Test 2 Lecture 30-31 Flashcards
DIC
bleeding disorder where all the clotting is used up and then the rest of the body bleeds out of every opening
Platelets adhere to subendothelial ____
collagen.
Platelets release ___ and _____, which stimulate platelet aggregation and vasoconstriction of smooth muscle.
ADP
thromboxane
blood encounters ___ on cells outside of the blood vessel. This triggers the formation of ___
tissue factor (protein) fibrin
Fibrin fibers, aggregated platelets and trapped red blood cells form a ___.
clot
platelets come from
cell fragment of megakaryocyte
platelet like cells in non mammals
thrombocytes- nucleated
Common pathway
Cofactor 5 (Thrombin)(Factor 10a)(calcium) =Cofactor 5a
Prothrombin (Factor 10a)(Cofactor 5a)(Ca2+)=Thrombin
Fibrinogen(Thrombin)(Ca2+)= Fibrin Monomer
Factor 13(Thrombin)(Calcium)(Fibrin)=Factor 13a
Fibrin Monomer(Factor 13a) =Fibrin Threads
How is thrombin formed
Prothrombin is cut at two spots (274,323)
large part of protein is lost, the two smaller pieces are held together by a disulfide bond
these two smaller pieces are Thrombin
Calcium ions are required
Prothrombin is cleaved at two specific sites, ___ and ___, to form ___
274
323
thrombin
___ are required for prothrombin to thrombin and many other steps in the common pathway
calcium ions
____ helps hold together the A and B chains of thrombin
Disulfide bond
explain fibrinogen into fibrin threads
fibrinogen (thrombin)= Fibrin monomer
Fibrin monomer (polymerization)= fibrin threads (long chains held together by covalent bonds)
___ has
three subunits: alpha, beta and gamma.
Fibrinogen
___ cleaves short peptides off the N-termini of the alpha and beta chains, to form the fibrin monomer.
thrombin
This exposes N-terminal structures that can
interact with other fibrin monomers, leading to the formation of ____that are held together by _____ interactions.
Fibrin fibers/threads
non- covalent bonds
Covalent cross-linking of the Fibrin Fiber by ___
Factor XIIIa
___ is also known as fibrin stabilizing factor.
Factor XIIIa
Factor XIIIa crosslinks ___ residues from one fibrin monomer to ____ residues in a different fibrin monomer.
glutamine
lysine
Defects in factor XIII lead to
delayed bleeding
clots from: stops bleeding: clot is broken down too quickly and bleeding restarts
common in DIC and Liver disease
pathway that is activated when blood comes in contact with tissue factor
extrinsic Pathway
pathway activated when blood comes in contact with anionic surfaces
intrinsic pathway
Pathway activated by tissue factor, a membrane protein present on most cells outside of the blood, but is not normally present on cells in the blood or the inner layer of the blood vessel
extrinsic pathway
pathway activated by exposure of the blood to anionic surfaces. This can occur in vivo when the blood leaves the vessel or in vitro when the blood contacts glass or other surfaces.
intrinsic pathway
(blood taken out and put in glass tube will clot on its own)
factors in the coagulation pathway are present as ___
zymogens- inactive precursors
Activation of factors in the coagulation pathway involves ___
proteolytic cleavage
(breaking proteins)
efficient and rapid
Most activated factors in the coagulation pathway are ___, exceptions are ___, ___ and ___
proteases
Cofactor proteins: Tissue factor, VIIIa, Va
Fibrin: structural component of clots
Factor XIIIa: cross links Fibrin monomers
extrinsic pathway of coagulation
Trauma: blood will spill out and interact with
Tissue factor binds to 7
these are cleaved by traces of active protease in the blood (Factor 10a, thrombin, factor 7a, Factor 9a) and calcium will form: 7a +Tissue Factor complex
7a +Tissue factor complex (Ca)cleaves 10 to 10a
Common Pathway
Xa + Cofactor Va will cleave Prothrombin to Thrombin
intrinsic pathway
12 (Kiniogen)(Kallikrein)=12a
11 (12a)=11a
9(11a)(calcium)=9a
10 (9a (cofactor 8a)(calcium))=10a
contact phase of coagulation pathway
12 (kiniogen)(kallikrein) = 12a
Deficiency of cofactor 8
hemophilia A
last step in intrinisc pathway
10((9a)(cofactor 8a))= 10 a
deficiency in factor 9
hemophilia B
3rd step of instrinsic pathway
9(11a)=9a
Thrombin can activate
Intrinsic pathway:
Factor 11 → Factor 11a
Cofactor 8 → (thrombin)(calcium)(Factor 10a)→Cofactor 8a
common pathway:
Cofactor 5 → (thrombin)(factor 10a)(Calcium)→ Cofactor 5a
Factor 13 →(thrombin)(calcium)(Fibrin)→ Factor 13a
Extrinsic Pathway can turn on Intrinsic pathway by
Factor 9 (Factor 7a +Tissue Factor complex)(Calcium)→ Factor 9a
Factor 9a then binds with Cofactor 8a
10 (9a +Cofactor 8a complex) → 10a
Thrombin can turn on intrinsic pathway by
Factor 11 (Thrombin)→ Factor 11a
Cofactor 8 (Thrombin)(Factor 10a)(Ca) → Cofactor 8a
thrombin can activate common pathway by
Cofactor 5 (thrombin)(Factor 10a)(Calcium)→ Factor 5a
Factor 13 (thrombin)(Fibrin)(Calcium)→ Factor 13a
Why are hemophilia A and B more common than most other genetic clotting disorders?
found on X chromosome
if males (XY) only get 1 bad copy and will express the trait
Females (XX) one bad copy → carries
Deficiencies in factors 8, 9 and factor 11 cause bleeding problems showing that intrinsic pathway is important. However, deficiencies in factor 12, kininogen and kallikrein do not. How can this be explained
Factor 12, kininogen and kallikrein =contact phase
not needed because other steps of intrinsic pathway can be turned on by thrombin
Initiation occurs by exposure to ____, which is present on the surface of most cells, but is normally absent from cells in the ___and _____
tissue factor
blood
endothelial cells
Intrinsic pathway is activated by _______, which activates XI to XIa and VIII
to VIIIa. In addition, the VIIa/tissue factor complex activates IX to IXa.
thrombin
Thrombin also activates factors _____ and _____ of the common pathway.
Factor 5
Factor 13
Intrinsic pathway required for ______ . Contact phase is not required for
initiation or amplification.
amplification
The concentration of early coagulation factors is___, and late factors are ___
low
high
(more of the things at the end then the things at the beginning)
Factor _____ has a short half-life in dogs and humans.
7
Most factors are made by the ________. Liver disease can lead to excessive or insufficient coagulation, because liver also makes ________ proteins and removes activated coagulation factors from the blood.
Liver
anticoagulant
What 4 factors are vitamin K dependent
Prothrombin(Factor 2), Factor 7, 9 and 10
Hemophilia A is a ___ deficiency
Factor 8
X linked recessive
intrinsic pathway
Cofactor 8 (thrombin)(Calcium)(10a)→ Cofactor 8a
Factor 10 (Cofactor 8a)(9a)(Calcium)→ Factor 10a
Von Willebrand disease
found in dogs
autosomal recessive, more commonly incomplete dominance
von Willebrand factor is produced by endothelial cells and circulates in the blood in a complex with factor 8. It is also released by platelets.
It promotes platelet adherence, and its deficiency can cause excess bleeding
Therapies: plasma, cryoprecipitate, DDAVP
Hemophilia B is ___
deficiency in Factor 9
X linked
intrinsic pathway
9(11a)(calcium)→ 9a
10 (9a + cofactor 8a complex+Calcium)→ 10a
Hageman Factor
Deficiency in Factor 12
contact phase- 12 (kinionogen)(kallikrein)→ 12a
11 (12a)→ 11a
autocomal recessive
absent in marine mammals, fowl and most reptiles
The most common hereditary coagulation deficiencies are
Hemophilia A ( Factor 8)and Hemophilia B (Factor 9) because they are X linked
Factor ________ deficiency is relatively common in the cat, but does not cause coagulation deficiency.
Factor 12
Hageman Deficiency in Factor 12
contact phase- 12 (kinionogen)(kallikrein)→ 12a
11 (12a)→ 11a
autocomal recessive
absent in marine mammals, fowl and most reptiles
___ is produced by endothelial cells and circulates in the blood in a complex with factor 8. It is also released by platelets.
Von Willebrand Factor
___ promotes platelet adherence, and its deficiency can cause excess bleeding.
Von willebrand factor
what types of dogs are common to get von willebrand
Dobermans
How to treat von Willebrand Factor
give von Willebrand Factor
plasma
Cryoprecipitate – material that comes out of solutions when frozen plasma is thawed. It is enriched in von Willebrand factor and some other coagulation factors.
DDAVP – derivative of arginine vasopressin that stimulates release of stored von Willebrand factor
Thromboxane does what ___
helps bind platelets to collagen
causes smooth muscle to constrict
The activity of four factors: ___ is dependent on ___
Factor 2(Prothrombin)
Factor 7,9,10
Vitamin K
Vitamin K is cofactor for:
protein carboxylase
(add carboxyl group to proteins)
add COOH (HO-C=O)
Specific glutamate residues are carboxylated to form a modified glutamate residue called ___
gamma carboxyglutamate
carboxylation of glutamate to gamma carboxyglutamate happens __
in the liver, before it is secreted into the blood (post translation modification)
gamma-carboxyglutamate residues bind
calcium ions (Ca2+)
2+ binds to the 2- of the gamma-carboxyglutamate
explain calcium sandwich
Vitamin K dependent coagulation factor has gamma carboxyglutamate (-2 charge) attached
this -2 charge attracts the +2 charge of calcium ions
the +2 charge of calcium ions also attracts the - charged phospholipids of the lipid bilayer of an activated platelet
The calcium sandwich allows the coagulation factors to bind to negatively charged ___
phospholipids on the lipid bilayer of activated platelets
Activated cofactor proteins ___ and ___also associate with platelet membranes this is not a vitamin ___ dependent association.
5a and 8a
Vitamin K
prothrombin (Cofactor 5a+10a complex)(Ca)→ Thrombin
Factor 10 (Factor 9a+Cofactor 8a complex)(Calcium))→ Factor 10a
The association of vitamin K dependent factors and activated cofactors with activated platelet membranes greatly _______ the coagulation cascade.
accelerates
clots occur in seconds
how does Vitamin K get recycled
vitamin K will give COOH to glutamate to make gamma- carboxyglutamate,
leaving Vitamin K inactive and oxidized with a hypoxide group (3 member ring with O)
this needs to be reduced back into active form of vitamin K
this can be inhibited by warfarin and dicourmarol
recycling of vitamin K is inhibited by ___
warfarin and discoumarol
Vitamin K is oxidized to an ______ by the carboxylation reaction.
inactive hypoxide form
(3 member ring with O)
Active vitamin K is regenerated by enzymatic ___, this process happens in the ____
reduction,
liver
Warfarin is used as an ____ in human medicine.
anticoagulant
It is also used as a ____ poison that causes death by bleeding. Warfarin resistant rats have emerged, leading to the development of different vitamin K recycling antagonists, such as ___. Unintended poisoning of pets and wildlife occurs.
rodent
brodifacoum
Treatment to inhibition of vitamin K recycling is ___
give plasma- short term source of vitamin K Factors
Give vitamin K
Dicoumarol is found in moldy ___. Can cause excess bleeding in cattle that eat it.
sweet clover.
treatment for dicoumarol
transfusion, plasma
give vitamin K
what is produced by endothelial cells to prevent clotting
PGI2 Prostacyclin
How does Prostacyclin work
inhibits thromboxane
which inhibits vasoconstriction and platelet aggregation
What is produced by the liver to stop clotting?
antithrombin III
Explain Antithrombin III
produced by the liver
inhibits Thrombin, Factor 9a, 10a, 11a
needs to be activated by Heparin
common in kidney disease: ATIII is lost in urine and low levels of ATIII leads to excessive clotting
Low levels of Antithrombin III leads to
thrombosis, excessive clotting
Heparin activates ____. Heparin is a negatively charged _______, and related molecules are present on the surface of endothelial cells.
antithrombin III
polysaccaride
how does thrombin act as anticoagulation
Thrombin activates protein C which inactivated Cofactor 5a and 8a
Thrombin activates the release of PGI2 by intact endothelial cells
Activated protein C – Inactivates cofactors ___ and ___ by proteolytic cleavage. Protein C is activated by _____. Protein C is a vitamin K dependent blood protein synthesized by the liver.
5a and 8a
thrombin
prothrombin (Cofactor 5a+10a complex)(Ca)→ Thrombin
Factor 10 (Factor 9a+Cofactor 8a complex)(Calcium))→ Factor 10a
Coagulation
Free thrombin activates platelets, clots fibrinogen, and converts inactive forms of coagulation factors ____ to their active (a) forms.
5, 8 and 11
(13 to 13a)
When thrombin bound to the cell-surface transmembrane protein, ____, thrombin’s procoagulant properties are neutralized and its ability to activate protein C is tremendously enhanced.
thrombomodulin
Activated protein C (aPC) is a potent anticoagulant that inactivates factors ___and ___ with assistance from the cofactor, protein S, yielding inactive factor ___ and ____
5a and 8a
5i and 8i
Thrombin when acting as coagulant helps activate ____, ___ and ____
factors 5, 8, 11 and 13
Fibrinogen to Fibrin
Platelet activation
___ is present on the surface of endothelial cells. Low levels of thrombin in circulation will have an anticoagulant effect when in contact with normal endothelium.
Thrombomodulin
____ of thrombin in circulation will have an anticoagulant effect when in contact with normal endothelium, ___ of thrombin in circulation will have an procoagulant effect
low levels
high levels
Plasminogen ___ is released from damaged tissue and endothelial cells.
activator
Plasminogen activator cleaves plasminogen to form ______, which is a protease that degrades fibrin.
plasmin
Plasminogen activator and plasminogen both bind to _______, leading to the selective formation of plasmin in the clot.
fibrin clots
how to break down clot
TPA
Tissue-type plasminogen activator leads to the dissolution of blood clots.
used to break up clots (stroke treatment)
not very effective in cats: feline aortic thromboembolism (FATE), because of side effects
how is heparin work as anticoagulant
activates antithrombin III
How does coumarin work as anticoagulant
inhibits the recycling of Vitamin K
no Vitamin K then glutamate cant change to gamma carboxyglutamate, cant bind to Calcium, wont bind to plasma membrane and trigger cofactors
Are these anticoagulants or thrombotic agents: Oxalate, citrate and EDTA
anticoagulants
Binds or percipitate Calcium ions
removes Calcium from the blood
no Calcium then factors and plasma membrane of platelets wont interact
