Interventional Lecture Series

Thrombin/LMWH/Heparin
Heparin and LMWH
• Given Vial ~ 2/3
molecules are
biologically inert
• To be biologically
active needs 5
repititions of the
pentasaccharide ->
this unit binds the
antithrombin
• No direct affinity to
thrombin but inhibits
formation of thrombin
Major Minor

Procoagulant
Heparin binds To inactivate
to thrombin,
Antithrombin heparin must
causing a simultaneously
conformational bind to AT and
change w/ Thrombin –
amplifies its therefore
anti-Xa activity molecule length
is important

Only exert effect

on antithrombin
and inhibit Xa
without action on
thrombin
 Antithrombin
• Serine Protease Inhibitor

• Large size
– does not penetrate clot well

• Responsible for anticoagulant effect of all heparins

– (UFH, LMWH, Pentasaccarides)

• Inhibits Xa

• Affinity for Xa is increased 2000x by pentasaccaride sequence of heparin

• Congenital and Acquired deficiencies

– Liver disease
– Nephrotic syndrome
– Continuous heparin therapy (50-60% decrease)
 Guidelines
• For patients not receiving IIb/IIIa
– 70-100U/Kg bolus, check ACT after 5 minutes
– Achieve Target ACT 250-300 Hemotec
– Achieve Target ACT 300-350 Hemochron
– ACT< 250 addt’l 2K-5K bolus

• For patients receiving IIb/IIIa

– 50-70U/Kg bolus, check ACT after 5 minutes
– Achieve Target ACT 200
 Early Trials

Overall improved clinical outcomes with increased minor

bleeding complications
UFH according to
current guidelines
with ACT
monitoring
 Guidelines
• Dosing of Lovenox depends on the last SQ dose given
(After administration of 2 SQ doses!!)
– Last SQ dose 8hrs or less -> no addt’l dosing
– SQ 8-12 hours -> 0.3mg/kg IV
– Greater than 12 hours -> 0.75 to 1mg/kg IV or SQ can be given

• Xa Level (reasonable if Weight >150Kg)

– 0.8 to 1.8 IU/ml is recommended

• Renal Dosing
– CrCl 30-60ml/kg – 0.75 mg/kg SQ bid
– CrCl <30ml/kg – 1 mg/kg QD

• Sheath Removal safe after 4-8 hours

Pentasaccarides
 Fondaparinux / Arixtra
• After 2.5mg dose therapeutic level achieved
after 2.5 hours
– !!!Oasis dosing and PE dosing are different –
Therefore Dr. Kern prescribes the wrong dose all the
time

• Renal Clearance
– 50% less renal clearance for CrCL 30ml/min

• ½ life 17-21 hours

Direct Thrombin Inhibitors in
PCI
 Early Angioplasty Trials
• HAT (Hirudin)

No significant
long term
benefit for
Hirudin
despite
somewhat
lower cardiac
event rates
 Early Angioplasty Trials
• Bivalirudin Trial
Early Angioplasty Trials
Contemporary PCI - Cachet
Contemporary PCI - Cachet
Contemporary PCI – REPLACE-1
Contemporary PCI – REPLACE-1
Contemporary PCI – REPLACE-1
Contemporary PCI – REPLACE-1
 Contemporary PCI
• Main limitation of previous studies is rather
small overall size.
• Setup for REPLACE -2: 6,000 patient,
large clinical trial on the use and effects of
bivalirudin in a contemporary PCI and
stenting.
Replace - 2
 Replace - 2
• Claim made by
study that
bivalirudin is
superior to
heparin
• Claim made
based on
Epistent/Esprit
data published
earlier
• NO
randomized
arm for heparin
alone in this
study
Replace - 2
Replace - 2
Replace - 2
Replace - 2
Replace - 2
 Replace - 2
• Bleeding major driver of
bivalirudin benefit
Replace - 2
 Replace - 2
• Major bleeding correlates with death
Replace - 2
Acuity Trial
ACUITY Trial
ACUITY Trial
ACUITY Trial
ACUITY Trial
 ACUITY Trial
• The hypothesis of this
randomization indicate that
compared to a routine
upstream use of a IIb/IIIa
inhibitor in all patients with
ACS, withholding the upfront
therapy with IIb/IIIa for a
deferred administration in the
cath lab only to those patients
undergoing PCI with result in:
– similar 30-day rates of death,
MI, or unplanned
revascularization for ischemia
– reduced bleeding, or major
bleeding complication
– improved cost effectiveness
ACUITY Trial
ACUITY Trial
 Heparin Induced
Thrombocytopenia
• HIT II
– Platelet drop >50% or 150K
– Usually seen 5 days after start of heparin
– Unexplained thrombosis (increases risk 40x)
• 50% risk of thrombosis @ 30 days
– Presence of Anti-Heparin PS4 complex, (NAP-2 receptor)
– Occurs with Heparin, Lovenox (no report of arixtra even though antibodies to PS4
have been discovered in patients)
– Qualitative and functional assay

• Differentiate from type I HIT

– 15% of patients receiving heparin
– transient decrease in platelet count (down to 50% normal) without any further
symptoms secondary to platelet sequesteration.
– Platelet counts recover even if heparin continues to be administered.
– Platelet counts rarely fall below 100,000.
– Type I HIT is not due to an auto-immune disorder (as Type II is).
 Therapeutic Options
• LMWH high cross-reactivity
• Warfarin initially can induce skin necrosis
• ASA is inadequate
• Options remain:
– Lepirudin
• (limited by significant anaphylaxis if agent is used more than
once)
– Argatroban
– Bivalirudin
• Treatment should be continued for at least 4
weeks – Coumadin may be added after Platelet
counts recovered to >150K
 Questions

Thank you for your attention and

participation