CYCLIC THROMBOCYTOPENIA TREATED WITH PLATELET TRANSFUSION AND ORAL
PREPARATION CONTAINING HYALURONIC ACID (ORALVISC®)
M. Benjamin1, R. Kotchetkov2*
1University of Ottawa, Faculty of Science, Ottawa, ON,
Canada, K1N 6N5
2Royal Victoria Regional Health Centre, Barrie,
Ontario, Canada, L4M 6M2
Short Title: A case of cyclic thrombocytopenia
*Corresponding Author: Rouslan Kotchetkov, M.D., Ph.D.
Royal Victoria Regional Health Centre, Barrie, Ontario, Canada L4M 6M2
Tel: +1-705-728-9090;
Fax: +1-705-739-5630;
Email:
KotchetkovR@rvh.on.ca
Number of Tables: 0
Number of Figures: 1
Word count: 1495
Key words: thrombocytopenia, cyclic, anti-inflammatory, transfusion,
hyaluronic acid, Oralvisc
KEY CLINICAL MESSAGE
Cyclic thrombocytopenia is a rare disorder characterized by periodic
platelet fluctuation with amplitude from low to high. There are no
standardized treatment guidelines. We present a patient who had
resolution of mucocutaneous bleeding with platelet transfusion at
platelet nadir, normalization of platelets with an oral preparation
containing hyaluronic acid (Oralvisc®).
INTRODUCTION
Cyclic thrombocytopenia (CTP) is a rare disorder characterized by
intense fluctuations of platelet counts in a cyclical pattern repeating
on an average of a 3-week basis.1 Platelet nadir can
be complicated by hemorrhage, and thrombocytosis can cause
hypercoagulable state and thrombosis. Initially, most CTP patients are
typically misdiagnosed as having primary immune thrombocytopenia (ITP).
Currently it is considered to be heterogenous in cause. Clinical
presentation is similar to immune thrombocytopenia (ITP), however most
treatments seem to be ineffective or even harmful if applied to patients
with CTP. CTP is a diagnosis of exclusion and is usually established, if
at all, much later, often at a time when ITP-specific therapies have
failed. Due to its rarity, in addition to the lack of research and
documentation surrounding it there are no standardized guidelines on
treatment. Here we present a case of chronic CTP, who reached
significant improvement in quality of life after initiation of
supportive platelet transfusions at platelet nadir. Moreover, platelet
count fluctuations decreased and eventually normalized after application
of oral preparation containing hyaluronic acid (Oralvisc®) for
concomitant arthropathy. With this case we want to illustrate
challenging aspects of non-standard management for such a rare disease.
CASE HISTORY / EXAMINATION
64-year-old female was referred to our institution for management of
chronic CTP. She was diagnosed at the age of 45, initially as ITP, when
routine blood work was performed prior to minor surgery. Past medical
history included calcium pyrophosphate deposition disease (CPPD),
hypertension, hearing impairment, myopia, peripheral neuropathy, atrial
fibrillation, chronic back pain, cholecystectomy, and excised squamous
cell carcinoma on floor of mouth. There was no history of alcohol or
substance abuse. She had 20 pack year history of smoking, quit one year
before CTP diagnosis. Family history was unremarkable. Platelet
fluctuations were not synchronized with patient’s menstrual cycle. At
the time of initial assessment at our institution her platelet count
fluctuated from mild thrombocytosis (~600,000 x
109/L) to severe thrombocytopenia (5,000 x
109/L) as shown in Figure 1. Bone marrow examination
at diagnosis did not reveal myelodysplastic changes, abnormal lymphoid
or plasma cell population. There was mild megakaryocytic hypoplasia. At
the time of diagnosis, she was asymptomatic, but after 12 months started
developing muco-cutaneous bleeding around nadir time of the platelet.
She has no major bleeding, including hemarthroses, hematuria,
hematoschezia.
METHODS (TREATMENT)
Given CHADS2 score of 1 at diagnosis of atrial fibrillation, she was
anticoagulated with warfarin. However, due to bleeding episodes it was
switched to low molecular dose heparin, and later to apixaban. That
allowed a better balance of bleeding and thrombosis risks during
thrombocytopenia and thrombocytosis.
After taking Prednisone 1 mg/kg she achieved partial response but
discontinued it due to recurrent mouth thrush. She switched to a pulse
dose of dexamethasone; however it was stopped because of vaginal pain
and bleeding, and feeling generally unwell. She had normalization of
platelet count on oral cyclophosphamide 100 mg daily and was able to
stop it. However, she relapsed shortly after discontinuation and had no
significant clinical response following restarting of cyclophosphamide.
Next line of therapy was course of intravenous infusion of Rituximab,
375 mg/m2 weekly x4. There was no platelet
improvement, but she developed significant daily headaches, visual
hallucinations, and blue vision discoloration. She declined splenectomy
and was on active surveillance until bleeding symptoms at her platelets
nadir progressed and started significantly affect her quality of life .
High doses of tranexamic acid (1,000mg three times a day) were given at
platelet nadir to improve symptomatic bleeding, but the patient had only
marginal improvement and it was discontinued. Due to risk of thrombosis
at platelet high, we considered it unsafe to administer thrombopoietin
receptor agonists, like eltrombopag or romiplostim.
OUTCOME
Due to lack of other options, we offered her platelet transfusion around
nadir time which led to marked improvement in bleeding episodes. Since
the timing of nadir was quite predictable, platelet transfusion improved
quality of life. When the patient required dental extraction, we chose a
time when the patient had a normal platelet count which resulted in an
unremarkable procedure with no bleeding or thrombosis. After 2 years of
platelet transfusion, the patient started taking oral preparation
containing hyaluronic acid (Oralvisc®) for worsening hip and knee
arthropathy. After five months her platelet count fluctuations improved,
ranging from 100,000 to 150,000 x 109/L and she became
transfusion independent. After 26 months the patient discontinued
Oralvisc® due to supply issues and switched to colchicine. For over 19
months platelet count remains within the same range, and she remains
asymptomatic and transfusion independent. Her physical examination is
unremarkable.
DISCUSSION
ITP or immune thrombocytopenia is a platelet disorder defined by a low
platelet count thought to be a result of the immune system destroying
platelets either alone or in conjunction with thrombopoeisis inhibition.
Common symptoms include skin and mucocutaneous hemorrhage, bruising,
fatigue. ITP is diagnosis of exclusion and requires an extensive work up
to rule out secondary causes and other platelet disorders.
Corticosteroids (prednisone or dexamethasone) are standard frontline
therapy. Platelet transfusions are not usually effective, since there is
rapid destruction of transfused platelets. For relapsed disease
rituximab, steroid-sparing immunosuppressants, or splenectomy are used.
CTP is a similar platelet disorder however it is characterized by
periods of low and high platelet counts in a reoccurring wave-like
pattern every few weeks. Currently CTP is considered to be heterogenous
in cause and the pathophysiology is largely unknown1.
Germline heterozygous loss-of-function thrombopoietin receptor MPL
mutation and pathogenic somatic gain-of-function (GOF) variants in
signal transducer and activator of transcription 3 (STAT3) were shown in
two patients with CTP. Interesting that 2 patients had also clonal
T-cell populations. It was suggested that these mutations along with
clonal T cells trigger exaggerated persistent thrombopoiesis
oscillations of their intrinsic rhythm upon homeostatic
perturbations2.
Many patients are usually treated for ITP initially prior to
diagnosis3. Two clinical features relatively unique to
CTP besides periodic thrombocytopenia are rebound thrombocytosis
unrelated to recent splenectomy and platelet nadirs occurring during
menses4. To establish a proper diagnosis, platelet
count needs to be measured every week over a period of 1-3 months to
establish the presence of a cyclical pattern to diagnose CTP, however it
is usually a diagnosis of exclusion. Currently it is considered to be
heterogenous in cause.1
Due to rarity of disease and alternating thrombocytopenia and
thrombocytosis the treatment options for CTP are limited. In addition to
detailed medical history and physical examination to rule out secondary
causes, in non-bleeding patients serial blood count check to establish
the platelet profile is recommended. In a patient with active bleeding,
platelet transfusion with post-transfusion blood count check would be
beneficial to assess whether platelets are actively destroyed as seen in
ITP or maintain the count, which would ne more suggestive as CTP. For
asymptomatic patients active surveillance is recommended until they
develop clinically significant and recurrent hemorrhage affecting organ
function or quality of life. Patients with CTP generally do not respond
to standard ITP treatments, including corticosteroids, splenectomy, and
intravenous immunoglobulin1,4. A recent publication
showed normalization of platelet count in a female patient treated with
danazol5. Hormonal contraceptive showed efficacy in
alleviating patient’s symptoms6.
Platelet transfusions in ITP patients are generally reserved for
critical bleeding when there is a need to raise the platelet count
immediately7. Due to antiplatelet antibodies that
destroy circulating platelets and megakaryocytes in the bone marrow the
response is transient and attenuated8. Based on our
experience, supportive single platelet transfusion per cycle at the
nadir of platelet is efficacious in long-term management of CTP. It
helps to minimize bleeding and improve quality of life. Given
predictable pattern of platelet count fluctuation, it is feasible to
arrange blood count check and transfusions. Transfusion of platelets
does not increase risk pf thrombosis. In contrast to ITP, there is not
rapid platelet destruction in CTP patients and the longevity of
transfused platelet is longer. This approach could also be used
perioperatively prior to major or minor surgeries. The sustained
response to platelet transfusion in CTP patient preoperatively was shown
recently9.
Efficacy of anti-inflammatory medications in ITP has not been shown.
Oralvisc® is an anti-inflammatory oral preparation containing hyaluronic
acid that reduces the levels of pro-inflammatory mediators leptin and
bradykinin10. Bradykinin receptors exist in
chondrocytes and on stimulation increase Interleukin-1. Bradykinins are
known to participate in innate immunity, inflammation, and
pain11. Hence, evidence of reduction in bradykinin
levels is clinically relevant. Though prior to starting Oralvisc® the
patient had no elevated markers of inflammation (C-reactive protein,
erythrocyte sedimentation rate, fibrinogen and ferritin were normal),
the anti-inflammatory effect may have contributed to normalization of
platelet count and clinical improvement. Alternatively, in our case
Oralvisc® may triggered spontaneous recovery, a feature previously
described in CTP1.
CONCLUSION
CTP is a rare disease, different from ITP, however it should be
considered at the initial presentation. In patients with recurrent
fluctuation in their platelet count, CTP should be considered. Serial
blood count check is recommended to establish a proper diagnosis and
avoid unnecessary therapies used for ITP but not effective in CTP.
Supportive platelet transfusion at the nadir of thrombocytopenia is an
effective management option in some symptomatic patients.
Anti-inflammatory medications, suppressing bradykinin and leptin may be
applied to alleviate platelet fluctuation and improve symptoms.
AUTHOR CONTRIBUTIONS
Marek Benjamin: Writing – original draft; writing – review and
editing. Rouslan Kotchetkov: Writing – review and editing, Supervision.
ACKNOWLEDGMENTS
None.
FUNDING INFORMATION
This research received no specific grant from funding agencies in the
public, commercial, or not-for-profit sectors.
CONFLICT OF INTEREST STATEMENT
None Declared.
CONSENT
Complete written informed consent was obtained from the patient for the
publication of this study and accompanying images.
FIGURE LEGEND
Figure 1: Fluctuating platelet count/µL over a period of the last 5
years. Arrow represents the point at which the patient started
Oralvisc®. Red line – lower limit of norm, grey line – upper limit of
norm