test 8 Flashcards
Alterations to Coagulation on CPB
- Heparinization
› Neutralized by protamine
› Some may be protein bound
- Excess Protamine
- Hemodilution
› Appx 25-35% decrease in circulating factors
- Hypothermia
› Slows enzymatic reaction timesSources of Post-Op bleeding
- Reduced concentration of coagulation factors
- Hyperfibrinolysis
- Thrombocytopenia (decreased platelets)
- Impaired Platelet Aggregation
- Platelet Fragmentation
- Increased inflammation after CPB impairs coagulation and increases blood loss.
Extrinsic Factors
- Residual Heparin / Heparin Rebound
- Excessive Protamine
- Hemodilution
- Hypothermia
Prevention of Post-Op bleeding
- Avoiding CPB
- Improved biocompatibility of foreign surfaces (coated circuits)
- Alter conduct of bypass
› Drug doses, hypothermia, hemodilution
- Use hematologic strategies
› Take off blood before bypass and give it at the end
- Improved surgical technique!!!!!*
- Making sure labs are normal pre-op
Antifibrinolytic agents
- stops breakdown of clot
- CPB activates the breakdown of fibrinogen and other procoagulant precursors AND TRY TO MAKE US CLOT
- ECC initiates contact activation
-induces thrombin generation - Heparin has mild fibrinolytic effect
› Stimulates release of serum urokinase plasminogen activator (UPA) which induces fibrinolysis
Tissue Plasminogen Activator (tPA)
- Breaks down clots
- More potent than UPA.
- Primary activator of fibrinolysis during heart surgery.
- Large surge of tPA after protamine is given
› Time of greatest response to thrombin produciton
- NO tPA = result in massive clots or DIC (Disseminated intravascular coagulation)
Trombin
- Produced throughout CPB
- Surge @ termination of bypass
- Surge after protamine administration
- Amplifier protein which activates inflammation, coagulation, and fibrinolysis
- Metabolically active in sites where heparin cannot reach it which results in clotting in these portions
Plasminogen Activator Inhibitor 1 (PAI-1)
- Tries to stop tPA
- Released by vascular endothelium and smooth muscle cells and find the tPA and bind to it
› Therefore, tPA must overcome circulating PAI-1 to initiate fibrinolysis
- PAI-1 is released in response to inflammatory mediators
- PAI-1 is Prothrombic
› Overcomes and suppresses fibrinolytic effect
of tPA - Hemostasis = thrombin makes clot and tPA breaks down clot and PAI-1 prevents tPA from breaking down clots
tPA and post op bleeding
tPA directly cleaves plasminogen -> Plasmin => exposing a lysing binding site where fibrinogen and fibrin bind
- Fibrin is needed to crosslink platelets to make a clot
› TPA breaks apart fibrin and therefore, the clot
› Leads to post-op bleeding
Lysing Analogs to prevent post op bleeding
› Aminocaproic Acid (ACA) / Amicar
› Tranexamic Acid (TA)
Aminocaproic Acid (ACA) / Amicar
- 2 lysine molecules stuck together
- Competitively binds to lysine sites of plasminogen/ plasmin
› Prevents plasmin from binding to fibrinogen/ fibrin which PRESERVES FIBRIN => still have coagulation factors at the end
Tranexamic Acid (TA)
- Reversibly binds to lysine receptors on plasminogen or plasmin.
- Roughly 10 times the antifibrinolytic activity of ACA.
› More potent
Aprotinin
- 58 amino acid polypeptide
- Single Lysine with a HIGH affinity for plasmin
- Non-specific serine protease inhibitor
› Inhibits fibrinolyis
› Inhibits thrombin generation
› Inhibits the inflammatory response
When to give lysine analogs
- giving it before you go on bypass after heparin was the safest time to give this
- Showed effective in decreasing blood loss.
Lysine analogs pharmacology
- IV Administration
- Uptake is immediate
- Small, water-soluble molecules
- Distributed readily into extravascular water spaced before being taken up into various cells and tissues.
- TA does bond weakly with protein so it can cross the BBB so don’t use in pregnant patients => USE AMICAR
Lysine analogs elimination
- Renal excretion
- Half-life: 1-2 hours with IV administration
Daily Protocol of ACA
- (aka: “10-10-10”)
› 10g given as slow bolus (5-10min) pre-CPB
› 10g in CPB prime
› 10g after CPB
- Pt with kidney disease because it’s excreted with the kidneys
-smaller loading dose
dosing of TA vs ACA
-the dose of TA is much smaller because it is more potent (1/7 to 1/10 of ACA)
Lysing analogs side effects
› Intravascular Clots in DIC patients
- Thromboembolic Complications
Patients with low risk of transfusion (despite CPB)
- may not benefit from prophylactic antifibrinolytics.
But may help tip the scales between transfusion or not if they are on the fence. - but in pts that are really sick these drugs can tip the scales between transfusions and no transfusions
Aprotinin
- Found in all mammalian lung tissue
- Isolated from bovine lung
- single lysine binding site where it binds to plasmin and competitively hopefully inhibit fibrin binding
Aprotinin pharmacology
- Full Hammersmith Regimen (Most common)
› 2 million iallokrein inhibing units (KIU) in pump
› 2 million KIU to pt over 30-60 minutes
› 500,000 KIU/hr infusion for pump run
› T1/2= 5 hours with this regimen
› Renal excretion (excreted via the kidneys)
› Blood loss and transfusions required are lowest with full dose regimen
Aprotinin allergic reactions
- Foreign protein from bovine source
- Size similar to protamine
- 1st time exposure reaction rare
- Test dose of 1mL given prior to loading dose
- Wait about 10 min after test dose before starting loading dose
- Found reaction in kids with less than 6 months between exposures
› FDA revised advisory to put 12 months between
exposures.
Aprotinin action
- Non-specific serine protease inhibitor
- Effects: (everywhere)
› Plasmin
› Kallikrein
› Bradykinin
› TPA
› Urokinase Plasminogen Activator
› Complement
Aprotinin history
- Used/known since 1960s
-did not have an effect on Pulmonary gas exchange and post op lung dysfunction
- The surgical field was dramatically DRY.
› Lead to the early publications of transfusion sparing and decrease chest tube drainage associated with Aprotinin.
› Aprotinin may have neurologic protective effects (perfect for old people and circ arrest)
- A LOT LESS BLOOD LOSS
Aprotinin dosing
- Came up with a formula they thought would drastically inhibit kallikrein production
› 2 million KIU pre-CPB
› 2 million KIU in pump
› 500,000 KIU/hr to cover metabolism/ clearance
So what does aprotinin do?
- Decreasing Kallikrein
› Decrease inflammation
- Kallikrein doesn’t affect bleeding
› DOES activate intrinsic cascade
› Activation of coagulation precursor proteins
› Activates pro-inflammatory WBCs
› Inhibits Platelet-WBC Interactions
- Inflammatory down regulation by protecting platelets
Aprotinin ability to produce desired results
- Decreased chest tube output (bleeding)
› 30% reduction in blood transfusions
› Less chest tube drainage
› Reduction in reoperations for bleeding
› 40-80% reduction in chest tube output compared to placebo
Aprotinin issues
- use creatinin as an indicator of renal function
- body is trying to clear creatinin and aprotinin and they both are competing for clearance => levels increase for a period of time
Kidney function and risk for dialysis
- Normal GFR – Low risk for dialysis
- 50% Normal GFR - >20% risk for dialysis
- <20% Normal GFR – 85% risk for dialysis
Aprotinin and clearance by the kidneys
- Aprotinin competes with creatinine in the ascending Loop of Henle.
› Expect the rise in creatinine with Aprotinin
Mangono study
› Increased risk of:
- Renal failure
- MI
- Heart Failure
- Stroke
- Encephalopathy
- Increased mortality
Comparing aprotinin to ACA, TA, and no antifibrinolytic
- Found that the use of Aprotinin was associated with an increased risk of renal and non-renal events compared to ACA, TA, and no antifibrinolytic
› Risk increases as the dose increases
ACA cost
› $1.50-$10 per 5gm vial
› Case: $5-$30
TA cost
› Case: $20-$300
Aprotinin cost
› $300-$450 per bottle
› Case: $1000-$1500
If ACA or TA given, you might need to give something for clotting issues
› Recombinant Factor VIIa - $5,000-$9,000 / dose
› RBC: $300-$500
› Platelets: $850
› FFP: $100
What surgery was aprotinin approved for?
› Aprotinin was only approved for use on CABG surgery patients
- BUT high risk non-CABG patients had best benefit
Aprotinin downfall: December 2006 – FDA Revised labeling
› Don’t give w/in 12 mo of prior exposure
› Only for patients who are at increased risk for blood loss and blood transfusion associated with CPB in the course of a CABG
Aprotinin downfall: 2007
- Temporarily withdrawn from the market worldwide
- STS guidelines - high dose aprotinin for high risk patients
Aprotinin downfall: 2008 (Bart study)
- permanently withdrawn from the market › Lower bleeding than lysine analogs › Significantly increased mortality - Europe and North America Temporarily suspended marketing authority for aprotinin.
Aprotinin downfall: 2011
- Health Canada lifted temporary marketing suspension
Aprotinin downfall: 2012
- European Medicines Agency recommended lifting suspension
Complications of lysine analogs and aprotinin
› Intravascular Thrombis
› Aprotinin increases serum creatinine transiently
Retrospective studies associate Aprotinin with:
- Renal Failure
- Stroke
- MI
- Increased Mortality
- **NOT seen with Lysine Analogs
Avoid post-op bleeding
- Rewarm the patient thoroughly
- Reverse Protamine
- Get all the surgical bleeders
- Be aware of hemodilution
- Consider use of antifibrinolytic/ lysine analog
