Hemostasis Flashcards
What are the 3 phases of hemostasis
Primary-formation of a plug
Secondary=coagulation
Tertiary-fibrinolysis
What is von willebrand factor?
vWF is a large, heterogeneous multimeric glycoprotein that protects factor VIII from rapid inactivation
how does von willebrand factor bind?
binds platelets via the glycoprotein Ib receptor complex
What makes vWF bind to platelets?
Change in shear rate.
Inactive vWF is globular.
As flow of blood is changed due to injured epithelium it opens into an extended chains exposing the glycoprotein Ib receptor complex
What two substances account for platelet adhesion?
vWF via gycoprotein Ib receptor.
collagen when exposed the gycoprotein VI receptor and a2b1 integrin on the platelet bind to the collagen
What is von Willebrand’s disease?
vW disease is the most common congenital bleeding disorder. It manifests as impaired platelet function.
What is the treatement for vW disease?
DDAVP–expresses vWF so may be usied for mild cases.
Humate-P is concentrated vWF/factor VIII, and is a go too.
Other treatments are FFP and cryoprecitipate.
What causes platelets to become activated?
Agonists at the site of injury.
Collagen and Thrombin are the most common.
Others included ADP and epinephrine.
What happens during platelet activation?
Platelets change morphology
They then release the contenst of their alpha granules and dense granules. These included ADP, serotinin, factor V, factor VIII, vWF, fibrinogen
Also substances s.a. thromboxaneA2 synthesiszed in the cytosol are released into the environment
New negatively-charged receptors are expressed on their surface membrane
How does aspirin stop platelet aggregation?
blocks cyclooxygenase enzymes, which lead to the formation of thromboxane from arachidonic acid. Thromboxane signals platelet aggregation. Moreover aracodonic acid converts to prostaglandin via the the cox-2 enzyme. this illustrates the connection between inflammation and platelet aggregation.
What receptors are on the platelets surface?
Thrombin-> Protease-activated receptors PAR1 and Par4
ADP->P2Y1 and P2Y12.
Fibrinogen-> glycoprotein IIb/IIIa
What may block the ADP receptors on platelets?
thienopyridines: ticlopidine and clopidogrel
What may block the fibrinogen receptors on platelets?
antagoists such as abciximab and tirofiban
What are the primary adhesive molecules for platelet aggregation?
Fibrinogen and vWF
Which platelet surface receptor mediates platelet aggregation?
glycoprotein IIb/IIIa receptor
How do fibrinogen and vWF cause platelet aggregation?
form bridges between platelets to create a plug
What is the sequence from a resting platelet to platelet aggregation?
GPIIb/IIIa receptors are in a ligand unreceptive state in the resting platelet.
In the presence of an agonist (ADP, thrombin, epinephrine) the platelet becomes activated and is ready to accept a ligand.
With fibrinogen present, the fibrinogen binds to the activated GPIIb/IIIa receptors. These form bridges with other fibrinogen bound platelets
What is the order of fibrinogen in a primary hemostatis?
fibrinogen->fibrin monomers->fibrin polymers
which factor is fibrin stabilizing factor?
Factor XIII
How does Aspirin affect fibrinogen and FXIII
Aspirin acetylates fibrinogen causing the clot structure to be looser and easier to lyse
how are most coagulation factors found in circulation?
inactive forms-proenzymes or zymogens. A portion is cleaved off to activate the coagulation factor
What is the necessary factor for proper interaction of coagulation factors?
presence of a negatively-charged phopholipid membrane
Where are (most) coagulation factors synthesized
liver
Which are the contact activation factors?
FXI and FXII
Which is the only factor that has extra hepatic origin?
FVIII
What are the Vit K dependent factors?
FII, FVII, FIX, and FX
What are the two portion of FVIII?
High molecular weight portion-carrier.
small molecular weight–coagulant activity
What reaxtion does vitamin k catalyze?
the carboxylation of glutamic acid glutamic acid->gamma-caroxyglutamic acid it is also possible for the factor to bind calcium
How is vitamin K found in the diet?
leafy greens-kale
What inhibits carboxylation of vitamin K dependent factors by vitamin K?
coumadin
Which of the vitamin K dependent factors has the shortes half life?
FVII
What is hemophilia A?
Deficiency of FvIII
What is Hemophilia B?
Deficiency of FIX
What are the hemostatic actions of thrombin in the cascade based model?
Cleaves fibrinogen to fibrin activates factor XIII to cross-link fibrin Activates Platelets Activats factors V, VII, VIII, IX Activates thrombin activatable fibrinolysis inhibitor Stimulates epithelial cells to produce TF and vWF stimulates subendothelial smooth muscle constriction
Which are the most importent factors in clotting?
VIII, and IX
What are teh stages of the cell based model of coagulation?
Initiation-procoagulant stimulus generates engough trombin to initiate the coagulation process Amplification: Platelects and coagulation factors are activated Propagation: large amounts of thrombin are generated on the activated platelet surface
What happens during initiation?
On the tissue factor bearing cell, just a liitle bit o thrombin is form. If enough is formed then the next step will begin
What happens during amplification?
What happens during propagation?
What is all the thrombin in the clell based model for?
Cleavage fo fibrinogen to fibrin
Activates factor XIII to cross-link fibrin
Activates platelets
activates V, VII, VIII, IX
Activate thrombin activatable fibrinolysis inhibitor
Stimulates epithelial cells to produce TF and vWF
Stimulates subendothelial smooth muscle contriction
How is coagulation regulated?
Tissue factor pathway inhibitor (TFPI): inhibits TF/FVIIa complex and TF/FVIIa/FXa complex
Antithrombin (AT) inhibits FXa and thrombin (this is the biggest regulator in adults)
Protein C (PS) with cofactor protein S inhibits FVa and FVIIIa
What is the role of heparin in coagulation?
Its primary anticoagulant action is its ability to inhibit thrombin activity
Binds to AT and causes a conformational change in the molecular structure of AT that transforms AT from a slow to rapid inhibitor of throm
Which step is tertiary hemostasis and how does it work?
fibrinolysis
how do neonates differ from adults in coagulant and anti coagulant factors
neonates have low leves of both procoagulant factors and anticoagulant factors, nevertheless neonates have a well balanced, efficient hemostatic system
(Vitamin K dependent factors, contact activation factors and coagulant inhibitors)
HOw do platelets differ in neonates vs adults?
Neonates have 100% of adult platelets with fully developed membrane glycoprotein expression.
however, tehese platelets contain half the amount of dense granules, and platelet aggregation is impaired in responding to ADP, EPI, collagen and thrombin. However, they still have efficient platelet function.
This is due to an increased concentraition of von Willebrand factor and increased number of large vWf multimers.
how is fibrinogen different in neonates vs adults
Neonatal fibrinogen is 100% adult value but it has a different chemical structure whci gives it a decreased rate of fibrin polymerization and the fibrin clot is characterized by a lower density. This fetal form of fibrinogen exists until 1 year of age.
how is neonatal plasminogen differnt from adult
Plasminogen in neonates is found to be 50% adult values. Further i has decreased functional activity due to a different chemical structure causing it to bind poorly to cellular receptors. Also the activation kinetics by tissue plasminogen activator are slow and inhibition kinetics by antiplasmin a2 are slower.
Overall neonatal plasminogen has less fibrinolytic activity because of both quantitative and qualitative deficiencies in plasminogen.
What are the FDA approved uses of Recombinant actvated factor VII?
Pts with hemophila A and B with inhibitors aganst FVIII and FIX
Pts with congential FVII deficiency for Tx of blleding , or prevention of bleeding during surgical or invasive procedures
What are the off label uses of Recombinant activated factore VII?
Liver failure
liver transplantation
drug induced cagulopathies
platelet disorders
renal failure
intracerebral hemorrhage
non-hemophiliac bleeding disorders
Intraoperative or postoperative hemostasis
Bleeding due to trauma
Post cardiopulmonary bypass
What are the disadvantages of rFVIIa?
It is very expensive-pt chare $2738
No accepted standard monitor for efficacy
Unknown safety
JAMA article–most thromboembolic events occured among off label uses (CVA, MI, arterial thrombses, PE)
What is the mechanism of action of rFIIa?
IN initiation FVIIa drives the reaction forward to ensure enough thrombin is formed to make push into amplification.
In propagation, in high doses it binds to activated platelet and activates FX bypassing VIII and IX such as in hemophilia
