Hemostasis Flashcards
3 parts of plateletfxn
(1) adherence- to exposed subendothelium (via vWF)
(2) activation- shape change and release of granule contents
(3) aggregation- recruitment of additional platelets
What is the most immediate response to vessel injury?
Vasoconstriction
What is primary hemostasis?
Platelet fxn including adherence, activation, and aggregation
What is secondary hemostasis?
Activation of coagulation (via tissue factor) and generation of thrombin (factor IIa)
Coagulation
(a) What initiates it
(b) What is the ultimate end product?
(c) What is this end product’s fxn?
Coagulation
(a) Initiated by tissue factor = membrane protein (not an enzyme)
(b) Ultimately terminates in thrombin (factor IIa)
(c) Thrombin converts fibrinogen into fibrin- the strand-like protein that provides tensile strength to a clot
What two factors does tissue factor directly activate?
Factor IX and factor X
What is the role of factor XIII?
Factor XIII is activated by thrombin to form covalent bridges btwn fibrin molecules
Where are coagulation factors produced?
In the liver
What is the function of factor VIII?
= cofactor for factor IXa
- In response to injury factor VIII is activated and separates from vWF
- active factor VIII (VIIIa) can then interaction w/ factor IX to set off additional reactions that end in formation of a blood clot
What is the function of factor V?
= Cofactor for Xa
What is the function of factor XI?
(a) What activates factor XI?
Factor XI activates the clotting cascade via an accessory pathway that is important in injury states
(a) Thrombin (factor IIa) activates factor XI
Describe the mechanism by which fibrinogen –> fibrin?
Cleavage of fibrinogen allows for assembly of fibrin
- Thrombin (IIa) removes four fibrinopeptides to produce fibrin
- then fibrin can polymerize end to end and side to side
What are protein C and protein S?
(a) What activates protein C?
Protein C and protein S are anticoagulation factors that together make a complex to inhibit factor VIII and V (cofactors that normally accelerate coagulation)
- PS = cofactor to increased PC activity
(a) Protein C is activates by thrombin (IIa)
What is thrombomodulin?
Thrombomodulin (TM) enhances the activation of protein C by IIa (thrombin)
What is the fxn of antithrombin?
Antithrombin = potent inhibitor of the coagulation cascade
-inhibits thrombin (IIa) and factor Xa
Action of TFPI
TFPI = tissue factor pathway inhibitor = natural coagulation inhibitor
-binds to Xa, then binds to and inhibits TF/factor VIIa complex and Xa
Mechanism of action for heparin
Heparin binds to AT (antithrombin) to make it a more potent inhibitor of Va and IIa (thrombin)
Describe how tpA and the fibrinolytic system work to lyse a clot
tPA (tissue plasminogen activator- released by various tissues) activates plasminogen to plasmin
-then plasmin can cleave cross linked fibrin molecules
What is the key terminal enzyme of the fibrinolytic system?
Plasmin
-cleaves up fibrin clots
What are D-dimers?
D-dimers are fibrin clot degradation particles that are measurable/visible in blood after plasmin breaks down a fibrin clot
-elevated in acute thrombosis
When is measuring D-dimer helpful?
Good negative predictive value (to rule out acute thrombotic event)
Ex: rule out DVT, PE, DIC
What is hemophilia?
(a) A vs. B
(b) Mode of inheritance
(c) How can it cause arthropathies?
An increased tendency to bleed
(a) Hemophilia A = deficiency in factor VIII. Hemophilia B = deficiency in factor IX
(b) X-linked
(c) Can cause recurrent bleeding, recurrent bleeding into joints can cause arthropathies and permanent damage
Is hemophilia seen more in males or females?
Males b/c it’s X-linked
About how much coagulation factor do you required to function
(a) Normally
(b) Abnormally after major surgery or trauma
(c) Abnormally after minor injury or surgery
Coagulation factor levels
(a) Normal is > 40% (so you don’t need anywhere near 100% to be perfectly normal)
(b) Mild hemophilia: 5-40% coagulation factor => bleeding after major post-op and post-trauma bleeding
(c) Moderate hemophilia: 1-5% => bleeding after minor injury or surgery
What is the manifestation of a coagulation factor level
= severe hemophilia
Clinical manifestation = spontaneous bleeding into soft tissue and joints
What is the treatment for hemophilia?
(a) Primary prophylaxis
(b) On demand treatment
Treatment = IV injections of factor VIII (type A) or IX (type B)
(a) primary prophylaxis = give continuous factor VIII/IX especially in children to prevent permanent damage to joints and muscle
(b) Most adults get on demand treatment- injections when they feel a bleed coming on
What are some improvements to infusing pure human produced factor VIII/IX?
- recombinant therapy so don’t risk any transmissions btwn donor/host
- longer half-life products so the pts can infuse less frequently
Factor XI deficiency
(a) mode of inheritance
(b) severity
Factor XI deficiency- rare but seen in Ashkenazi jews
(a) Autosomal dominant
(b) Mild disorder- factor XI not part of the main coagulation cascade, part of accessory pathway
Describe how the PT is evaluated in lab?
PT = prothrombin time
(i) Draw blood into tube w/ sodium citrate (anticoagulation factor)
(ii) Add calcium to reverse the sodium citrate
(iii) Add tissue factor to activate the extrinsic coagulation pathway- time how long it takes the blood to clot after adding TG
Reduction of what factors will prolong PT?
Reduction of the factors involved in the extrinsic clotting pathway: VII, X, V, and II (and fibrinogen)
What clotting factors are not tested by PT?
Factors VIII, IX, XI, XIII
Therefore, to test these factors use the PTT
What is PTT?
(a) What clotting factors does it measure the activity of?
PTT = partial thromboplastin time- measure how long it takes the intrinsic clotting pathway to work => evaluates more of the clotting factors than PT
(a) PTT is prolonged if any factor except factor VIII is low
Which test: PT or PTT is used to test factor VIII?
Neither! Level of factor XIII doesn’t affect the PT or PTT
Normal PT value
11-14 seconds
Normal PTT value
30-38 seconds
How does liver dysfunction cause a bleeding disorder?
All coagulation factors are made in the liver => liver dysfunction = coagulopathy
What coagulation factors require vitamin K?
(a) Mechanism
Factors II, VII, IX, and X
- also protein C and S
(a) Vitamin K needed as a cofactor for coagulation factors so they can bind calcium and bind phospholipid membranes
What is thrombophilia?
(a) Increased risk of MI
= an increased tendency to clot/thrombose
(a) Doesn’t really increase risk of stroke/MI b/c the clotting is usually venous => increases risk of DVTs/PE
Deficiency in what three enzymes may cause inherited thrombophilia?
Antithrombin, protein C, or protein S deficiency
What is factor V Leiden?
Mutated form (variant) of factor V that cannot be inhibited by protein C (the APC/PS complex) => increased clotting
-one of the most common inherited thrombophilias
Mechanism of Heparin
Indirect acting anticoagulant
-enhances the inhibitor effect of antithrombin on thrombin
What are two new direct anticoagulant meds?
- direct thrombin inhibitor = Dabigatran
- direct Xa inhibitor = Apixaban and Rivaroxaban
What is the INR?
(a) What is its function
INR = international normalized ratio
INR = (PT value of pt) / (PT normal)
(a) Way of standardizing PT values among different labs
Normal/expected INR value for
(a) Unmediated pt
(b) Pt on warfarin/coumadin
Expected INR value for
(a) Unmedicated pt = 1.0
(b) Pt on warfarin/coumadin = 2-3
Which anticoagulant medication is safe for pts w/ mechanical heart valves?
Warfarin
Mechanism of warfarin
Warfarin inhibits enzyme used in vitamin K synthesis => inhibits the vitamin-K activation/synthesis of the Ca2+ dependent clotting factors = factors II, VII, IX, and X
How to treat DIC
Treat the underlying condition
-treat the bacterial sepsis, burn etc
Why was APC previously used to treat sepsis
(a) Why was this stopped?
APC (activated protein C) inhibits the coagulation cascade, but also has an anti-inflammatory effect
- this highlights the strong link/association btwn coagulation and inflammatory pathways
(a) APC no longer given for sepsis b/c of its anti-coagulation effects and pts w/ sepsis are at risk for bleeding
Describe the mechanism of the following in DIC
(a) Coagulation
(b) Bleeding
DIC = disseminated intravascular coagulation
(a) Coagulation: blood exposed to tons of tissue factor (due to endothelial injury) which activates the coagulation cascade in vessels, causing occlusion of capillaries w/ fibrin thrombi.
- microthrombi in vascular beds
(b) Bleeding when coagulation factors are activated faster than they’re synthesized
What is the blood marker of DIC?
Positive D-dimer
-D-dimer (+) due to systemic activation of the fibrinolytic system => fibrin in vessels are lysed so D-dimer levels are measurable in the blood
