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American Journal of  Medical 
Science and Innovation (AJMSI) 

Approach to the Diagnosis and Management of  Essential Thrombocytosis in a
Resource-Limited Setting

Vonwicks C. Onyango1*, Anne W. Theuri1, Samuel M. Gachie1, Collins P. Malalu1, William C. Fryda1

Volume 3 Issue 1, Year 2024
ISSN: 2836-8509 (Online)

DOI: https://doi.org/10.54536/ajmsi.v3i1.2312
https://journals.e-palli.com/home/index.php/ajmsi

Article Information ABSTRACT

Received: December 02, 2023
Accepted: December 29, 2023
Published: January 02, 2024

Essential thrombocytosis (ET) is a myeloproliferative neoplasm (together with polycythemia 
vera, chronic myelogenous leukemia, and primary myelofibrosis) characterized by clonal 
proliferation of  megakaryocytes, usually due to the presence of  JAK2, CALR, or MPL 
mutations. Whereas a bone marrow aspirate and genetic testing for these mutations are 
necessary for an accurate diagnosis of  ET, in resource-limited settings, these are often either 
inaccessible or limited by prohibitive costs. A nuanced clinical approach is necessary to 
diagnose and manage ET in these settings. In this study, we present a case of  ET diagnosed 
and managed in a resource-limited rural setting in Kenya with hydroxyurea and aspirin. 
We highlight the importance of  individualized therapeutic targets, the challenges with dose 
adjustments in the setting of  hydroxyurea-induced neutropenia, and how extrapolated data 
from the use of  hydroxyurea elsewhere may help guide such dose adjustments. Finally, we 
propose a rationalized approach to treating ET in a resource-limited clinical setting.

Keywords
Essential Thrombocytosis, 
Myeloproliferative Neoplasms, 
Hydroxyurea, Aspirin, 
Hydroxyurea-Induced Neutropenia, 
Vasomotor Symptoms, Thrombo-
Hemorrhagic Complications, Kenya

1 St. Joseph Rift Valley Hospital, Gilgil, Nakuru County, Kenya
* Corresponding author’s e-mail: drvonczelo@gmail.com

INTRODUCTION
Essential thrombocytosis (ET), also called essential 
thrombocythemia or primary thrombocytosis, is one of  
the myeloproliferative neoplasms (MPN) whose hallmark 
is the clonal proliferation of  various myeloid cells with 
varying morphology, maturity, and efficiency. The 
other main MPNs are polycythemia vera (PV), chronic 
myelogenous leukemia (CML), and primary myelofibrosis 
(PMF) (Arber et al., 2016). ET is characterized by sustained 
megakaryocyte proliferation that leads to increased 
numbers of  circulating platelets, often of  various sizes 
(platelet anisocytosis). Figure 1, panel by Schafer et al., 
shows the appearance of  ET on a peripheral blood film 
and on a bone marrow assay. (Tefferi & Pardanani, 2019). 
Approximately 85-90% of  patients with MPNs will 
demonstrate mutually exclusive mutations in the 
JAK2 (60-65%), CALR (20-25%), or MPL (5%) genes 
(Cazzola & Kralovics, 2014; Klampfl et al., 2013; Nielsen 
et al., 2013). About 10-15% of  patients have no such 
mutations (the so-called ‘triple-negative’) (Tefferi et al., 
2014). ET constitutes approximately a third of  all cases 
of  MPNs in developed countries, with a median age at 
diagnosis of  60 years. Most patients enjoy a normal life 
expectancy, but survival is decreased in older patients 
and those with thrombotic complications (Hultcrantz et 
al., 2015; Roaldsnes et al., 2017; Srour et al., 2016; Tefferi 
& Barbui, 2017). The main features of  ET include a 
persistently elevated platelet count of  >450,000/µL on 
a complete blood count, a clinical course characterized 
by thrombotic and/or hemorrhagic events with a 
possible splenomegaly, and marked thrombocytosis and 
hyperplasia of  megakaryocytes on peripheral blood smear 

Figure 1: Histologic Features of  Essential Thrombocythemia 
(Schafer, 2004)
In Panel A, a peripheral-blood smear from a patient with essential 
thrombocythemia contains an increased number of  platelets, 
including giant platelets (arrow; Wright’s stain, ×100). In Panel 
B, a specimen of  bone marrow from a patient with essential 
thrombocythemia contains an increased number of  megakaryocytes 
(hematoxylin and eosin, ×100). (Courtesy of  Dr. Scott Murphy, 
American Red Cross Blood Services, Penn–Jersey Region, 
Philadelphia.)



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and bone marrow assays, respectively (Tefferi & Barbui, 
2020). Asymptomatic patients with ET (about 50% of  
all cases) may be found when persistent thrombocytosis 
is noted on routine complete blood counts for other 
reasons. Disease-related symptoms of  ET are largely 
vasomotor due to disturbances in microvascular 
circulations and include headaches, dizziness, fainting, 
blurring or transient loss of  vision (e.g., amaurosis 
fugax, ocular migraines), non-specific fatigue, atypical 
chest pains, myalgias, acral paresthesia, erythromelalgias, 
and livedo reticularis, etc. (Wolanskyj et al., 2005). 
Patients may also present with complications related 
to thrombosis (due to both quantitative and qualitative 
plate dysfunctions) in various organs, e.g., strokes, acute 
coronary syndromes, superficial thrombophlebitis, deep 
vein thrombosis, pulmonary embolism, hepatic or portal 
vein thrombosis, digital ischemia, thrombosis-related 
first-trimester pregnancy losses, etc. (Tefferi & Barbui, 
2017). Hemorrhagic manifestations tend to occur in cases 
of  extreme thrombocytosis (platelet counts >1000,000/
µL) as well as following treatment with high doses of  
non-steroidal anti-inflammatory drugs (Bellucci et al., 
1986; Landolfi et al., 2006). Treatment of  ET is based 
on individualized stratification of  the risks and/or 
occurrence of  thrombosis or bleeding (Barbui et al., 2015) 
and generally includes observation and cytoreductive 
therapy with medications such as low-dose aspirin and 
hydroxyurea (first-line therapy) (Rocca et al., 2020; Tefferi 
& Barbui, 2020). Interferon alfa, anagrelide, ruxolitinib, 
and apheresis may be used as second-line agents 
(Birgegård, 2016; Tefferi & Barbui, 2020). Older agents 
like busulphan and phosphorus-32 (32P) may also be 
used as second-line agents but have been associated with 
increased risks of  acute myelogenous leukemia (Finazzi et 
al., 2005; Tefferi & Barbui, 2020).

CASE SUMMARY
History and Physical Examination
A 60-year-old married father of  three adults, a tailor 
by profession from Pipeline Estate, Nakuru County, 
Kenya, with no preceding significant medical history, first 
presented to us in February 2022, with concerns of  pain 
and darkish discoloration of  the small left toe. This was 
associated with a ≥6-month’ history of  bilateral lower 
limb numbness, paresthesia, and burning pain of  both 
hands and feet in a stocking-and-gloving distribution. 
He’d also experienced recurrent global headaches, 
blurring of  vision, occasional dizziness, myalgias, general 
fatigue, reduced effort tolerance, and mild bipedal edema. 
However, he had no history to suggest heart failure, 
bleeding diatheses, stroke-like symptoms, or deep venous 
thrombosis. He had no known family history of  any 
hematological or cardiovascular diseases. The rest of  the 
systemic inquiry was unremarkable.
On examination, he was in fair general health. His lower 
limb examination revealed multiple macular-to-patchy 
non-tender, non-blanching discrete skin lesions on both 
legs and thighs, mild bilateral pitting ankle edema, with 

the left small toe appearing remarkably darkened but 
non-tender, and with an associated septic wound on its 
tip. The neurovascular exam of  both legs as well as the 
rest of  the musculoskeletal exam were normal. He had no 
features of  chronic liver disease but had a dull percussion 
note over Traube’s space, indicating splenomegaly. A 
full neurological exam only showed mild impairment 
in the peripheries of  light touch and vibration, while 
examination of  the other systems was unremarkable.

Diagnostic Evaluation
During that first encounter, it was noted on a complete 
blood count that his total platelet count was markedly 
elevated at 2306 x103/µL (the normal range is 150-
450 x103/µL), while the total leucocyte count and 
hemoglobin were both normal at 10.4 x103/µL and 14 
g/dl, respectively. He had normal random blood glucose, 
normal renal and liver panels, a negative HIV rapid test, 
a negative COVID-19 rapid antigen test, a normal chest 
x-ray and electrocardiogram, and a normal erythrocyte 
sedimentation rate of  8 mm/hr. Ultrasonography 
showed a mild splenomegaly of  14cm and early bilateral 
leg varicose veins, but no deep venous thrombosis. He 
was assessed to have features of  a possible underlying 
myeloproliferative disorder, predominantly of  the ET 
phenotype. He got lost to follow-up until nine months 
later, when he re-presented with a worsening of  similar 
symptoms. His platelet count had further increased to 
2733 x103/µL. A peripheral blood film showed extreme 
thrombocytosis with both giant and small platelets, 
consistent with primary (essential) thrombocytosis. Due to 
severe financial and logistical challenges, it was impossible 
to do a bone marrow aspirate or any genetic tests.

Management and Follow-Up
His clinical syndrome was most consistent with ET, 
with predominant vasomotor symptoms and associated 
sensory peripheral neuropathy. He was put on oral 
hydroxyurea (HU) starting at a dose of  1g daily and 
aspirin at 75mg daily. For the neuropathy, he was put 
on pregabalin 75mg daily (and amitriptyline 25mg nocte 
was later added during follow-up). The septic wound 
was surgically managed to full healing. While on HU, 
he developed symptomatic hyperuricemia due to HU-
induced platelet degradation (with a clinical syndrome 
of  non-tophaceous acute gouty polyarthritis), which was 
successfully managed with allopurinol and analgesics. 
Besides, the dose of  HU was adjusted to a maximum 
tolerable dose of  1.5 g/day, aiming to keep an absolute 
neutrophil count of  ≥1.5 x103/µL. Significantly, 
whenever his absolute neutrophil count reduced to <1.5 
x103/µL, he developed a recurrent triad of  oropharyngeal 
candidiasis, septic grade 2 tonsillitis, and cystitis. This was 
fully treated with antimicrobials and supportive therapy. 
The HU in each case was stopped for a week and 
subsequently restarted at a much lower dosage, resulting in 
the resolution of  the neutropenia and the recovery of  the 
target absolute neutrophil count. However, the platelets 



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and the uric acid levels rose precipitously when HU 
was stopped (or dosage reduced), with a corresponding 
recurrence of  mild-to-moderate vasomotor symptoms 
and gouty polyarthritis. These have been fully controlled 
with a corresponding adjustment of  the various drug 
dosages. He is currently on follow-up at the medical clinic 
with ongoing clinical and laboratory monitoring to target 

the individualized therapeutic goals described earlier and 
clinical surveillance for infections, transformation to 
other MPNs, and any adverse effects of  the various drugs.
Table 1 below shows a composite summary of  his 
complete blood count, uric acid levels, and relevant 
interventions.

Table 1: Summary of  the Complete Blood Count, Uric Acid Levels, and Interventions
Date Total Platelets Total WBC Hemoglobin Uric acid Interventions

(150-450 x103/µL) (4-11 x103/µL)
N=neutrophils, 
L=lymphocytes
ANC=absolute 
neutrophil count

(11-16 g/dl) (3.4-7mg/dl) HU=hydroxyurea, 
ASA=aspirin, 
ALP=allopurinol, 
CTX= cotrimoxazole, 
OD= once daily
Abx= antibiotics

22/2/2022 2306 10.4 14.0 -
15/11/2022 2733 11.4 11.7 2.3 HU 1g +ASA 75mg 

OD started
22/11/2022 2472 10.9 12.1 - HU 1g +ASA 75mg 

OD
2/12/2022 2124 9.7 12.0 13.2 HU 1.5g +ASA 75mg 

+ ALP 100mg OD
29/12/2022 942 7.0 12.4 7.9 HU 1.5g +ASA 75mg 

+ ALP 200mg OD
27/1/2023 918 3.6(N=67%, 

ANC=2412/µL, 
L=28%)

12.3 12.9 HU 1.5g +ASA 75mg 
+ ALP 300mg OD

10/3/2023 745 3.1 (N=64%, 
ANC=1984/µL, 
L=28%)

13.0 4.6 HU 1.5g +ASA 75mg 
+ ALP 300mg OD

5/5/2023 675 2.2 (N=63%, 
ANC=1386/µL, 
L=31%)

12.6 3.0 HU 1g +ASA 75mg 
+ ALP 100mg OD 
+ Abx

3/7/2023 977 2.6 (N=59%, 
ANC=1534/µL, 
L=34%)

13.3 4.6 HU 1.5g +ASA 
75mg+ ALP 100mg 
OD

14/8/2023 673 2.8 (N=57%, 
ANC=1596/µL, 
L=38%)

13.4 4.0 HU 1.5g +ASA 
75mg+ ALP 100mg 
OD

11/9/2023 535 2.5 (N=59%, 
ANC=1475/µL, 
L=30%)

13.0 3.5 HU 0.5g +ASA 
75mg+ ALP 100mg 
OD + Abx

9/10/2023 1445 4.0 13.0 8.6 HU 1g +ASA 75mg + 
ALP 200mg OD

8/11/2023 899 3.8 (N=63%, 
ANC=2394/µL, 
L=31%)

12.7 2.5 HU 1.5g +ASA 75mg 
+ ALP 200mg OD

Key: Note the adjustment of  HU dosages whenever the absolute neutrophil count dropped below 1500/µL, and the subsequent precipitous 
increase in platelet counts and uric acid levels

RESULTS AND DISCUSSION
A diagnostic evaluation of  suspected ET includes a 
medical history focused on the occurrence of  thrombotic 
and hemorrhagic manifestations, with a careful search for 
concomitant cardiovascular risk factors in the setting of  

thrombotic complications. The diagnostic criteria of  ET 
by the World Health Organization and the International 
Consensus Classification (Arber et al., 2022) require either 
all four of  the major criteria or the first three major criteria 
plus the minor criterion, as shown in Table 2 below.



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In our patient, it was not possible to do a bone marrow 
aspiration and trephine biopsy (BMAT) or any genetic 
tests for JAK2, CALR, or MPL mutations due to severe 
financial challenges. These services are not readily available 
in the vast majority of  our health centers, and their access 
upon referrals to regional reference laboratory centers is 
severely hindered by their prohibitive costs. 
The main differential diagnosis for ET is reactive 
thrombocytosis (RT). Platelets are also members of  
the acute phase reactant superfamily, which will be 
elevated in many inflammatory and other conditions, 
e.g., infections, iron deficiency anemia, acute bleeding, 
trauma, asplenia, etc.) Patients with RT will have evidence 
of  these conditions as well as elevation of  other acute 
phase reactants (e.g., C-reactive protein, erythrocyte 
sedimentation rate, ferritin, etc.). (Schafer, 2004). Other 
MPNs must also be excluded prior to initiating treatment 
for ET. In our patient, a targeted clinical evaluation 
ruled out alternative diagnoses. He had no features of  
inflammation or trauma; he had a normal ESR; he 
maintained a persistently normal leucocyte count (pre-
treatment) and normal hemoglobin; and his platelets 
were too high to be compatible with just a RT. A validated 
simple laboratory scoring system based on a complete 
blood count that distinguishes ET from RT is consistent 
with our assessment of  ET in this case (Shen et al., 2021). 
At any rate, one would expect massive splenomegaly with 
CML (and severe leukocytosis) and PMF (and severe 
anemia), while PV would have marked polycythemia.
The goals of  treatment in ET are to alleviate vasomotor 
symptoms, reduce the complications related to thrombosis 
and/or hemorrhage, and control splenomegaly (if  
present). Decisions on therapeutic choices are based 
on individual risk stratification and the availability and 
tolerability of  the various agents. Low-dose aspirin (40-
100 mg orally administered once daily) and HU (at 15 
mg/kg/day orally administered at a usual starting dose of  
500mg once or twice daily) are first-line agents (Tefferi & 
Barbui, 2020). Aspirin can reduce vasomotor symptoms 
and thrombo-hemorrhagic complications in most cases 
of  ET. Higher doses are associated with increased risks 

of  gastritis and gastrointestinal bleeding. HU is effective 
in reducing platelet counts, controlling splenomegaly, and 
reducing vasomotor symptoms in ET. The dose of  HU is 
adjusted to a target platelet count of  100,000-450,000/µL 
while limiting leukocytopenia and anemia by doing weekly-
to-monthly complete blood count monitoring (Tefferi & 
Barbui, 2020). The response rates of  HU vary from about 
80% complete response to 15% partial response using 
the International Working Group-Myeloproliferative 
Neoplasms Research and Treatment (IWG-NRT) and 
the European LeukemiaNet (ELN) criteria (Hernández-
Boluda et al., 2011). Adverse effects of  HU include 
oral ulcers, skin rashes, hyperpigmentation, long-term 
lung and liver toxicities, etc. HU is contraindicated in 
pregnancy and lactation. HU-induced neutropenia due to 
myelosuppression may manifest as recurrent infections 
presenting with fever, sore throat, urinary tract infections, 
etc. (Antonioli et al., 2012; Luchtman-Jones et al., 2016). 
These effects are reversible by withholding HU for 1 to 
2 weeks and then re-initiating at a lower dosage (Wang et 
al., 2011). When our patient got recurrent HU-induced 
neutropenia-related infections, the HU was withheld for 
one week in each case and successfully re-started at lower 
dosages tailored to therapeutic targets. 
There are no studies that specifically address the 
modification of  doses of  HU for ET in cases of  severe 
HU-induced neutropenia. However, extrapolation of  
expert consensus recommendations from the use of  
HU in sickle cell anemia in children may give guidance 
on the definition of  HU-related myelosuppression and 
toxicities, as well as dose adjustments to the maximum 
tolerated dosages (MTD) in such cases (McGann et al., 
2016; McGann & Ware, 2015). This is demonstrated in 
Table 3 below.
Based on these recommendations, an absolute neutrophil 
count of  ≥1500/µL was adopted for our patient as the 
target for defining the maximum tolerated dosage of  the 
HU, with the uppermost dosage of  1.5 g/day. So far, the 
recommended target platelet count of  100,000-450, 000/
µL while on HU treatment has not been achieved due to 
the concurrence of  HU-related neutropenia, as highlighted. 

Table 2: WHO diagnostic criteria for Essential Thrombocythemia (Arber et al., 2022)
Major criteria
1. Platelet count ≥450 × 109/L
2. Bone marrow biopsy showing proliferation mainly of  the megakaryocyte lineage with increased numbers of  
enlarged, mature megakaryocytes with hyper-lobulated nuclei. No significant increase or left shift in neutrophil 
granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers
3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid 
neoplasms
4. Presence of  JAK2, CALR, or MPL mutation
Minor criterion
1. Presence of  a clonal marker or absence of  evidence for reactive thrombocytosis
Diagnosis of  ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion.

Key: CML: chronic myeloid leukemia; ET: essential thrombocythemia; PMF: primary myelofibrosis; PV: polycythemia vera; WHO: 
World Health Organization



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Interestingly, the patients’ subjective symptoms have 
almost completely resolved on HU and aspirin.
Therefore, in resource-limited clinical settings, we 

propose a practical and rational approach to the diagnosis 
and treatment of  ET, as summarized in the algorithm 
shown in Table 4 below.

Table 3: Hematological parameters used to define the hydroxyurea maximum tolerated dose (MTD) with mild 
marrow suppression (McGann et al., 2016; McGann & Ware, 2015)
Parameter Toxicity criteria Escalation criteria Target MTD value
Absolute neutrophil count (ANC, x 109/l) < 1.0 > 3.0 1.5–3.0
Absolute reticulocyte count (ARC, x 109/l) < 80 (unless Hb ≥ 9.0) > 200 100–200
Platelets (x 109/l) < 80 > 150 > 80
Hemoglobin (Hb gm/dl) Hb <4.0 or Hb <6.0 

unless ARC >100
>6.5

Table 4: An Algorithm for the Diagnosis and Management of  Essential Thrombocytosis in a Resource-Limited Setting
A. Platelet count: 450-1000 x 103/µL
1. Rule out RT: inflammatory conditions, trauma, iron deficiency anemia, etc., elevated CRP, ESR, procalcitonin, 
and other acute phase reactants.
2. If  no evidence of  RT, go to B.
B. Platelet count: >1000 x 103/µL
1. Clinically: vasomotor symptoms, thrombotic and/or hemorrhagic complications.
2. Peripheral blood film: presence of  marked/severe/extreme thrombocytosis with platelet anisocytosis.
3. Clinically rule out other MPNs using a complete blood count, targeted clinical examination, and peripheral blood film.
4. Bone marrow aspirate and trephine biopsy, where possible: findings meeting the major criteria for ET diagnosis.
5. Make a presumed or definitive diagnosis of  ET and go to C.
C. Diagnosis of  ET
1. Start on low-dose aspirin and hydroxyurea.
2. Therapeutic target platelet counts of  150-450 x 103/µL, and an absolute neutrophil count of  ≥ 1.5 x 103/µL.
3. Individualize therapeutic targets.
4. Monthly follow-ups with complete blood counts (and any other relevant tests).
5. Monitor for therapeutic targets, drug adverse effects, and disease transformations (e.g., into leukemias).

Key: ET=essential thrombocytosis, RT=reactive thrombocytosis, CRP=C-reactive protein, ESR=erythrocyte sedimentation rate, and 
MPNs=myeloproliferative neoplasms.

CONCLUSION
In resource-limited settings, a diagnosis of  ET must 
still be made through a high index of  suspicion and a 
nuanced approach that incorporates compatible clinical 
features, persistent thrombocytosis (especially with 
platelet counts >1000 x 103/µL), and a simple peripheral 
blood smear that shows extreme thrombocytosis with 
platelet anisocytosis. This is followed by a meticulous, 
targeted evaluation to rule out reactive thrombocytosis 
and other MPNs. A BMAT biopsy and genetic testing 
for JAK2, CALR, or MPL mutations are ideally required 
for proving a diagnosis of  ET, but in resource-limited 
settings, obtaining these tests is usually hopelessly 
vetoed by their inaccessibility and prohibitive costs. HU 
and aspirin are widely available in most clinical settings 
and should judiciously be used to treat ET with careful 
monitoring based on individualized treatment targets.

RECOMMENDATIONS
HU-induced neutropenia is a dose-limiting adverse 
effect of  HU therapy that may complicate ET treatment 

and hinder the attainment of  target platelet levels. 
Unfortunately, no robust data currently exists in the 
literature that would give guidance on dose adjustments 
in such cases. More clinical trials and expert consensus 
recommendations are necessary to bridge this gap, 
especially with a focus on resource-limited clinical 
contexts.

Acknowledgement
The authors acknowledge Nurse Pauline Nyagah, 
Laboratory Technicians Paul Njuguna, Peter Kibet, and 
Zebedeo Machuka, as well as Hospital Administrators 
Seth Manera and Steve Nyagah, for their direct 
involvement in the management of  the patient.

REFERENCES
Antonioli, E., Guglielmelli, P., Pieri, L., Finazzi, M., 

Rumi, E., Martinelli, V., Vianelli, N., Luigia Randi, M., 
Bertozzi, I., De Stefano, V., Za, T., Rossi, E., Ruggeri, 
M., Elli, E., Cacciola, R., Cacciola, E., Pogliani, E., 
Rodeghiero, F., Baccarani, M., . . . Vannucchi, A. M. 



Pa
ge

 
6

https://journals.e-palli.com/home/index.php/ajmsi

Am. J. Med. Sci. Innov. 3(1) 1-7, 2024

(2012). Hydroxyurea-related toxicity in 3,411 patients 
with Ph’-negative MPN. Am J Hematol, 87(5), 552-
554. https://doi.org/10.1002/ajh.23160 

Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, 
M. J., Le Beau, M. M., Bloomfield, C. D., Cazzola, 
M., & Vardiman, J. W. (2016). The 2016 revision 
to the World Health Organization classification 
of  myeloid neoplasms and acute leukemia. Blood, 
127(20), 2391-2405. https://doi.org/10.1182/
blood-2016-03-643544 

Arber, D. A., Orazi, A., Hasserjian, R. P., Borowitz, M. J., 
Calvo, K. R., Kvasnicka, H. M., Wang, S. A., Bagg, A., 
Barbui, T., Branford, S., Bueso-Ramos, C. E., Cortes, 
J. E., Dal Cin, P., DiNardo, C. D., Dombret, H., 
Duncavage, E. J., Ebert, B. L., Estey, E. H., Facchetti, 
F., . . . Tefferi, A. (2022). International Consensus 
Classification of  Myeloid Neoplasms and Acute 
Leukemias: integrating morphologic, clinical, and 
genomic data. Blood, 140(11), 1200-1228. https://doi.
org/10.1182/blood.2022015850 

Barbui, T., Vannucchi, A. M., Buxhofer-Ausch, V., 
De Stefano, V., Betti, S., Rambaldi, A., Rumi, E., 
Ruggeri, M., Rodeghiero, F., Randi, M. L., Bertozzi, 
I., Gisslinger, H., Finazzi, G., Carobbio, A., Thiele, 
J., Passamonti, F., Falcone, C., & Tefferi, A. (2015). 
Practice-relevant revision of  IPSET-thrombosis 
based on 1019 patients with WHO-defined essential 
thrombocythemia. Blood Cancer J, 5(11), e369. https://
doi.org/10.1038/bcj.2015.94 

Bellucci, S., Janvier, M., Tobelem, G., Flandrin, G., 
Charpak, Y., Berger, R., & Boiron, M. (1986). 
Essential thrombocythemias. Clinical evolutionary 
and biological data. Cancer, 58(11), 2440-2447. 

Birgegård, G. (2016). The Use of  Anagrelide in 
Myeloproliferative Neoplasms, with Focus on 
Essential Thrombocythemia. Curr Hematol Malig Rep, 
11(5), 348-355. https://doi.org/10.1007/s11899-
016-0335-0 

Cazzola, M., & Kralovics, R. (2014). From Janus kinase 
2 to calreticulin: the clinically relevant genomic 
landscape of  myeloproliferative neoplasms. Blood, 
123(24), 3714-3719. https://doi.org/10.1182/
blood-2014-03-530865 

Finazzi, G., Caruso, V., Marchioli, R., Capnist, G., Chisesi, 
T., Finelli, C., Gugliotta, L., Landolfi, R., Kutti, J., 
Gisslinger, H., Marilus, R., Patrono, C., Pogliani, E. 
M., Randi, M. L., Villegas, A., Tognoni, G., & Barbui, 
T. (2005). Acute leukemia in polycythemia vera: an 
analysis of  1638 patients enrolled in a prospective 
observational study. Blood, 105(7), 2664-2670. https://
doi.org/10.1182/blood-2004-09-3426 

Hernández-Boluda, J. C., Alvarez-Larrán, A., Gómez, M., 
Angona, A., Amat, P., Bellosillo, B., Martínez-Avilés, L., 
Navarro, B., Teruel, A., Martínez-Ruiz, F., & Besses, C. 
(2011). Clinical evaluation of  the European LeukaemiaNet 
criteria for clinicohaematological response and 
resistance/intolerance to hydroxycarbamide in essential 
thrombocythaemia. Br J Haematol, 152(1), 81-88. 

https://doi.org/10.1111/j.1365-2141.2010.08430.x 
Hultcrantz, M., Wilkes, S. R., Kristinsson, S. Y., Andersson, 

T. M., Derolf  Å, R., Eloranta, S., Samuelsson, J., 
Landgren, O., Dickman, P. W., Lambert, P. C., & 
Björkholm, M. (2015). Risk and Cause of  Death 
in Patients Diagnosed With Myeloproliferative 
Neoplasms in Sweden Between 1973 and 2005: A 
Population-Based Study. J Clin Oncol, 33(20), 2288-
2295. https://doi.org/10.1200/jco.2014.57.6652 

Klampfl, T., Gisslinger, H., Harutyunyan, A. S., Nivarthi, 
H., Rumi, E., Milosevic, J. D., Them, N. C., Berg, 
T., Gisslinger, B., Pietra, D., Chen, D., Vladimer, 
G. I., Bagienski, K., Milanesi, C., Casetti, I. C., 
Sant’Antonio, E., Ferretti, V., Elena, C., Schischlik, 
F., . . . Kralovics, R. (2013). Somatic mutations of  
calreticulin in myeloproliferative neoplasms. N Engl 
J Med, 369(25), 2379-2390. https://doi.org/10.1056/
NEJMoa1311347 

Landolfi, R., Cipriani, M. C., & Novarese, L. (2006). 
Thrombosis and bleeding in polycythemia vera and 
essential thrombocythemia: pathogenetic mechanisms 
and prevention. Best Pract Res Clin Haematol, 19(3), 617-
633. https://doi.org/10.1016/j.beha.2005.07.011 

Luchtman-Jones, L., Pressel, S., Hilliard, L., Brown, R. C., 
Smith, M. G., Thompson, A. A., Lee, M. T., Rothman, 
J., Rogers, Z. R., Owen, W., Imran, H., Thornburg, 
C., Kwiatkowski, J. L., Aygun, B., Nelson, S., Roberts, 
C., Gauger, C., Piccone, C., Kalfa, T., . . . Ware, R. E. 
(2016). Effects of  hydroxyurea treatment for patients 
with hemoglobin SC disease. Am J Hematol, 91(2), 
238-242. https://doi.org/10.1002/ajh.24255 

McGann, P. T., Tshilolo, L., Santos, B., Tomlinson, G. 
A., Stuber, S., Latham, T., Aygun, B., Obaro, S. K., 
Olupot-Olupot, P., Williams, T. N., Odame, I., & Ware, 
R. E. (2016). Hydroxyurea Therapy for Children With 
Sickle Cell Anemia in Sub-Saharan Africa: Rationale 
and Design of  the REACH Trial. Pediatr Blood Cancer, 
63(1), 98-104. https://doi.org/10.1002/pbc.25705 

McGann, P. T., & Ware, R. E. (2015). Hydroxyurea 
therapy for sickle cell anemia. Expert Opin Drug Saf, 
14(11), 1749-1758. https://doi.org/10.1517/147403
38.2015.1088827 

Nielsen, C., Birgens, H. S., Nordestgaard, B. G., & 
Bojesen, S. E. (2013). Diagnostic value of  JAK2 
V617F somatic mutation for myeloproliferative cancer 
in 49 488 individuals from the general population. Br 
J Haematol, 160(1), 70-79. https://doi.org/10.1111/
bjh.12099 

Roaldsnes, C., Holst, R., Frederiksen, H., & Ghanima, 
W. (2017). Myeloproliferative neoplasms: trends in 
incidence, prevalence and survival in Norway. Eur 
J Haematol, 98(1), 85-93. https://doi.org/10.1111/
ejh.12788 

Rocca, B., Tosetto, A., Betti, S., Soldati, D., Petrucci, G., 
Rossi, E., Timillero, A., Cavalca, V., Porro, B., Iurlo, 
A., Cattaneo, D., Bucelli, C., Dragani, A., Di Ianni, 
M., Ranalli, P., Palandri, F., Vianelli, N., Beggiato, E., 
Lanzarone, G., . . . De Stefano, V. (2020). A randomized 



Pa
ge

 
7

https://journals.e-palli.com/home/index.php/ajmsi

Am. J. Med. Sci. Innov. 3(1) 1-7, 2024

double-blind trial of  3 aspirin regimens to optimize 
antiplatelet therapy in essential thrombocythemia. 
Blood, 136(2), 171-182. https://doi.org/10.1182/
blood.2019004596 

Schafer, A. I. (2004). Thrombocytosis. N Engl J Med, 350(12), 
1211-1219. https://doi.org/10.1056/NEJMra035363 

Shen, C. L., Hsieh, T. C., Wang, T. F., Huang, W. H., 
Chu, S. C., & Wu, Y. F. (2021). Designing a Scoring 
System for Differential Diagnosis From Reactive 
Thrombocytosis and Essential Thrombocytosis. Front 
Med (Lausanne), 8, 736150. https://doi.org/10.3389/
fmed.2021.736150 

Srour, S. A., Devesa, S. S., Morton, L. M., Check, D. P., 
Curtis, R. E., Linet, M. S., & Dores, G. M. (2016). 
Incidence and patient survival of  myeloproliferative 
neoplasms and myelodysplastic/myeloproliferative 
neoplasms in the United States, 2001-12. Br J Haematol, 
174(3), 382-396. https://doi.org/10.1111/bjh.14061 

Tefferi, A., & Barbui, T. (2017). Polycythemia vera and 
essential thrombocythemia: 2017 update on diagnosis, 
risk-stratification, and management. Am J Hematol, 
92(1), 94-108. https://doi.org/10.1002/ajh.24607 

Tefferi, A., & Barbui, T. (2020). Polycythemia vera and 
essential thrombocythemia: 2021 update on diagnosis, 
risk-stratification and management. Am J Hematol, 
95(12), 1599-1613. https://doi.org/10.1002/
ajh.26008 

Tefferi, A., Lasho, T. L., Finke, C. M., Knudson, R. 
A., Ketterling, R., Hanson, C. H., Maffioli, M., 
Caramazza, D., Passamonti, F., & Pardanani, A. 
(2014). CALR vs JAK2 vs MPL-mutated or triple-
negative myelofibrosis: clinical, cytogenetic and 
molecular comparisons. Leukemia, 28(7), 1472-1477. 
https://doi.org/10.1038/leu.2014.3 

Tefferi, A., & Pardanani, A. (2019). Essential 
Thrombocythemia. N Engl J Med, 381(22), 2135-2144. 
https://doi.org/10.1056/NEJMcp1816082 

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, 
J. F., Minniti, C. P., Rana, S., Thornburg, C. D., Rogers, 
Z. R., Kalpatthi, R. V., Barredo, J. C., Brown, R. C., 
Sarnaik, S. A., Howard, T. H., Wynn, L. W., Kutlar, 
A., Armstrong, F. D., Files, B. A., Goldsmith, J. C., . . 
. Thompson, B. W. (2011). Hydroxycarbamide in very 
young children with sickle-cell anaemia: a multicentre, 
randomised, controlled trial (BABY HUG). Lancet, 
377(9778), 1663-1672. https://doi.org/10.1016/
s0140-6736(11)60355-3 

Wolanskyj, A. P., Lasho, T. L., Schwager, S. M., McClure, 
R. F., Wadleigh, M., Lee, S. J., Gilliland, D. G., 
& Tefferi, A. (2005). JAK2 mutation in essential 
thrombocythaemia: clinical associations and long-term 
prognostic relevance. Br J Haematol, 131(2), 208-213. 
https://doi.org/10.1111/j.1365-2141.2005.05764.x


