Newer Anticoagulant Therapies

Newer Anticoagulant Therapies Outline

Newer Anticoagulant Therapies Chris Ferrell MT(ASCP), CLS/H(NCA) Special Coagulation Lead Harborview Medical Center (206) 731-2621 cferrell@u.washington.edu

Heparin Therapy  How do we monitor patients on heparin? Is this a direct or indirect method? What concentration of heparin are we trying to achieve?  What is the therapeutic range? What does that mean?

Lupus Anticoagulant and PTT  How does a lupus anticoagulant affect the PTT? What’s the target for a lupus anticoagulant? Why is this a problem for monitoring heparin therapy?  What kind of test would work in the presence of a lupus anticoagulant?

Monitoring Heparin Therapy in Patients with LA  aPTT reagent insensitive to the lupus anticoagulant  Thrombin time  Direct heparin assay – Anti-Xa – Protamine sulfate titration Bartholomew,Kottke-Marchant, J of Cl Rheum, Vol.4, No.6, Dec.98

Warfarin Therapy  How do we monitor patients on warfarin? What is the therapeutic range? What does that mean?

Lupus Anticoagulant and Protime  How does a lupus anticoagulant affect a protime? Why does this occur less often on a protime than an aPTT?  What’s the target for a lupus anticoagulant? Why is this a problem for monitoring warfarin therapy?  What kind of test would work in the presence of a lupus anticoagulant?

Monitoring Coumadin Therapy in Patients with LA  Protime/INR (thromboplastins insensitive to the lupus anticoagulant)  Chromogenic assays of Factor X or Protein C  Prothrombin-proconvertin time  Thrombotest Bartholomew,Kottke-Marchant, J of Cl Rheum, Vol.4, No.6, Dec.98

Low Molecular Weight Heparin What is it?  Purified smaller fractions of heparin – Fraxiparin– Lovenox– Fragmin– Normiflo– Innohep– Reviparin

Low Molecular Weight Heparin Antithromb Thrombin Antithromb Factor Xa in in Unfractionated Low Molecular Heparin Weight Heparin Pentasaccharide Pentasaccharide

LMWH Comparisons Product Mol. Wt. Heparin 11,400 Ardeparin 6000 Dalteparin 5819 Enoxaparin 4371 Nadroparin 4855 Reviparin 4653 Tinzaparin 4500

Low Molecular Weight Heparin Advantages  More predictable anticoagulant response needing little or no laboratory monitoring – Unfractionated heparin is mixture of large and small heparin fractions – Unfractionated heparin metabolism • Removes larger biologically inactive fractions quickly• Leaves behind smaller active fractions removed more slowly – Low molecular weight heparin is uniform size– Low molecular weight heparin is metabolized at a slower rate  Longer half-life

Low Molecular Weight Heparin Advantages  Same incidence of bleeding Lower incidence of thrombocytopenia Lower incidence of bone loss Safe for use during pregnancy More practical for long term use

FDA Approved Indications of LMWHs Indications Ardeparin Dalteparin Enoxaparin Tinzaparin DVT-OPT X Treatment X X DVT/PE Prophylaxis in: General X X X surgery Total hip X X X replacement Total knee X replacement UA X X

LMWH Administration  Subcutaneous injection  Once every 12 or 24 hours Outpatient

LMWH Monitoring When?  Trough – right before next dose Patients that need monitoring – Pregnant– Pediatric– Renal– Prolonged therapy– Those at risk for bleeding

Low Molecular Weight Heparin How Do You Monitor It?  Unfractionated heparin has primarily antithrombin (factor IIa) activity that results in a linear increase in the PTT – Monitor UFH with PTT  Low molecular weight heparin has anti-Xa activity but PTT not sensitive enough to pick this up consistently, therefore need a more sensitive test – Monitor LMWH with anti-Xa

PTT and LWMH “LMWH fractions … have progressively less effect on the aPTT as they are reduced in molecular size, while still inhibiting activated factor X. The aPTT activity of heparin reflects mainly its anti-factor IIa activity.” Hirsh J., Circulation 2001; 103:2994

XII XIIa {Antithrombin + UF Heparin} XI XIa IX IXa LMWH VIII VIIIa + Ca + PF3 VII + TF VIIa X Xa V + Ca + PF3 Va Prothrombin Thrombin Fibrinogen Fibrin

Low Molecular Weight Heparin Antithromb Thrombin Antithromb Factor Xa in in Unfractionated Low Molecular Heparin Weight Heparin Pentasaccharide Pentasaccharide

Other Tests to Monitor Heparin  Anti-Xa: – Able to measure both unfractionated heparin and low molecular weight heparin – Chromogenic assay– No interference from lupus anticoagulant

Heparin Assay AT HEPARIN AT-HEP Xa X AT-HEP-Xa a Color ed Chromoge chro n moge n

Problems with Monitoring Heparin Therapy with PTT’s  Individual patient response is variable – Antithrombin concentration– Factor VIII concentration– Liver function– Kidney function– Age of patient

Problems with Monitoring Heparin Therapy with PTT’s  Lupus anticoagulant falsely prolongs PTT Different manufacturer’s PTT reagents vary in sensitivity to heparin  Large lot-to-lot variation from a single manufacturer  Each lot of heparin used by the pharmacy contains different activity

Why Use LMWH vs. UFH?  LMWH more expensive drug but overall costs about the same – No monitoring in majority of patients– Subcutaneous vs. IV– Outpatient vs. inpatient– Lower incidence of HIT

Heparin Induced Thrombocytopenia What Is It?  Mode of action – Immune – Heparin acts as a “cofactor” with PF4– Causes platelet • activation• aggregation  Rate of occurrence – Bovine – 15%– Porcine – 5%  Type I – HIT Type II – HITT(with thrombosis) – Arterial thrombosis – 0.4%

Heparin Induced Thrombocytopenia  Begins 3 – 15 days after start of heparin  If patient exposed to drug before thrombocytopenia can occur within a few hours  Platelet count returns 4 days after stopping heparin

HIT Testing How Do You Diagnose It?  Platelet aggregation and serotonin release Sensitivity – 65 – 80% Use normal donor “responder” platelets Heparin + patient’s plasma If antibody present will produce aggregation or serotonin release

HIT Testing by Aggregometry Light Detector Detector source (PRP + Patient plasma) (PRP + Patient plasma + Heparin)

Positive HIT Test T POS RAN S M I T AN NEG C E TIME

ELISA Assays Patient Plasma Step 1 + Incubate, then wash Heparin + PF4 Coated Microtiter Plate Step 2 + Incubate, Second Ab then wash Peroxidase tag A492 Step 3 0.6 Add Substrate – 0.4 Color Development 0.2 Time

Heparin Induced Thrombocytopenia  Treatment – Stop heparin immediately– Use other drugs for anticoagulation

Advances in Anticoagulation  Thrombin inhibitors – Direct– Indirect  Enhanced Protein C pathway Fibrinolytic agents Platelet function inhibitors

Sites of Action of New Antithrombins XII XIIa (Direct and indirect) XI XIa Monoclonal AB IX IXa Pentasaccharide VIII VIIIa + Ca + PF3 IdraparinuxVII + TF VIIa X Xa RazaxabanDX9065a TF P I V + Ca + PF3 Va Hirudin N A Pc 2 Prothrombin Thrombin Bivalirudin Argatroban Fibrinogen Fibrin Dabigatran

Direct Thrombin Inhibitors  Advantages – Bound thrombin readily inhibited– More predictable patient response– Not neutralized by PF4  Disadvantages – No antidote should bleeding occur– Higher cost of the drugs

Direct Thrombin Inhibitors Hirudin and Derivatives  Lepirudin – Leech saliva– Cleared by kidneys– Half-life • IV: 40 minutes• SubQ: 120 minutes – Inhibits clot bound thrombin– Clot associated Xa will trigger generation of more thrombin once treatment stops

Thrombin and Hirudin Hirudin Thrombin

Direct Thrombin Inhibitors Hirudin and Derivatives  Bivalirudin – Semisynthetic– Lower affinity inhibitor – Cleared by liver– Half-life • Shorter than lepirudin – Safer drug

Direct Thrombin Inhibitors Hirudin and Derivatives  Indications: – HIT– Cardiopulmonary bypass– Hip replacement surgery– Unstable angina

Direct Thrombin Inhibitors Argatroban  Small molecule Carboxylic acid derivative Competitively binds to thrombin active site Used to treat HIT

Thrombin and Argatroban Argatroban Thrombin

Direct Thrombin Inhibitors Dabigatran etexilate  Oral dosing – Dabigatran etexilate absorbed from GI tract– Transforms to active dabigatran  Future – replace warfarin – Wider therapeutic range– Acceptable bleeding risk – Little or no lab monitoring

Clinical Trials of Direct Thrombin Inhibitors Ximelagatran – Exanta Dabigatran etexilate  EXANTA METHRO – MElagatran for THRombin inhibition in Orthopedic surgery  EXULT – EXanta Used to Lessen Thrombosis SPORTIF – Stroke Prevention using ORal Thrombin Inhibitors in atrial Fibrillation  THRIVE – oral direct THRombin Inhibitor ximelagatran for Venous thromboEmbolism  DABIGATRAN ETEXILATE BISTRO – Boehringer Ingelheim Study in ThROmbosis

Direct Thrombin Inhibitors Effect on Laboratory Testing  Inhibit thrombin and will prolong all clot- based assays – PT, PTT, TT, FIB, factor assays, clottable PC and PS  Inhibit chromogenic antithrombin III assay

Direct Thrombin Inhibitors Effect on Laboratory Testing PT PTT TT FIB PS HEPARIN 14.4 89 >100 568 16 DEHEP 14.4 32 16 568 DTI 16.6 64 >100 290 >100 DEHEP 16.6 64 >100 290

Low Molecular Weight Heparin Antithromb Thrombin Antithromb Factor Xa in in Unfractionated LMW Heparin Heparin Pentasaccharide Pentasaccharide

Fondaparinux  Arixtra Pentasacharide Approved to DVT and PE Approved for surgery prophylaxis – General– Total hip replacement– Total knee replacement

Inhibition of VIIa/TF  TFPI – tissue factor pathway inhibitor NAPc2 – nematode anticoagulant peptide

Tissue Factor Pathway Inhibitor