Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
57 Cards in this Set
- Front
- Back
|
What is hemostasis?
|
no bleeding
|
|
|
What is Phase 1 of hemostasis?
|
Procoagulation - the process of clot formation
|
|
|
What is Phase 2 of hemostasis?
|
Anticoagulation - the process of stopping clot formation
|
|
|
What is Phase 3 of hemostasis?
|
Fibrinolysis - the process of clot dissolution
|
|
|
What is the approximate volume of blood in the human body?
|
~ 1.5 gallons or ~ 5 L (est is 4.7L)
|
|
|
What are the two pathways of procoagulation and what is their merger point?
|
Intrinsic contact factor pathway and the extrinsic tissue factor pathway. Both pathways merge at factor X
|
|
|
What initiates the intrinsic pathway in blood coagulation?
|
The anionic surfaces exposed upon rupture of the endothelial lining forms clots. Hageman factor (FXII) binds to the expose anions, has a conformational change, and becomes active (FXIIa). FXIIa activates prekallikrein and high molecular weight kininogen which in turn proteolytically activate FXIIa from its confomationally active state so that it is no longer required to be bound to the anionic surface.
|
|
|
What initiates the extrinsic pathway in blood coagulation?
|
Factor III (or tissue factor, TF). Tissue factor is an integral membrane protein that is exposed upon rupture of blood vessels. TF converts inactive Stuart factor (Factor X, FX) to active Stuart facto (Factor Xa, FXa). This results in a cascade effect to produce a large local response.
|
|
|
What is hemophilia?
|
Hemophilia is an inherited disorder with permanent tendency for spontaneous or traumatic hemorrhages
|
|
|
What is the cause of Hemophilia A?
|
X-linked recessive disorder deficient of FVIII
|
|
|
What is the cause of Hemophilia B?
|
dysfunction of FIX
|
|
|
Hemophilia affects which branch of coagulation?
|
intrinsic
|
|
|
What does prothrombin contain that facilitates its activation?
|
10 gamma-carboxyglutamate residues in its N-terminus. This is a highly negatively charged region which attracts and binds Ca2+ ions. The calcium ions facilitate binding to membrane surfaces and to the prothormbinase complex (FXa:FVa) at an injury site.
|
|
|
What activates prothrombin? What is the structure of the active thrombin?
|
Prothrombin is activated by two proteolytic cleavages C-terminally to Arg residues. The active thrombin enzyme (alpha-thrombin, FIIa) consists of two chains linked by a disulfide bond
|
|
|
What reacts with fibrinogen to form a soft blood clot?
|
FIIa
|
|
|
What drug can bind to FIIa to affect is pharmacological response?
|
heparin
|
|
|
What is the structure of fibrinogen?
|
Fi consists of six chains (alpha, beta, gamma)2 that are linked at their N-terminal regions by disulfide bonds. The N-terminal regions of the alpha and beta chains are negatively charged. The negative charge-charge repulsions keep the soluble fibrinogen molecules away from each other.
|
|
|
What is the cause of Hemophilia B?
|
dysfunction of FIX
|
|
|
Where does thrombin cleave fibrinogen? What is the effect?
|
Thrombin cleaves off the alpha and beta N-terminae converting fibrinogen into fibrin. Removing the negative charges allows the fibrin monomers to aggregate.
|
|
|
Hemophilia affects which branch of coagulation?
|
intrinsic
|
|
|
What is the composition of a soft clot? What holds the soft clot together?
|
Fibrin monomers are attracted to each other and self associate in a half-staggered soft clot. The soft clot is held together by electrostatic interactions and hydrophobic interactions
|
|
|
What activates Factor XIII?
|
Thrombin; factor XIII is a transglutamidase
|
|
|
What does prothrombin contain that facilitates its activation?
|
10 gamma-carboxyglutamate residues in its N-terminus. This is a highly negatively charged region which attracts and binds Ca2+ ions. The calcium ions facilitate binding to membrane surfaces and to the prothormbinase complex (FXa:FVa) at an injury site.
|
|
|
What activates prothrombin? What is the structure of the active thrombin?
|
Prothrombin is activated by two proteolytic cleavages C-terminally to Arg residues. The active thrombin enzyme (alpha-thrombin, FIIa) consists of two chains linked by a disulfide bond
|
|
|
What reacts with fibrinogen to form a soft blood clot?
|
FIIa
|
|
|
What drug can bind to FIIa to affect is pharmacological response?
|
heparin
|
|
|
What is the structure of fibrinogen?
|
Fi consists of six chains (alpha, beta, gamma)2 that are linked at their N-terminal regions by disulfide bonds. The N-terminal regions of the alpha and beta chains are negatively charged. The negative charge-charge repulsions keep the soluble fibrinogen molecules away from each other.
|
|
|
Where does thrombin cleave fibrinogen? What is the effect?
|
Thrombin cleaves off the alpha and beta N-terminae converting fibrinogen into fibrin. Removing the negative charges allows the fibrin monomers to aggregate.
|
|
|
What is the composition of a soft clot? What holds the soft clot together?
|
Fibrin monomers are attracted to each other and self associate in a half-staggered soft clot. The soft clot is held together by electrostatic interactions and hydrophobic interactions
|
|
|
What activates Factor XIII?
|
Thrombin; factor XIII is a transglutamidase
|
|
|
How does FXIIIa change the interactions holding the blood clot together?
|
FXIIIa forms covalent isopeptide cross-links between the delta-amide of Gln and the epsilon-amine of Lys joining two fibrin monomers. The covalent cross-links confer structural strength to the blood clot
|
|
|
What mediates clumping of platelets at the injury site?
|
thrombin; endothelial cells contain a throbin receptor that is exposed upon injury. thrombin activates the receptor and then blood platelets bind to it forming a physical plug
|
|
|
What do bound platelets release?
|
ADP, serotonin, von Willebrand factor (vWF)
|
|
|
What is the function of vWF?
|
von Willebrand factor links the platelets to the receptor
|
|
|
What is the function of ADP and thromboxane A2 released from the platelets that are bound?
|
to activate more platelets
|
|
|
When does anticoagulation begin?
|
almost simultaneously with procoagulation. anticoagulation is slightly slower than the procoagulation cascade. it restricts procoagulation from spreading far from the injury but does not stop procoagulation immediately at the injury. as inactive procoagulat enzymes are consumed, their activating rxns slow down. anticoagulation eventually stops the procoagulation
|
|
|
What is the function of TFPI?
|
Tissue factor pathway inhibitor inhibits the extrinsic pathway. Once TF is active and complexed with FVIIa, Ca2+, and FXa, then TFPI will bind to the complex. It has three binding domains.
|
|
|
What are the three binding domains of TFPI?
|
TFPI has three domains that irreversibly bind a different molecule. Domain 3 binds to an endothelial cell and signals for endocytosis. The complex is endocytosed and degraded. Domain 2 bind FVIIa. Domain 1 binds FXa
|
|
|
What is another name for AT3?
|
Antithrombin III
|
|
|
What is the function of AT3?
|
AT3 is a serpin that inhibits thrombin, FXa, and others. AT3 inhibition is increased toward IIa by 9000 fold and increased toward FXa by 17000 when complexed with heparin
|
|
|
What variation of heparin can affect its inhibition?
|
It has a size dependent inhibition (its a mixture of oligosaccharides). At least 18 saccharide units are required for effective thrombin inhibition in vivo.
|
|
|
What class of molecule is heparin?
|
Proteoglycan - contains 95% or more carbohydrate linked to very little protein
|
|
|
What is the structure of a repeat unit of heparin?
|
A glucuronic acid alpha-1,4 linked to glucosamine. Heparin may contain a few saccharides or hundreds
|
|
|
What is the structure of glucuronic acid?
|
Its a glc with a carboxylate at C6
|
|
|
What is the structure of a glucosamine?
|
its a glc with an amine at C2
|
|
|
What attracts heparin to antithrombin III?
|
the negatively charged sulfates and carboxylates are attracted to positively charged aas of AT3
|
|
|
Where is heparin found?
|
in mast cells that line arterial walls and is released through injury. Heparin is thought to prevent runaway blood clot formation
|
|
|
What is ZPI?
|
Protein Z-dependent protease inhibitor; plasma protein; It complexes with protein Z (PZ; another plasma protein); it complexes along with Ca2+ and FXa on a membrane surface to inhibit FXa. The inhibition is increased if heparin is also complexed
|
|
|
How can thrombin act as an anticoagulant?
|
Thrombin, which cleaves FV and FVIII to activate them, can be directed to cleave protein C (PC). Thrombin can complex with thrombomodulin (TM, an integral protein), CA2+, and PC to activate PC. This changes thrombin from a procoagulant to an anticoagulant. PCa complexes with cofactor protein S (PS) to cleave FVa and FVIIIa inactivating them
|
|
|
What occurs in fibrinolysis?
|
Plasminogen and tissue plasminogen activator (t-PA) both have a high affinity for fibrin clots. Both localize to a fibrin clot where t-PA activates plasminogen to plasmin. Plasmin digests the fibrin blood clot into fragments. After the fibrin clot has been broken into soluble fibrin fragments t-PA and plasmin are inhibitied. t-PA is inhibited by plasminogen activator-inhibitor type 1 (PAI-1) and by plasminogen activator-inhibitor type 2 (PAI-2). Plasmin is inhibited by alpha2-antiplasmin
|
|
|
What are the hemostatis molecules which involve Gla residues?
|
Prothrombin, Factor VII, Factor IX, Factor X, and protein C. The Gla residues are usually located near the N-terminus
|
|
|
What is a Gla residue?
|
gamma-carboxyglutamyl residues. Synthesized by posttranslational modifications of Glu. The -2 charge of Gla makes it an excellent chelator of Ca2+. The electrostatic charge of Gla is necessary in binding and conformation changes of blood coagulation and anticoagulation enzymes
|
|
|
What converts Glu to Gla? where does this occur? What is an essential cofactor for this action?
|
Glu is converted to Gla by a carboxylase located on the luminal side of the rough ER. Vitamin K is an essential cofactor for this carboxylase
|
|
|
How does Vit K contribute to coagulation enzymes?
|
Vit K is reduced by K-reductase to dihydroquinone. This combines with molecular oxygen to for a strong base which deprotonates the gamma-methylene carbon of Glu forming a carbanion. The nucleophile carbanion adds to C02 forming Gla. The Gla is required for the conformation changes to allow the function of the coagulation enzymes. The end product that Vit K is converted into is an epoxide.
|
|
|
What converts the epoxide generated while synthesizing Gla back into dihydroquinone?
|
dithiol dependent KO-reductase and then dithiol dependent K-reductase to form dihydroquinone
|
|
|
What happens is either dithiol dependent KO-reductase or dithiol dpendent K-reductase is inhibited?
|
Gla cannot be formed on the coagulation enzymes rendering them useless
|
|
|
What drugs inhibit dithiol dependent K-reductase and KO-reductase?
|
dicoumarol and warfarin
|
