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A Controlled Trial of Tranexamic Acid Therapy for

the Reduction of Bleeding During Treatment of Acute
Myeloid Leukemia
a a a a b a a
O. Shpilberg , R. Blumenthal , O. Sofer , Y. Katz , A. Chetrit , B. Ramot , A. Eldor & I. Ben-
Bassat
a
The Institute of Hematology, Department of Hematology, Hadassah University Hospital,
Jerusalem
b
The Institute of Hematology, Department of Clinical Epidemiology, The Chaim Sheba
Medical Center, Tel-Hashomer and Sackler School of Medicine. Tel-Aviv University, Jerusalem
Published online: 02 Jun 2015.

To cite this article: O. Shpilberg, R. Blumenthal, O. Sofer, Y. Katz, A. Chetrit, B. Ramot, A. Eldor & I. Ben-Bassat (1995) A
Controlled Trial of Tranexamic Acid Therapy for the Reduction of Bleeding During Treatment of Acute Myeloid Leukemia,
Leukemia & Lymphoma, 19:1-2, 141-144, DOI: 10.3109/10428199509059668

To link to this article: http://dx.doi.org/10.3109/10428199509059668

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 Luirkemia und Lymphornu. Vol. 19, pp. I 4I - 144 0 1995 Hawood Academic Publishers GmbH
Reprints available directly from the publisher Printed in Singapore
Photocopyingpermitted by license only

A Controlled Trial of Tranexamic Acid Therapy

for the Reduction of Bleeding During Treatment
of Acute Myeloid Leukemia
0. SHPILBERG, R. BLUMENTHAL,* 0. SOFER, Y.KATZ,* A. CHETRIT,** B. RAMOT,
A. ELDOR* and I. BEN-BASSAT
Downloaded by [RMIT University] at 04:48 12 August 2015

The Instituteof Hematology **Department of Clinical Epidemiology, The Chaim Sheba Medical Center, Tel-Hashomer and
Sackler School of Medicine. TeI-Aviv University, the *Department of Hematology, Hadassah University Hosphal. Jerusalem.

(ReceivedNovember 2 5 1994)

In order to determine the efficacy ofthe antifibrinolytic agent tranexamic acid (TA) in reducing bleed-
ing and platelet transfusions during the treatment of acute myeloid leukemia (AML), we conducted
a randomized placebo-controlled double-blind study. Patients with A M L undergoing induction or
postremission consolidation chemotherapy were randomized into TA or placebo groups. Patients
were not given platelet transfusions prophylactically but only when bleeding occurred. The severity
of any bleeding event was scored. Thirty eight patients were randomized during induction. There
were no significant differences between the two groups in the number of bleeding events and their
severity or in the number of platelet transfusions given.
Eighteen patients were studied during consolidation. I n contrast, to the induction period, during
consolidation there was a significantly less scvcre bleeding tcndency in the T A group resulting in a
lower platelet transfusion requirement 13.7 f 4. I vs. 9.3 f 3.3 platelet units ( p < .OS)l. T A was well
toleratedand no side effects were seen and no specific thromboembolic event.. were noticed. We con-
clude that giving T A during the thrombocytopenic period of A M L patients undergoingconsolidation
chemotherapy i s beneficial and safely reduces platelet transfusions.

KEY WORDS: acute myeloid leukemia antifibrinolytic agents tranexamic acid

platelet transfusions

INTRODUCTION rinolysis.l-6 Therefore. in an attempt to reduce platelet

transfusions and their risks, we conducted a pilot study
Severe thrombwytopenia is most common in patients
using the antifibrinolytic drug, tranexamic acid (TA). We
with acute myeloid leukemia (AML) and is the main cause
found T A to be effective in reducing the need for platelet
o f serious or life-threatening bleeding. Platelet transfu-
transfusions, safe with respect to thromboembolic or
sions have become a mainstay of the supportive care for
haemorrhagic complications and well tolerated.' Here we
A M L patients during thrombocytopenic periods.
report the early results o f a randomized placebo-controlled
However, platelet administration is costly, limited in sup- double-blind study on the efficacy and safety of TA ad-
ply, i s associated with transmission of infectious agents.
ministration i n a small group of A M L patients undergo-
causes transfusion reactions and induces alloimmuniza-
ing intensive chemotherapy.
tion. Antitibrinolytic agents have been shown to decrease
the bleeding tendency of thrombocytopenic patients, even
i n those without an associated coagulopathy such as tib- P.4TIENTSAND METHODS
Patients
Patients with de-tiovo A M L who were admitted to the
Addrc\s lor correspondence: Prof. 1. Ben-Bassat. Head. Institute
of Hemetology. The Chaiin Sheba Medicill Center. Tel-Hishomer Departments of Haematology in the Sheha and Hadassah
5262 I, lwei. Medical Centers in Tel Aviv and Jerusalem during the pe-
111
 I42 0. SHPILBERG ETAL
riod of 199&1992 were included in the study. Patients
were excluded if they had a recent history of a throm-
boembolic event, clinical evidence or suspicion of throm-
boembolism or any laboratory signs of disseminated
intravascular clotting. Patients up to the age of 65 years
were treated by an induction regimen consisting of con-
tinuous infusion of cytarabine 100mg/m2/day for 7 days
and daunorubicin 45mg/mZ/day for 3 days. Patients fail-
ing to achieve remission were treated by a second cycle of
the same drugs. After remission, a consolidation course
consisting of high dose cytarabine (3g/m2 twice daily for
6 days) was given. Patients aged 5 I d 5 years were treated
with a reduced dose of cytarabine (2g/m2). Patients aged
66-75 were treated with 30mg/m2 of daunorubicin during
Downloaded by [RMIT University] at 04:48 12 August 2015
induction and the cytarabine dose during consolidation
was reduced to 500mg/m2.
Methods
Patients were randomized to receive TA or placebo. TA
was given to the study group at a dose of 1g every 6 hours.
The control group received an identically-appearing
placebo. Treatment in both groups was begun when the
platelet count was less than 20 x 1OVL or in a falling trend
and less than 50 x 10%. Treatment was continued until
the platelet count was above 20 x I O 9 L on at least 2 con-
secutive counts. Random donor pooled platelet transfu-
sions were given at a dose of 4 units/m*, irrespective of
the count but only whenever clinically significant bleed-
ing occurred. Packed red cell transfusions (PRC) were
given to maintain the haemoglobin level above 9g/dL.
Patients were carefully examined daily by one of the in-
vestigators and the severity of any bleeding event or man-
ifestation was scored on a scale of 0-3. Score 0 = no
bleeding; score I = few minor mucosal or cutaneous
bleedings; score 2 = extensive mucosal or cutaneous
bleedings; score 3 = major bleeding episodes which in-
cluded any gastrointestinal bleeding, hematuria, hemop-
tysis, retinal or CNS bleeding, irrespective of whether
Table 1 Patient characteristics
Inducrion
TA
No. 16
Age (yn)
Mean
Range
Sex (ck)
Male
Female
FAB classification
I
1
3
4
blood transfusions were required or if any bleeding re-
quired PRC transfusions.
RESULTS
Thirty eight patients received induction treatment (16 in
the TA group and 22 in the placebo). There were no sig-
nificant differences in age, sex and leukemia subtype be-
tween the two groups (Table 1). Eighteen patients were
studiedduringconsolidationtreatment ( 10 in theTA group
and 8 in the placebo) and once again, there were no sig-
nificant demographic differences. During the entire study
no thromboembolic events or fatal bleeding occurred in
either group. TA was well tolerated and no side effects
were observed. No occlusive events were seen in any of
the patients who had right atrial catheters.
Effects of TA during induction therapy
There were no significant differences between the study
and control groups in terms of the duration of hospitaliza-
tion or the period of significant thrombocytopenia (e.g.,
less than 20 x loUn) or days with fever (e.g., temperature
above 38.5' (Table 2). No significant differences were
noted between the groups regarding the number of bleed-
ing episodes or in the number of platelet and PRC trans-
fusions. Bleeding events distribution according to score
was also similar in both groups.
Effects of therapy during consolidation therapy
As shown in Table 2, again there was no significant dif-
ference between the treatment groups in respect to the du-
ration of hospitalization or to the period of
thrombocytopenia.However, a significantly greaterbleed-
ing tendency was seen in the control group compared with
the TA group. The bleeding events in the control group
had a higher bleeding score, i.e., were more severe, than
Consoliddon
Ctinrrril TA Conrrol
22 10 8
 TRANEXAMIC ACID IN ACUTE LEUKEMIA
Table 2 Bleeding events and platelet transrusion%
Indi~rion
TA
NO. 16
Hospitalization
duration (days) 28.2 f S.8 35 2 f 16.6
Fever (day\) 4.2 f 3.2
Thromhocytopcnic
pericwl (day\)' 17.3 f 3.5 19.0 f
Bleeding
event\ 6.2 f 3.9 4.5 f
Cumulative
bleeding score 8.3 f 4.8
Platelet units 22.1 f 13.2 23.1 f 11.7
PRC units 7.5 f 4.7
Downloaded by [RMIT University] at 04:48 12 August 2015
in the TA group. The bleeding events led to a significantly
greater platelet transfusion requirement in the placebo
group (9.3 k 3.3 platelet units compared to 3.7 f 4. I , p <
.05),while there was no significant difference i n the num-
ber of PRC transfusions given. As during the induction
course, no TA-related thromboembolic complications or
any untoward side- effects were noted.
DISCUSSION
The long standing clinical practice o f routinely transfus-
ing platelets to patients with acute leukemia whenever the
count drops below 20 x IWL, has recently been criticized
and a more medically sound practice advocated.%-")
However, platelet transfusions are still widely used ex-
posing the patient toall the potential hazardsofblood prod-
ucts. Therefore, any measure that will safety reduce the
need for platelet transfusions may be most beneficial.
There are several reports on the efficacy o f antifibrinolytic
agents in controlling bleeding in thrombocytopenia o f di-
verse etiologies.'" When a clot is formed in a thrombo-
cytopenic patient, it is friable and lyses rapidly resulting
i n a poor haemostatic plug. Antitibrinolytic agents could
stabilize the clot by decreasing the level o f fibrin degra-
dation products(FDP) that inhibit not only fibrin monomer
polymerization but also platelet aggregation.11 I n addition,
antifibrinolytic agents would prevent plasmin l i o m cleav-
ing the platelet membrane glycoprotein Ib, which i s nec-
essary for the interaction with von Willebrand factor and
for platelet adhesion.l'.l.l
The complex coagulation disorder that i s found in A M L
patients. and particularly APL, i s believed to be the result
0 1 imbalance between the thrombin and plasmin genera-
tion in vivo with various degrees of severity o f dissemi-
nated intravascular clotting (DIC) and fibrinolysis.1' 1c'
DIC in patients with A M L is attributed to procoagulants
such as tissue factor released from the leukaemic cells. On
I43
Consolidulioit
Coitrrol TA Coiitrrol
22 10 x
23.3 f 2.7 22.3 f 6.8
4.3 f 2.9 1.6 f 1.2 2.5 f 2.9
3.6 9.4 f 1.9 11.5 f 7.7
3.6 1.1 f 11" 2.6 f 2.2
5.6 f 1 . 8 1.3 f 1.8" 5.1 f 3.6
3.7 f 1.1" 9.3 f 3.3
7.3 f 3.3 4.1 f 2.X 4.1 f 3.4
the other hand, increased fibrinolysis can also occur due
to the release of plasmin activators from the leukaemic
cells and a decrease in a2-plasmin inhibitor. Monitoring
the thrombin-antithrombin 111 complex (TAT) and plas-
min-a?-plasmininhibitor complex (PAP) ratio may allow
one to assess the contribution o f the different coagulation
disorders in an individual ~atient.1~ I n this study, we ex-
cluded patients with overt DIC or clinical evidence of
thrombosis. TA was safe in all patients and we have not
encountered any thrombotic event or clinical evidence o f
DIC in the present study nor in the previous one, which
involved a total o f 9 7 patients given I87 cycles o f marrow
ablative chemotherapy.
The present study shows that TA was only beneticial dur-
ing consolidation while i t was not effective during induc-
tion. Although the number o f patients studied during
consolidation chemotherapy is relatively small (only 18 pa-
tients), thedifferencesin the bleedingevents, bleedingscore
and number o f platelet transfusions given are highly sig-
nificant. The recorded difference in the action o f TA given
during induction and/orconsolidation is probably due to the
more complex coagulopathy found in the induction phase.
This is probably due to the presence of the leukaemic cells
during induction, in contrast to isolated thrombocytopenia
with far fewer blasts during the period of consolidation.
Another possibility is that the dose o f TA could have been
too low and the drug levels subtherapeutic during induc-
tion. Therefore. in view ol'thr results of this pilot study, a
trial on it larger scale with TA dose ad,justiiient with moni-
toring o f the librinolytic system i s justiticd.
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