1. Mechanical Clot Detection
Stago’s Viscosity-based Clot Detection System

2. Viscosity based Detection System

3. Viscosity based Detection System

4. Viscosity based Detection System

5. Viscosity based Detection System

6. Viscosity based Detection System

7. NEW ANTICOAGULANTS Diagnostica Stago, Inc.
Katy Whelchel MT(ASCP)SH
Diagnostica Stago, Inc.
Technical Support Specialist
February 23, 2006

8. Maintain hemostatic balance
the body must maintain a fluid equilibrium
need to maintain balance between bleeding & clotting
Fluid equil – regulate clotting process
Controlling bleeding has historically been the focus of coag studies - CONSIDERABLE PROGRESS IN THROMBOSIS INFO IN THE PAST 30 YRS. THE IMPORTANCE OF THESE NEW ANTICIAGULANTS HAS INCREASED AS MORE STUDY HAS BEEN DONE ON THROMBOSIS
vessels
“Coagulation”
Proteins
Platelets
Fibrinolysis/ Inhibitors

9. ANTICOAGULANT THERAPY
Decrease the risk of post-op thrombosis
Decrease the risk of thrombosis in patients with risk factors
Decrease the risk of spontaneous abortions in patients with Anti-Phospholipid Syndrome (APS) - lupus anticoagulants
APS= antiphospholipid syndrome

10. STANDARD ANTICOAGULANTS
HEPARIN (UFH)
COUMADIN (warfarin)
LAST YEAR’S TOPICS AT INDY SEMINAR GAVE ME BETTER VISION OF HOW DIFFICULT IT IS TO OTAIN & MAINTAIN THERAPEUTIC DOSING.
HAS LEAD TO THE DEVELOPMENT OF NEW ANTICOAGULANTS – MORE PREDICTABLE – MONITORING IS NOT AS ESSENTAIL IN MOST CASES
HAS LEAD TO

11. UFH – a few things to remember
Will affect PTT- how much depends dosing and your reagent system
Easily monitored (accurately!) with the Anti-Xa method
Can be used in patients with renal failure
HAS an antidote (protamine sulfate)

12. Coumadin –a few things to remember
Can be monitored by the PT/INR
Can be given long term for high risk patients
Can be used in patients with renal failure
HAS an antidote (Vitamin K)

13. St. Lucia Island flowers

14. 2 classes of NEW ANTICOAGULANTS
Antithrombin Dependant
LMWH – Lovenox, Fragmin, Innohep
(tinzaparin – has been used on CAP surveys)
DANAPROID (not available in US)
FONDAPARINUX (Arixstra)
Direct Thrombin Inhibitors
HIRUDEN – LEPIRUDEN (Refludan)
ARGATROBAN (Novastan)
Bivalirudin
Ximelagatran- the “new” coumadin
AT DEPENDENT = accelerates AT activity – not an anticoagulant alone
DIRECT THROMBIN INHIB – do just that – not AT dependant
NEW ANTICOAGULANTS - more predictable anticoagulation responses – many don’t need the stringent monitoring needed for UFH & Coumadin
AT dep – anti-Xa assays to monitor when needed
Direct Thrombin Inhib – CANNOT use anti-Xa – ANOTHER MONITORING ISSUE - these drugs will prolong the PT, which may cause trouble in monitoring Coumadin – Refludin: patient should be have IV stopped for 4 hrs then draw specimen.

15. Why do we care about these new anticoagulants??
They are advertised
as “no monitoring
needed”!

16. Why do we care about these new anticoagulants??
They can and DO interfere with our current coagulation tests
Can you say how much of this new drug is in the patient’s system?
What do you do for these patients?
Patient is bleeding
Patient is clotting – despite therapy
Pre-op assessment?
PT and PTT may or may not be “normal”

17. Why do we care about these new anticoagulants??
Special patient populations need special consideration:
Pregnancy
Renal dysfunction
Liver dysfunction
Anorexic or morbidly obese patients

18. Heparins UFH work on the activated factors
LMWHs work where the extrinsic and intrinsic factors come together with Factor Xa
Both use the patient’s ATIII to work

19. Coag Cascade

20. LMWH Action

21. LMWH HEPARINS LMWH – better bioavalibility than UFH Created from UFH
Since it’s a smaller molecule it can be administered as a subcutaneous injection – given in fixed doses for MOST patients
Therapeutic Ranges: – 1.1 (2 injections/day)
1.0 – 2.0 (1 injection/ day)
Timing of specimens - peak at about 4 hours after sub Q injection

22. Heparin Family picture

23. LMWH Action

24. LMWH HEPARIN
Doesn’t change the APTT (much) – an increased APTT may signify an overdose of LMWH or some other influence on the APTT (platelet antibodies)
Difficult to reverse with protamine sulfate (antidote for UFH)
Cleared through the kidneys

25. LMWH HEPARIN LMWH available in the US:
Enoxaparin (Lovenox): prevent DVT/PE around surgery, treat DVT/PE, unstable angina
Dalteparin (Fragmin): prevent and treat DVT/PE, treat unstable angina
Tinzaparin(Innohep): treat DVT/PE

26. Who should be monitored for LMWH?
Patients with kidney problems (need to check creatinine clearance)
Patients that are obese or have a very low body weight
Children, burn patients
U MASS – just started in time for burn patients (night club fire in RI) – having trouble with all drugs. This assay really has become QUITE popular now that the docs know it is done in house – having expected trouble of finding out which heparin patient is on
NOTE: When LMWH was first available, said we needed to make each curve with the exact LMWH patient was receiving – found this to be unnecessary – same will be true for HYBRID curve? Dartmouth-Hitchcock has seen no clinically significant difference using their own hybrid curve – they do however use Stacrome heparin (not rotachrome)

27. How should LMWH be monitored?
Monitor with an anti-Xa method, using LMWH calibrators and controls.
Samples should be drawn 4 hours after dosing.
U MASS – just started in time for burn patients (night club fire in RI) – having trouble with all drugs. This assay really has become QUITE popular now that the docs know it is done in house – having expected trouble of finding out which heparin patient is on
NOTE: When LMWH was first available, said we needed to make each curve with the exact LMWH patient was receiving – found this to be unnecessary – same will be true for HYBRID curve? Dartmouth-Hitchcock has seen no clinically significant difference using their own hybrid curve – they do however use Stacrome heparin (not rotachrome)

28. Marigot Bay, St. Lucia

29. Danaproid, Fonduparinux

30. DANAPROID (not available in the US)
Mixture of heparinoids
Usually given to HIT patients
Works through antithrombin to inhibit factor Xa (little effect on other factors)
Administered twice a day – IV or Sub Q
Therapeutic ranges – IV=0.5 – Sub Q=
Monitored by anti-Xa (like LMWH) – using danaproid as the calibrator.
Bioavailibilty virtually 100%
½ life – 8 hrs
Excreted thru kidney

31. Danaproid (cont’d)
It may prolong the PTT,as well as affect the PT, TT and ACT.
Used successfully in HIT – however, platelet count should be monitored.
No agent that will reverse the effects of the drug.
Platelet count should be monitored because some patients have antibodies that cross-react with Danaproid.

32. FONDAPARINUX (Arixtra)
Synthetic pentasaccharide – accelerates the binding of AT to Xa – the “ultimate LMWH”
Pure anti-Xa effect
Commonly used to prevent VTE in orthopedic surgery
Administered Sub Q
Half-life of 13 – 15 hours, so only 1 dose per day.
Excreted through kidney (check creatinine clearance…..)

33. Fondaparinux (cont’d)
PT and PTT are relatively insensitive to this drug, but may be slightly prolonged.
Low bleeding incidence.
Has not been shown to cause HIT
No direct inhibitor for Arixtra which can reverse it’s anticoagulant effect.
May be monitored by an Anti-Xa method using the drug as a calibrator.

34. Fondaparinux (cont’d)
Remember – there is no antidote. So if the patient has too much “on board”, the PT and PTT may be normal, but they may still be bleeding…….can use Factor VIIa concentrate (novoseven) or activated prothrombin concentrates to reverse effect.

35. Ship: The Brig Unicorn

36. DIRECT THROMBIN INHIBITORS
Hirudin – Lepirudin (Refludan)
Hirudin: Medicinal Leech
Refludan: recombinant polypeptide with same action
Agatroban
Bivalirudin (Angiomax)
Do not cause thrombocytopenia; used successfully with HIT
Directly blocks Thrombin
Administered by IV or Sub Q
REQUIRES MONITORING
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

37. Direct Thrombin Inhibitors

38. DIRECT THROMBIN INHIBITORS
These drugs have a very short half life.
Agatroban cleared by the liver
Lepirudin is cleared by the kidneys.
Bivalirudin is cleared by the kidneys
Have to be aware of these factors with the patient!
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

39. ARGATROBAN Derivative of amino acid arginine
Directly binds to Thrombin
Metabolized by the liver, and excreted through the kidney – so can be an alternate for patients with renal disease.
Must be monitored by APTT (can also be monitored by the ACT). Therapeutic range is x Baseline APTT.
Excreted by liver – alternative for patients with renal disease
MUST BE MONITORED – Chromogenic assay being developed
NO HIT
MUST HAVE CONTINOUS INFUSION

40. Argatroban: Advantages & Disadvantages
Better predictive anticoagulant activity
Will affect PT results – difficult to monitor Coumadin therapy.
Short ½ life – so must be administered by continuous IV infusion. But short ½ life also makes reversal easier.
No reversal therapy
Cost - expensive

41. REFLUDAN - Lepirudin APTT – IV=1.5 – 3.0 x patient baseline
Sub Q= 2.2 – 2.7 X baseline APTT
(specimen drawn 3 hours after administration)
HOWEVER, APTT reagents vary in their sensitivity to Refludin
ECARIN CLOTTING TIME (used in some facilities)
CHROMOGENIC ASSAY BASED ON THROMBIN INHIBITION (developed for research only at this point) – most accurate assay
WE SEE HOW APTT REAGENTS VARY IN REGARD TO UFH – “REFLUDIN THERAPEUTIC RANGES”????
ECARIN CLOTTING TIME – snake venom is VERY sticky – a lot of contamination issues
Anti-IIa -????? Dartmouth Hitchcock developed assay
Refludan causes extreme Protein S values – and may also affect Protein C results.

42. DIRECT THROMBIN INHIBITORS
These drugs will affect the PT/INR – since they work at the bottom of the cascade
Lepirudin: recommend stopping drug once INR>2.0
Agatroban: recommend stopping drug once INR>4.0
Levels are PT reagent dependent!! Literature says that reagents with a lower ISI have less variability in reactivity. Higher ISI reagents have greater variablity in response.
Will affect results if patient is also on Coumadin!
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

43. DIRECT THROMBIN INHIBITORS
Since these drugs affect the PT/INR system – and since they have a very short half-life – the good news is that if they are discontinued for a couple of hours, the PT should return to normal.
The bad news is that the kidneys and liver have to be working for this to happen.
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

44. Bivalirudin Approved for use in the cardiac cath lab
Bivalent thrombin inhibitor
Short half-life ( min)
Exclude patients with creatinine >3.0

45. Live Volcano, St. Lucia

46. DIRECT THROMBIN INHIBITORS
Ximelagatran – the “new Coumadin”
Oral tablet
Direct thrombin inhibitor
Converts to melagatran in the stomach
Cleared by kidneys
Irreversible – factor VII concentrate recommended for severe hemorrhage
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

47. DIRECT THROMBIN INHIBITORS
Ximelagatran – the “new Coumadin” (cont’d)
it’s supposed to work better than our current LMWHs in preventing DVTs in people who have had hip surgery
Theoretically: NO MONITORING! It doesn’t matter how old you are, how much you weigh, etc. it is supposed to be safe…..however it causes liver damage in 6-10% of patients who take it long term. And remember – it is cleared by the kidneys.
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

48. DIRECT THROMBIN INHIBITORS
Ximelagatran – the “new Coumadin” (cont’d)
Not approved by FDA – yet.
If you were going to monitor Ximelagatran, remember it is a thrombin inhibitor – so you’d have to monitor the APTT – NOT a PT even though it is the “new Coumadin”!!
APTT’s response again will be variable depending on reagent system.
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

49. DIRECT THROMBIN INHIBITORS
Ximelagatran – the “new Coumadin” (cont’d)
So – for the time being, we’ll still be doing PT/INR for coumadin therapy.
Hirudin – medicinal leech
Refluden – recombinant polypeptide – same anticoag activity as hirudin
Directly block thrombin – active site & substrate binding site

50. Summary Many of these anticoagulants are currently in use.
They may affect routine and specialty coagulation tests – remember where they affect the cascade!
If abnormal results are obtained, and not expected – ask what drugs the patient is on.
Remember many will act differently if the patient has renal or hepatic impairment.
The “tried and true” may still be the easiest to use if monitored correctly.

51. St. Lucia Sunset

52. The end.