SOP Heparin Pathologies Total.pdf - Oscp.ca

HEPARIN PATHOLOGIES STANDARD OPERATING PROTOCOL
PURPOSE
a. Describe the coagulation physiology, heparin pharmacology, dosing and monitoring, and the
diagnosis and treatment of pathologies associated with heparin anticoagulation.
b. Define evidence based best-practices surrounding the management of heparin anticoagulation
in standard cases and in the presence of heparin pathologies for the clinical perfusionist.
SCOPE
a. Applicable to clinical perfusionists practicing under the supervision of a licensed physician in the
arena of cardiopulmonary bypass only.
b. All applications of the operating procedures described herein are subject to approval and
alteration by the attending physician on a case by case basis.
DEFINITIONS
a. ACT= activated clotting time;
b. APTT= activated partial thromboplastin time;
c. AT= antithrombin;
d. AT-III = antithrombin III;
e. BMI = body mass index
f. CPB = cardiopulmonary bypass
g. CI = confidence interval;
h. d = daltons
i. HIT = heparininduced thrombocytopenia;
j. IU = international units
k. INR = international normalized ratio;
l. LMWH = low-molecular-weight heparin;
m. PF4 = platelet factor 4;
n. tPA = tissue plasminogen activator;
o. UFH = unfractionated heparin
BACKGROUND
A. Coagulation Physiology
i. Pediatric coagulation
a. The coagulation system is quantitatively deficient at birth, with
maturational improvement in factor levels occurring during the
first six months of life ( Andrew M. et al., 1988)
b. TEG revealed no defects in coagulation between newborn infants
and adults. In fact, children less than 12 months were shown to
initiate clot faster than adult. (Miller BE et al., 1997)

ii. Adult coagulation
1. Understanding current concepts of coagulation is important in
determining the preoperative bleeding risk of patients and in managing
hemostatic therapy perioperatively. (Tanaka KA., 2009)
2. Below is a diagram (A) of the intrinsic and extrinsic pathways. (B)
represents the regulation of thrombin generation.
B. Heparin pharmacology is complicated by variability in molecular composition, activity, and
clearance as well as multiple binding sites and storage capabilities.
i. Heterogeneous molecular size ranging from 3000 to 30000 d (Johnson 1976)
ii. Negatively charged repeating sulfated disaccharide units referred to as a
glycosaminoglycan (Ng 2009)
iii. 1/3 rd binds with antithrombin, thus only 1/3 rd of heparin dose is responsible
for the majority of anticoagulant activity (Lam 1976)
iv. Binds to multiple plasma proteins, platelets, macrophages, and endothelial
cells (Hirsh 2001)
v. Heparin-AT complex inactivates factors IIa, IXa, Xa, XIa, XIIa with greatest
affinity for factor Xa (Rosenberg 1994)
vi. Inactivating thrombin prevents fibrin formation and inhibits factors V and
VIII, increases secretion of tissue factor pathway inhibitor, and reduces VIIa
complex efficacy (Ofosu 1987)
vii. Amplifies vessel wall permeability, reduces vascular smooth muscle cell
production, and has an osteopenic effect (Clowes 1977, Shaughnessy 1995)
viii. Cleared first by saturable phase, secondarily by renal clearance, therefore
half-life is dose dependent ranging from 30 minutes for 25U/kg to 150
minutes for 150U/kg (de Swart 1982)

. Dosing Protocols
i. Empirical Dosing vs. Heparin Concentration Dosing- conflicting reports
1. No significant difference in ACT, protamine requirement, or post
operative bleeding found, however greater heparin was administered
in Heparin Concentration Regimen in pediatrics (Olshove 2000)
2. Individualized heparin and protamine management in pediatrics has
been shown to reduce platelet activation and coagulopathies,
although the immature systems of neonates needs further study
(Gruenwald 2010)
3. HDR protocol resulted in less heparin administered and a significant
reduction in post-operative blood loss in adults (Runge 2009)
ii. Algorithm Dosing
1. An evidence-based decision tree can be used to arrive at an adequate
heparin dosage and guide healthcare providers to a consistent and
cost-effective use of resources. (McKinney 2007)
iii. Obese patient dosing
1. LBM can be used to reduce the amount of heparin and protamine
administered up to 25% in patients with a BMI >30 (Baker2007)
c. Anticoagulation Monitoring: no definitive test accurately represents the entire
picture of anticoagulation and is reproducible laboratory to laboratory, device to
device, or operator to operator.
i. ACTs have little evidence of their accuracy and multiple studies have shown
significant lack of agreement between devices, yet the standard of 480
seconds is widely used. It has been quoted that “target times employed
stem more from historical clinician comfort than outcome studies” (Ng
2009).
ii. aPTT is useful in the detection of coagulation disorders when used in
combination with PT with the ability to differentiate between the intrinsic,
extrinsic, common and multiple pathway deficiencies (Cowell 2007). PTT is a
measure of the intrinsic pathway with the prolongation of PTT as a result of
the inhibition of thrombin activity. A PTT of 1.5-2.5 normal is historically
considered therapeutic for thromboembolic prophylaxis, however wide interlaboratory
variations in testing make comparison and correlation of values
difficult (Ng 2009).
iii. PT test is instrumental in detecting Factor VII deficiency and will not be
detected by the aPTT or ACT tests alone (Cowell 2007).
iv. Heparin concentration of whole blood as measured by the HMS has had
conflicting reports of efficacy. Multiple reports state a higher heparin dose is
used, yet a lower protamine dose is needed, possibly due to less coagulation
system activation. Some have confirmed this and also demonstrated a
reduction in inflammation marker activation (Dunning 2008). However, one
study found the Hepcon does not correlate to plasma heparin concentration
using a chromogenic substrate for factor Xa and is not recommended for
monitoring heparin concentrations during bypass (Hardy 1996). The HMS
was not been shown in a large study to be significantly more efficacious than
an ACT-based heparinization protocol with regards to length of stay and
blood usage (Slight 2008). The STS report gives the HMS system a grade B
level of evidence, thus its use is recommended where available.

v. Anti-factor Xa heparin assay determined by the amount of anti-Xa factor by a
chromogenic substrate which releases a colored compound detected by a
spectrophotometer is the most reliable form. Many different tests are
available, and variability is large.
vi. TEG is useful in the guidance of blood product administration. TEG may
decrease blood product administration when used with a specific algorithm
in the post-operative period (Dunning 2008). TEG was found to be superior
to ACT, PT, and PTT in predicting bleeding with the need for blood products
versus bleeding from surgical sources (Ti 2002).
d. Heparin Associated Pathologies and Problems
i. Heparin Induced Thrombocytopenia Type I & II
1. HIT type I is a benign, non-immune mediated, transient drop in
platelet count found in 10-20% of patients treated with IV heparin
(Newkirk 2010). Although monitoring is needed for these patients,
without treatment platelet counts will return to normal within a few
days and should not drop below 100000/mm3.
2. HIT type II is suspected with a 30-50% drop in platelet count 5 to 10
days after IV heparin therapy is started and found in less than 5% of
patients on IV heparin (Newkirk 2010).
a. HIT II is potentially fatal: platelet count decreases to less than
100000/mm3, and thrombosis begins. Disseminated
intravascular clotting is a serious risk.
b. PT and PTT are prolonged. Platelet aggregation and serotonin
assays are useful in the differential diagnosis.
c. Alternative anticoagulation therapy should be started
immediately.
ii. Heparin Allergy
1. Few cases of heparin anaphylaxis have been reported. Bottio 2003
and Berkun 2004 each published case studies in which heparin
anaphylaxis were confirmed. In one case danaparoid was used as an
anticoagulant alternative for hemodialysis, and in the other
cardiogenic shock ensued with heparin bolus for CPB. The CPB
patient required large doses of epinephrine and methylprednisone,
but was weaned from bypass and recovered uneventfully.
iii. Heparin Resistance
1. Heparin resistance can be defined as the need for higher than normal
heparin concentrations (>600USP units/kg) to achieve a safe ACT for
the initiation of CPB. (Hensley, Martin and Gravlee, 2005). In fact,
failure to attain an ACT>300 seconds after >600 USP units/kg of
heparin is a presumptive process. (Gravlee, 1993)
a. ATIII deficiency (inherited or acquired) can be linked to
heparin resistance in most patients.
b. True heparin resistance is rare. Acquired ATIII deficiency is
common among the critically ill, but should not decrease ATIII
levels to that of hereditary/inherited ATIII deficiency (Ng
2009).
i. AT III deficiency is treated with fresh frozen plasma
(FFP) or human AT III concentrate.

1. Normally, 2 to 3 units of FFP is sufficient to
increase the ACT to a safe level for CPB.
(Gravlee, 1993)
2. Human AT III is pooled from human plasma, but
it is has been heat treated so that it should be
free of disease transmission risk. ATIII is only
approved by the FDA for hereditary ATIII
deficiency.
a. Recommendations for the
administration of AT III, is 100 x (weight
in kgs) to increase AT III levels from 0%
to 100%. (Gravlee, 1993)
b. The half life of AT III is 22 hours.
c. Other causes of heparin resistance include nitroglycerin
administration, thrombocytosis, hemodilution, and immature
coagulation systems.
iv. Heparin Rebound
1. Heparin is bound nonspecifically to plasma proteins which lead to
incomplete neutralization of heparin by protamine. Heparin rebound
occurs when heparin which is not neutralized exhibits an
anticoagulant effect 1-6 hours after neutralization (Teoh 2004).
2. A slow continuous protamine infusion post-operatively can
significantly reduce heparin rebound (Teoh 2004).
SAFETY
e. Medication administration safety.
i. The six “rights” will be verified before any and all drug administration. These
include:
1. Right patient: patient will be verified by two identifiers upon entry to
the operating suite as well as all known allergies.
2. Right drug: all drugs will be checked by two licensed providers
(perfusionist and RN, MD, or another perfusionist) for proper drug
name, concentration, and expiration date.
3. Right dosage: dose will be verified by perfusionist and anesthesia
resident or attending.
4. Right route: the location for drug administration (IV, central/cpb, etc)
will be verified with anesthesia before administering via the CPB
mannifold.
5. Right time: perfusionist will verify with anesthesia that the drug is
indeed to be administered at that time.
6. Right documentation: the perfusionist will document the time and
dose of the drug administered. If the administration is a variance
from the standard protocol, “per (ordering physician’s name)” is to be
added to the pump record.
ii. All vials will be entered in a sterile fashion using a five second alcohol wipe,
and new sterile needle and syringe.
f. Heparin storage and labeling: multiple incidences of Heparin overdose and related
deaths have been reported.

i. The ONLY concentration of heparin to be stored in the operating suite is
1000 units per ml. These may be in 30 or 10 ml vials and will have orange
labeling.
ii. The ONLY concentration of heparin to be used in the pediatric and neonatal
intensive care areas is 100 units per ml.
1. Heparin is NOT to be stored in pediatric and neonatal treatment areas
with the exception of factory pre-drawn heparin flush/heplock
syringes.
2. Heparin for systemic anticoagulation in pediatric and neonatal
patients must be obtained from the pharmacy in pre-mixed diluted
bags, labeled for individual patient administration only.
RESPONSIBILITIES
g. The perfusionist is responsible for:
i. An accurate and up to date patient history including the discovery of all
pertinent laboratory data.
ii. Making the surgical and anesthesia team aware of the discovery of any
information which may influence the anticoagulation process.
iii. Obtaining and recording patient demographics, calculating the BSA, BMI, and
heparin bolus dose.
iv. Obtaining and recording the initial ACT.
v. Communicating to the attending anesthesiologist the recommended heparin
bolus.
vi. Obtaining, recording, and communicating any heparin sensitivity or HDR tests
run.
vii. Obtaining, recording, and communicating all subsequent ACTs and heparin
doses on bypass.
viii. Obtaining and recording the post-protamine ACT.
PROCEDURES
h. Evidence-based heparin dosing protocol
i. Thoroughly review the cardiac surgical patient record.
1. Note the age, sex, height, weight, BSA, and BMI of the patient and
any allergies.
a. If the patient is obese (BMI>30, calculate ideal or lean body
mass for use in calculations).
b. Calculate the patient blood volume and initial standard
heparin loading dose (300IU/kg).
2. Has the patient been administered pre-operative heparin Have a
platelet count > 300k/mm3, or have an albumin concentration less
than 3.5 grams per dL Will the patient be profoundly hemo-diluted
or undergo deep hypothermia
a. If yes to any of these questions, an HDR may be warranted,
and a heparin concentration management protocol may be
more appropriately followed or a simple heparin sensitivity
test may be performed.

. If HDR < 80 sec/U/cc, ATIII activity should be measured where
availbale, and recombinant ATIII made available. If ATIII
activity is less than 60%, administration is warranted.
c. Alternatively, where HDR testing is not available, a simple in
vitro heparin sensitivity test is recommended.
ii. Measure the initial activated clotting time.
1. If the ACT is less than 95 seconds or greater than 145 seconds, a
repeat ACT should be drawn. If the ACT is still out of range the
history of the patient and laboratory tests should be revisited to
determine a source/reason for the deviation.
2. If the history is all clear and the initial ACT is consistent with the
clinical history of the patient, the heparin loading dose may be
administered at the appropriate time.
3. A simple heparin sensitivity test is recommended at this time.
a. In a syringe add 6IU of heparin/ml of blood, mix well, and
clearly label.
b. Run the heparin sensitivity ACT.
i. If ACT

heparin resistance
(thromocytosis).
4. Re-measure the ACT after any action and repeat steps as necessary.
i. Evidence-based anticoagulation management protocol
i. Maintain ACT >600 seconds for all patients with heparin anticoagulation on
cardiopulmonary bypass.
1. Those patients being anticoagulated with heparin alternatives will
need to be treated according to the alternate drug-specific protocol.
2. Obtain an ACT at an interval no greater than every 30 minutes while
on CPB for adult patients and no greater than every 20 minutes while
on CPB for pediatric and neonatal patients. Obtain ACTs more
frequently while warming, especially on DHCA cases.
3. Treat ACTs less than 600 seconds with 1/5 or 20% of the heparin
loading dose. (ie for a loading dose of 30k IU to the patient and 10k
IU in the pump, a subsequent heparin dose would be 8k IU).
4. If repeat heparin administration is required, an ACT is to be drawn
within 10 minutes of administration, and anesthesia is to be
informed.
ii. Anesthesia will reverse heparin with Protamine after cardiopulmonary
bypass. (See Anesthesia Protamine protocol for more information- this is
provided for information purposes.)
1. Protamine dose should be diluted in 100ml of NSS.
2. Dose may be determined by the HMS, or calculated @ 1mg per 100IU
of heparin given.
3. A test dose of 1microgram/ml of Protamine is recommended after
venous decannulation. Cardiotomy suction should be terminated at
this point.
4. If no reaction to Protamine test dose, a slow infusion of no more than
50mg/10min should be started after arterial decannulation.
5. If a Protamine reaction is suspected, it may be necessary to resume
cardiopulmonary bypass. See protamine reaction protocol.
6. A slow Protamine drip is recommended upon transfer to the ICU for
the prevention of heparin rebound.
j. Guidelines for heparin pathologies in the cardiac operating room.
i. Heparin resistance is addressed in the heparin dosing protocol.
ii. History of heparin anaphylaxis and current HIT type II (surgeon preference)
may warrant an alternative anticoagulation strategy. The preference in such
cases will be anticoagulation with bivalirudin. See the bivalirudin protocol
for further information. The CDI cell contains heparin and should not be
used on these patients. Current circuitry is NOT heparin coated.
1. Unknown heparin anaphylaxis (or heparin contamination) may
require immediate commencement of cardiopulmonary bypass.
2. Plasmapheresis should be considered for these patients.
iii. A current history of a positive HIT type I, as well as HIT type II patients
(surgeon preference) will be anticoagulated with heparin and on-bypass
plasmapheresis, as well as post-operative plasmapheresis will be utilized.
Careful monitoring of condition with frequent platelet counts and
coagulation profiles will be performed post-bypass.

iv. A remote history of HIT type I will proceed on bypass with the usual heparin
anticoagulation protocol. Platelet counts should be monitored carefully in
the post operative period.
v. A small, slow continuous Protamine infusion should be used
(anesthesiologist’s preference) with any suspicion of heparin rebound (Teoh
2004). TEG and anti-factor Xa assays can help determine cause of nonsurgical
bleeding and best course of action.
ASSOCIATED MATERIALS
k. Heparin
l. Sterile syringes
m. Sterile needles
n. ACT machine
o. ACT tubes or cartridges
p. Other laboratory testing equipment as needed by laboratory technicians
ADDITIONAL INFORMATION
q. See Bivalirudin Protocol.
r. See Anesthesia Protamine Protocol.
REFERENCES
s. Bottio, T., Pittarello, G., Bonato, R., & Fagiolo, U. (2003). Life-threatening
anaphylactic shock caused by porcine heparin intravenous infusion during mitral
valve repair. J Thoac Cardiovasc Surg, 126, 1194-1195.
t. Berkun, Y., Haviv, Y., Schwartz, L., & Shalit, M. (2004). Heparin-induced recurrent
anaphylaxis. Clinical and Experimental Allergy, 34, 1916-1918.
u. Brown, M., Gallagher, J., & Armitage, J. (2000). The use of antithrombin III
concentrate for treatment of heparin resistance during cardiopulmonary bypass.
JECT, 32(2), 75-78.
v. Clowes AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell
proliferation in injured arteries. Nature 1977; 265: 625-626.
w. Conley, J., & Plunkett, P. (1998). Antithrombin III in Cardiac Surgery: An Outcome
Study. JECT, 30(4), 178-183.

x. DeBois, W., Liu, J., Elmer, B., & Ebrahimi, H. (2007). Heparin sensitivity test for
patients requiring cardiopulmonary bypass. JECT, 38, 307-309.
y. Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Joiner-Maier D, Santoro SA,
Spitznagel E, Weitz JI, Goodnough LT. (1996) More effective suppression of
hemostatic system activation in patients undergoing cardiac surgery by heparin
dosing based on heparin blood concentrations rather than ACT. Thrombosis and
Haemostasis. Dec;76(6):902-8.
z. Gravlee GP, Davis RF, (&) Utley JR. (1993) Heparin Resistance. Cardiopulmonary
Bypass: Principles and Practice. Williams and Wilkins Publishing. Section III, Chapter
14: 362-64.
aa. Grayoso, J. (1999). 5-year incidence of thrombocytosis and the effect on heparin
dose response and heparin requirements. JECT, 31(4), 184-190.
bb. Gris et al. Monitoring the effects and managing the side effects of anticoagulation
during pregnancy. Obstetrics and Gynecology Clinics. Volume 33(3):397-411.
cc. Hirsh, J., Anand, S. S., Halperin, J. L., & Valentin, F. (2001). Mechanism of Action and
Pharmacology of Unfractionated Heparin. Journal of the American Heart Association,
21, 1094-1096.
dd. Hirsh, J., Warkentin, T.E., Shaughnessy, S.G., Sonia S , Ohman, M., Dalen J.E.,
Halperin, J., Raschke, R., Granger, C.,. (2001) Heparin and Low Molecular Weight
Heparin Dosing, Monitoring, Efficacy, and Safety Mechanisms of Action,
Pharmacokinetics Chest 119;64S-94S
ee. Johnson EA, Mulloy B. The molecular weight range of commercial heparin
preparations. Carboydr Res 1976; 51: 119-127.
ff. Krishnaswamy A, Lincoff AM, Cannon CP. (2010) The Use and Limitations of
Unfractionated Heparin. Critical Pathways in Cardiology. Mar;9(1):35-40.

gg. Lam LII, Silbert JE, Rosenberg RD. The separation of active and inactive forms of
heparin. Biochem Biophys Res Commun 1976; 69:570-577.
hh. Marco Ranucci, Giuseppe Isgrò, Anna Cazzaniga, Giorgio Soro. (1999) Predictors for
heparin resistance in patients undergoing coronary artery bypass grafting. Perfusion;
14: 437–442.
ii. Mirow, N., Zittermann, A., Koertke, H., Maleszka, A., Knobl, H., Coskun, T., Kleesiek,
K., & Koerfer, R.. (2008). Heparin-coated extracorporeal circulation in combination
with low dose systemic heparinization reduces early postoperative blood loss in
cardiac surgery. Journal of Cardiovascular Surgery, 49(2), 277-84. Retrieved June 28,
2010, from ProQuest Nursing & Allied Health Source. (Document ID: 1499767111).
jj. Newkirk, C.E., 2010 Heparin-induced Thrombocytopenia (HIT): A Case Study. Clinical
Laboratory Science, VOL 23(1): 5-11
kk. Ng, V. (2009) Anticoagulation Monitoring. Clin Lab Med 29: 2833-304.
ll. Ofson FA, Sie P, Modi GJ, et al. The inhibition of thrombin-dependent feedback
reactions is critical to the expression of anticoagulant effects of heparin. Biochem J
1987; 243:579-588.
mm.
Oliver WC. (2005) Hemostasis, Coagulation, and Transfusion in the Pediatric
Cardiac Patient. Pediatric Cardiac Anesthesia. Chapter 16:304-314.
nn. Priziola, et al., (2010) Drug-induced thrombocytopenia in critically ill patients. Critical
Care Medicine, 38(6); Suppl. S145-S154
oo. Rosenberg RD, Bauer KA. The heparin-antithrombin system: a natural anticoagulant
mechanism. In: Cohman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and
thrombosis: basic principles and clinical practice. 3 rd ed. Philadelphia, PA: JB
Lippincott, 1994; 837-860.

pp. Shaughnessy SG, Young E, Deschamps P, et al. The effects of low molecular weight
and stardard heparin on calcium loss from the fetal rat calvaria. Blood 1995; 86:
1368-1373.
qq. Tanaka KA, Key NS, Levy JH. (2009) Blood coagulation: hemostasis and thrombin
regulation. Anesth Analg. May;108(5):1433-46.
rr. Teoh, K.H., Young, E., Blackall, M.H., Roberts, R.S., Hirsh, J., (2004) Can extra
Protamine eliminate heparin rebound following cardiopulmonary bypass surgery
Journal of Thoracic and Cardiovascular Surgery 128; 211-209.
ss. Uprichard J, Manning RA, Laffan MA. (2010) Monitoring heparin anticoagulation in
the acute phase response. British Journal of Haemotology. May;149(4):613-9.
tt. Van Cott EM. (2009) Point of care testing in coagulation. Clinical Laboratory
Medicine. Sep;29(3):543-53.
uu. Warkentin T.E., (2006) Think of HIT, Hematology. 408 - 414.
vv. Welsby IJ., (2010) Plasmapheresis and Heparin Reexposure as a Management
Strategy for Cardiac Surgical Patients with Heparin-Induced Thrombocytopenia.
Anesthesia and Analgesia; 110(1):30-35.