Topic 2 Flashcards
circulating mast cells called?
Basophils
Heparin structure
Sulfated glycosaminoglycan present in mast
cells
Heparan
close relative to heparin
lower sulfated form present on endothelial cells
Heparin works predominantly via potentiation of …
potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and other activated serine proteases (VII, IX, X, XI, XII)
Unfractionated Heparin
most commonly used type of heparin by perfusionists (because it is cheaper)
Long chains of unfractionated Heparin
(higher MW) bind better with AT-III and thrombin
In unfractionated Heparin_____ required for AT-III interaction
Specific pentasaccharide sequence along heparin chain
Unfractionated Heparin molecular weights
Range 3,000 - 40,000+ Daltons
Distribution of MW varies depending on source
Highest negative charge density of any biological molecule
Heparin (very! acidic)
Heparin Predominantly works via potentiation of Antithrombin III (AT III) to neutralize circulating thrombin and and other
activated serine proteases which are?
Activated serine proteases (VII, IX, X, XI, XII)
Mucosal Heparin MW
lower than Lung Heparin
Lung Heparin potency
greater potency than mucosal heparin so need a lower dose
Heparin more likely to cause HIT ?
Lung Heparin
Why does Lung Heparin need a larger protamine dose compared to Mucosal Heparin?
Lung Heparin requires more protamine due to having more ATIII interactions than Mucosal Heparin
Mucosal Heparin protamine dose needed compared to Lung Heparin
Need 25-30% less Protamine to neutralize
Lower MW which uses Xa inhibition– not reversed by Protamine
1 United States Pharmacopoeia (USP) unit
amount of heparin that maintains fluidity
of 1mL of citrated sheep plasma for 1 hour after
recalcification
British Pharmacopoeia (BP) units
Sulfated ox blood activated with thromboplastin
European Pharmacopoeia (EU) units
Recalcified sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes therefore constituting an aPTT for sheep plasma
Heparin half life with 100U/kg dose = __ min
61 ± 9minutes
Heparin half life with 200U/kg dose = __ min
93± 6 minutes
Heparin half life with 400U/kg dose = __ min
126 ± 24 minutes
Heparin pharmacokinetics
_______ elimination with peak effects at __ minutes post administration via central line
—Delayed in states of ___ or with peripheral injection
Biphasic
1-2
low CO
Heparin pharmacokinetics
Redistribution after ____ to normal elimination
4 - 5 min
Hypothermia effect on Heparin
delays clearance and increases half-life
Heparin at 25*C
virtually constant for 40-100 min
Celsius to Fahrenheit
[°F] = [°C] × 9 / 5 + 32
short cut way (not totally accurate)
F = (C x 2) + 30
Fahrenheit to Celsius
[C] = [F] - 32 x 5 / 9
AT III in the presence of Heparin
is increased 1,000-10,000X
Size Chains of heparin that bind to AT III?
Only larger chain molecules (1/3) of heparin
Smaller Heparin chains primarily have ___ effect?
anti-Xa effect and minimal anti-IIa effects
In regards to the Initial Heparin dose:
- What is the loading does? - What is the dose added to prime?
- Loading dose of 200-400U/kg given
- 5,000 to 20,000U added to prime
Heparin Empiric dosing amount?
The loading dose is given now what additional heparin amount do you give?
Loading dose given and ACT verified.
After that, give additional heparin (50 to 100U/kg) every 30 minutes or as infrequently as every 2 hours.
(No ACT checked due to theory of existing variables that make ACT
inaccurate)
Young et al (1978) found fibrin formation when ACT dropped _____
(study involving 9 rhesus monkeys)
below 400 seconds
Recommended minimum value of 480 seconds do to 10% interspecies variation and 10% test variability
Gravlee Heparin Protocol STEPS (6)
**Prime ECC with 3U of heparin per milliliter of pump prime
**Initial dose 300U/kg IV
**Draw sample for ACT 2 to 5 minutes after infusion
**Give additional heparin as needed to achieve ACT above 400 seconds
before initiation of bypass
Give additional heparin as needed to maintain ACT above 400 seconds
during normothermic bypass
**Give additional heparin as needed to maintain ACT above 480 seconds
during hypothermic bypass (24 to 30C)
**Monitor ACT every 30 minutes during bypass or more frequently if patient
shows heparin resistance
Heparin Complications
- *Heparin binds to platelets
- *Insufficient heparinization on bypass causes consumption of clotting factors.
- *Bleeding
Heparin binding to platelets causes
- Transient decrease in platelet count
- Prolonged bleeding time
Heparin binding to platelets decreases with what?
Binding decreases with decreased MW (i.e.. LMWH)
Heparin binding site to platelets
No specific binding site yet determined
Heparin Resistance
When more than 600u/kg given and ACT still is <300 seconds
Higher than normal heparin doses for sufficient anticoagulation for bypass
Extreme thrombocytosis
Platelet count > 500,000
ATIII Deficiency causes?
Familial/ Congenital
Acquired (Due to continued heparin therapy or estrogen based contraceptives)
Nitroglycerin
rare
Clinically relevant only when > 300 mcg/min
Heparin Resistance causes (5)
Extreme thrombocytosis Septicemia Hypereosinophilic Syndrome (rare) Nitroglycerin (rare) ATIII Deficiency
ATIII Deficiency Inherited (Familial/Congenital)
Factors precipitating occurrence: (3)
- Pregnancy
- Infection
- Surgery
Thrombosis after surgery
Inability to get adequate anticoagulation for cardiac surgery
ATIII Deficiency Inherited (Familial/Congenital) affects __ people?
1/2000 to 20,000 people
ATIII Deficiency Inherited (Familial/Congenital)
Presents at what age range? and with what physical expression?
Presents @ 15-30 years old with low limb venous thrombosis or Pulmonary Embolism
ATIII Deficiency Inherited (Familial/Congenital)
Gene expression?
Autosomal dominant
ATIII Deficiency Inherited (Familial/Congenital) :
Treatment ?
Life long antithrombotic therapy after diagnosis
Decreases incidence of thromboembolic events by 65%
Infants and newborns have __ levels of ATIII
60-80% adult ATIII levels
they dont have problems because Newborns don’t have thrombotic activity like adults do
@ 3 months ATIII Levels
90% of adult levels
Acquired ATIII Deficiency occurs how?
Occurs when patients are on Heparin pre-op or have chronic DIC
ATIII levels plateau around 60% of normal
Acquired ATIII Deficiency treatment: (2)
Transfusion of FFP
Administration of Recombinant ATIII (Thrombate or ATryn)
Platelet dysfunction can lead to
HIT
Heparin (Lrg MW) readily binds to platelets inducing release of : (4)
PF4
activation of GPIIb/IIIa receptors
platelet degranulation
platelet aggregation
HIT - Clinical condition characterized by a drop in platelet counts to ____ or _____from baseline
drop in platelet counts to <100,000 or 50% reduction from baseline
HIT - typically seen in ?
5-28% of patients receiving heparin
2-10 days after initiation of heparin therapy (can w/in hours)
HIT is less common with what types of Heparin?
LMWH and porcine mucosal heparin
HIT Type 1 — appears when?
—platelet count normalizes when?
- not immune mediated
- appears withing first two days of heparin exposure (LMWH/unfractionated)
- platelet count normalizes with continues heparin therapy
NOT Clinically significant
HIT Type II - appears when?
- resolves?
- immune mediated
- appears 4-14 days after heparin exposure (mostly unfractionated)
- can be life threatening
- does not spontaneously resolve with continued heparin therapy
HIT syndrom and HIT antibody have what correlation?
have a 90% correlation
Hit antibody causes HIT (but antibody presence alone does not mean they will get HIT!)
ELISA assay
measures IGG antibodies to heparin/PF4 complexes
Sensitivity >90% (low specificity - many false positives)
4 HIT antibody diagnostic test
1) ELISA assay
2) HIPA
3) C-SRA
4) PaGIA
HIPA (Heparin-Induced Platelet Aggregation Assay)
Measures presence of antibodies to heparin/PF4 coplexes
High specificity/ ~50% sensitivity
C-SRA (serotonin Release Assay)
- measures serotonin released by platelets activated by the HIT antibodies
- Sensitivity ~90% / Specificity ~100%
- GOLD STANDARD
- slow turn around/expensive/complex
PaGIA (Particle Gel Immunoassay)
Uses polystryrene particles coated with PF4-heparin complexes, patient serum added and compared to a standard
- quick and easy
- high specificity, but lots of false positives
How do you diagnosis HIT
- Clinical Diagnosis
- Thrombocytopenia (absolute or relative drop from baseline)
- THROMBOSIS
- Timing
- Greinacher Scoring System
HIT Risk Factores
- Race (African Americans more likely)
- Sex (females more likely)
- does not occur in pregnant women - post organ transplant (very prone)
- cardiac and orthopedic(more) patients prone
% of HIT syndrome patients that are cardiac surgery patients
50%!
% of HIT national prevalence in all heparin esposures
~0.2%
Includes quick procedures
% of HIT patients that require limb amputation
~11%
% HIT patients that die
25-30%
HIT Anticoagulation treatments (3):
- DTIs (Direct Thrombin Inhibitors)
- Factor Xa inhibitors
- Heparinoids
NEVER WARFARIN (if they did get warfarin give vitamin K)
Lepirudin (Refludan)
- what?
- T1/2
- Measured by?
- given?
HIT, DTI anticoagulation treatment
- recombinant leech-saliva anticoagulant
- T1/2 ~80 minutes (up to 48hrs with renal dysfunction)
- Measures by aPTT or ECT(eccrine clotting times)
- Given SubQ or IV
- Fairly immunogenic (allergic reaction)
Bivalirudin (Angiomax)
- what?
- T1/2
- immunogenic?
- Measured/monitored by?
- given?
HIT, DTI anticoagulation treatments
- synthetic form of hirudin(leech saliva)
- T1/2 ~25 min (3-4hrs with renal dysfunction)
- IV only
- less immunogenic than lepirudin (bc artificial)
- Measured by aPTT or ECT
- not common (newish/short half life
Argatroban
- T1/2
- clearance?
- immunogenic?
- Measured/monitored by?
HIT, DTI anticoagulation treatment
- MOST COMMON
- T1/2 ~50min
- clearance - hepatic
- much less immunogenic (better for long term use)
- Measured by aPTT or ECT
- 50% lower incidence of hemorrhagic incidents than leech derived drugs
Fondaparinux (Arixtra)
- what
- binds to
- T1/2
- clearance?
- given?
- Measured/monitored by?
HIT, Factor Xa Inhibitor, anticoagulant
- a synthetic cousin of LMWH (but w/no heparin probs) does not directly inhibit thrombin
- binds to ATIII
- T1/2 ~ 20 hours
- cleared unchanged by kidneys
- SubQ only
- Monitored by Anti-Xa assay or ACT
Danaproid (orgaron)
- what ?
- available?
HIT, Factor Xa Inhibitor, anticoagulant
- mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate
- cross-reacts with HIT sera, so difficult to diagnosis
- Not available in the US
What to do when you have a HIT patient? (6)
- Non-heparinized everything
- monitor - ACT/ECT
- NO stasis of blood
- discontinue coagulation agent 20-30 min prior bc no reversal agent
- MUF
- recirculate with added agent and drain circuit asap
ACT
whole blood clotting time accelerated bu using celite or kaolin activator (XII, XI)
normal value 92-128seconds
ACT results can be artificially prolonged by what? (3)
hypothermia, hemodilution, and aprotinin (celite)
aPTT
- tests INTRINSIC coagulation pathway (VIII, IX, XI)
- normal value - 26-39seconds
- very sensitive to heparin, NOT useful during CPB
PT
Tests Extrinsic Pathway VII
Normal value 10-14 seconds (lrg institutional variances)
-less sensitive to heparin than aPTT
aPTT and PT how do they do test?
plasma is separated in citrated tube and spun to activate XII, known concen of …
aPTT- platelet phospholipid and Ca++ are added.
PT - tissue phospholipid and Ca++ are added
Thrombin Time
Specific for measuring Common pathway
Normal value <17 seconds
sensitive to effects of heparin
TT - how test works?
plasma isolated in citrated collection tube, Ca++ and concentration of thrombin are added to trigger clots
Lrg doses of thrombin convert this test to a measurement of Fibrinogen
Fibrin degradation (split) products
- elevated levels can lead to?Product of clot lysis
Elevated levels can lead to inhibition of fibrin monomer cross-linking and even induce platelet dysfunction
TEG measures ? (5)
The efficiency of clot formation:
- time takes for clotting to begin
- speed of clot formation
- clot strength
- fibrinolysis
- platelet function (platelet mapping)
