Fung-Coagulation Flashcards
What is hemostasis?
balance between clotting and thrombosis
Precisely orchestrated process involving platelets, clotting factors and endothelium
Occurs at the site of vascular injury and culminates in the formation of a blood clot
What are the 2 types of disorders of hemostasis?
Hemorrhagic
Thrombotic
What are the normal steps of hemostasis?
- vasoconstriction
- platelet aggregation
- fibrin formation
What’s involved in vasoconstriction?
Purpose: reduces blood flow to the area
MOA: mediated by reflex neurogenic mechanisms, augmented by secretion of endothelin
Lasts how long? Transient!
What is primary hemostasis?
aggregation of platelets on endothelium
beginnings of a clot
What is secondary hemostasis?
cascade of reaction b/c of exposure of tissue factor @ site of vascular injury
thrombin formation
What are the 3 layers of blood vessels?
Intima: endothelium
Media: smooth muscle
Adventitia: CT
What is the role of vascular endothelium in hemostasis?
Inhibiting platelets
Suppressing coagulation
Promoting fibrinolysis
Modulating vascular tone and permeability
What are antithrombotic agents?
heparin Protein C & Protein S Tissue Plasminogen Activator Prostacyclin Nitric Oxide Thrombomodulin Protein C receptor Tissue Factory Pathway Inhibitor (TFPI)
What are prothrombotic agents?
Factor V Tissue Factor Plastinogen Activator INhibitor-1 (PAI-1) Thromboxane Platelet Activating Factor vWF
WHich substance is released after vascular injury?
Which layers of the blood vessel mediate vasoconstriction?
Tissue Factor
Media & Adventitia
The presence of which 2 things sets the stage for platelet adherence & activation?
collagen
vWF
What is the role of heparin in the body?
anti-thrombin
What is the role of prostacyclin & NO in the body?
vasodilators…that’s why they are anti-thrombotic
Where do platelets come from? What do they consist of?
come from megakaryocytic
consist of no nucleus, but have a cytoskeleton & cytoplasmic granules
alpha & dense granules
Which are more numerous in platelets–alpha or dense granules?
alpha are more numerous!
What does GP Ib/V/IX on the cytoskeleton of the platelet bind?
vwf
What does GpIIb/IIIa bind?
fibrinogen
What does GP1c/IIa bind?
fibronectin
WHat does CD62P (P selection) do?
these are adhesion molecules
What does the thrombin receptor on platelets do?
initiates platelet activation
along with ADP (found in dense granules)
What does the GP1a/2a bind?
collagen
What are the red cell antigens on platelets?
ABO, P, I, i Le (no Rh)
Which substances are found in the alpha granules (more numerous)?
alpha: vwf fibrinogen Factor V Promotes Angiogenesis: VEGF, EGF, PDGF Inhibits Angiogenesis: angiostatin, thrombospondin, endostatin INflammatory Factors: PF-4, IL-8, CCL5
Which substances are found in dense granules?
ATP
ADP
Calcium
Serotonin
Describe platelet adhesion & aggregation after vascular injury.
Collagen & vwf exposed after injury
Unactivated Platelets adhere to gp1b receptor on vwf
GP2b3a receptor on platelets active & bind fibrinogen that cross links & causes aggregation!
Describe all that is involved in the activation of platelets.
shape change
release of granules, including ADP in the dense ones
initiation of thromboxane A2 pathway (recruits more platelets)
GP2b/3a receptor active–fibrinogen welcome!
Describe how the coagulation pathways interact.
Extrinsic pathway activated by the presence of tissue factor. 7–7a
7a will activate factor 10 & apparently 9 (crossover to intrinsic)
Proximity of factors 11 & 12 activates 12–12a.
12a causes 11–11a
11a causes 9–9a.
9a activates 10–10a too.
Once 10a is active…what happens?
prothrombin w/ 10a–>thrombin (2a)
thrombin causes fibrinogen–fibrin.
13a causes fibrin to cross link.
What makes up the prothombinase complex?
Va & 10a
What makes up the tenase complex?
8a, 10a, Ca++
Which coagulation factor is fibrinogen?
Factor 1
Which coagulation factor is prothrombin?
Factor 2
Which coagulation factor is anti hemophilic factor? Where is it made?
Factor 8
made in the Kupffer cells of the liver
Where are most coagulation factors made?
liver
What is the coagulation factor for hagemann factor?
factor 12
Which coagulation factor is fibrin stabilizing factor?
Factor 13
Where does vwf come from?
endothelial cells
megakaryocytes
Give a summary of primary hemostasis?
Collagen & vwf exposed after injury Circulating platelets adhere & become activated. Shape change. GpIIb (fibrinogen receptor) exposed. Degranulate. Thrombaxane A2 pathway Release ADP More platelets recruited Activation of intrinisc pathway. Fibrinogen cleaved to fibrin. Clot formed.
What are 4 important coagulation regulators?
Antithrombin
Activated protein C (APC)
Tissue Factor Pathway Inhibitor
Plasmin
What does antithrombin regulate?
thrombin factor 9a factor 10a factor 11a factor 12a
What composes the activated protein C complex?
thrombin
thrombomodulin
Protein C
Protein S
What does tissue factor pathway inhibitor regulate?
tissue factor
7a
10a
What does plasmin do?
degrades fibrin
What are the 4 thing that seem to activate 10–10a?
7a
9a
8a
5a
With feedback inhibition, what does thrombin inhibit?
conversion of 8-8a & 5-5a
What are the labs that can help you evaluate platelets?
Platelet count
Bleeding time
Platelet aggregometry (function tests)
Platelet flow cytometry
What are the labs that can help you evaluate coagulation?
aPTT
PT
Thrombin time
Others
When should you order a bleeding time test? What is a normal range?
only used when a patient has a hx of excessive bleeding
Normal range: 1.5-9.5 min
When do you see prolongations in bleeding time?
von Willebrand disease Inherited platelet disorders Uremia Aspirin ingestion Low platelet counts (<100,000)
What is platelet aggregometry?
in vitro evaluation of platelet aggregation
stir plasma
subject to agonists
look for aggregation–if present you will have more light transmitted thru vial.
Which agonists to aggregation are added to the plasma in the platelet aggregometry studies?
ADP Epinephrine Arachidonate Collagen Ristocetin aka vwf
What’s the deal with platelet flow cytometry? What is it used to diagnose?
**looks at cell surface markers by using fluorescently labeled antibodies
Used to diagnose:
platelet surface glycoprotein deficiencies
disorders of platelet activation
How do you measure platelets via platelet count? What is a normal range?
automated counter
140K-400K
Which pathways does Prothrombin Time (PT) evaluate? How is this test done?
used to evaluate extrinsic & common pathways
Used to monitor warfarin therapy!
tissue factor & thromboplastin added w/ Ca++. Measure the time to clot.
What is the reference range for normal PT times?
11-13.5 seconds
Prolongation of PT can be caused by which factor deficiencies/inhibitors?
Factor 7 Factor 10 Factor 5 Factor 2 Fibrinogen
T/F INR is helpful in monitoring warfarin therapy along with PT.
True.
Which pathways is activated partial thromboplastin time (aPTT) used to evaluate? How is it done?
intrinsic & common
phospholipid is added to plasma w/ Ca++
What is normal value for aPTT?
27-35 seconds
Which factor deficiencies/inhibitors could cause aPTT prolongation?
Which therapy is it used to monitor?
Monitors heparin, hirudin, & argatroban therapy Factor XII Factor XI Factor IX Factor VIII Factor X Factor V Factor II Fibrinogen
What is thrombin time (TT) used to test? How is it done?
tests presence of functional fibrinogen
thrombin added to plasma & time to clot is measured
What is a normal TT range? What might cause TT prolongation?
15-19 seconds
heparin, hirudin, argatroban
problems with fibrinogen
What are mixing studies used to determine?
deficiency or inhibitor?
done when PT, PTT, or TT is off
What is the process involved in a mixing study?
MIx patient’s plasma with normal plasma…
If better: deficiency
If not better: inhibitor present
What forms D dimers? What is the significance of their lab presence?
plasmin mediated degradation of fibrin forms
fibrin is goin down!
What is another name for the von willebrand factor assay? How is it done?
aka Ristocetin cofactor assay
patient plasma added to formalin fixed normal platelets in presence of ristocetin
if normal: platelet agglutination
If vwf deficient: decreased aggregation
What is the anti-10a assay used to measure?
monitor heparin
When do you do factor assays?
after mixing study shows that there is a factor deficiency
What are the characteristics of platelet type bleeding?
petechiae common
mucosal bleeding common
more often in females
What are the characteristics of coagulation type bleeding?
hemarthroses
deep hematomas
delayed bleeding
more often in males
Excessive bleeding due to platelet defects is seen in which conditions?
von willebrand disease bernard soulier syndrome glanzmann thrombastenia platelet storage pool disorders drugs ITP TTP HUS HIT
What are some disorders that cause excessive bleeding due to coagulation defects?
von willebrand disease Hemophilia A Hemophilia B Liver Disease Vit K Deficiency DIC
How is it that von willebrand disease is both a platelet defect & coagulation defect bleeding disorder?
vwf circulates bound to factor 8 to prevent its early degradation
in vwf deficiency–factor 8 gets destroyed earlier.
