Coagulation Flashcards
4 steps of hemostasis
- Vascular spasm
- Platelet plug formation (primary hemostasis – fastest)
- Coagulation and formation of fibrin (secondary hemostasis– slower)
- Fibrinolysis once is clot is no longer needed
These are procoagulants in the blood
Factors 1-13
Fibrinogen
Fibronectin
vWF
These are anticoagulants in the blood
Proteins C & S
Antithrombin 3
Tissue pathway factor inhibitor
These are fibrinolytics in the blood
tPA
Plasminogen
Urokinase
These are antifibrinolytics in the blood
2 things and both work against plasminogen (which is a fibrinolytic)
1) alpha- antiplasmin
2) Plasminogen activator inhibitor
Half life of platelets
1-2 weeks
How to plts travel in the blood
Because they are small, they are pushed towards the vessel wall and slide against it, which places them close to their site of action
These are inside plts
Actin and myosin (plt contaction)
Thrombosthenin (assists with contraction)
ADP (plt acivation and aggregation)
Calcium (Factor 4 – has many functions in the coagulation cascade)
Fibrin stabilizing factor (Factor 13 – crosslinks fibrin)
Serotonin (Activates nearby plus)
GF (helps to repair the damaged vessel)
The healthy endothelium inhibits plt functioning by secreting
- Prostaglandin I2 (inhibits vWF, TxA2, and release of storage granules)
- NO (inhibits the TxA2 receptor, which is a platelet activator)
How does the vessel contract in response to damage
The tunica media contracts as a result of SNS reflexes, myogenic response, and release of vasoactive substances like TxA2
Purpose of vessel spasm
1) Reduces bloos loss
2) Keeps procoagulants in the area so they can do their job
3 steps of platelet plug formation (primary hemostasis)
1) Adhesion
2) Activation
3) Aggregation
How long does it take to make the plt plug?
About 5 minutes
Plt adhesion
- Endothelial injury exposes collagen, which binds to plts at the Gp1a/2a and Gp IV receptors
- vWF is made and released from the endothelium, binding to GpIb plt receptor, anchoring the plt to the subendothelium
Overall, collagen is exposed and vWF is made and released, these bind to the plt via various receptors and adheres the plt to the vessel wall
Plt activation
- Injured endothelium releases TF, and the TF activates plts
- Activated plts release ADP and TxA2 (these activate other nearby plts to facilitate aggregation. TxA2 is also a vasoconstrictor)
- Activated plts then contract to release the contents of their alpha granules (fibrinogen, fibronectin, vWF, PF4, and platelet growth factor). These call other plts to the site.
- Activated plts become swollen, weirdly shaped, and sticky. This weirdly shaped, sticky mass helps plts adhere to the injured vessel and other plts.
- Activated plts express two extra GPs on their surface (GpIIb and GPIIIa)
Platelet Aggregation
- GpIIb/IIIa receptors form complexes with fibrinogen (which was released by the granules) to form a platelet plug
- ADP and TxA2 are needed for the receptor complex to accept fibrinogen
For microinjuries, a plt plug is good enough.
For larger vascular injury, the coagulation cascade is needed to make fibrin threads that will strengthen the clot.
Pneumonic to remember the factors by name
Foolish people try climbing long slopes after christmas. Some people have fallen.
How are the intrinsic and extrinsic pathways activated?
Extrinsic is activated when the cascade is initiated OUTSIDE of the vascular space
Intrinsic is activated when the cascade is initiated INSIDE the vascular space
What is the cell based model of coagulation?
Our current understanding of coagulation, which is a hybrid of the intrinsic and extrinsic pathways.
In this model, coagulation is started by release of TF (3), which is the extrinsic pathway. The intrinsic pathway serves to AMPLIFY the thrombin generating effect of the extrinsic pathway.
Called cell based, bc it starts with the injured cells releasing TF. Remember that TF is released by the injured tissues, setting off the extrinsic pathway and activating platelets.
Classical Extrinsic Pathway
1) TF is released from the subendothelium, initiating the extrinsic pathway and activating plts
2) TF activates factor 7. Activated factor 7 in the presence of calcium then activates factor X (Common final pathway).
3) Prothrombin Activator (as well as tissue phospholipids), turn prothrombin (Factor 2) into Thrombin. Prothrombin activator is another term for the collection of coagulation factors that leads to thrombin activation.
Is the extrinsic pathway fast or slow?
Fast, only taking about 15 seconds. Remember, it’s fast because there are fewer steps compared to the intrinsic pathway.
By contrast, the intrinsic pathway takes about 6 minutes to form a clot.
Classical Intrinsic Pathway
1) As blood is exposed to collagen, factor 12 is activated
2) 12a then activates 11
3) 11a then activates 9
4) Factors 9a and 8 work together to activate factor 10.
5) Then, just like in the extrinsic pathway, prothrombin activator and phospholipids work together to activate thrombin (turning factor 2 into 2a).
The final common pathway begins with ___ and ends with _____
begins with thrombin (Factor 2a) and ends with the production of cross-linked fibers of fibrin
Classical Common Final Pathway
1) Basically, the purpose of both intrinsic and extrinsic pathways are to make the factors that make up Prothrombin Activator, so that we can activate prothrombin to thrombin (Factor II to IIa)
2) The final common pathway begins the activation of II to IIa.
3) Thrombin (IIa), is an enzyme that changes fibrinogen (Factor I) into fibrinogen monomer.
In the presence of Calcium (Factor 4), these fibrin monomers form strands to make fibrin fibers.
4) Remember that the platelet plug is created first (it’s the fastest), and then it is stabilized by incorporating these fibrin fibers. Activated fibrin-stabilizing factor (Factor XIII) facilitates cross linkage of these fibers to complete the clot. Woohoo! This clot will stay in place until the underlying vascular tissue has healed itself.
Proteins C & S inhibit these factors
III, V, and VII
Process of Fibrinolysis
1) It starts with plasminogen, which is a proenzyme made by the liver and is incorporated into the clot as it’s formed. It lays dormant in the clot until it is activated.
2) Plasminogen is activated by tPA and urokinase into it’s active form plasmin.
- tPA is released by the injured tissue over a period of several days (major mechanism)
- Urokinase is made by the kidneys and released into circulation (minor mechanism)
3) Plasmin goes on to break up fibrin into various fibrin degradation products (which are measured by d-dimer).
How is the fibrinolytic process turned off?
1) tPA inhibitor (tPAI) inhibits the conversion of plasminogen to plasmin
2) Alpha-2 antiplasmin inhibits plasmin’s action on fibrin
Basics of the contemporary cell based model of coagulation
1) Initiation Phase
- Extrinsic pathway is activated by the expression of TF by damaged cells. Enters common final pathway and a small amount of thrombin is made, but not enough to convert fibrinogen to fibrin.
2) Amplification phase
- The small amount of thrombin that was made on the TF-bearing cells amplifies the coagulation response by activating platelets, factor 5 and factor 11.
3) Propagation Phase
- Begins with factor X becoming activated by Factors 4, 8, and 9 on the surface of a platelet. This results in a positive feedback mechanism that produces enough thrombin to activate fibrin.
Heparin inhibits these pathways
Intrinsic and common final
How does heparin work?
It binds to antithrombin III (AT3), which is a naturally occurring anticoagulant that circulates in the plasma. Once bound, heparin increases it’s anticoagulant ability 1000x
This heparin-AT3 complex neutralizes thrombin (IIa), and activated factors 9, 10, 11, and 12 (basically the entire intrinsic pathway).
Heparin also inhibits platelet function.
What could be the cause of a failed heparinization?
The patient may have an AT3 deficiency.
How is heparin eliminated?
Degradation by macrophages and renal excretion
Is heparin safe in pregnancy?
Yes, it does not cross the placenta and is safe in pregnancy.
Heparin dosing
Cardiac surgery: 300-400 units/kg
DVT prophylaxis: 5000 units SQ BID or TID
If active VTE, give 5000 units IV, then infuse at 1250 units/hour to maintain aPTT 1.5-2.5x normal (25-35 seconds)
Unstable angina/acute MI: Give 5000 units IV, then infusion at 1000 units/hr
Activated Clotting Time (ACT)
Normal is 90-120 seconds
Should be > 400 for CPB
ACT should be measured before heparin is given, 3 minutes after it’s given, and every 30 minutes after that
ACT is affected by
Hypothermia
Thrombocytopenia
A lack of fibrinogen (I), and factors 7, and 12
Protamine (MOA, dose, clearance, and SE)
MOA: Is a highly alkaline compound with strong positive charge. Brings to the negative charge of heparin, which results in heparin’s inactivation.
Dose = 1mg for each 100 units of heparin given
Complex is cleared by the reticuloendothelial system
When given alone, it’s actually an anticoagulant
SE:
Hypotension (d/t histamine release)
Pulm HTN (due to TxA2 and serotonin release)
Allergic reaction (previous use of NPH insulin or fish allergy)
How do aminocaproic acid and tranexamic acid work?
They are plasminogen activation inhibitors
How does Plavix work?
ADP receptor inhibitor
List some GpIIb/IIIa receptor antagonists
Abciximab
Eptifibatide
Tirofiban
Name some COX 1 inhibitors
Rofecoxib
Celecoxib
What is vitamin K needed to make?
Factors 2, 7, 9, and 10
Proteins C & S
What medication is a factor X inhibitor?
Fondaparinux
Warfarin needs to be stopped this many days prior to surgery
2-4 days
Name some fibrinolytics
tPA Streptokinase Urokinase Reteplase Alteplase
vW Disease is the most common inherited disorder of ____ function
Platelet function.
In this dz, the patient has a normal number of plts, but they don’t function properly due to a lack of vWF.
Classes of vW Disease
1- mild to moderate reduction in ant produced
2- vWF produced doesn’t work well
3- no vWF is produced
Lab findings in vWD
Increase in PTT and bleeding time
No change in other coagulation studies
What is desmopressin used to treat? Also, talk about this medication
- Can treat Type I vWD (but not type III)
- Synthetic analogue of ADH that causes release of vWF and Factor 8
- Dose is 0.3-0.5 mcg/kg IV
- Bleeding time will be improved for 12-24 hours
SE- vasodilation and hypotension with rapid administration
Blood products that can be used to treat vWD
1) Cryoprecipitate
- Has vWF and factors 1, 8, and 13.
- Can be used for all types of vWD
2) FFP
- Has ALL of the clotting factors, so can be used for this patient, but is not the best option.
3) Purified Factor 8/vWF concentrate reduces the risk of transmitting a disease. This is the first line agent for Type III disease.
Hemophilia A
- X linked disease leading to lack of Factor 8
- Mild disease associated with increased surgical bleeding
- Severe disease (factor 8 activity
Anesthetic implications for hemophilia A
- Pt should have factor 8 prior to surgery
- Half life of factor 8 is 8-12 hours, so may need to be reduced. Therapy is continued for 2-6 weeks postop.
- FFP and cryo can also be used
- DDAVP ok in mild disease
- Antifibrinolytics like TXA or amicar can be used to minimize bleeding in dental procedures
- Need type and cross for all procedures
Hemophilia B
Factor 9 deficiency
Mild disease may not even be diagnosed until unexplained bleeding after surgery
Severe disease is associated with severe bleeding (but not as bad as type A)
Will have prolonged PTT
Anesthetic considerations are same as with type A
Factor IX - prothrombin complex
Can be used to replace factor 9, but can cause excessive clotting, so must assess benefit/risk ratio
Half life of 18-24 hours. Longer half-life than Factor 8
What is DIC? What lab values do you see?
Disorganized clotting and fibrinolysis that leads to the simultaneous occurrence of hemorrhage and systemic thrombosis.
Basically, some underlying disorder tell the body to start coagulating. Increased fibrin formation leads to microvascular thrombosis and organ failure. On the other hand, plts and clotting factors are consumed, resulting in bleeding.
Increased PT, PTT, and D-dimer
Decreased plts and fibrinogen
Patho of DIC
In the pt with DIC, TF (Factor III) is released in the absence of vascular injury. This activates the EXtrinsic cascade throughout the entire body (not just locally!)
- Microvascular clots cause tissue necrosis and organ failure
- Plts and clotting factors are all used up leading to hemorrhage.
- tPA and urokinase-type plasminogen activator are released to break down all these clots that are forming. You have simultaneous clot formation and destruction. D dimer levels are elevated.
S/S of DIC
Bruising Petechiae Mucosal bleeding Bleeding at IV site Prolonged PT and PTT Elevated D dimer Decreased fibrinogen and antithrombin
Treatment of DIC
1) Treat the underlying cause
2) Give activated protein C (which will inhibit factors V and VIIIa in the intrinsic cascade)
3) Give FFP, cryo, and plts to replace these things that have been depleted. Remember the patient is actively hemorrhaging as well.
What is the MOA of warfarin?
Inhibits the enzyme responsible for activating vitamin K
These are the antidotes for warfarin
Vitamin K (antagonist for warfarin) FFP (replaces the deficient clotting factors)
Vitamin K can can be used for simple non-emergent cases
Use FFP for emergent or high risk procedures like cranis
Synthetic vitamin K is also called
Phytonadione
Dose of vitamin K
10-20mg PO, IV, or IM
IV route has been associated with anaphylaxis. Because of this, IV is not preferred, but if given, do not give faster than 1mg/min
Antithrombin Deficiency
Cause and tx
Refers to lack of AT3, the body’s natural anticoagulant that heparin works on.
AT3 inhibits factors 7, 9, 10, and 11.
Repeated heparin administration can consume the body’s supply of AT3, and produce an acquired form of the dz.
Patients with the congenital form of this disease are at risk of developing VTE
Tx: AT concentrate and FFP
Overall, what happens in HIT?
Clot formation throughout the body!
Basically, an allergic response to heparin. IgG antibodies activate platelets, resulting in uncontrollable clot formation. Plt count calls because they are being used up.
Which is worse, type 1 or type 2 HIT?
Type 2
- High risk of amputation and death
Type 1 is self resolving even if heparin is continued. Minimal morbidity.
Onset of HIT (type 1 vs 2)
Type 1
- Onset is 1-4 days after large administration
Type 2
- Onset is 5-14 days and can occur after ANY dose of heparin is given.
Treatment of HIT
Type 1
- Self resolving
Type 2
- ANTICOAGULATE!! Use a direct thrombin inhibitor (Factor IIa) like bivalrudin, hirudan, or argatroban.
Proteins C & S block this
Tissue factor (III)
Factor V Leiden Mutation
Causes a resistance to protein C. Because it’s not responding to this natural anticoagulant, a hyper coagulable state develops.
Lifelong anticoagulation is not warranted unless the patient develops clots.
Normal aPTT values
25-32 seconds
Normal PT
12-14 seconds
Plts below ____ place at risk for surgical bleeding and spontaneous bleeding once below _____
50,000 = surgical
20,000 = spontaneous
Bleeding time
what it measures and normal value
Measures plt function
Normal is 2-10 minutes
ASA and NSAIDS prolong
Not usually used
ACT normal value
Used to guide heparin dosing
Normal ACT is 90-120 seconds
What is in Cryoprecipitate?
vWF and factors 1, 8, and 13
