| Abstract |
Introduction:
The recommended duration of post-operative Low-Molecular-Weight-
Heparins
(LMWHs) thromboprophylaxis in high risk for VTE surgical patients (as those who
undergo Total-Hip-Replacement (THR) and Total-Knee-Replacement (TKR) surgery)
is controversial.
Our aim is to study the thrombin generation (TG) modifications induced by
surgery and to evaluate the effect of LMWH on TG during and after the
recommended duration, as well as to investigate biological resistance to enoxaparin’s
antithrombotic action, and rebound effect in reactivation of coagulation mechanism
after thromboprophylaxis withdrawal, using Thrombin Generation (TG) assay.
Finally, we aimed to evaluate antiplatelet effect as adjuvant antithrombotic treatment
in TG modifications during the LMWH somministration period and after LMWH’s
withdrawal.
Patients/Methods:
1st category (Orthopaedic-THR vs TKR- patients):Thirty-one patients received
4000IU anti-Xa/day of enoxaparin, 8-hours postoperatively (15 THR for 30-days and
16 TKR for 15-days). TG assay sensitive to enoxaparin was performed, preoperatively
(D0), 7-hours post-surgery (D1), 8-days post-surgery (D8), and 2-days
after thromboprophylaxis withdrawal (D32 and D17), evaluating: lag-time,
endogenous thrombin potential (ETP), peak amount of generated thrombin (Peak),
time-to-Peak (tt-Peak), and the Mean- Rate-Index [MRI=Peak/(tt-Peak-lag-time)].
2nd category (Orthopaedic vs Vascular patients): Fifteen-patients undergoing
femoro-popliteal bypass grafting (receiving enoxaparin 4000 antiXa IU + 75 mg
clopidogrel), and 15-patients undergoing total-hipreplacement (THR) (receiving
enoxaparin alone).
TG-assay parameters [lag-time, Endogenous-Thrombin-Potential, Peak-, time-to-
Peak, and Mean-Rate-Index] were assessed to investigate heparin resistance and
rebound
[76]
effect after prophylaxis interruption. Measurements were obtained pre-op, 7-hours
post-op
and before prophylaxis initiation, 8-days post-op, and 48-hours after anticoagulant
withdrawal (Day 32).
Results:
1st category :TKR surgery decreased lag-time and tt-Peak and increased MRI on
D1vs.D0 (p&λτ0.05). In contrast, THR did not significantly modify TG. Enoxaparin
effectively reduced thrombin generation in both groups. Thromboprophylaxis
withdrawal resulted in rebound increase of TG in the TKR patients (ETP, Peak &
MRI increased on D17vs.D0;p΄&λτ0.05, and vs.D1;p΄&λτ0.05) but not in THR patients.
Variability in the response to enoxaparin was observed among patients of the same
group.
2nd category : Surgery increased TG in vascular patients despite intra-operative
unfractioned heparin administration when compared to orthopaedic patients
(MRI:p=0.039, ETP:p=0.001, PGT:p=0.003), but this peri-operative pro-thrombotic
status was reversed by post-operative thromboprophylaxis. No arterial or venous
thrombotic events were observed. Vascular patients were adequately protected after
prophylaxis withdrawal, probably due to the synergic action of clopidogrel (similar
TG parameters between the 8th and 32nd post-op day), while orthopaedic patients
increased TG on Day-32 compared to the 8th post-op day (p=0.03, for both lag-time
and ttPeak). Furthermore, on the 32nd, a prothrombotic status (increased TG) was
observed in the orthopaedic patients (p=0.034, and 0.004 for ttPeak and lag-time,
respectively) compared to the vascular patients. Inter-individual variability to
enoxaparin response was observed in both groups: 7/15 vascular and 10/15
orthopaedic patients increased TG despite anticoagulant administration, which reveals
resistance to heparin (HR).
Among the HR patients 4 of the Vascular and 6 of the Orthopaedic further increased
TG after
anticoagulant withdrawal depicting a rebound effect in activation of coagulation.
[77]
Conclusions:
TKR surgery is more thrombogenic than THR surgery. In THR patients TG was
efficiently inhibited by 30-day thromboprophylaxis, whereas, in TKR patients treated
for 15-days TG was not effectively inhibited. Individual variability of the response to
enoxaparin was observed in both groups revealing some form of biological resistance
to enoxaparin. TG assay may represent the breakthrough step to efficient
antithrombotic strategy in clinical settings with high thrombotic risk. Additonally,
Heparin Resistance is not a rare phenomenon in clinical practice and was found in a
considerable percentage of our patients. A rebound effect of coagulation activation
after thromboprophylaxis withdrawal is observed in the extended post-operative
period. This phenomenon is attenuated with the addition of concomitant anti-platelet
(clopidogrel) treatment.
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Εκτίμηση της πηκτικότητας του αίματος σε ασθενείς υψηλού κινδύνου για θρομβοεμβολική νόσο που λαμβάνουν προφύλαξη με ηπαρίνη χαμηλού μοριακού βάρους
