Management of Post-Op Bleeding-Exam 2 Flashcards
What is heparin rebound?
Some heparin may be protein bound and unavailable for reversal. It may become free post-CPB resulting in heparin rebound.
What will happen with excess protamine?
bleeding
How much of a decrease of circulating factors normally occurs on CPB due to hemodilution?
25-35% decrease; institution depending
How much does hypothermia slow enzymatic reaction times?
10 degree C decrease in temp, 50% decrease in enzymatic activity
What drives the clotting cascade?
Enzyme driven; enzymatic rxn times slowed during hypothermia
What are some sources of post-op bleeding?
Reduced concentration of coag factors Hyperfibrinolysis Thrombocytopenia Impaired plt aggregation Plt Fragmentation Loss of membrane receptors
What impairs coagulation and increases blood loss after CPB?
Increased inflammation
What are some extrinsic factors that can be a source of post-op bleeding?
Residual Heparin/Heparin Rebound
Excessive protamine
Hemodilution
Hypothermia
What are some ways to prevent post-op bleeding?
Avoid CPB (off pump procedures) Improved biocompatibility of foreign surfaces Alter conduct of bypass Hemtalogic strategies Improved surgical technique Make sure labs are normal pre-op
What are some hematologic strategies that can help prevent post-op bleeding?
Harvest whole blood/plasma
PRP
What is a major factor in use of blood products and post op bleeding?
Improved surgical technique
What drug has a mild fibrinolytic effect? Describe the effect.
Heparin; stimulates release of serum urokinase plasminogen activator (UPA) which induces fibrinolysis
CPB activates the breakdown of what?
Fibrinogen and other procoagulant precursors
Which is more potent? UPA or TPA?
TPA is more potent that UPA
What is the primary activator of fibrinolysis during heart surgery?
Tissue Plasminogen Activator (TPA)
When is there a large surge of TPA?
After protamine is given
When is the time of greatest thrombin production?
After protamine is given
If there was no fibrinolysis (left unchecked by TPA) what would happen?
Could result in large scale clotting or diffuse intravascular coagulation
When is thrombin produced?
Throughout CPB
When is there a surge of thrombin?
At termination of bypass
After protamine administration
What type of protein is thrombin?
Amplifier protein; activates many cell lines
What cell lines does thrombin activate?
Inflammation
Coagulation
Fibrinolysis
What is metabolically active in sites where heparin cannot reach it?
Thrombin
What regulates TPA?
Plasminogen Activator Inhibitor 1 (PAI-1)
What releases plasminogen activator inhibitor 1?
Liver and endothelial cells
What does PAI-1 bind to as it’s exported from endothelial cells?
Binds to TPA; therefore TPA must overcome circulating PAI-1 to initiate fibrinolysis
How is PAI-1 a buffer?
It’s a buffer to surges of TPA
When is PAI-1 released?
in response to inflammatory mediators
How does PAI-1 work as a prothrombotic?
Overcomes and suppresses fibrinolytic effect of TPA
What makes up a clot?
Thrombin
What breaks up a clot?
TPA
PAI-1 prevents what from breaking down clots?
TPA (hemostasis)
How does TPA factor into post-op bleeding?
TPA directly cleaves plasminogen (to make plasmin); exposes lysine binding sites, fibrinogen and fibrin bind at these lysine binding sites; proteolytic attack leads to breakdown products
What is needed to crosslink platelets to make a clot?
Fibrin
What does TPA do to fibrin?
TPA breaks down fibrin and therefore, the clot; leads to post op bleeding
What are antifibrinolytic agents?
Lysine Analogs
Aprotinin
What are the two lysine analogs that are commercially available?
Aminocaproic Acid (ACA)/ Amicar Tranexamic Acid (TA)
What is aminocaproic acid (ACA) made out of?
2 lysine molecules stuck together
What is aminocaproic acid’s mechanism of action?
Competitively binds to lysine sites of plasminogen/plasmin; prevents plasmin from binding to fibrinogen/fibrin
What is aprotinin made out of?
58 amino acid polypeptide Single lysine (high affinity for plasmin at this site)
What type of drug is aprotinin?
Non-specific serine protease inhibitor; but has other actions
What is aprotinin’s mechanism of action?
Catalyzes multiple reactions of inflammation, coagulation, and other cellular attack mechanisms
How long have lysine analogs been clinically available?
40+ years
How long do the prophylactic use in cardiac surgery of lysine analogs date back to?
1960’s
When are lysine analogs primarily thought to use?
After CPB
What study showed lysine analogs are effective in decreasing blood loss?
1989- Del Rossie, et al.
Large placebo controlled group (350 pts)
Pre-CPB administration of ACA decreased post operative chest tube drainage and transfusion without inducting thrombotic complications
What type of administration do lysine analogs use?
IV
What type of uptake do lysine analogs have?
Uptake is immediate
What type of molecules are lysine analogs?
Small, water-soluble molecules
How are lysine analogs distributed?
Distributed readily into extravascular water spaced before being taken up into various cells and tissues
What lysine analog is weak protein-bound and crosses BBB and Placenta?
TA
How are lysine analogs eliminated?
Renal excretion
What is the half-life of lysine analogs?
1-2 hours with IV administration
Describe the loading dose for lysine analogs pre CPB.
Loading dose pre-CPB over 1-15 min followed by a continuous IV infusion; sometimes a pump dose
What is the loading dose of ACA?
75-150 mg/kg (5-10 gm in adults)
What is the IV infusion dose for ACA?
10-15 mg/kg/hr; continues until the end of CPB or until protamine is given
What is the pump dose for ACA?
2-2.5 g/ L; some add/some don’t; makes sense to add b/c of added plasma volume on pump
What is the “10-10-10” protocol for ACA dosing?
Daily et. al protocol
10g given as slow bolus (5-10 min) pre CPB
10g in CPB prime
10g after CPB
What type of loading dose of ACA is used in patients with kidney disease?
Normal/reduced
What type of infusion rate of ACA is used in patients with kidney disease?
Reduced continuous infusion rate
ACA: 5mg/kg/hr
What is the infusion rate of TA used in patients with kidney disease?
0.5 mg/kg/hr
When should you dose lysine analogs?
As early as induction and incision; reports of clot formation on PA catheter and EKG ST-segment changes
Await full anticoagulation with heparin prior to administration
What study showed that ACA is acceptable to give prior to CPB but after heparin?
Kluger et al.
90 primary CABG pts
Given ACA pre-incision, after heparin and placebo; both ACA protocols decreased chest tube drainage and there was no difference between groups
How does TA dosing compare to ACA dosing?
TA dosing is 1/7 to 1/10th of ACA
What are the doses for TA?
Loading dose: 10-15 mg/kg over 10-15 minutes
Infusion: 1-1.5 mg/kg/hr
Pump: 2-2.5 mg/L
What are the side effects of lysine analogs in DIC patients?
Intravascular clots
What are the thromboembolic complications that can occur with lysine analogs?
Reduced graft patency DVT PE Stroke MI *All theoretically possible after heparin neutralization but no association has been found
Why are anti-fibrinolytics something to consider when thinking about transfusions?
Patients at low risk for transfusion (despite CPB) may not benefit from prophylactic anti-fibrinolytics. But it maye help tip the scales between transfusion or not if they are on the fence
Where is aprotinin found?
Found in all mammalian lung tissue
Isolated from bovine lung
Describe the activated sites on aprotinin.
Contains single lysine; binding site for most serine proteases it inhibits
What is the name of the most common regimen of aprotinin?
Full Hammersmith Regimen
What is the Full Hammersmith Regimen of Aprotinin?
2 million KIU in pump
2 million KIU to pt over 30-60 min
500,000 KIU/hr infusion for pump run
What’s the 1/2 life and excretion method of aprotinin with the full hammersmith region?
5 hours; renal excretion
What’s a major advantage of the full hammersmith regimen?
Blood loss and transfusion required are lowest
Aprotinin has a similar size to what?
Protamine
What can cause an allergic rxn to aprotinin?
Foreign protein from bovine source (1st time exposure reaction rate)
Describe the test dose of aprotinin.
1 mL given prior to loading dose
Wait 10 min after test dose before starting loading dose
When are aprotinin reactions in kids less?
Kids with less than 6 months between exposures; FDA revised advisory to put 12 months between exposures
What dose aprotinin affect?
Trypsin Chymotrypsin Plasmin Kallikrein Bradykinin TPA Urokinase Plasminogen Activator Complement
How long has aprotinin been used?
1960’s
When was aprotinin used in cardiac surgeries and by which surgeons?
1980’s by Ben Bidstrup and Kenneth Taylor and an anesthesiologst, David Royston.
What hospital was aprotinin first used in open heart surgeries?
Hammersmith Hospital, London
1st 20 patients tested with aprotinin had what kind of effect?
No effect on pulmonary gas exchange and post op lung dysfunction, BUT the surgical field was dramatically dry
What is the main advantage of aprotinin which is the reason its widely used in open heart surgeries?
Transfusion-sparing and decrease chest tube drainage associated
What is an example of blood loss data with aprotinin?
Aprotinin patients: 245 mL
Placebo patinets: 1979 mL
How does aprotinin affect kallikrein?
Decreases Kallikrein Decreases inflammation (doesn't affect bleeding)
What cascade does aprotinin activate?
Intrinsic cascade; activation of coagulation precursor proteins; activates pro-inflammatory WBCs; inhibits platelet-WBC interactions
What does inflammatory down regulation of aprotinin do?
Protects platelets; GPIb and IIb/iiia receptors are better preserved
Describe aprotinin efficacy.
Decreased chest tube output in re-operation cases, complex CABG, CABG with ASA/Plt inhibits on board
Aprotinin results in what percent reduction in chest tube output?
40-80% reduction in chest tube output compared in placebo
Why was aprotinin called into question?
Called to question graft patency with its use
Describe the Bidstrup that looked at aprotinin issues with graft patency.
Bidstrup: via MRI at 7 and 12 days post op
90 primary CABG
No difference in vein graft patency
All arterial grafts patent at 12 days
Describe the Lemmer study that looked at aprotinin’s effect on MI rates.
Lemmer et al. CT scans
151 primary CABG, 65 reop CABG
7 and 30 days post-op
Randomized, placebo controlled; no significant difference in graft patency; trend toward lower patency rates in aprotinin groups; no difference and no trend in MI rates
What study looks at aprotinin affect on neurologic function?
Levy et al.
Aprotinin may have neurologic protective effects
How does aprotinin affect risk of stroke?
No strokes in any patient who received mid/high dose of aprotinin
Describe aprotinin’s affect on renal function
Pts with worse renal function before bypass have greatest risk for further renal impairment/failure requiring dialysis with or without aprotinin
What is risk for dialysis with normal GFR
low risk
What is risk for dialysis with 50% normal GFR
> 20% risk for dialysis
What is risk for dialysis with <20% normal GFR
85% risk for dialysis
What does aprotinin compete with?
Competes with creatinine in the ascending loop of henle; expect the rise in creatinine with aprotinin not necessarily indicator of renal damage
Describe the creatinine rise with aprotinin.
Higher 3-7 days post op
Statistical significance at day 7
By day 14-30 post op, return to identical levels in both groups
Cost of ACA (generic)
$1.50 - $10 per 5gm vial
Case: $5-$30
Cost of TA (generic)
Case: $20-$300
Cost of aprotinin
Off patent, but costly to extract
$300-$400 per bottle
per case: $1000-$1500
Cost of recombinant factor VIIa
$5000-$9000/ dose
may require multiple doses
RBC cost
$300-$500
Platelets cost
$850
FFP cost
$100
When did the FDA revise labeling of aprotinin?
December 2006
How did the FDA revise labeling of aprotinin?
Don’t give w/in 12 mo of prior exposure; only for patients hwo are at increased risk for blood loss and blood transfusion associated with CPB in the course of a CABG
Are TA and ACA approved for prophylactic use in cardiac surgery?
no
Aprotinin Downfall: 2007
Temporarily withdrawn form the market worldwide
Aprotinin Downfall: 2005/8
permanently withdrawn from the market; use is limited to very select research
What complications are seen with both lysine analogs and aprotinin?
Intravascular thrombis
aprotinin increases serum creatinine transiently
Retrospective studies associate aprotinin with:
renal failure
stroke
mi
increase mortality (not seen with lysine analogs)
How to avoid post op bleeding?
Rewarm the patient thoroughly Reverse protamine Get all the surgical bleeders be aware of hemodilution consider use of antifibrinolysis lysine analog
