Final, Lecture 3 Flashcards
Hemostasis Tripod
Primary hemostasis- mediated by platelets
Coagulation (chemical)
Vasoconstriction (mechanical)
Platelets adhere to disrupted vessel wall via
- Surface membrane glycoprotein receptor Ib
- Von Willebrand Factor
Platelets adhere to eachother via
- Surface receptor glycoprotein IIb/IIIa
- Fibrinogen
Platelet actions
Primary hemostasis
Arachidonic acid vasoconstriction
Release of proteins from platelet storage granules
Site for generation of thrombin and then fibrin
Coagulation: Extrinsic Pathway
Tissue factor exposed to blood and forms complex w/ Factor VII –> activates factor X –> converts prothrombin to thrombin (factor V is a required cofactor for this)
Coagulation: Alternate/Secondary Pathway
Tissue factor-Factor VIIa complex activates Factor IX –> along w/ cofactor VI it activates Factor X –> converts prothrombin to thrombin
Coagulation: 3rd Pathway
Thrombin activates Factor XI –>activates Factor IX –> converts prothrombin to thrombin
Thrombin- what does it do?
Essential for conversion of fibrinogen to fibrin
Activates coagulation factors and cofactors facilitating its own formation
Activates platelet aggregation
Mediates fibrinogen cleavage
Factor responsible for crosslinking of Fibrin in ultimate step of coag cascade
Factor XIII
Anticoagulation processes
TFPI
Protein C
Antithrombin III
TFPI
Acts on Tissue Factor-Factor VIIa complex
Protein C
Activated by thrombomodulin and Protein S
Degrades Factors V and VIII
Antithrombin III
Forms complexes and inactivates Thrombin and Factor Xa
Enhanced by presence of heparin
Fibrinolysis
tPA and uPA in endothelial cells- released due to several stimuli like hypoxia, acidosis
Inactivation of fibrinolysis
PAI’s inactivate it
circulating protease inhibitors
Most common congenital coagulation disease
von Willebrand disease
Occurence of milder von Willebrand disease
1-5:1000
3 Types of von Willebrand Disease
1: Reduced conc of vWF’s
2: Dysfunctional vWF’s
3. Absent vWF- homozygous for gene defectTr
Treatment for von Willebrand Disease
Types I and IIa - Desmopressin - stimulates release of more vWF. Contraindicate in type IIb vWD
More severe types - replacement w/ transfuced factors
Continue treatment for 4-7 days after surgery
Most commonly inherited coagulation disorder
Hemophilia A - sex-linked recessive - 1:100,000 male births
Hemophilia A
Varied levels of Factor VIII - mild up to 40% of normal, severe less than 1%
Severe cases will develop anti-factor VIII antibodies
Hemophilia A Treatment
Mild to moderate - DDAVP (desmopressin) –> release of Factor VIII and vWF
Severe disease - Factor VIII transfusion
Hemophilia B
Like Hemophilia A but affects Factor IX
If severe- factor transfusion
Protein C or Protein S Deficiency
Causes hypercoagulation - can predispose to thrmobosis
Both proteins are liver synthesized, Vit K dependant
Factor V Leiden
Causes hypercoagulation
Polymorphic factor V which resists inactivation by Protein C–> deep venus thrombosis
Present in about 5% of North American Caucasians
Source of coagulation factors
Liver
Source of protein C, S, and fibrinogen
Liver
Liver Disease complications
Decreased coagulation factors
Thrombocytopenia may exist
Thrombocyte function impaired
MELD
Formula based on serum bilirubin, creatinine, and INR
Predicts 3 mo mortality- the higher the score the better
Renal failure complications
Often has coagulation abnormalities, at risk for enhanced bleeding- impaired platelet adhesion, aggregation and release
Impaired primary hemostasis w/ a low hematocrit
Treatment for coagulation problems due to renal disease
DDAVP (Desmopressin)
Aspirin
Irreversible inhibitor of platelet membrane-associated cyclooxygenase –> blocks formation of thromboxane A2
Aspirin - consequences
Can cause significant impairment of primary hemostasis and mild enhancement of bleeding
Platelet life span: 10 days
5-7 days usually required after termination of aspirin use to achieve platelet function and effective hemostasis
most important adverse effects of aspirin
Bleeding and hemorrhagic gastritis or gastric ulceration
Clopidogrel (Plavix)
Blocks ADP receptor on the platelet
Causes more bleeding than aspirin
Generally safe to continue through surgery
Dypyramidole
Inhibits phosphodiesterase–> accumulation of cyclic AMP–> anti-aggregating effect
No significant efficacy in fighting thromboembolic disease tho
Glycoprotein Receptor IIb/
IIIA Inhibitors
Most potent platelet aggregation inhibitors
Competitively inhibit fibrinogen binding to platelet IIb/IIIa receptor
Oral forms are not effective- use IV
Antiplatelet Drugs
Aspirin, Clopidogrel (Plavix), Dipyramidole, Glycoprotein Receptor IIb/IIIA inhibitors
Coumadin
Blocks vit K dep carboxylation of coagulation factors II, VII, IX, and X- formation of inactive proteins
Coumadin - when effects kick in and how long they last
Takes 2-3 days to work
Takes 3-5 days after termination of Coumadin before normal coagulation
Coumadin - how to monitor drug effect
PT and INR
May cause skin necrosis
Coumadin
Often assoc w/ protein C deficiency
Factor Xa Inhibitors
oxaban’s, dabigatran
Oxabans/dabigatran characteristics
Inhibit factor Xa Don't require regular lab monitoring- not affected by diet ,etc Rapid onset and short half life Prevents strokes like Coumadin Same risk for extracranial bleeding
Factor Xa Inhibitors and dental surgery
May be prudent to discontinue them for 1-2 days before procedure
Reversal of oxabans/dabigatran
Idarucizamab
For emergency surgery or life-threatening/uncontrollable bleeding
Reverses anticoagulation immediately
Solution contains Sorbitol- can’t give to fructose intolerant people
Other reversal options for oxabans/dabigatran
Andexanet Alfa- reverses anticoagulation in less than 5 min
PER977- nonspecific agent
Both in early clinical trials
Heparin
Parental
Binds to antithrombin III–> potentiates inhibition of factors IIa (thrombin) and Xa 1000 fold
Dose-dependant half-life
Mix of glycosaminoglycans from pig, cow lungs
Heparin consideration
Anticoagulation effect may be variable–> frequent lab monitoring is required
Low Molecular Weight Heparins
4-6 kDa
More favorable response than w/ unfractionated heparin
Longer half life and more predictable
Effective in preventing venous thromboembolism in surgical patients
Pentasaccharides
Fondaparinux
synthetic
antithrombin exlcusive inhibition of Factor Xa
Good for hip/knee surgery
Heparin derivatives complications
Most frequent adverse effect is bleeding
HIT- 5-7 days after initial exposure
Long-term use–> osteopenia
Thrombolytic agents
Plasminogen activators
Signs that point to possible defect in coaguation
Abnormal bruising
Petechiae
Splenomegaly
Pts that have negative med history
Don’t need lab tests
Pt that have signs/symptoms of bleeding tendency
Get platelet count, PTT, PT and INR
If abnormality in primary hemostasis is suspected
Check bleeding time and measure vWF
PT/INR
Add Ca and thromboplastin to blood and time for clot formation
Normal is 12+-2 sec
INR accounts for differences in labs
Prolonged PT due to deficiencies in
Factor VII Factor X Factor V Prothrombin Fibrinogen
PTT
Measures the intrinsic, slower pathway
Normal is 25-40 sec
Requires presence of all factors other than Factor VII
Deficiencies in factors VII and XIII will not be detected
When PT is used more and when PTT is used more
PT- coumadin drugs
PTT - heparin drugs
aPTT
if prolonged, may indicate use of heparin, hemophilia, sepsis, antiphospholipid antibody, presense of antibodies against coagulation
Bleeding time test
Not used anymore- not sensitive or specific, poorly reproducible, can be affected by skill of performer and often leaves scars
PFA-100
Measures platelet function
Runs blood sample through tube- promotes platelet adherence and aggregation- measure closure time
PFA-100 tests
First run collagen/EPI- if negative, no platelet dysfunction
If positive, then do collagen/ADP test to confirm
Gold standard for platelet function analysis
PAA
PAA
shows response of blood to specific aggregation inducing agents
As platelet aggregation occurs, light transmission increases
