Fondaparinux-associated HIT – Conclusion

Fondaparinux-Associated
Heparin-Induced
Thrombocytopenia
Phn. Valentine Minet
Heparins
One of the most widely used anticoagulant
Numerous indications : Pulmonary embolism, DVT, ischemic heart
disease, cerebral vascular accident…
Anticoagulant by action on antithrombin III
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Heparin-induced thrombocytopenia
o Type-I and Type-II = immune
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Heparin-induced thrombocytopenia
o
o
o
o
Type-I and Type-II = immune
Thrombocytopenia (>40%)
Paradox
UFH (1,0 to 5,0%) and LMWH (0,1 to 1,0%)
5-14 days
< 1 day
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Physiopathology
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Physiopathology
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Physiopathology
Risk of developing HIT dependent of concentrations, chain length,
degree of sulfation, clinical situation….
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Physiopathology
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Physiopathology
Mullier et al, Thrombosis
Research, 2013
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Iceberg model
Kelton, Blood, 2008
Kelton et al,–Blood,
2008
Introduction
Heparin-induced
thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Clinical manifestations
Extensive superficial skin necrosis and blistering
surrounding saphenous vein
Dandekar, Interact Cardiovasc Thorac Surg, 2004
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis
An essential diagnosis…
Missed diagnosis:
Risk for life-threatening thrombosis!
Overdiagnosis:
Alternative non heparin anticoagulants expensive and risk
of bleeding without effective reversing agents
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis
But a challenging diagnosis!
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis
o Platelet count monitoring : every 2 or 3 days from day 1 to day 14
for typical HIT (and within 12-24 hours for rapid onset), ACCP
guidelines, 2012
o Immediate discontinuation of all heparins once HIT suspected and
switch to non cross-reactive anticoagulant
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
4Ts rule
Greinacher et al, Hämostaseologie, 2010
0
Low
3
Intermediate
6
High
8
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis algorithm
Adapted from Greinacher, 2009
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis algorithm
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Diagnosis algorithm
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Fondaparinux
o Synthetic pentasaccharide mimicking the site
where heparin binds to antithrombin III
o Indications :
- Prevention of venous thromboembolic events in major surgery
- Treatment of superficial venous thrombosis
- Treatment of deep venous thrombosis or pulmonary embolism
- Treatment of unstable angina or myocardial infarction
o Off-label use : appears to be an effective agent for the treatment
of HIT
o ACCP 2012 propose fondaparinux for treatment in patients with
HIT or history of HIT (grade 2 C)
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Fondaparinux-associated HIT
o In 2007, first cases of HIT reported in 2 patients who exclusively
received fondaparinux for antithrombotic prophylaxis
o Paradox : Fondaparinux used to treat HIT and induce HIT?
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Fondaparinux-associated HIT
o Prevalence of fondaparinux-associated HIT?
o Causality?
Kelton et al,–Blood,
2008
Introduction
Heparin-induced
thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Published cases
o 8 cases published in the literature
Age
Author/Year
sex
Warkentin et al., 2007 48/F
Rota et al., 2008
71/F
Warkentin et al., 2008 87/F
Modi et al., 2009
68/M
Salem et al., 2010
67/M
Burch et al., 2012
47/M
Burch et al., 2012
63/M
Warkentin et al., 2012 74/F
Clinical
scenario
Joint replacement
Joint replacement
Joint replacement
Spinal cord compression
Joint replacement
Joint replacement, sepsis
Joint replacement, sepsis
Sepsis, MI and ventilation
Nadir
platelet
39 000/µL
50 000/µL
73 000/µL
75 000/µL
35 000/µL
50 000/µL
38 000/µL
51 000/µL
Time
interval
5-10
5-10
6
14
9
10
7-10
5
New
thrombosis
Yes
No
No
Yes
Yes
Yes
Yes
No
4Ts
rule
8
6
?
7
8
7
7
6
Exposure
to heparin
None
None
UFH <5 days
None
None
UFH <24h
Brief UFH use
None
Diagnostic test
Ab
Functional
Pos
SRA pos
Pos
/
/
SRA pos
?
/
Pos
/
Pos
/
Pos
/
Pos
SRA pos
Outcome
complicated
recovery
recovery
died
complicated
recovery
recovery
recovery
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Published cases
o 8 cases published in the literature
o Some controversial cases
Age
Author/Year
sex
Warkentin et al., 2007 48/F
Rota et al., 2008
71/F
Warkentin et al., 2008 87/F
Modi et al., 2009
68/M
Salem et al., 2010
67/M
Burch et al., 2012
47/M
Burch et al., 2012
63/M
Warkentin et al., 2012 74/F
Clinical
scenario
Joint replacement
Joint replacement
Joint replacement
Spinal cord compression
Joint replacement
Joint replacement, sepsis
Joint replacement, sepsis
Sepsis, MI and ventilation
Nadir
platelet
39 000/µL
50 000/µL
73 000/µL
75 000/µL
35 000/µL
50 000/µL
38 000/µL
51 000/µL
Time
interval
5-10
5-10
6
14
9
10
7-10
5
New
thrombosis
Yes
No
No
Yes
Yes
Yes
Yes
No
4Ts
rule
8
6
?
7
8
7
7
6
Exposure
to heparin
None
None
UFH <5 days
None
None
UFH <24h
Brief UFH use
None
Diagnostic test
Ab
Functional
Pos
SRA pos
Pos
/
/
SRA pos
?
/
Pos
/
Pos
/
Pos
/
Pos
SRA pos
Outcome
complicated
recovery
recovery
died
complicated
recovery
recovery
recovery
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Published cases
o 8 cases published in the literature
o Some controversial cases
Age
Author/Year
sex
Warkentin et al., 2007 48/F
Rota et al., 2008
71/F
Warkentin et al., 2008 87/F
Modi et al., 2009
68/M
Salem et al., 2010
67/M
Burch et al., 2012
47/M
Burch et al., 2012
63/M
Warkentin et al., 2012 74/F
Clinical
scenario
Joint replacement
Joint replacement
Joint replacement
Spinal cord compression
Joint replacement
Joint replacement, sepsis
Joint replacement, sepsis
Sepsis, MI and ventilation
Nadir
platelet
39 000/µL
50 000/µL
73 000/µL
75 000/µL
35 000/µL
50 000/µL
38 000/µL
51 000/µL
Time
interval
5-10
5-10
6
14
9
10
7-10
5
New
thrombosis
Yes
No
No
Yes
Yes
Yes
Yes
No
4Ts
rule
8
6
?
7
8
7
7
6
Exposure
to heparin
None
None
UFH <5 days
None
None
UFH <24h
Brief UFH use
None
Diagnostic test
Ab
Functional
Pos
SRA pos
Pos
/
/
SRA pos
?
/
Pos
/
Pos
/
Pos
/
Pos
SRA pos
Outcome
complicated
recovery
recovery
died
complicated
recovery
recovery
recovery
o Existence of spontaneous « HIT » cases
o Chondroitin sulfate?
o Lipopolysaccharide?
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Mechanistic investigations
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Mechanistical investigations
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Mechanistical investigations
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Mechanistical investigations
Physiopathology of heparin-induced thrombocytopenia FP4 : platelet factor 4 ; HS : heparan
sulfate ; CS : chondroitin sulfate. Gruel et al, La Revue de médecine interne, 2013
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Pharmacovigilance evaluation
PRAC
(Pharmacovigilance Risk Assessment Committee)
Conclusion :
« Taking all available documentation into account the
Rapporteur is of the opinion that a causal relationship
between treatment with fondaparinux and HIT cannot be
considered established. »
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Conclusion
HIT is a severe immune secondary effect, immediate
discontinuation of all heparins once HIT suspected and
switch to other anticoagulant is required!
The development of fondaparinux-associated HIT is very rare.
Epidemiologic studies are required to determine whether
fondaparinux is associated with a frequency of HIT greater
than the “background” rate observed with warfarin.
New oral anticoagulants are theoreticaly attractive for the
treatment of HIT attractive for the treatment of HIT, but
further evaluation is needed for all of these agents.
Introduction – Heparin-induced thrombocytopenia – Fondaparinux-associated HIT – Conclusion
Thank you
for your attention
Thank you to all people
involved
Carlos Graux, Fabienne Georges, Philippe Devel, Lutfiye Alpan, Justine
Baudar, Sébastien Walbrecq, Nicolas Bailly, Nicolas Neyman, Alex
Dromelet, Adrien Collard, Maité Guldenpfennig, Stéphane Lucas, Jorge
Mejia, Omar Lozano Garcia, Jean-Michel Dogné, François Mullier, Bernard
Chatelain, Christian Chatelain, Maximilien Gourdin