Heparin Resistance“Heparin resistance is a term used to

describe the situation when patients require unusually high doses of heparin to achieve a therapeutic APTT”

“True resistance” refers to a situation where the low APTT is reflective of a true absence of anticoagulation

“Psuedoresistance” refers to a situation where the patient is adequately anticoagulated despite a low APTT

Has been arbitrarily defined as the requirement for >35,000 units/24 hours

~25% of patients with VTE fulfill this requirement

Chest 2001;119:64S-94S

MOA •Catalyzes antithrombin’s irreversible binding to clotting factors Xa and IIa (thrombin)• Prevents further coagulation but is not a thrombolytic

PK Elimination1. Rapid, saturable clearance through

binding to endothelial cells/proteins2. Renal elimination

T1/2 – dose dependant, but typically between 1-2 hours

Heparin: Background

Heparin: Mechanism

Unique Pentasaccharide sequence that interacts with antithrombin

Only heparin molecules with at least 18 saccharides (~6000 daltons)can bind both antithrombin and thrombin

ATIII forms irreversible covalent bonds with thrombin or Xa

Only activated coagulation factors are targeted

AT III

Heparin: MonitoringAPTT Evaluates the activity of the

intrinsic pathway (factors I,II, V, VIII, IX, XI, XII,).

Not affected by inhibition of Xa.

(target 1.5 to 2.5 times normal)

Anti-factor Xa

Evaluates the amount of factor Xa that the heparin in the blood is able to neutralize

(target 0.35 to 0.7 units/ml ref: http://www.ncbi.nlm.nih.gov/pubmed/8267489)

http://www.fritsmafactor.com/newfritsmafactor/?p=2489

APTT

Heparin Resistance: Mechanisms

Heparin Resistance: Mechanism

Mechanisms

Effects

clearance due to binding to acute Phase reactants(true resistance)

•Levels of certain acute phase reactants and other plasma proteins that bind to and clear heparin are increased in inflammatory states. • A study found septic patients have more heparin bound to plasma proteins (Young Arteriosclerosis Thrombosis and vascular biology 1997;17:1568)). •Another study found acute-MI patients(an inflammatory condition) have more heparin bound to proteins and associated lower aPTT (Rich J Thromb Thrombolysis 2007;23:93)•Another study found acute-PE patients have lower free heparin levels than acute-DVT patients (Hirsh. Circulation 1976;53:691)

ATIII Deficiency(true resistance)

productionCirrhosis LossNephrotic Syndrome

Enhanced consumptionSepsis with DICBurn injuriesHepatic veno-occlusive diseaseCABGLarge hemotomas

Genetic: Autosomal dominant, fatal if homozygotic with prevalence rate between 1:500-1:5000

Heparin Resistance: Mechanism

Mechanisms

Effect

Factor VIII(?psuedo resistance)

•Mean factor VIII level in heparin resistant patients of 2.39 U/ml vs 1.60 U/ml in non resistant patients. APTT lower in patients with high factor VIII. Anti-Xa assay may be more accurate reflective of degree of anticoagulation (Levine. Ach Intern Med 1994;154:49) but some authors disagree (British J Haematology;2010:613)

•Some observational studies have found that with progressively increasing Factor VIII levels there is an increasing risk of venous thrombosis. (Kamphuisen. Arterioscler Thromb Vasc Biol 2001;21:721)

•Factor VIII levels are increased in association with obesity, diabetes, fibrinogen, triglycerides, increased age and is an acute phase reactant (malignancy, chronic disease, infection) (Kamphuisen. Arterioscler Thromb Vasc Biol 2001;21:721)

LMWH in patients with heparin resistance?

Mechanisms

Effects

Increased clearance due to binding to acute Phase reactants

•LMWH have reduced binding to plasma proteins and as a result have much more consistent anti-Xa and anti-IIa activity. (Cosmi. Circulation 1997;95:118) (Hirsh. Blood 1992;79:1)

ATIII Deficiency

Dependant on ATIII for their activity.

Factor VIII Unclear effect

Fondaparinux in patients with heparin resistance?

Mechanisms

Effect

Increased clearance due to binding to acute Phase reactants

•At therapeutic concentrations fondaparinux is highly (94%) and specifically bound to antithrombin III. Would indicate that increased clearance via protein binding is unlikely (Clin Pharmacokinetics 2002;41 Suppl 2:11)

ATIII Deficiency

Dependant on ATIII for activity

Factor VIII Unclear effect

Rivaroxaban in patients with heparin resistance?

Mechanisms

Effect

Increased clearance due to binding to acute Phase reactants

•Mainly eliminated through metabolism (3A4, 3A5, 2J2) with remainder removed via kidneys. No indication that pharmacokinetics are altered in sepsis

ATIII Deficiency

Independent of ATIII

Factor VIII Unclear effect

Dabigatran in patients with heparin resistance?

Mechanisms

Effect

Increased clearance due to binding to acute Phase reactants

•Not highly bound to plasma proteins. Mainly eliminated via urine/fecal routes.

ATIII Deficiency

Independent of ATIII

Factor VIII Unclear effect

Heparin Resistance SummaryShould be evaluated for when patients are

receiving >35,000 units/24 hour periodPatients with heparin resistance may be

over or under anticoagulated depending on the etiology of their resistance

If possible consider switching to alternative agent (LMWH, fondaparinux or oral anticoagulant)

If not possible consider testing anti-factor Xa levels (target 0.35 to 0.7 u/ml). If therapeutic with low aPTT then likely psuedoresistance