasmin, thrombin
Role of thrombin-activatable fibrinolysis inhibitor (TAFI)
Thrombin/thrombomodulin complex/activated TAFI cleaves plasminogen/tPA binding sites from fibrin = reduce plasmin concentration
Antiinflamm = inactive bradykinin and complement C3a/C5a
role of alpha2-macroglobulin
Major plasma inhibitor of activated protC
Role of alpha1-antitrypsin
Weak inhibitor of fibrinolysis
Potent inhibitor of factor 11a
Plasma inhibitor of activated protC
Autosomal deficiency in coag factors
Factor 12 = no increase bleeding
Factor 10 = severe hemorrhage
Factor 8-9 = subclinical to severe
3 congenital types of vW disease
1- + common = partial decrease of all multimers
2. Decrease in HMW multimers, severe, rare
3. Virtual absence of vWF activity, severe, autosomal recessive
Acquired vW disease, who, test, gene
Doberman, ELISA
ADAMTS13 = cleave ultralarge vWF multimers (to appropriate size)
Deficiency = large vWF = greater reactivity with platelets = hemolytic anemia and thrombocytopenia
Morphology of venous thrombi
In area of stasis
Dark red
Almost always occlusive but very loose
By what are initiated immunothrombosis
TF, factor 12 and neutrophils elastase = microthrombi that can localize pathogens and host products
If excessive = CIVD
CIVD :
1. Fibrinolytic form
2. Thrombotic form
- Fibrinolytic = associated with excessive activation of tPA with consumption of factors = widespread hemorrhage
- Thrombotic = associated with excessive PAI-1 activity = widespread microthrombosis and multiple organ failure due to ischemia
In blood vessels, where are de B2-receptors and the a-receptors?
B2 = cardiac and skeletal muscle -> vasoD when stimulated by epinephrine
aR = most organs (not brain) -> vasoC when stimulated by norepinephrine
Action of ATP in ischemia
After brief ischemia ATP degraded to adenosine (vasoD) to relieve ischemia
After prolonged ischemia = Hypoxanthine (breakdown product of ATP) -> damage
Localisation of infarcts due to blood supply to organs
Most susceptible = brain, heart, spleen, kidney
Parallel blood supply = skeletal muscle, TGI
Dual blood supply = less susceptible = liver (hepatic artery, portal vein) and lungs
LPS on coagulation
Endothelial activation by LPS = inhibe prod of anticoag (TFPI, thrombomodulin)
Induced release of TNF, IL1, IL6, IL8
Directly activates factor 12 = promote intrinsic coag (kinins, fibrinolysis, complement)
Effects of cytokines on coagulation
TNF + IL1 induce TF expression = endo activation and extrinsic coag
IL1 stimule release of PAF (aggregat, thrombosis, permeability, stimule PGI2 and TxA2) and PAI = enhance coag
TNF and IL1 induce NO production = vasoD, hypotension
Composition of platelets granules
A- granule :
- P-selectin on membrane
- Prots for coag = fibrinogen, factor V, vWF
- Prots for wound healing = fibronectin, PF4, factor 8, thrombospondin, PDGF
Dense granule :
- ADP (platelet activation ++), ATP, ionized Ca, serotonin, epinephrin, histamine
Platelet adhere to collagen with what R?
To vWF?
Collagen = GpIa/IIa
vWF = GpIb
How does thrombin contribute to platelet activation? ADP? Consequence?
Thrombin : Active platelets through protease activated receptor-1 (PAR1) = switched on by proteolytic cleavage by thrombin
ADP : Binds to P2Y1 et P2Y12 receptors
—> lead to change of shape = filpodia (stimulated by ADP, collagen, EPI, thrombin, Tx, PAF) + secretion of granule content
Impact of prothrombin deficiency
Incompatible with life
Inflammatory effects of PAR
Expressed on inflamm cells and endothelium = active thrombin = mediate pro-inflamm effects, tissue repair and angiogenesis
Anti-coagulants on endothelium
Endothelial protein C-R = binds protC
Heparin-like molecules = binds/active antithrombin3 = inhibe thrombine and factor 9-10-11-12
TFPI = need protein S = binds and inhibe TF/VIIa complex
Hypercoagulability :
Role
Factor V (Leiden)
Homocysteinemia
Old age
Important role in venous thrombi
V : most common, autosomal dominant, factor V resistant to cleavage/inactivation by protein C
Homocysteinemia : prothrombic (homocysteine+++), inherited deficiency of cystathione B-synthetase, acquired deficiency in vitB6, B12, acid follicles
Old age : reduced PGI2 production
Pathophysiology of antiphospholipid antibody syndrome (APS)
- aPL AC against anionic membrane phospholipids or proteins associated with phospholipids (cardiolipin, B2-glycoprotein I)
- B2-glycoprotein I AC active endo cells, monocytes, platelets
- Complement activation, inhibe fibrinolytic process
- AC-mediated interference with growth/differenciation of trophoblasts = failure of placentation
Pathogeny of procoagulant state in septic shock
Proinflamm cytokines: increase TF production, decrease endothelial anticoag factors (TFPI, thrombomodulin, protC), reduce fibrinolysis (increase PAI1)
NET stimule both pathway of coagulation
Vascular leak + edema decrease blood flow in small vessels = stasis
Systemic activation of thrombin
Pathogeny of hyperglycemia in septic shock
Cytokine TNF, IL1, stress induced hormone, catecholamines drive gluconeogenesis
Cytokines suppress insulin release and promote insulin resistance by impairing expression of GLUT4
What is Waterhouse-Friderichsen syndrome?
Sepsis sometimes followed by adrenal insufficiency with deficit in GC
