To review the difference between: aPTT versus anti-Xa test To understand the advantages and disadvantages of using aPTT versus anti-Xa test To explain what could affect the results of aPTT versus anti-Xa test To clinically assess the cause of mismatch of target therapeutic ranges

1. Anti-Xa versus aPTT Monitoring
for Intravenous Heparin
Administration in DVT/PE
Dieu LinhThiVo. Intensive Care Pharmacy Intern. COP2019
Preceptors: Faith Lin, Catherine Lai,Vivian Lin
Touro University California
November 9th, 2018

2. Learning Objectives
• To review the difference between: aPTT versus anti-Xa test
• To understand the advantages and disadvantages of using aPTT versus anti-
Xa test
• To explain what could affect the results of aPTT versus anti-Xa test
• To clinically assess the cause of mismatch of target therapeutic ranges

3. Patient AB
• 79yoM with a PMH of CHF with EF 23%, cardiomegaly, moderate to severe aortic
stenosis, MR,TR, CAD, HTN, paroxysmal afib, OSA, and CVA BIBA with a CC
multiple “dark” stool, dizziness, hematemesis and was found to have SOB,
hemorrhagic shock s/s acute upper GI bleed was then admitted to ICU due to
requiring NE drips, intubation and sedation. During hospital stay, patient
developed LLE DVT complicated with PE now requiring continuous IV heparin drip.
MR: Mitral valve regurgitation,TR:Tricuspid valve regurgitation, OSA: obstruction sleep apnea, SOB: shortness of breath,
ARF: Acute respiratory failure, CS: cardiogenic shock, HFREF: heart failure reduced ejection fraction
• Active hospital problems
• AKI due to cardiorenal syndrome
• Acute liver failure, transaminitis s/s liver shock
• Paroxymal afib on rivaroxaban
• Elevated total bilirubin

4. Patient AB
• Past Medical History
• CHF with EF 23%
• Moderate aortic stenosis, MR,TR
• CAD
• HTN
• Paroxysmal afib on rivaroxaban
• OSA
• CVA
MR: Mitral valve regurgitation,TR:Tricuspid valve regurgitation, OSA: obstruction sleep apnea
• Past Surgical History
• Hx of CABG 2009
• Hx of endartectomy carotid
• FH
• Mother: CAD/Stroke, HTN, hyperlipidemia
• Father: CAD, HTN, hyperlipidemia, sudden
cardiac death
• SH:
• Married to a life-partner, dancer-ballet teacher,
never smoke cigarette or alcohol or drugs used
• walk with a walker at home, wheelchair for any
farther distances

5. Home Medications
• Rivaroxaban (Xarelto) 15mg PO daily
• Last dose 9/26
• Aspirin 81mg PO daily
• Atorvastatin (Lipitor) 80mg PO daily
• Ezetimide (Zetia) 10mg PO daily
• Metoprolol tartrate (Lopressor) 75mg PO every morning
• Enalapril (Vasotec) 10mg PO every morning
• Furosemide (Lasix) 40mg PO daily

6. Inpatient Medications
• 10/16 - 10/21 Heparin 0-2,500 Units/hr titration IV drips per Non-Cardiac (DVT/PE) on Anti-Xa
protocol
• Norepinephrine 0-30mcg/min titration IV for goal MAP >65
• Propofol 0-50mcg/kg/min IV titrate for RASS score of 0 to -1
• Furosemide 4mL/hr IV continuous drip for UO goal >200mL /hour for more than 3 hours
• Ceftriaxone 1000mg IV q24h
• Metronidazole 500mg IV q8h
• Nystatin 100,000 units/g powder topical BID
• Fentanyl PF 25mcg IV q4h
• Insulin Lispro 1-6 units SC q4h
• Ipratropium/Albuterol (DUONEB) 0.5mg/2.5mL Neb soln 3mL q4h
• AcetylCYSTeine (MUCOMYST) 20% Neb Soln 3mL q4h
• Pantoprazole 40mg IV q12h
• Potassium Chloride 20mEq IV, contingent order

7. Patient AB’s aPTT versus Anti-Xa

8. Heparin Indications and Mechanism of Action
• Indications:
• Prophylaxis and treatment of:
• VTE (DVT/PE)
• Prevention of post-op DVT/PE
• Prevention of clotting in surgery
• Treatment of acute coronary
syndromes (NSTEMI/STEMI)
• Atrial fibrillation with embolism
• Treatment of acute and chronic
consumptive coagulopathies (DIC)
• MoA:
• Heparin binds to Anti-thrombin III (AT III) and stimulates the inhibitory
• Anti-thrombin III (AT III) inactivates serine proteases: thrombin (II), IXa, Xa, XIa and XIIa
Heparin

9. Heparin
Source • Biologic
Factor Inhibition • IIa, Xa, IXa, XIa, and XIIa
Anti-Xa:Anti-IIa • 1:1
Common Assays • aPTT, anti-Xa, ACT
PK/PD • Onset: IV immediately, SubQ ~20 to 30minutres
• Absorption: IV 100%, SubQ erratic
• Distribution:Varied by age and BSA, Adult IVVd 4 – 37mL/kg
• Metabolism: Complex, by de-polymerization and de-sulfation via reticuloendothelial
system primarily in the liver and spleen
• Half life: is dose dependent, ranges from 0.5 to 2hrs, and affected by obesity, renal
function, malignancy, and infection
• Excretion: urine (small amount as unchanged drug)
Side effects • Thrombocytopenia (0% to 30%), immunologically medicated HIT (1-2%)
• Bleeding
• Osteoporosis (chronic therapy effect)
Contraindications • Hypersensitivity to heparin or any component of the formulation
• Severe thrombocytopenia
• History of immunological mediated heparin induced thrombocytopenia (HIT)
• Uncontrolled active bleeding except disseminate intravascular coagulation (DIC)
Monitoring • Hemoglobin, hematocrit, signs of bleeding; fecal occult blood test; aPTT (or anti-factor Xa
activity levels) or ACT depending upon indication

10. What DoesTherapeutic Range Mean?
aPTT therapeutic range
• 2012 ACCP recommends therapeutic
range for the aPTT 1.5 to 2.5 times the
baseline as it was associated with
reduction in recurrentVTE
• Therapeutic range of aPTT varied
depending on reagents and
coagulometers used
Anti-Xa therapeutic range
• 2012 ACCP and the College of American
Pathologists agreed that aPTT 1.5 to 2.5
corresponded to a heparin level of 0.3 to
0.7 units/mL anti-Xa based on a protamine
titration of known therapeutic range of
0.2 to 0.4 IU/mL
CHEST 2012; 141(2)(Suppl):e24S–e43S

11. HEPARIN INFUSION PER NON-CARDIAC (DVT/PE) PROTOCOL
aPTTTest Monitoring
• Start at **18 units/kg/hr. INITIAL INFUSION RATE NOTTO
EXCEED 2,000 UNITS/HR.
• **Pharmacist to convert any units/kg/hr starting rate to units/hr
equivalent and add to administration instructions. Update dose
field to 0-2,500 units/hr.**
• TITRATE between 0 - 2,500 units/hr per instructions below:
• PTT less than 35 seconds: HIGHDOSE REBOLUS **60
units/kg/dose (Max 6,000 units) and increase by 200 units/hr (see
PRN HEParin order);
• PTT 35-75 seconds: LOW DOSE REBOLUS **30
units/kg/dose (Max 3,000 units) and increase by 100 units/hr (see
PRN HEParin order);
• PTT 76-115 seconds: No change;
• PTT 116-125 seconds: Decrease by 50 units/hr;
• PTT 126-135 seconds: HOLD infusion for 30 min, then restart
at 100 units/hr LESS than previous infusion;
• PTT 136-150 seconds: HOLD infusion for 60 min, then restart
at 150 units/hr LESS than previous infusion;
• PTT above 150 seconds: HOLD infusion for 60 min, then restart
at 300 units/hr LESS than previous infusion. Notify Provider.
Anti-Xa Assay Monitoring
• Start at **18 units/kg/hr. INITIAL INFUSION RATE NOTTO
EXCEED 2,000 UNITS/HR.
• **Pharmacist to convert any units/kg/hr starting rate to units/hr
equivalent and add to administration instructions. Update dose
field to 0-2,500 units/hr.**
• TITRATE between 0-2,500 units/hr per instructions below:
• Antifactor Xa less than 0.2 units/mL: HIGH DOSE REBOLUS
**60 units/kg/dose (Max 6,000 units) and increase by 200 units/hr
(see PRN HEParin order);
• Antifactor Xa 0.2-0.29 units/mL: LOW DOSE REBOLUS
**30 units/kg/dose (Max 3,000 units) and increase by 100 units/hr
(see PRN HEParin order);
• Antifactor Xa 0.3-0.7 units/mL: No change;
• Antifactor Xa 0.71-0.86 units/mL: Decrease by 50 units/hr;
• Antifactor Xa 0.87-0.95 units/mL: HOLD infusion for 30
min, then restart at 100 units/hr LESS than previous infusion;
• Antifactor Xa 0.96-1.03 units/mL: HOLD infusion for 60
min, then restart at 150 units/hr LESS than previous infusion;
• Antifactor Xa greater than 1.03 units/mL: HOLD infusion for 60
min, then restart at 300 units/hr LESS than previous infusion.
Sutter health’s hospital protocol

12. • aPTT measures functional activity of the intrinsic and common
pathways of the coagulation cascade
• Evaluates the coagulation factors XII, XI, IX,VIII, X,V, II
(prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and
high molecular weight kininogen (HK)
• aPTT Methodology
• Step 1: Blood is drawn into a test tube containing oxalate or citrate,
molecules which act as an anticoagulant by binding the calcium in a
sample
• Step 2: Blood is mixed and centrifuge. A sample of plasma is then
transferred into a measuring test tube containing excess Ca2+
suspended in phospholipids (the anticoagulant by oxalate or citrate
is now reversed)
• Step 3:To activate intrinsic pathway of coagulation, an activator
such as: Silica, celite, kaolin or ellagic acid, is added into the
measuring test tube
• Step 4:The time it takes to clot again is measured
aPTTTest
2018 AACC lab test online, “PartialThromboplastinTime (PTT, aPTT)”

13. What Could Affect or Alter aPTT Level?
1998 ACCP recognized three groups that deviate the results of aPTT:
Andy D Jones, MD, Pathology Resident, “Anti-Factor Xa for Monitoring of Unfractionated HeparinTherapy.”. By Laboratory Best Practice Blog| October 16, 2017

14. What Could Affect or Alter aPTT Level?
1998 ACCP recognized three groups that deviate the results of aPTT:
Andy D Jones, MD, Pathology Resident, “Anti-Factor Xa for Monitoring of Unfractionated HeparinTherapy.”. By Laboratory Best Practice Blog| October 16, 2017

15. Chromogenic Anti-factor XaTest
• To estimate the concentration of heparin in
the blood by detecting color changed when
chromogenic substrate binds to the residual Xa
• Anti-Xa Methodology
• Excess AT III is added, AT III complexed with heparin
(heparin is a rate limiting agent)
• AT III-Heparin complexed binds Factor Xa à leaving
unbound Xa called residual Xa in the sample
• A chromogenic substrate is then added
• Chromogenic substrate complexes with residual Xa
to then produced a color change that can be
detected by spectrophotometer
• The color changed is directly proportional to the
amount of unbound Xa and inversely proportional to
UFH level
Labs MM. Anti-Xa Assay for Heparin Monitoring [HotTopic]. In:Theresa N. Kinard M, ed2017

16. What Could Affect or Alter Anti-Xa Level?
• Falsely elevated Anti-Xa by:
• Hypertriglyceridemia >360mg/dL
• Receiving DOAC designed to inhibit factor Xa (including Apixaban, Rivaroxaban, Edoxaban,
Betrixaban)
• Recent use of LMWH
• Falsely decreased Anti-Xa by:
• Hyperbilirubinemia withTbili >6.6mg/dL
• Any substances that could interfere with light absorbance of 405nm
Andy D Jones, MD, Pathology Resident, “Anti-Factor Xa for Monitoring of Unfractionated HeparinTherapy.”. By Laboratory Best Practice Blog| October 16, 2017

17. Advantages and Disadvantages of aPTT versus
Anti-Xa Assays
aPTT Anti-Xa
Advantages • Global clotting factors I, II,V,VIII, IX, X, and XII
• Inexpensive
• Widely available
• Less affected by: biologic factors (e.g. lupus
anticoagulants, liver disease or DIC) or other labs
collection variations
• Less so affected by patient receiving warfarin
• Therapeutic range does not need to be adjusted
with every change in lot, reagent or coagulometer
Disadvantages • Non-specific to UFH
• Altered by many variables:
• Samples collection in the morning vs evening
• Different reagents use (e.g. different amount of
citrate or oxalate)
• Prolong aPTT at baseline (e.g. liver disease,
lupus anticoagulant, DIC, other clotting factor
deficiencies, sepsis or infections)
• Affected by patient receiving warfarin
• Therapeutic range needs to be adjusted with every
change in lot, reagent or coagulometer
• Measures specific Xa
• Many anticoagulants or DOAC can elevate Anti-Xa
level
• High level of triglycerides or bilirubin can impact
the color changed and detection

18. Anti-Xa vs. aPTT in ClinicalTrials
Vandiver 2013 (1) Guervil 2011 (2) Rosborough 1999 (3)
Anti-Xa aPTT Anti-Xa aPTT Anti-Xa aPTT
Achieve therapeutic goal
per 24 hours period
69% 41% 66% 42% 67% 38%
Numbers of monitoring
tests per 24 hours
2.1 2.7 2.5 2.8 1.5 1.7
Numbers of dosing changes
per 24 hours
0.6 1.5 0.8 1.6 0.5 0.8
Time to therapeutic range
(hours)
22 40 28 48 x x
Jeremy W. Vandiver PD, Vondracek, Thomas G, Pharm D. Antifactor Xa Levels versus Activated Partial Thromboplastin Time for Monitoring Unfractionated
Heparin. Pharmacotherapy. 2012;32(6):546-558

19. Bleeding Risk
• Price et al. 2013: 2 consecutive high aPTT to anti-Xa values had increased
21-day major bleeding (9% vs 3%; p = 0.0316) and 30-day mortality (14% vs
5%; p = 0.0202) compared with patients with consistently concordant
values.
• Future studies are needed to determine clinical efficacy of aPTT vs Anti-Xa
Price et al., “Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin.”. 2013 Feb;47(2):151-8. PMID: 23386070

20. Patient AB: aPTT versus Anti-Xa Monitoring

21. Patient AB CoagulationWorkup
• Antiphospholipid Antibody
Panel (09/2017)
• Cardolipin Ab-IgA: 2.2 <20
APL (0924), negative
• Cardiolipin Ab-IgG: 1.6 <20
GPL (0924) , negative
• Cardiolipin Ab-IgM: 9.7 <20
MPL (09/24), negative
LFT panel

22. Patient AB
Andy D Jones, MD, Pathology Resident, “Anti-Factor Xa for Monitoring of Unfractionated HeparinTherapy.”. By Laboratory Best Practice Blog| October 16, 2017

23. Take Home Points
• aPTT measures coagulation time or times for blood to clot again
• Anti-Xa measures the concentration of heparin in the blood
• Both aPTT and Anti-Xa tests had its own advantages and disadvantages
• High aPTT may mean that patients’ having a liver disease, clotting factors deficiency,
or with history of antiphospholipid syndromes
• LMWH and Anti-Xa inhibitors will increase Anti-Xa
• Anti-factor Xa provides a shorter time to therapeutic anticoagulation and
fewer dose adjustments when compared with aPTT

24. Credits and References
• CHEST 2012; 141(2)(Suppl):e24S–e43S
• AACC lab test online, “PartialThromboplastinTime (PTT, aPTT).”. November, 2018
• Andy D Jones, MD, Pathology Resident, “Anti-Factor Xa for Monitoring of Unfractionated HeparinTherapy.”.
By Laboratory Best Practice Blog| October 16, 2017
• JeremyW.Vandiver PD,Vondracek,Thomas G, Pharm D. Antifactor Xa Levels versus Activated PartialThromboplastin
Time for Monitoring Unfractionated Heparin. Pharmacotherapy. 2012;32(6):546-558
• RosboroughTK. Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests
and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacotherapy. 1999;19(6):760-
766.
• Labs MM. Anti-Xa Assay for Heparin Monitoring [HotTopic]. In:Theresa N. Kinard M, ed2017
• Price et al., “Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous
unfractionated heparin.”. 2013 Feb;47(2):151-8. PMID: 23386070
• Thank you to my preceptors: Faith Lin, Catherine Lai, andVivian Lin that helped choose this topic, as well as, reviewed and
critiqued my presentation.

25. Questions?