Topic 8 Management of postop bleeding Flashcards
Heparin that becomes protein bound:
-Unavailable for reversal
-May become free post-CPB
“HEPARIN REBOUND”
Excess Protamine induces
Induce bleeding
Hemodilution what % decrease is there in circulating factors ?
Appx 25-35% decrease in circulating factors
Institution dependent
Sources of Post Op Bleeding (7)
-Reduced concentration of coagulation factors -Hyperfibrinolysis -Thrombocytopenia -Impaired Platelet Aggregation -Platelet Fragmentation -Loss of Membrane Receptors -Increased inflammation after CPB impairs coagulation and increases blood loss
Extrinsic Factor of Post Op Bleeding (4)
- Residual Heparin / Heparin Rebound
- Excessive Protamine
- Hemodilution
- Hypothermia
Prevention of Post-Op Bleeding
- Avoiding CPB
- Improved biocompatibility of foreign surfaces
- Alter conduct of bypass
- Use hematologic strategies
- Harvest whole blood / Plasma/PRP
- Improved surgical technique
- Making sure labs are normal pre-op
Heparin has mild fibrinolytic effect
-Stimulates release of serum urokinase
plasminogen activator (UPA)
-Induces fibrinolysis
Tissue Plasminogen Activator (TPA)
-More potent than UPA.
-Primary activator of fibrinolysis during
heart surgery.
Large surge of what after protamine is
given
TPA
At the time of greatest thrombin production
If left unchecked, could result in large scale
clotting or diffuse intravascular
coagulation.
TPA (i.e.. No fibrinolysis)
Thrombin Produced/Surges when?
- Produced throughout CPB
- Surge @ termination of bypass
- Surge after protamine administration
Thrombin
-Amplifier protein
-Activates many cell lines
-Inflammation
-Coagulation
-Fibrinolysis
-Metabolically active in sites where
heparin cannot reach it
Plasminogen Activator Inhibitor 1 (PAI-1)
- regulates? - released by?
- Regulates TPA
- Released by Liver and Endothelial Cells
Plasminogen Activator Inhibitor 1 (PAI-1)
-binds to what?
- PAI-1 binds to TPA as it’s exported from endothelial cells
- Therefore, TPA must over comecirculating
- Initiate fibrinolysis
- Buffer to surges of TPA
- Released in response to inflammatory mediators
Plasminogen Activator Inhibitor 1 (PAI-1)
- is Prothrombic
-Overcomes and suppresses fibrinolytic effect
of TPA
How does PAI-1 overcomes and supresses finbrinolytic effect of TPA?
-Thrombin–makes clot
-TPA breaks up clot PAI-1 prevents TPA from breaking down clots
›Hemostasis!
TPA directly cleaves ?
plasminogen-> Plasmin
When TPA cleaves plasminogen to plasmin what happens? (3)
- Exposes Lysine binding sites
- Fibrinogen and fibrin bind @ these lysine binding sites
- Proteolytic attack leads to breakdown products
TPA breaks apart what?
- Breaks apart fibrin and therefore, the clot
- Leads to post-op bleeding
Fibrin
crosslinks platelets to make a clot
Antifibrinolytic Agents
Lysing Analogs
›Aminocaproic Acid (ACA) / Amicar
›Tranexamic Acid (TA)
Aprotinin
Antifibrinolytic Agents
Lysing Analogs
›Aminocaproic Acid (ACA) / Amicar ›Tranexamic Acid (TA)
Aminocaproic Acid (ACA) / Amicar
Antifibrinolytic Agents
- 2 lysine molecules stuck together
- Competitively binds to lysine sites of plasminogen/ plasmin
- Prevents Plasmin from binding to fibrinogen/fibrin
Aprotinin is?
Antifibrinolytic Agent
- 58 amino acid polypeptide
- Single Lysine>High affinity for plasmin at this site
- Non-specific serine protease inhibitor
- Has other actions
Aprotinin catalyzes what?
Catalyzes multiple reactions of inflammation,
coagulation, and other cellular attack mechanisms
2 commercially available lysine analogs
ACA and TA
Clinically available for 40+ years
Lysine Analogs Pharmavology
- IV Administration
- Uptake is immediate
- Small, water-soluble molecules
Where are Lysine Analogs Distributed ?
Distributed readily into extravascular water spaced before being taken up into various cells and tissues.
TA specific pharmacology?
Weak protein-bound
›Crosses BBB and Placenta
Lysine Analogs excretion
Renal excretion
Lysine Analogs T1/2
Half-life: 1-2 hours with IV administration
ACA loading dosing
Loading Dose: 75-150mg/kg (5-10gm in adults)
ACA IV infusion dose?
IV Infusion: 10-15mg/kg/hr
›Continues until end of CPB or until Protamine is given
ACA Pump dose
Pump Dose: 2-2.5g/L
›Some add/ some don’t
›Makes sense to add b/c of added plasma volume on pump
ACA Daily, et al Protocol (aka: “10-10-10”) dosing?
›10g given as slow bolus (5-10min) pre-CPB
›10g in CPB prime
›10g after CPB
ACA dosing Pt with kidney disease
›Normal/reduced LD
›Reduced continuous infusion rate
ACA: 5mg/kg/hr
TA: 0.5mg/kg/hr
ACA timing of initial dose
-As early as induction and incision
-Reports of clot formation on PA Catheter and EKG ST-segmen changes
›Await full anticoagulation with heparin prior to administration
TA stand for?
Tranexamic Acid
Tranexamic Acid what is it?
Antifibrinolytic agent
Lysing Analogs
TA Loading Dose:
10-15mg/kg over 10-15min
TA Infusion Dose:
1-1.5mg/kg/hr
TA Pump Dose
2-2.5mg/L
TA doses compared to ACA dose
1/7 to 1/10th of ACA
what is DIC?
Disseminated intravascular coagulopathy/tion or less commonly as consumptive coagulopathy,
- pathological process characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body. This leads to compromise of tissue blood flow and can ultimately lead to multiple organ damage.
Lysing Analogs Side affects in DIC patients
Intravascular Clots
Lysing Analogs Side affects in Thromboembolic Complications (5)
›Reduced Graft Patency ›DVT ›PE ›Stroke ›MI ›**All theoretically possible after heparin neutralization, but no association has been found
Patients at low risk for transfusion (despite
CPB) may not benefit from what type of drugs?
(something to consider)
— may not benefit from prophylactic anti-fibrinolytics. But may help tip the scales between transfusion or not if they are on the fence.
Aprotinin - structure?
found where?
- 58 amino acid polypeptide
- Found in all mammalian lung tissue
- Isolated from bovine lung
Aprotinin activated site?
-contains single lysine
-Binding site for most serine proteases it
inhibits
KIU
Kilo international units
Aprotinin: Full Hammersmith Regimen (Most common) – pump/pt/infusion?
›2 million KIU in pump
›2 million KIU to pt over 30-60 minutes
›500,000 KIU/hr infusion for pump run
Aprotinin T1/2
5 hours with this regimen
›Renal excretion
Aprotinin Blood loss and transfusions required are lowest with what dosing?
with full dose regimen
Aprotinin Allergic reactions caused by?
found in peds when?
-Foreign protein from bovine source
-Size similar to protamine
-1st time exposure reaction rare
-Found reaction in kids with less than 6
months between exposures
›FDA revised advisory to put 12 months between exposures
Aprotinin how to test dose for an allergic reaction?
-Test dose of 1mL given prior to loading dose
-Wait about 10 min after test dose before
starting loading dose
Aprotinin effects what substances? (8)
Non-specific serine protease inhibitor Effects: ›Trypsin ›Chymotrypsin ›Plasmin ›Kallikrein !!!! (Know this one) ›Bradykinin ›TPA ›Urokinase Plasminogen Activator ›Complement
Kallikrein does what?
>Decrease inflammation >Doesn’t affect bleeding ›DOES activate intrinsic cascade ›Activation of coagulation precursor proteins ›Activates pro-inflammatory WBCs ›Inhibits Platelet-WBC Interactions
Are TA and ACA FDA approved for prophylactic use in cardiac surgery?
NO
Aprotinin - FDA Revised labeling (2006)
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
Recombinant Factor VIIa cost?
$5,000-$9,000 /dose
May require multiple doses
Aprotinin competes with what in the Acending Loop of Henle?
COmpetes with creatinine in the
ascending Loop of Henle.
›Expect the rise in creatinine with Aprotinin
> this does not mean there is necessarily renal damage
What is the cheapest? ACA, TA or Aprotinin?
ACA < TA < Aprotinin
--ACA–generic›$1.50-$10 per 5gm vial
›Case: $5-$30
--TA–generic›Case: $20-$300
--Aprotinin–off patent, but costly to extract›$300-$450 per bottle
›Case: $1000-$1500In 2008 what happened to Aprotinin ?
Permanently withdrawn from the
market
›Use is limited to very select research
Retrospective studies associate Aprotinin with: (adverse side effects {4])
- Renal Failure
- Stroke
- MI
- Increased Mortality
- *NOT seen with Lysine Analogs
How to avoid post op bleeding - in general?
-Rewarm the patient thoroughly
-Reverse Protamine
-Get all the surgical bleeders
-Be aware of hemodilution
-Consider use of antifibrinolytic/ lysine
analog
