¿Cuál es la utilidad real de la determinación de actividad anti Xa en

el tratamiento con heparinas?

JC ReverterServicio Hemoterapia y HemostasiaHospital Clínic Barcelona

Heparinas de Bajo Peso Molecular

Actividad SemividaFármaco anti-Xa / anti-IIa intravenosa

(razón) (min)Bemiparina 8,0 246-318Dalteparina 2,1 119-139Enoxaparina 2,7 129-180Nadroparina 3,2 132-162Tinzaparina 1,9 132-162

De Caterina R. Thromb Haemost 2013, 109: 769-786

• AVK INR

• UFH aPTT

• LMWH antiXa

• Fondaparinux antiXa

• Dabigatran Diluted Thrombin Test

• Rivaroxaban antiXa

• Apixaban antiXa

• Edoxaban antiXa

Monitoring anticoagulants

WoolGD. Am J ClinPathol 2013;140:623-34

Chromogenic anti–factor Xa assay

• Razones de concepto

• Razones relacionadas con la determinación de laboratorio

• Razones clínicas

Uso de anti-Xa

Razones para NO

• LMWHs have predictable pharmacodynamic profiles and wide therapeutic windows that do not require routine coagulation monitoring in clinically stable and uncomplicated patients

Smythe MA. J Thromb Thrombolysis. 2016; 41:165–186

Farmacocinética HBPM

• Anti-Xa (and anti-IIa) activity represents the amount of heparin present but not necessarily the antithrombotic function of LMWH, because the same concentration of heparin may have varying effects in different plasmas and patients

Razones para NO

• LMWHs have predictable pharmacodynamic profiles and wide therapeutic windows that do not require routine coagulation monitoring in clinically stable and uncomplicated patients

• Anti-Xa activity is a surrogate marker that measures the anticoagulant effect of LMWH and is assumed to correlate with hemorrhagic and thromboembolic events.

Smythe MA. J Thromb Thrombolysis. 2016; 41:165–186

Anti-Xa en Heparina: Historia

• The McMaster Group, demonstrated that an aPTT level of 1.5–2.5 times control prevented extension of established experimental thrombi in rabbits.

• Based on the concordance of these clinical and experimental findings, an aPTT therapeutic range of 1.5–2.5 times control subsequently gained wide acceptance.

• Additional studies using the “McMaster thromboplastin reagent” showed that this range corresponded to an unfractionated heparin level of 0.2 to 0.4 IU/ml by protamine titration and of 0.3 to 0.7 IU/ml by anti-Xa assay.

Niveles de anti Xa

Levine MN. Arch Intern Med 1994; 154:49–56

• Pacientes con TVP y requerimiento de más de 35.000 UI/día de heparina. Control por APTT o anti Xa.

Rango objetivo de anti-factor Xa: 0.35 - 0.67 U/mLRango objetivo de APTT: 60 - 85 segundos

Niveles anti Xa

Bemiparina (datos ficha EMA) 1.1

Target anti-factor Xa range of therapeutic LMWH

• Anti-Xa (and anti-IIa) activity represents the amount of heparin present but not necessarily the antithrombotic function of LMWH, because the same concentration of heparin may have varying effects in different plasmas and patients

• The comparability between commercially available anti-Xa chromogenic assays is poor.

Correlation between one stage chromogenic assays

http://www.technoclone.com/pdf/folder/neues-format/files/c002e.006_technochrom-antixa.pdf

Anti-Xa. Estandarización pobre

How useful is the monitoring of (low molecular weight) heparin therapy by anti-Xa assay? A laboratory perspective. (Favaloro EJ. Lab Hematol. 2005;11:157-62). Royal College of Pathologists of Australasia Quality Assurance Program.

• 35 laboratories. • Samples: Median [range]):

no added heparin 0.01 [0-.11]LMWH 0.5 U/mL 0.43 [.33-.80]unfractionated heparin 0.5 U/mL 0.23 [.10-.49]LMWH 1.0 U/mL 0.90 [.60-1.30]

The high variability of anti-Xa assay results coupled with the widely variable TRs suggests that therapeutic heparin monitoring is poorly standardized, and this raises some concerns over the clinical value of such monitoring.

anti-Xa: Efecto de la concentración de AT

Kostousov V. Int J Lab Hematol 2013; 35:72-73

Influence of antithrombin level on APTT and anti-Xa assay

AT level (%)  APTT (sec)UH 0.33 U/mL

Anti‐Xa (IU/mL) UH 0.33 U/mL

APTT (sec)UH 0.66 U/mL

Anti‐Xa (IU/mL), UH 0.66 U/mL

21.9±2.1 39.9±1.1 0.03±0.02 65.6±1.8 0.2±0.01

50.6±2.7 46.7±0.6 0.09±0.01 83.5±1.2 0.35±0.01

77.9±2.3 57.4±5.0 0.21±0.03 107.7±6.8 0.49±0.01

102.8±1.9 65.7±8.3 0.29±0.05 123.8±16.3 0.59±0.03

p 0.0009 <0.0001 0.0002 <0.0001

Bechmann LP. Liver Int 2011; 31: 75

anti-Xa: Efecto de la concentración de AT

Bechmann LP. Liver Int 2011; 31: 75

anti-Xa: Efecto de la concentración de AT

HemosIL®

El kit Heparin consta de:

S Chromogenic substrate (N° Cat. 00020009410): 1 x 4 mL vial de substrato cromogénico liofilizado S-2765, N-α-Z-D-Arg-Gly-Arg-pNA.2HCL (3 mg/vial) y estabilizantes.

E Factor Xa reagent (N° Cat. 00020009420): 1 x 5 mL vial de una preparación liofilizada que contiene Factor bovino Xa (68 nkat/vial), tampón Tris, EDTA, cloruro sódico y Albúmina de suero bovino.

A Antithrombin (N° Cat. 00020009430): 1 x 3 mL vial de una preparación liofilizada que contiene Antitrombina humana (3 IU/vial), tampón Tris, EDTA, cloruro sódico y Albúmina de suero bovino.

B Buffer (N° Cat. 00020009440): 1 x 8 mL vial de solución concentrada que contiene tampón Tris, pH 8,4, EDTA, cloruro sódico y detergente.

anti-Xa: Efecto de la concentración de FVIII

Kostousov V. Int J Lab Hematol 2013; 35:72-73

Influence of FVIII activity on APTT and anti-Xa assay

FVIII activity (%) APTT (sec)UH 0.33 U/mL

Anti‐Xa (IU/mL) UH 0.33 U/mL

APTT (sec)UH 0.66 U/mL

Anti‐Xa (IU/mL), UH 0.66 U/mL

111±3 72±10.7 0.42±0.03 128.5±14 0.70±0.0

204±2 59.5±6.8 0.39±0.03 104±13.3 0.70±0.0

404±36 51±5.8 0.39±0.03 84.3±9.9 0.69±0.02

562±73 46.3±4.8 0.37±0.03 75.6±8.9 0.69±0.01

p 0.012 0.30 0.0018 0.58

Razones para NO

• LMWHs have predictable pharmacodynamic profiles and wide therapeutic windows that do not require routine coagulation monitoring in clinically stable and uncomplicated patients

• Anti-Xa activity is a surrogate marker that measures the anticoagulant effect of LMWH and is assumed to correlate with hemorrhagic and thromboembolic events.

• The clinical trials evaluating LMWH did not use anti-Xa levels to guide dosing and anti-Xa levels have not been evaluated in large studies. Target anti-Xa levels are not clinically validated.

• Importantly, there are no data to suggest that making dosing adjustments based on peak levels is correlated with improved safety or efficacy.

Smythe MA. J Thromb Thrombolysis. 2016; 41:165–186

In one prospective multicenter study was evaluated the potential advantage of monitoring to reduce thrombus extension or recurrence• 122 patients with acute proximal DVT • Dalteparin (100 anti-FXa IU /kg)1 b.i.d.). Plasma anti-FXa activity,

measured daily in all patients, was used to adapt the dose (peak activity 0.5–1.0 IU mL) in half of the patients.

• Among the 64 patients randomized in this group, the dose remained unchanged in 44, was increased in 15 and was decreased in 5.

• The mean phlebographic Marder’s score reduction after 10 days of treatment was identical among the monitored patients and the 58 patients in whom no dose adjustment was made.

• The mean dose that was actually delivered in the monitored patients was nearly identical to the fixed dose administered in the unmonitored group.

HBPM. Ajuste de dosis.

Alhenc-Gelas M. Thromb Haemost 1994; 71: 698.

• Anti-Xa (and anti-IIa) activity represents the amount of heparin present but not necessarily the antithrombotic function of LMWH, because the same concentration of heparin may have varying effects in different plasmas and patients

• The comparability between commercially available anti-Xa chromogenic assays is poor.

• Anti-Xa level has not been demonstrated to be a good predictor of bleeding risk and antithrombotic efficacy (in thromboprophylaxis and in treatment withLMWH).

Utilidad anti Xa

Yenz S. Thrombosis 2015

Only 56% (94/167) had their anti-Xa level checked correctly (drawn 4-6 hours after LMWH administration and after the patient had received ≥3 consecutive doses of LMWH).

11% (19/167) of patients had any change in management. Dose adjustment in current regimen (17) or switching to an alternative agent (2).

Interestingly, of patients with a change in management, 53% (10/19) had an anti-Xa level that was drawn incorrectly.

Razones para NO

• LMWHs have predictable pharmacodynamic profiles and wide therapeutic windows that do not require routine coagulation monitoring in clinically stable and uncomplicated patients

• Anti-Xa activity is a surrogate marker that measures the anticoagulant effect of LMWH and is assumed to correlate with hemorrhagic and thromboembolic events.

• The clinical trials evaluating LMWH did not use anti-Xa levels to guide dosing and anti-Xa levels have not been evaluated in large studies. Target anti-Xa levels are not clinically validated.

• Importantly, there are no data to suggest that making dosing adjustments based on peak levels is correlated with improved safety or efficacy.

• Promoted by national guidelines despite data challenges to its validity.

Smythe MA. J Thromb Thrombolysis. 2016; 41:165–186

Guías Chest

• In 2008, the ACCP VTE treatment guidelines:

‘‘it is uncertain if adjustment of heparin dose in response to the aPTT or heparin levels improves efficacy or safety”

https://www.youtube.com/watch?v=llJ03954S54

Razones para SÍ

Laposata M. Arch Intern Med 1998; 122: 807.

Pacientes con insuficiencia renal:

- ClCr 15 –30 o- ClCr >30 si tratamiento prolongado

Pacientes con resistencia a la heparina

Pacientes con déficit de factores

Monitorización de anti-Xa

LMWH requirements in pregnancy to maintain therapeutic levels of anticoagulation

Barbour LA. Am J Obst Gynecol 2004; 191: 1024

Data from pharmacokinetic studies of various LMWHs in pregnant women have shown conflicting results with regard to the need for dose escalation to maintain levels within the therapeutic range.

VokeJ. Br J Haematol 2007;139: 545.LepercqJ. BJOG 2008;115: 453.Smith MP. Am J Obstet Gynecol 2004; 190: 495.RodieVA . BJOG 2002; 109:1020.Rey E. Int J Gynaecol Obstet 2000; 71: 19.Gibson PS. Thromb Res 2013; 131: e71.BarbpurLA. Am J Obstet Gynecol 2004; 191: 1024.Jacobsen AF. BJOG 2003;110: 139.BerresheimM. Thromb Res 2014; 134: 1234.

Guidelines for anticoagulation therapy in pregnant with mechanical heart valves

1.-Bonow RO. J Am Coll Cardiol 2008; 52: e1.2.-Guyatt GH. Chest 2012;1 4: 7S.3.-Eur Socof Gynecol Eur Heart J 2011; 32: 3147.

Conclusiones

• La monitorización rutinaria de las HBPM con determinación de la actividad anti-Xa no está justificada tanto en tratamientos como en profilaxis.

• Su empleo sistemático no añade seguridad ni mejora la eficacia, resulta caro y puede llevar a acumular errores.

• Debe considerarse en algunas situaciones especiales: Pacientes con insuficiencia renalNiños de corta edadPesos extremosGestantes que reciban HBPM a dosis anticoagulantes Pacientes con resistencia a la heparinaPacientes con déficit de factores