Francesco Autore1, Patrizia Chiusolo1,2, Federica Sora’1,2, Luca Laurenti1,2, Livio Pagano1,2, Andrea Bacigalupo1,2, Valerio De Stefano1,2 and Simona Sica1,2.
di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia,
Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
2Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma, Italy.
Correspondence to: Dr.
Francesco Autore. Fondazione Policlinico Universitario A. Gemelli
IRCCS, Largo Agostino Gemelli 8, I-00168 Rome, Italy. Tel:
+39-06-30155300, Fax: +39-06-3017319. E-mail: email@example.com
Published: January 1, 2023
Received: October 11, 2022
Accepted: December 22, 2022
Mediterr J Hematol Infect Dis 2023, 15(1): e2023009 DOI 10.4084/MJHID.2023.009
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
To the editor
with acute promyelocytic leukemia (APL) often show some clinical and/or
laboratory features of coagulopathy. However, the evidence of
alterations in blood clotting tests seems not to correspond to
clinically significant thrombotic or hemorrhagic complications in low
and intermediate risk APL patients.
Presentation of patients with APL is often characterized by coagulopathy.
diagnosis, a percentage close to 76% of APL patients have some clinical
and/or laboratory features of coagulopathy, from skin or soft tissue
bleedings to intracranial hemorrhage.[2-3] While
physicians pay attention to bleeding-related complications in APL, it
is also important to note that it is not uncommon to develop thrombotic
events, particularly in patients on treatment.
the introduction of new drugs such as all-trans retinoic acid (ATRA)
and arsenic trioxide (ATO) allowed for reducing complications: bleeding
events were predominant rather than severe thrombotic events (29% vs.
The major cause of death during induction was due to hemorrhage;[6-7]
even if with the administration of ATRA or ATO, overall mortality due
to bleeding complications has been halved from 14% of the pre-ATRA era.[5,8]
is characterized by a coagulopathy which is unique among leukemias. At
presentation, most patients showed abnormalities in their coagulation
profile, such as prolonged prothrombin time (PT), partial
thromboplastin time (PTT), and thrombin time (TT), but it happens to
observe normal values. Typical laboratory features of coagulation
factors consumption are represented by fibrin degradation products and
D-dimer increase, and fibrinogen level decrease. Thrombocytopenia was common and often severe.[4,10]
two main mechanisms behind the coagulopathy of APL are tissue factor
(TF)-induced disseminated intravascular coagulation (DIC) and primary
In the pre-ATRA era, chemotherapy exacerbated bleeding manifestations.
if the introduction of ATRA seemed to reduce the risk of
bleeding-related complications because the balance of prothrombotic
factors shifts toward thrombosis, the risk of thrombosis did not appear
to reduce. Clinical features improved after
starting treatment; in particular, their improvement was faster when
ATRA was added to chemotherapy, but it may take several days. In fact,
laboratory parameters and clinical manifestations were often
The effect on the hemorrhagic
risk of ATO addition on induction therapy was less studied.
Incorporating ATO into induction therapy should reduce hemorrhagic
complications; ATO, in combination with ATRA, may reverse coagulopathy
even more promptly than ATRA alone. Heparin prophylaxis during treatment with ATO was not recommended, except for the treatment of thrombotic events.
laboratory alterations are typically reversed following treatment with
ATRA plus ATO: it seemed that coagulopathy generally abates by 5–7
days, and the abnormal coagulation and fibrinolytic profiles returned
to normal after 14 days or longer.[5,8,18]
this scenario of patients treated with ATO plus ATRA, since little data
about coagulation patterns are available, our study aimed to evaluate
coagulation-related parameters in low/intermediate risk APL patients at
presentation and investigate mechanisms of APL coagulopathy by
measuring changes in these values prior to and during ATO plus ATRA
From our data analysis, we investigated coagulative patterns through our real-life monocentric experience.
included each patient affected by APL, treated according to the ATO
plus ATRA regimen, which was part of the standard treatment for APL. We
included patients at low and intermediate risk according to Sanz’ risk
score; high-risk patients were excluded by treating physicians as per
Each patient was treated
with intravenous ATO (0.15 mg/kg/die) and oral ATRA (25 mg per square
meter of body-surface area) as first-line treatment. Platelets
transfusion was administered with a target of platelet count over 30×109/L or 50×109/L
in the presence of bleeding. The administration of fresh frozen plasma
(FFP) was performed in patients with a prolonged PT value>3 ec
compared to normal and/or a fibrinogen level less than 150 mg/dl.
DIC score for all patients in this study was calculated using the overt
DIC criteria of the International Society on Thrombosis and Hemostasis
The study was approved by our institutional ethics committee and conducted in accordance with the Declaration of Helsinki.
patients admitted to our Department of Hematology between January 2009
and June 2021 were included in the study: fifteen male and ten female
patients with a median age of 45 years (range 18-72), mostly
intermediate risk (18 patients, 72%). Characteristics of the patients
at diagnosis are shown as median values in Table 1.
1. Patients’ clinical and laboratory characteristics at diagnosis.
and PTT median values were in the normal range. Elevated D-dimer levels
were seen in all patients. The overall incidence of thrombocytopenia
requiring platelets transfusion was 68% (17 out of 25) of patients.
Only three patients had fibrinogen <150mg/dl; however, fibrinogen
level<200 mg/dl was seen in 13 patients (in 8 patients from the
diagnosis and in 5 patients after a median of 4 days from the ATRA
introduction). When calculating the ISTH-DIC score, 14 patients had an
overt DIC (defined as a score ≥5) at presentation, and 11 patients
showed a condition of subclinical DIC.
We followed the dynamic changes in the hemostatic parameters during induction therapy, as summarized in Table 2.
2. Median of the times of normalization of coagulation parameters abnormal at presentation.
first parameter to normalize was fibrinogen, after a median time of 11
days (range 3-44 days) after the beginning of the therapy; only five
patients received FFP, and 17 patients required platelet transfusion
reaching the count >30x109/L
without transfusion after a median of 25 days (range 11-31). A median
of 8 units (range 3-23) was the need for platelet transfusion. No major
hemorrhagic events were registered during ATO plus ATRA treatment.
levels normalized after a median of 38 days without any clinical
evidence of complications except for two thrombotic events (one deep
vein thrombosis and one superficial vein thrombosis of the leg after 34
days from ATRA introduction) properly managed with low molecular weight
All patients were discharged after ATO plus
ATRA induction and achieved complete hematologic remission in a median
time of 36 days (range 25–47 days). In addition, all patients obtained
molecular remission after a median time of 3 months (range 1-6), and
all but one patient, dying of progressive disease, are alive and in
molecular response at a median follow-up of 43 months (range 1-145).
in APL is of utmost importance even because previous studies did not
aim to measure the coagulation parameters and analyze them as potential
Retrospective analysis pointed out predictive risk
factors for bleeding and thrombosis, but a major limitation of these
studies was the inherent bias linked to the effect caused by treatment.
For example, the administration of FFP in APL patients with reduced
ﬁbrinogen levels makes diﬃcult the evaluation of it as a bleeding risk
factor, and in general, the blood product administration makes
difficult to stratify patients on bleeding or thrombotic risk.
As far as low and intermediate-risk patients are concerned, bleeding
symptoms disappeared in most patients rapidly with the beginning of ATO
plus ATRA treatment.
A direct comparison between our study and others[13-14]
is difficult due to the different populations and treatments
considered; our analysis included APL patients in low and intermediate
risk who did not necessitate chemotherapy; moreover, we did not use the
oral formulation of arsenic.
Our coagulation pattern data are in
line with previously published data in terms of characteristics at
baseline and dynamic changes in hemostatic variables. Our data are the
product of a real-life experience in a single center in Western Europe,
but with the administration of intravenous ATO and the collection of a
complete coagulation pattern.
In conclusion, parameters often
did not return to normal in the first month of treatment, suggesting
that the coagulopathy did not fully recover and persisted. Therefore,
prolonged monitoring of coagulation and fibrinolysis parameters was
still required. Also, increased D-dimer levels, which reﬂect the
product of ﬁbrinolysis of cross-linked ﬁbrin, suggested the
long-standing activation of coagulation.
The evidence of
alterations in blood clotting tests seems not to correspond to
clinically significant thrombotic or hemorrhagic complications. ATO
plus ATRA regimen shows a series of advantages compared to
chemotherapy, allowing to treat patients and reducing possible
complications, also in the setting of coagulopathy.
and S.S. designed the study; P.C, F.S., L.L., L.P., A.B. and V.D.S.
analyzed data; F.A., S.S. and V.D.S. wrote the initial manuscript; all
the authors revised the paper and approved the final version.
authors acknowledge the support of ‘Centro di Ricerca sulle cellule
staminali emopoietiche e le terapie cellulari “Università Cattolica S.
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