© 2004 Schattauer GmbH, Stuttgart
Case Report
Neuropharmacological treatment of refractory idiopathic thrombo-
cytopenic purpura: roles of circulating catecholamines and serotonin
R
efractory idiopathic thrombocytopenic purpura (ITP) is a
pathophysiologic disorder affecting millions of children
and adults. We present here five consecutive cases in
whom conventional therapies had previously failed, and who
were successfully treated through neuropharmacological thera-
py. All patients submitted to neuroautonomic plus immunologi-
cal investigation. Circulating noradrenaline (NA), adrenaline
(Ad), dopamine (DA), platelet serotonin (p-5HT), plasma sero-
tonin (f-5HT) and plasma tryptophan (Trp) were assessed during
supine-resting / one-minute orthostasis / five-minute moderate
exercise stress test (1). Neuroautonomic investigation showed
that all patients had a lowered NA/Ad ratio which did not in-
crease either at orthostasis or at exercise. This profile is typical
of central nervous system (CNS) noradrenergic (NA) exhaus-
tion (uncoping stress profile) (1,2). The immunological investi-
gation demonstrated that all patients showed a TH-2 autoim-
mune profile (low CD4/CD8 ratio + low NK-cell cytotoxicity +
CD5 autoreactive B cells + increased plasma levels of Ig E) (3).
Normalization of clinical, neuroautonomic, haematological and
immunological parameters was obtained by neuropharmacolog-
ical therapy. One of the most important findings of this study is
the demonstration that restoration of platelet serotonin levels,
rather than the platelet count, correlated with improvement.
Patient #1
Patient #1 is currently a 54-year-old white man, who was diag-
nosed with ITP in May 1996. He had tested positive for platelet
autoantibodies (ELISA method). A bone marrow aspirate and bi-
opsy specimen were unrevealing at this time. He had received
several immunosuppressant treatments including steroids and
methotrexate. However, frequent and uncontrollable relapses
led to splenectomy in 1998. A kidney biopsy and several immu-
nological tests excluded a diagnosis of SLE. He came to our in-
Correspondence to:
Dr. Fuad Lechin, MD, PhD
Apartado 80.983
Caracas 1080-A,Venezuela
Tel.: +58 212 961 1048, Fax: +58 212 961 0172
E-mail: flechin@telcel.net.ve
Received December 12, 2003
Accepted after resubmission March 29, 2004
Financial support:
This work has been supported by grants from Fundaime
and Fundaneuroinmunologia.
Thromb Haemost 2004; 91: 1254 – 6
1254
stitute on May 5, 1998. At that time his platelet count was
11,000/mm3 and ecchymoses and petechiae were present despite
the fact he continued steroid treatment.
Neurochemical plus immunological investigations revealed
an uncoping stress profile and a TH-2 autoimmune profile.
Platelet serotonin (p-5HT) was very low (12.3 ng/ml, normal
150-250 ng/ml); and platelet count was also low (41,000/mm3).
Tryptophan (Trp) value was also below normal (6,050 ng/ml),
reflecting low CNS serotonergic activity.
A neuropharmacological treatment was prescribed in order
Downloaded by: Washington University. Copyrighted material.
to revert the uncoping stress profile. It included: a) an NA-up-
take inhibitor (desipramine 25 mg) before breakfast + an NA-
precursor (L-tyrosine 50 mg) before breakfast + an NA-releas-
ing agent (alpha-2 antagonist such as yohimbine, 2 mg) after
breakfast. Ten to 20 mg of propranolol was added when neces-
sary during the first days of treatment to interfere with several
undesirable side effects that are associated with yohimbine-in-
duced Ad-peak. The above neuropharmacological manipulation
required the addition of 25-50 mg of 5-OH-tryptophan before
bed to replace depleted stores of CNS serotonin.
Steroid therapy was progressively reduced, reaching complete
discontinuation on July 5, 1998. Platelet count increased progres-
sively but remained lower than normal (Figure). Both the unco-
ping stress and the TH-2 immunological profiles were found nor-
mal on November 6, 1999. Platelet serotonin (p-5HT) increased to
84.6 ng/ml. Disappearance of platelet autoantibodies was also obser-
ved on that date. Up to the present no relapses have been recorded.
Patient #2
Patient #2 is currently a 41-year-old white woman, who was di-
agnosed as having ITP in May 1995. She had positive platelet
autoantibodies at presentation. A bone marrow aspirate and bi-
opsy specimen were unrevealing. She had undergone many im-
munosuppressant treatments. Splenectomy was performed in
June 1996. At the time of referral to our institute (August 10,
2000), she was taking steroids; despite this her platelets re-
mained low (19,000/mm3). Neuroautonomic + immunological
investigation revealed an uncoping stress + TH-2 autoimmune
profile. Platelet serotonin was very low (18.6 ng/ml).
We prescribed a similar treatment to that of patient #1. The
treatment began on August 15, 2000 and lab tests were carried
out monthly until March 26, 2001, and subsequently every two
months up to the present. Steroid therapy was totally suppressed
in October 2000 and by December 15 clinical, neuroautonomic
 Case Report
Figure: Platelet count and platelet serotonin throughout
neuropharmacological therapy. Case 1: Although both plate-
let count and platelet serotonin (P-5HT) showed significant in-
creases throughout the neuropharmacological therapy period,
bleeding stoppage was observed as of the first month of therapy,
at which time a significant fall of the former and a sudden rise of
the latter were observed. Case 2: Although both platelet count
and platelet serotonin (P-5HT) showed significant increases
throughout the neuropharmacological therapy, bleeding stoppage
was observed from the first month of therapy, at which time a
slight rise of the former (23.000/mm3) and a more significant in-
crease of the latter (45.83 ng/ml) were seen. P-5HT but not
platelet count reached normal values during the following
months. Case 3:Although both platelet count and P-5HT showed
significant increases throughout the neuropharmacological ther-
and immunological parameters were absolutely normal. Al-
though the platelet count showed only a slight increase
(33,000/mm3), p-5HT showed a significant rise (68.3 ng/ml), at
the same time that ecchymoses and petechiae disappeared. No
relapses have been observed up to the present.
1255
Downloaded by: Washington University. Copyrighted material.
apy, P-5HT but not platelet count reached significant increases
within the first month of therapy (bleeding stoppage). Normaliza-
tion of P-5HT but not platelet count values was observed de-
spite discontinuation of neuropharmacological treatment after
seven months. Case 4: Significant and non-significant increases of
P-5HT and platelet count, respectively, were observed at the first
month of neuropharmacological therapy, at which time bleeding
stopped. Both parameters were normalized, further. Case 5:Al-
though significant and non significant rise of platelet count and
P-5HT values, respectively, were observed at the first month of
neurophar-macological therapy, bleeding did not stop at this peri-
od. However bleeding disappeared in the second month, when an
abrupt increase of P-5HT opposed a fall in platelet count.These
phenomena occurred 15 days after the drug’s dose was doubled.
Patient #3
Patient #3 is currently an 11-year-old girl. She had been diag-
nosed in July 2000 as having ITP. A biopsy specimen and bone
marrow aspirate were unrevealing. She tested positive for plate-
let autoantibodies. There was no splenectomy. She came to our
 Case Report

institute on September 29, 2001 (20,000 platelets/mm3), after
suffering frequent relapses despite taking steroid therapy as well
as methotrexate. Neurochemical and immunological investiga-
tions revealed similar findings to those seen in patients 1 and 2.
Platelet serotonin was very low (24.6 ng/ml).
The neuropharmacological therapy began on October 24,
2001. Monthly lab tests were performed until July 2002. Predni-
sone was totally discontinued in December 2001. Complete im-
provement (clinical + neuroautonomic + immunological) was
observed in February 2002, at which time platelet count rose to
123,000/mm3 and p-5HT increased to 134.2 ng/ml. Neurophar-
macological therapy ceased in March 2002. No relapses have
been observed up to the present.
Patient #4
Patient #4 is currently a 9-year-old girl. She had been treated for
ITP from March, 1995 until August 2000 when she came to our
institute. She presented ecchymoses and petechiae in spite of
and petechiae, despite receiving prednisone. There was no sple-
nectomy. Neuroautonomic and immunological investigations
revealed similar results to those of the previous four patients.
Neuropharmacological therapy was started on April 2, 2003
(37,000 platelets/mm3). Steroid discontinuation was accom-
plished within four weeks. At that time, despite an increase in
platelets to 60,000/mm3, the p-5HT remained very low (35.6
ng/ml). Ecchymoses and petechiae did not disappear. A new la-
boratory evaluation performed 15 days after increasing the
drug’s dose (June 20, 2003) showed that platelets fell to
43,000/mm3. However, curiously, p-5HT increased to 107.6
ng/ml (Figure). Platelet autoantibodies were found negative.
These findings were paralleled by disappearance of both petech-
iae and ecchymoses. The patient continues under treatment and
remains asymptomatic up to the present (February, 2004).
The successful results obtained with neuropharmacological
therapy in these five cases of ITP are in line with similar suc-
cesses obtained in treating other autoimmune diseases (4). An-

Downloaded by: Washington University. Copyrighted material.

taking prednisone, 50 mg daily. Splenectomy had been per-
formed in February 1996 and she had undergone several cours-
es of methotrexate and other immunosuppressant drugs. We
found a low platelet count (23,000 platelets/mm3) and low p-
5HT (32.5 ng/ml). Platelet autoantibodies were found positive.
Neuroautonomic and immunological investigations revealed
similar results to those of patients 1, 2 and 3.
Neuropharmacological therapy was started on September
20, 2000 (23,000 platelets/mm3). Complete discontinuation of
prednisone was reached five weeks after starting neuropharma-
cological therapy (30,000 platelets/mm3). Platelet count rose to
110,000 platelets/mm3 by March 26, 2001. Clinical, haemato-
logical, immunological and neurochemical improvements con-
tinue up to the present. All drugs were stopped on November 29,
2002. (Figure).
Patient #5
Patient #5 is currently a 4-year-old boy. He was brought to our
Institute on March 14, 2003. He had been treated with predni-
sone plus gammaglobulins because of ITP. Positive platelet
autoantibodies were found. He presented extensive ecchymoses
other finding emanating from our case reports strongly suggests
that platelet serotonin content rather than platelet count is the
appropriate index for measuring the clinical severity of ITP.
The above findings are consistent with the fact that seroto-
nin is stored in the delta granules of platelets. The release of se-
rotonin is considered as the “golden standard” assay for the de-
tection of thrombocyte activation. With respect to this, serotonin
is released upon platelet activation (5). The presence of seroto-
nin is covalently linked to fibrinogen bound on the surface of the
activated platelet where it increases the retention of procoagu-
lant factors on the cell surface (6). Serotonin, therefore, occu-
pies a central role in haemostatic process and its release is con-
sidered the most reliable assay for platelet activation (5). Our
findings are in line with those obtained by Dominguez et al. (7),
who showed lack of correlation between platelet count and
bleeding in an experimental model of immune thrombocyto-
penic purpura in mice.
Fuad Lechin, Bertha van der Dijs, Beatriz Orozco,
Eduardo Jahn, Simón Rodríguez, Scarlet Baez

References
1. Anisman H, Suissa A, Sklar LS. Escape defi-
cits produced by uncontrollable stress: antago-
nism by dopamine and norepinephrine ago-
nists. Behav Neural Biol 1980; 28: 34–47.
2. Lechin F, van der Dijs B, Orozco B, et al.
Plasma neurotransmitters, blood pressure and
heart rate during supine-resting, orthostasis
and moderate exercise in severely ill patients:
A model of failing to cope with stress. Psycho-
ther Psychosom 1996; 65: 129–36.
3. Lechin F, van der Dijs B, Lechin ME. Neuro-
autonomic, neuroendocrine and neuroimmune
interactions. In Neurocircuitry and Neuroauto-
nomic Disorders. Reviews and Therapeutic
Strategies. Karger 2002; 57-59.
4. Lechin F, van der Dijs B, Lechin ME. Neuro-
pharmacological therapy of diseases associat-
ed with uncoping stress profile (Th-2 autoim-
mune diseases). In: Neurocircuitry and Neuro-
autonomic Disorders. Reviews and Therapeu-
tic Strategies. Karger 2002; 75-82.
5. Gobbi G, Mirandola P, Tazzari PL, et al. Flow
cytometry detection of serotonin content and
release in resting and activated platelets. Br J
Haematol 2003; 121: 892-6.
6. Dale GL, Friese P, Batar P, et al. Stimulated
platelets use serotonin to enhance their reten-
tion of procoagulant proteins on the cell sur-
face. Science 2002; 415: 175–9.
7. Dominguez V, Govezensky T, Gevorkian G, et
al. Low platelet counts do not cause bleeding
in an experimental model of immune thrombo-
cytopenic purpura in mice. Haematologica
2003; 88: 679-87.

1256