819450
review-article2018
AOPXXX10.1177/1060028018819450Annals of PharmacotherapyVo and Thompson
Review Article
A Review and Assessment of
Drug-Induced Thrombocytosis
Annals of Pharmacotherapy
2019, Vol. 53(5) 523­–536
© The Author(s) 2018
Article reuse guidelines:
sagepub.com/journals-permissions
https://doi.org/10.1177/1060028018819450
DOI: 10.1177/1060028018819450
journals.sagepub.com/home/aop
Quyen T. Vo1, and Dennis F. Thompson, PharmD, FASHP, FCCP1
Abstract
Objectives: The purpose of this article is to review the current literature on drug-induced thrombocytosis with the goal
of critically assessing causality and providing a comprehensive review of the topic. Thrombopoietic growth factors, such
as thrombopoietin-receptor agonists (romiplostim and eltrombopag) and erythropoietin are not included in our review.
Data Sources: The literature search included published articles limited to the English language and humans in MEDLINE,
EMBASE, and Web of Science databases. MEDLINE/PubMed (1966 to September 2018) was searched using the MeSH
terms thrombocytosis/chemically-induced and thrombocytosis/etiology. EMBASE (1980 to September 2018) was searched using
the EMTAGS thrombocytosis/side effect. Web of Science (1970 to September 2018) was searched using the search term
thrombocytosis. References of all relevant articles were reviewed for additional citations and information. Study Selection
and Data Extraction: Review articles, clinical trials, background data, case series, and case reports of drug-induced
thrombocytosis were collected, and case reports were assessed for causality using a modified Naranjo nomogram. Data
Synthesis: Drug-induced thrombocytosis, a form of reactive thrombocytosis cannot be easily differentiated from more
common etiologies of reactive thrombocytosis. In all, 43 case reports of drug-induced thrombocytosis from a wide variety
of drugs and drug classes were reviewed using a modified Naranjo probability scale that included criteria specific for
thrombocytosis. Conclusions: Drug-induced thrombocytosis is a relatively rare adverse drug reaction. The strongest
evidence of causality supports low-molecular-weight heparins and neonatal drug withdrawal. Weaker evidence exists for
all-trans retinoic acid, antibiotics, clozapine, epinephrine, gemcitabine, and vinca alkaloids.
Keywords
adverse drug reactions, hematology, thrombocytosis, reactive thrombocytosis
Introduction
Thrombocytosis can be defined as the abnormal accumulation of platelets in the blood. Normal platelet count for
adults is 300 × 109 cells/L ± 150 × 109 (mean ± 2
SDs).1-3 We have adopted ≥450 × 109 cells/L as the
threshold to define thrombocytosis. This is the threshold
for essential thrombocytosis established by the World
Health Oganization4 and is generally consistent with
other studies investigating the incidence and etiology of
thrombocytosis (see Table 15-13). Thrombocytosis can be
categorized into primary (essential) and secondary (reactive). The vast majority of thrombocytosis cases seen in
adults and children are secondary, as can be seen in Table
1. Primary thrombocytosis is generally characterized as
essential thrombocytosis, a myeloproliferative disorder of
the bone marrow, which is extremely rare in children.2-3,9,11
Only 1 study specifically categorized drug-induced causes
of thrombocytosis, recording an incidence of 3% of all secondary thrombocytosis.6 The other studies evaluating the
etiology of thrombocytosis have probably categorized
drug-induced causes as unknown (see Table 1).
Thrombocytosis is an area of increasing interest in the
medical literature. Despite this significant increase in the
literature, the number of English-language review articles
on chemically induced thrombocytosis has been minimal.
Only 7 English-language review articles are available on
the MEDLINE database for all years, with only 1 comprehensive review published in 1993.14
The purpose of this article is to review the current literature on drug-induced thrombocytosis with the goal of critically assessing causality and providing a comprehensive
review of the topic. Thrombopoietin-receptor agonists
(romiplostim and eltrombopag) are not included in our
review. It is important for pharmacists to be able to assess
the medications a patient is on to eliminate drug-induced
thrombocytosis before doing invasive diagnostic procedures
1
Southwestern Oklahoma State University, Weatherford, OK, USA
Corresponding Author:
Dennis F. Thompson, College of Pharmacy, Southwestern Oklahoma
State University, 100 Campus Drive, Weatherford, OK 73096, USA.
Email: dennis.thompson@swosu.edu
524
Annals of Pharmacotherapy 53(5)
Table 1. Incidence and Etiology of Thrombocytosis.
Author (Year)
Number
of
Patients
Definition of
Thrombocytopenia
(×109 cells/L
Type of Patients
Number (%)
of Primary
Thrombocytosis
Number (%)
of Secondary
Thrombocytosis
Drug-Related or
Unknown Etiology
Griesshammer et al5 (1999)
732
500
Adults and children in
Germany
89 (12.3%)
643 (87.7%)
Unknown = 23 (3.1%)
Rose et al6 (2012)
801
500
Adults in the United
States
42 (5.2%)a
784 (97.8%)a
Drug related = 26 (3%)a
2000
500
Adults in Turkey
66 (3.3%)
1934 (96.7%)
Buss et al8 (1994)
280
1000
Adults and children in
the United States
38 (13.5%)
231 (82.5%)
Unknown = 11 (4%)
Chan et al9 (1989)
94
900
Children in Canada
0 (0%)
94 (100%)
Unknown = 4 (6%)
Santhosh-Kumar et al10 (1991)
777
500
Adults in Saudi Arabia
26 (3.4%)
751 (96.6%)
Unknown = 17 (2.2%)
Ozcan et al11 (2013)
484
500
Children in Turkey
0 (0%)
484 (100%)
Unknown = 43 (8.9%)
Robbins and Barnard12 (1983)
372
500
Adults and children
in the United
Kingdom
6 (1.6%)
366 (98.4%)
Unknown = 36/372
(9.7%)
Yohannan et al13 (1994)
663
500
Children in Saudi
Arabia
0 (0%)
663 (100%)
Unknown = 40 (6%)
134 (3%)a
0 (0%)
267 (6%)a
3469 (97%)a
1241 (100%)
5950 (96%)a
Aydogan et al7 (2006)
Total
Total
All totals
3578
1241
6203
Adults
Children
Children and adults
Unknown = 83 (4.2%)
Most Common Causes of
Secondary Thrombocytosis
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
••
Tissue damage
Infection
Malignancy
Chronic inflammatory disease
Infection
Tissue damage
Malignancy
Iron-deficiency anemia
Chronic inflammatory disease
Infection
Iron-deficiency anemia
Chronic inflammatory disease
Malignancy
Infection
Postsplenectomy
Malignancy
Trauma
Infection
Malignancy
Respiratory disease
Tissue damage
Infections
Rebound thrombocytosis
Tissue damage
Chronic inflammatory disease
Malignancy
Infection
Chronic inflammatory disease
Anemia
Tissue damage
Infection
Surgery
Malignancy
Collagen disease
Infection
Rebound thrombocytosis
Tissue damage
Hemolytic anemia
Chronic inflammation
a
Because some patients had multiple etiologies of thrombocytosis, the total number of cases exceeds the number of patients in the Rose et al6 study.
such as a bone marrow biopsy for suspected essential
thrombocytosis.
Methods
The literature search included published articles limited
to the English language and humans in the databases
MEDLINE, EMBASE, and Web of Science. MEDLINE/
PubMed (1966 to September 2018) was searched using
the MeSH terms thrombocytosis/chemically-induced and
thrombocytosis/etiology. EMBASE (1980 to September
2018) was searched using the EMTAGS thrombocytosis/
side effect. Web of Science (1970 to September 2018) was
searched using the search term thrombocytosis. References
of all relevant articles were reviewed for additional citations and information. To assess causality for druginduced thrombocytosis, we utilized the Naranjo
probability scale.15 To improve the application of the data
to the Naranjo probability scale, adaptations were made
by adding thrombocytosis-specific criteria to improve the
grading of case reports for causality, as seen in Table 2.
For the purpose of this review, reports of suspected
thrombocytosis were systematically assessed for causality (Table 316-45). The following criteria will be utilized to
assess causality of a drug by case report: number of cases
described by independent investigators and the Naranjo
score associated with causality. These strategies to determine causality have been adapted from a previous study.46
Case report data will be evaluated along with alternative
causes, probable mechanism, and epidemiological or drug
utilization data to provide an overall assessment of causality for each drug or drug class. These alterations allow
the authors to assess causality by both quantitative and
qualitative data.
Thrombocytosis
Thrombocytosis can generally be divided into 1 of 2 groups:
primary or essential and secondary or reactive. The most
common causes of reactive thrombocytosis are infection,
525
Vo and Thompson
Table 2. Modified Naranjo Scale With Thrombocytosis-Specific Criteria.
Criteria
a
1. ≥5 Previous reports on this reaction
2. Documented platelet count of ≥500 × 109 cells per Liter
3. Temporally related resolution of thrombocytosis after withdrawal of suspected drug
4. Reappearance of thrombocytosis temporally related to drug administration
5. Patient has no infection, cancer, tissue damage, anemia, recent surgery, post-splenectomy,
or chronic inflammatory process
6. Did the reaction reappear when a placebo was given?
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic
8. Was the reaction more severe when the dose was increased, or less severe when the
dose was decreased?
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
10. Was thrombocytosis confirmed by serial platelet counts ≥500 × 109 cells per Liter?
Yes
No
Do Not Know
+1
+2
+1
+2
−1
0
−1
0
−1
+2
0
0
0
0
0
−1
+1
+1
+1
0
0
0
0
0
+1
+1
0
0
Score
0
0
Total Score =
Score Interpretation
Probability
Score
Possible
Probable
Definite
1-4
5-8
>9
a
From at least 3 separate investigators with 1 case of probable or better using the Naranjo scale.
surgery, blood loss, anemia, malignancy, chronic inflammation, asplenia or ruptured spleen, and drug reactions.1-3 The
mechanism underlying the rise in platelet counts in patients
with reactive thrombocytosis is probably mediated through
the release of interleukin (IL)-6 and IL-11. IL-6, in particular, can cause a rise in thrombopoietin and the development
of reactive thrombocytosis.2 Clinical findings cannot readily differentiate reactive and essential thrombocytosis; however, the chances of bleeding and thrombotic complications
in essential thrombocytosis are much greater than in reactive thrombocytosis regardless of the degree of platelet
elevation. Vascular complications are the main clinical
problem with essential thrombocytosis. These include arterial thrombosis (30%-40%), venous thrombosis (5%), and
ischemia caused by microcirculatory disorders.47 Reactive
thrombocytosis is usually a transient process and generally
requires no therapeutic interventions other than treating the
underlying disease.2 Although it is difficult to differentiate
reactive thrombocytosis from essential thrombocytosis
clinically, a bone marrow biopsy will usually reveal abnormal findings in essential thrombocytosis and normal findings in reactive thrombocytosis.2 Recent findings suggest
that the presence of the Janus kinase (JAK2) mutation along
with calreticulin, THPO, and MPL mutations are associated
with the presence of myeloproliferative disorders, seen in
essential thrombocytosis.3,48
Drug-induced thrombocytosis is considered a type of
reactive thrombocytosis but is relatively rare. Rose et al6
are the only investigators who assessed a drug-induced
classification of thrombocytosis and report an incidence of
3% in their study. This was a retrospective review of 801
sequential patients with thrombocytosis at a large Veterans
Affairs hospital over a 9-month period. Drug-induced
thrombocytosis was defined as a rise in platelets (>500 ×
109 cells/L) in patients receiving vinca alkaloids, gemcitabine, iron sulfate, ciprofloxacin, or piperacillin/tazobactam (see Table 1). Thrombopoietin-receptor agonists,
romiplostim and eltrombopag, both increase platelets by a
direct stimulatory effect and have been utilized as therapeutic agents in the treatment of primary immune thrombocytopenia.49,50 Because these agents are considered to
be thrombopoietic growth factors, this group of drugs will
not be considered in our analysis of drug-induced causes
of thrombocytosis. Iron-deficiency anemia is also a known
cause of thrombocytosis.51,52 The mechanism behind the
stimulation of platelets is not known, although Franchini
et al53 describe an elevation of erythropoietin in iron deficiency anemia, which subsequently decreased with iron
therapy. Erythropoietin can cause an increase in platelets
through several pathways.52 By stimulating red blood cell
production, erythropoietin can cause a depletion of iron,
leading to iron deficiency anemia and subsequent thrombocytosis with iron therapy. In addition, erythropoietin has
a structural similarity to thrombopoietin and could directly
stimulate thrombopoietin receptors.54 IL-6 has been implicated as a cause in reactive thrombocytosis. Tefferi et al55
found that elevated IL-6 levels are rare in uncomplicated
essential thrombocytosis but were increased in 60% of
526
50-Year-old male
19-Year-old male
Finsterer and
Kotzailias
(2003)21
Eranti and
Chaturvedi
(1998)22
Efalizumab 0.7 mg/kg sq once
weekly and subsequently 1 mg/
kg as per label for 9 months
Cyclosporin 200 mg twice daily
for approximately 2 months
36-Year-old male
24-Year-old male
Davidovici et al
(2010)25
Wynn et al
(1995)26
Dapsone (dosage not reported)
Cyclosporin 5 mg/kg/d in 2
divided doses
Ciprofloxacin 800 mg/d
combined with tazobactam/
piperacillin 9 g/d during
hospital day 6-16
Clozapine started with 25
mg daily and then gradually
increased to 200 mg daily over
a period of 1 month
Clozapine started with 25 mg/d
and then increased to 300
mg/d the next day. Stopped
for 36 hours and then
restarted at 100 mg twice daily
Ceftazidime IV 2 g every 8 hours
for 14 days
Amoxicillin/Clavulanate 1000
mg/200 mg every 8 hours
Itami et al (1988)24 5-Year-old female
Hampson (2000)23 Middle-aged male
54-Year-old male
54-Year-old male
65-Year-old female
Chen et al
(2008)20
Yang et al (2006)
50-Year-old female
Balaji et al
(2017)18
19
ATRA 45 mg/m²/d orally
49-Year-old
(unknow gender)
Kentos et al
(1997)17
75-Year-old patient
ATRA 50 mg/m² daily
16-Year-old female
Amoxicillin/Clavulanate (dosage
not reported)
Amoxicillin/Clavulanate (dosage
not reported)
Amoxicillin/Clavulanate 1 g
All-trans retinoic acid (ATRA)
50 mg/m² daily
23-Year-old male
Losada et al
(1996)16
Drug and Dosage
Patient Age and Sex
Author (Year)
280
287
3
5
470
704
454
Not
reported
410
536
122
344
288
310
16
Not
reported
Not
reported
5
6
7
8
3
3
3
4
4
4
2
2
2
Modified
Naranjo
Score
920
850
750
978
774
707
1132
942
1420
559
785
785
1071
1200
1500
Initial
Peak
Platelet
Platelet
Count
Count
(×109 cells (×109 cells
/L)
/L)
Table 3. Case Reports of Suspected Drug-Induced Thrombocytosis.
62 Days
14 Days
9 Weeks
10 Days
28 Days
26 Weeks
8 Days (from
hospital day
8 to 16)
13 Days
10 Days
8 Days
8 Days
11 Days
30 Days
38 Days
30 Days
Time to Peak
Platelet Count/
Duration of
Treatment
Other Therapy
63 Days with
treatment of
etanercept
14 Days with
treatment of
adalimumab
21 Days
3 Weeks
5 Days
2 Weeks
19 Days
26 Days
33 Days
Not reported
Not reported
Zidovudine, thalidomide, acyclovir,
fluconazole, prednisolone 30 mg/d
orally ×3 weeks, primaquine/
clindamycin + subsequently with
nebulized pentamidine
Adalimumab
3-Day course of 500-mg oral
azithromycin at the time amoxicillin/
clavulanate started
IV Ampicillin 1 g + sulbactam 0.5 g q6
hours and 3-day course of 500-mg oral
azithromycin before ceftazidime started
Clonidine 5.4 mg/d from day 1-28;
lisinopril 10-20 mg/d from day 1 to
>27; doxazosin 8-16 mg/d from day 1,
ongoing
Trifluoperazine (20 mg/d) for a year and
a half, discontinued, then restarted for
8 weeks, and stopped before starting
clozapine
Haloperidol 25 mg/d, chlorpromazine
500 mg/d, and olanzapine 20 mg/d
for 6 weeks and then stopped before
starting clozapine. Continued to receive
droperidol 20 mg/d and zopiclone 7.5
mg
Full-dose prednisolone for >4 weeks,
then gradually withdrawn before
cyclosporin
Etanercept 50 mg twice weekly after
efalizumab stopped
None
None
18 Days after
Recombinant interferon alfa (3 million
starting
units intramuscularly every other day)
recombinant
interferon alfa
treatment
3 Days after starting Recombinant interferon alfa (3 million
recombinant
units intramuscularly every other day)
interferon alfa
treatment
14 Days
Idarubicin every 2 days for 8 days and
insulin; antibiotic given for postsurgical
prophylaxis
7 Days
Meropenem
Time to Recovery
After Drug
Discontinuation
(continued)
AIDS, Pneumocystis carinii
pneumonia
Severe plaque-type
psoriasis
Steroid-resistant nephrotic
syndrome
Schizophrenia
Paranoid schizophrenia
Moderate alcohol abuse,
hemorrhage cerebral
vascular accident
Pneumonia
Malignant melanoma of the
right 4th toe; metastatic
Adenocarcinoma rectum
with bladder infiltration
Pneumonia
Ovarian carcinoma
Acute promyelocytic
leukemia
Anemia and
thrombocytopenia
Pancytopenia
Disease/Conditions
527
Firmin et al
(2008)27
Hummel et al
(2006)28
47-Year-old female
14-Year-old male
61-Year-old male
Bierman et al
(1952)32
Uwagawa et al
(2013)33
GCSF started at 10 µg/kg and
then increased to 20 µg/kg
after 3 days of treatment
Isotretinoin 10 mg/d (0.17
mg/kg)
Leflunomide 100 mg/d for 3
days, then 20 mg/d for 1
month, then 30 mg/d
45-Year-old female
Full-term
(38-weeks) male
infant
51-Year-old female
50-Year-old male
Dihingia et al
(2012)35
Osovsky et al
(2007)36
Jansen and
Altmeyer
(2000)37
Koenig and
Abruzzo
(2002)38
Granulocyte colony-stimulating
factor with cytokines like
granulocyte colony-stimulating
factor (GCSF) 300 µg daily
for 7 days
68-Year-old female
Docobo et al
(2017)34
58-Year-old male
Enoxaparin (dosage not
reported)
67-Year-old female Enoxaparin (dosage not
reported)
35-Week gestational Enoxaparin 1.5 mg/kg every 12
age female
hours for 10 days
Epinephrine 0.1 mg IV
Epinephrine 0.2 mg IV
Erlotinib/Gemcitabine
combination (DOSAGE not
reported)
Erlotinib/Gemcitabine
combination (dosage not
reported)
Ertapenem (dosage not
reported)
63-Year-old female
Liautard et al
(2002)29
Rizzieri et al
(1996)30
Tonbul et al
(2010)31
42-Year-old male
Drug and Dosage
Efalizumab 1 mg/kg/wk
subcutaneously
Enoxaparin 40 mg/d sq for 16
days and then stopped for 6
days, then readministered for
5 days
Patient Age and Sex
37-Year-old female
Author (Year)
Table 3. (continued)
475
253
3
4
413
120
484
320
6
6
3
5
3
3
5
175
165
630
320
6
2
Not
reported
285
131
245
6
6
6
Modified
Naranjo
Score
1175
693
921
800
610
840
660
580
920
954
1114
621
1005
791
Initial
Peak
Platelet
Platelet
Count
Count
(×109 cells (×109 cells
/L)
/L)
84 Days
2 Weeks
6 Days
7 Days
6 Days
32 Days
120 s
220 s
30 Days
10 Days
4 Weeks
3 Days
15 Days
12 Months
Time to Peak
Platelet Count/
Duration of
Treatment
14 Days
Not reported
1 Year
7 Days
2 Days
27 Days
Not reported
Not reported
77 Days
5 Days
1 Week
Not reported
5 Days
9 Weeks
Time to Recovery
After Drug
Discontinuation
Other Therapy
Disease/Conditions
Pancreatic body
cancer with distal
pancreatectomy
Diverticulosis
Hypertension and
polysubstance abuse,
including alcohol and
narcotics; sustained a
head injury and multiple
facial fractures
Thrombophlebitis,
orthopedic surgery
Adrenal cortical carcinoma
and liver cancer
Macroscopic hematuria,
palpable abdominal mass,
and nonfunctional and
atrophic left kidney
Cylindroma
Osteogenic carcinoma
Pancreatic tail cancer with
distal pancreatectomy
Psoriasis
Prednisone, hydroxychloroquine,
azathioprine, and methotrexate before
leflunomide started; levofloxacin 500
mg daily for 6 days, prednisone taper,
and ocular steroids during leflunomide
treatment; prednisone, methotrexate,
etanercept, cholestyramine, and
risedronate sodium after leflunomide
stopped
(continued)
Relapsing polychondritis
Doxycycline 100 mg/d before isotretinoin Papulopustular rosacea
started
IV ciprofloxacin 400 mg bid and
metronidazole 500 mg tid before IV
ertapenem started
Olanzapine 20 mg/d for 5 weeks and
Schizophrenia
standard dose of risperidone and
undifferentiated type
long-acting haloperidol, clozapine
started with 25 mg daily with increment
of 25 mg every 3 to 5 days. A target
clozapine dose of 400 mg was achieved
after 1 month and continued for 2
weeks; broad-spectrum antibiotics and
antifungal after clozapine stopped and
before GCSF started
None
Leukopenia and
neutropenia
Warfarin, aspirin, and heparin after
erlotinib/gemcitabine stopped
Not reported
Not reported
Aspirin after erlotinib/gemcitabine
stopped
Ranitidine, metoclopramide,
dexamethasone, vitamins, and warfarin
Dalteparin 100 U/kg every 12 hours after
enoxaparin stopped
Not reported
Subcutaneous unfractionated heparin
5000 U every 8 hours after enoxaparin
stopped; 40 000 U of erythropoietin
subcutaneously given with enoxaparin
Fluoxetine for several years
528
39
40-Year-old male
Patient Age and Sex
18-Year-old female
72 Years old
(unknown gender)
53 Years old
(unknown gender)
15 Years old
(unknown gender)
53 Years old
(unknown gender)
37 Years old
(unknown gender)
51-Year-old male
42 Years old
(unknow gender)
4
4
4
5
Miconazole 74 g total
Miconazole 48 g total
Miconazole 30 g total
Ruxolitinib 10-25 mg bid
Vincristine 0.6 mg/m2 IV on day
1 plus 6-MP 300 mg/m2 po
days 2 and 3 every 3 months
Vincristine 0.6 mg/m2 IV on day
1 plus 6-MP 300 mg/m2 po
days 2 and 3 every 3 months
Vincristine 0.6 mg/m2 IV on day
1 plus 6-MP 300 mg/m2 po
days 2 and 3 every 3 months
Vincristine 0.6 mg/m2 IV on day
1 plus 6-MP 300 mg/m2 po
days 2 and 3 every 3 months
130
270
420
350
2
2
2
713
103
610
250
300
180
195
260
607
Not
reported
382
1000
1000
1160
2600
1066
1250
990
710
776
720
515
800
913
808
571
Initial
Peak
Platelet
Platelet
Count
Count
(×109 cells (×109 cells
/L)
/L)
2
3
4
Miconazole 54.6 g total
Ticarcillin/Clavulanic acid 3.1 g
IV every 6 hours for 11 days
4
6
3
3
6
Modified
Naranjo
Score
Miconazole 21.4 g total
Methylphenidate started with 10
mg and gradually increased to
40 mg/d over several months
for 9 months then reduced to
30 mg/d
Miconazole 63.6 g total
Methimazole 20 mg/d for 50
days
Methotrexate 10 mg/wk
Drug and Dosage
Abbreviations: IV, intravenous; 6-MP, 6-mercaptopurine.
70-Year-old female
26-Year-old female
46-Year-old male
Feliu et al (1980)45 49-Year-old male
Moody and
Pawlicki
(1987)44
Polverelli et al
(2015)43
Marmion et al
(1976)42
Kaydok and Salbas 56-Year-old female
(2018)40
7-Year-old male
Sood et al
(1994)41
Oh et al (2007)
Author (Year)
Table 3. (continued)
Not reported
2 Months
Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
2 Years
2 Weeks
8 Days
Time to Recovery
After Drug
Discontinuation
After the third
course
Not reported
1 Month after the Not reported
first course
1 Month after the Not reported
first course
1 Month after the Not reported
first course
9 Days
5 Months
5-23 Days
5-23 Days
5-23 Days
5-23 Days
5-23 Days
5-23 Days
9 Months
8 Weeks
50 Days
Time to Peak
Platelet Count/
Duration of
Treatment
Quiescent chronic
granulocytic leukemia
Pneumonia
Polycythemia vera and
splenomegaly
Coccidioidal meningitis
Coccidioidal meningitis
Coccidioidal meningitis
Pulmonary
coccidioidomycosis
Coccidioidal meningitis
Coccidioidal meningitis
Narcolepsy, tonsillitis,
adenoiditis
Rheumatoid arthritis
Graves’ disease
Disease/Conditions
Busulfan for 2 months and stopped before Quiescent chronic
vincristine/6-MP started
granulocytic leukemia
Busulfan for 2 months and stopped before Quiescent chronic
vincristine/6-MP started
granulocytic leukemia
Busulfan for 2 months and stopped before Quiescent chronic
vincristine/6-MP started
granulocytic leukemia
Allopurinol on day 10 of therapy;
Systemic Amphotericin B before
miconazole administration
Systemic, amphotericin B before
miconazole administration
Systemic, amphotericin B before
miconazole administration
Systemic, amphotericin B before
miconazole administration
Systemic, amphotericin B before
miconazole administration
Systemic, amphotericin B before
miconazole administration
Phlebotomies and low-dose acetylsalicylic
acid 100 mg/d were given and
stopped before ruxolitinib started;
hydroxyurea 3 mg/kg/d was given to
treat thrombocytosis after ruxolitinib
stopped; fedratinid 300 mg/d for 6
months after ruxolitinib stopped
Penicillin G 2 million units IV every 4
hours, metronidazole 500 mg 3 times
daily, and cefotaxime 2 g IV every 6
hours were stopped before ticarcillin/
clavulanic acid started
Busulfan for 2 months and stopped before
vincristine/6-MP started
Not reported
Broad-spectrum antibiotics, GCSF, and
methylprednisolone
Prednisolone 10 mg/d
Other Therapy
529
Vo and Thompson
patients with reactive thrombocytosis. The authors suggested that measuring C-reactive protein, as a surrogate
measure of IL-6, might be a method to help discriminate
between essential and reactive thrombocytosis. IL-6
receptor antagonists (tocilizumab and sarilumab) have
recently been approved for the treatment of rheumatoid
arthritis.56,57 Although it may seem tempting to utilize
these agents to treat reactive thrombocytosis, it would not
be rational to treat a laboratory value that carries little
prognostic significance.
Case Reports and Case Series
A total of 43 case reports and 8 case series of drug-induced
thrombocytosis were identified in our literature search
(Tables 3 and 429,58-64). In the 43 case reports, 19 were male
patients (44%), 16 were female patients (37%), and 8 were
not gender classified (19%), with an average age of 43 years
ranging from 38 weeks to 75 years old. Time to peak platelet
count was an average of 43 days (median = 13 days; mean
= 43 ± 78 days; range = 2-365 days). Time to recovery
after drug discontinuation was 60.8 days (median = 14 days;
mean = 60.8 ± 151 days; range = 2-730 days). There are
several outliers in the time data, which are not normally distributed. Median central tendency measures in this case are
perhaps more realistic. Median Naranjo scores averaged 4
(range = 2-8). In addition to the drugs and drug classes mentioned below, at least 1 case report was located on the following drugs: cyclosporin, efalizumab, granulocyte colony
stimulating factor, isotretinoin, leflunomide, methylphenidate, methotrexate, miconazole, and tyrosine kinase inhibitors (erlotinib and ruxolitinib), which are not discussed
further in the current review.
All-Trans Retinoic Acid (ATRA)
ATRA-combined chemotherapy is the first-line therapy of
newly diagnosed acute promyelocytic leukemia. Initially,
ATRA, as a single agent, can produce cure rates in up to
80% of cases without inducing myelosuppression. ATRA
chemotherapy as induction and consolidation therapy has
resulted in long-term survival rates greater than 90%.65
Three cases of ATRA-induced thrombocytosis have been
reported from 2 investigators.16,17 The platelet counts from
these patients progressively increased and reached the
maximal values of greater than 1000 × 109/L after about a
month (range = 30-38 days) of starting the ATRA regimen. The average recovery time of platelet counts was 12
days (range = 3-18 days). In 2 cases,16 the elevated platelet count normalized after intramuscular administration of
recombinant interferon alfa without discontinuing the
ATRA regimen. One patient was rechallenged with ATRA
without resultant thrombocytosis.17 In these cases, ATRA
doses were not modified, no complications secondary to
thrombocytosis were observed, and the patients subsequently achieved complete remission. Several investigators have investigated the underlying mechanism in
ATRA-induced thrombocytosis. It appears that ATRA can
directly stimulate megakaryocytopoiesis through enhancing thrombopoietin production.66,68 This effect seems to be
a direct effect of ATRA on the bone marrow stromal cells.
Although patients with acute promyelocytic leukemia
receiving ATRA also demonstrate increases in IL-1β,
IL-6, IL-8, and tumor necrosis factor α,69 some of which
can contribute to thrombocytosis, the primary mechanism
for the platelet increase is probably an increase in
thrombopoietin.
Evidence for thrombocytosis with ATRA is weak. The 3
case reports of ATRA-associated thrombocytosis are insufficient quantitative evidence coupled with low Naranjo
scores, and a failed rechallenge provides scant qualitative
data. Although the mechanism for thrombocytosis related to
ATRA is convincing, little clinical evidence is available at
the present time of true causality.
Antibiotics
A significant number of antibiotics have been implicated in
the development of thrombocytosis.18-21,26,34,39,44 We have
identified 10 cases of thrombocytosis attributed to antibiotics, from 8 different investigators with at least 1 case >5 on
the Naranjo assessment score. This is good evidence that, as
a class, antibiotics would be considered causative in the
development of thrombocytosis. However, as has been
pointed out previously, a variety of inflammatory conditions,
including acute infectious disease, can cause reactive thrombocytosis.2,3 Parry et al70 have investigated this phenomenon
in a retrospective study of 350 patients receiving a variety of
antibiotics (penicillins, cephalosporins, aminoglycosides,
clindamycin, erythromycin, trimethoprim-sulfamethoxazole,
and tetracycline). A total of 50 patients were used as a control
group with noninfectious conditions (36 with acute myocardial infarction and 14 with surgical procedures). The study
groups did not differ in respect to blood transfusions, bleeding, or splenectomy. The authors found no statistical difference in the incidence of thrombocytosis between these
groups; however, the study was underpowered to detect small
differences because of sample size limits.
Despite the fact that antibiotic agents have strong case
report evidence for causality, they must be considered
unproven, at present, because of the possibility of an acutephase reaction being the cause of the platelet rise in patients
with infectious disease.
Clozapine
Clozapine is an effective antipsychotic drug that may be beneficial for selected patients who are refractory to other
530
Annals of Pharmacotherapy 53(5)
Table 4. Case Series of Suspected Drug-Induced Thrombocytosis.
Number
of
Author and
Patients Drug and Dosage
Year
Liautard
et al
(2002)29
51
Ziaja et al
(1999)58
290
Cestac et al
(2003)59
13
Rossi et al
(2001)60
22
ŚwiebodaSadlej
et al
(2012)61
6
Initial Platelet
Count (×109
cells/L)
Peak Platelet
Count (×109
cells/L)
Disease/
Conditions
Not reported
Not reported
11-15 Days
Not reported
postoperative
Not reported
965
Not reported
Not reported
All patients
underwent
surgery.
Patients had
underlying
cancer with
blood loss and
transfusions
Not reported
401-596 In
10 patients;
606-781 in
9 patients;
more than
800 in 3
patients
After the first Not reported
cycle in 16 of
22 patients,
just 1 week
before day 1
of the second
cycle or a few
days after
Not reported
The 8th day
of the third
cycle
Mean 547
(range 2231059)
Ahmed et al
(2012)62
220
Gemcitabine
(dose not
specified)
Not reported
Median baseline Median count
= 632 (range
= 300 (range
457-1385)
44-449)
Canova
et al
(2017)63
Pazdur et al
(1982)64
318
Gemcitabine
(dose not
specified)
Vindesine 3 mg/
m2 IV weekly
Median baseline Six patients had Approximately
63 days
peak levels
= 250 (range
>600
111-430)
161-450
610 (Range
4 Weeks
150-610)
15
Other Therapy
Mean time of 13
Mean time of
days (2-48 days)
15 days (4-35
was noted in 27
days)
reports
Mean peak of
Reported as
Enoxaparin in
758 (range
“normal”
23 patients,
516-1173)
before or
nadroparin in
shortly after
17 patients,
LMWH
dalteparin in 7
administration
patients and,
in 24 patients
reviparin in 4
patients (dosage
not reported)
Enoxaparin
Not reported
“Some
reported >
600”
Not reported
LMWHs
(enoxaparin
61% of total)
Gemcitabine 1000 Not reported
mg/m2 on day
1 and 8; 120
cycles were
delivered with
median of 3 per
patient in all
cases
Gemcitabine 1000 “Normal”
mg/m2 on the
1st, 8th, and
15th day of a
28-day cycle
Time to Peak
Platelet Count/ Time to Recovery
After Drug
Duration of
Discontinuation
Treatment
Not reported
Cisplatin 80 mg/ Locally
m2 on day 2
advanced and
metastatic
every 28-days;
non–small-cell
120 cycles
lung cancer
were delivered
with a median
of 3 per patient
in all cases
Pancreatic
1 Patient
cancer
received
combined
treatment with
erlotinib 100
mg/d
“Malignant
Median duration of Carboplatin or
cisplatin
disease”
thrombocytosis
= 14 days (range
3-63 days)
Not reported
Carboplatin or
Non–small-cell
cisplatin
lung cancer
Not reported
Not reported
Colon cancer
Abbreviations: IV, intravenous; LMWH, low-molecular-weight heparin.
antipsychotic drugs. However, its use is limited because of
serious adverse effects such as agranulocytosis. Two cases22,23
of thrombocytosis that developed during clozapine treatment
have been reported. In the case report by Eranti and
Chaturvedi,22 significant variation in platelet counts occurred
on different doses of clozapine. On a dose of 150 to 200 mg/d,
the patient developed thrombocytosis. However, there were
no fluctuations in platelet count observed at a dose of 37.5
mg/d. Hampson23 describes a patient experiencing thrombocytosis, pyrexia, malaise, nausea, arthralgia, and hypotension,
both when he was first prescribed clozapine 275 mg/d and
when he was initially rechallenged with clozapine 300 mg/d.
Lee et al71 published a retrospective review study about
the effect of clozapine on hematological indices. Of 101
patients initiated on clozapine, 3 incidences of thrombocytosis occurred within a mean time of 12 weeks (range =
4-32 weeks), and all these patients were reported to have
recovered within a week. These investigators found evidence of increased levels of proinflammatory and antiinflammatory cytokines, including IL-6, which might play a
role in the development of reactive thrombocytosis.
531
Vo and Thompson
Thrombocytosis, secondary to clozapine, resolved
within 10 days on average either by termination of the drug
or reducing the dose. Both case reports received definite
causality assessment scores of 9. These 2cases, combined
with the 3 cases from the retrospective review, provide
modest evidence that clozapine can be considered causative
in thrombocytosis.
Epinephrine
Leukocytosis and thrombocytosis have been reported after
the intravenous administration of epinephrine. Bierman
et al32 described 12 patients with neoplastic diseases given
intravenous epinephrine 0.1 to 0.3 mg administered at a uniform rate over a 30- to 60-s period. Leukocytes and platelet
counts were drawn simultaneously from venous and arterial
blood and determined within 30 to 120 s after initial administration of epinephrine. In 4 patients, the platelet counts
increased by more than 100% in the arterial blood and
decreased by more than 50% in venous blood. However,
only 2 of them had platelet counts that increased more than
450 × 109/L after epinephrine administration (range = 580
× 109/L to 660 × 109/L). The increase in platelets and leukocytes continued for at least 5 minutes before it declined.
The proposed mechanism is the demargination of platelets
present in the pulmonary vasculature being released into the
circulation by epinephrine.32 The pulmonary vasculature is
a rich source of platelets and leukocytes, which are released
in response to stimulation.
Epinephrine can cause a transient increase in circulating
platelets because of the demargination of platelets from the
pulmonary vasculature; it is likely that other catecholamines
possess this same effect. However, the thrombocytosis is
transient, and only a small number of patients have high
enough platelet counts to meet the threshold of >450 ×
109.
Gemcitabine
Gemcitabine is a nucleoside analogue of deoxycytidine commonly used for treatment of pancreatic cancer and non–
small-cell-lung cancer. Gemcitabine has been reported as
being associated with an increased incidence of thrombocytosis. Two case reports of thrombocytosis during gemcitabine
treatment have been reported by Uwagawa et al,33 and 2 case
series,60,61 with a total of 30 patients who experienced thrombocytosis during gemcitabine therapy, have been described.
Rossi et al60 described a case series of 37 patients with non–
small-cell lung cancer or pancreatic cancer treated with gemcitabine 1000 mg/m2 on days 1 and 8 combined with cisplatin
80 mg/m2 on day 2 of a 28-day cycle. Of these patients, 22
(59.4%) developed thrombocytosis, with 10 having platelet
counts ranging from 401 × 109/L to 596 × 109/L, 9 having
platelet counts ranging from 606 × 109/L to 781 × 109/L,
and 3 having platelet counts >800 × 109/L during treatment
with gemcitabine. Świeboda-Sadlej et al61 reported a series of
6 patients (2 men and 4 women from 60 to 78 years of age)
receiving gemcitabine 1000 mg/m2 on the 1st, 8th, and 15th
day of a 28-day cycle; one of them received a combination
treatment with erlotinib 100 mg/d for pancreatic cancer.
Before the treatment, these patients’ platelet counts were
reported as normal. After administration of gemcitabine, the
number of platelets increased gradually and reached their
peak on the first and eighth day of the second and third cycles.
The highest mean platelet count of 547 × 109/L (range = 223
× 109/L to 1059 × 109/L) was recorded on the eighth day of
the third cycle. Platelet counts normalized on the 15th day of
each cycle. The chemotherapy combination alone often
suppresses platelet production causing thrombocytopenia.
In this case series, the investigators suggested that thrombocytosis occurred as a rebound production of platelets
after the period of thrombocyte nadir.61 Two additional
studies determined the incidence of thrombocytosis associated with gemcitabine. Thrombocytosis rates of 46%
(142/220)62 and 49% (156/318)63 were found in 2 retrospective reviews of gemcitabine therapy of patients with
malignancy also receiving carboplatin or cisplatin. Little
additional details are given in these studies on gemcitabineinduced thrombocytosis, because the primary objective of
these reviews was not to determine the epidemiology of
drug-induced thrombocytosis.
Two case reports with Naranjo scores of 5 and 2 and 2
case series involving 28 patients suggest a possible association of gemcitabine with thrombocytosis. Thrombocytosis
with gemcitabine appears to be high, with retrospective
studies reporting an incidence between 46% and 49%.
However, no mechanism has been described to account for
the platelet rise. Because thrombocytosis could simply be a
rebound effect from the chemotherapy-induced nadir in
platelets and subsequent excessive stimulation or through a
paraneoplastic reaction, we must conclude that gemcitabine
is unproven as a causative agent for thrombocytosis. Finally,
3 of the 30 total patients were treated with erlotinib, and 22
of them were treated with cisplatin in combination with
gemcitabine. It is possible that erlotinib and cisplatin in
combination with gemcitabine could play a role in the
development of thrombocytosis. Additional studies are
needed to clarify the role of gemcitabine in patients developing thrombocytosis.
Low-Molecular-Weight Heparins
Low-molecular-weight heparins (LMWHs) have an established role in preventing and treating venous thromboembolism. Among the LMWHs, enoxaparin is the most widely
used agent.72-75 Four cases28-31 and 2 case series29,58 describing thrombocytosis after LMWH administration have been
reported. On average, thrombocytosis developed 14 days
532
Annals of Pharmacotherapy 53(5)
(range = 3-35 days) after LMWH administration and persisted for 7 days (range = 2-48 days). Two patients in the
case reports by Hummel et al28 and Liautard et al29 were
rechallenged with enoxaparin, resulting in thrombocytosis.
Individual cases received Naranjo scores of 7, 6, 2, and 6,
respectively.28-31
Liautard et al,29 using the French Pharmacovigilance
System, reported a case series of 51 patients who developed
thrombocytosis associated with LMWH. The patient population included 26 women and 25 men, with the mean age of
50 years ranging from 14 to 103 years. Among these
patients, 23 were treated with enoxaparin, 17 with nadroparin, 7 with dalteparin, and 4 with reviparin. Peak platelet
count was 758 × 109/L on average, ranging from 516 ×
109/L to 1173 × 109/L, within the mean time of 15 days.
Cestac et al59 prospectively reviewed the use and safety
of LMWH in 2 French teaching hospitals. A total of 334
patients were prospectively followed. Enoxaparin was used
in 61% of the patients; 13 patients (3.9%) developed thrombocytosis (platelet count not defined). None of the patients
had any clinical effect from the thrombocytosis. Few details
were reported because thrombocytosis was not a major outcome parameter in the study. In a prospective multicenter
study by Ziaja et al,58 involving 290 patients who received
20 or 40 mg of enoxaparin once daily subcutaneously postoperatively to prevent thromboembolism, the investigators
report a “slight, but statistically significant increase in
platelet count postoperatively.”(p.65) Unfortunately, because
this was an incidental finding in the study, no specific data
are presented in the article to clarify these results.
Although the mechanism of LMWH-induced thrombocytosis is unclear, 4 individual case reports yielding 3 probable causality assessments with 2 rechallenges and 3 case
series where thrombocytosis developed after LMWH
administration suggest a strong association of LMWH therapy with the development of thrombocytosis.
factor for the development of thrombocytosis.1,2 Without
rechallenging patients with the suspected drug and reassessment of platelet counts after chemotherapy was completed,
these 4 cases received a low Naranjo score of 2.45 In a study
conducted by Pazdur et al,64 12 of 14 patients who were
treated with vindesine 3 mg/m2 IV weekly for colon cancer,
had peak platelet counts ranging from 150 × 109/L to 610
× 109/L during the fourth week of treatment. The investigators observed a progressive linear increase of the mean
platelet counts with weekly injections. Carbone et al76 studied 40 patients with untreatable malignancies in an early
study of vincristine. Of the 40 patients, 13 developed thrombocytosis in a dose-dependent manner. Platelet levels were
>600 × 109/L in 6 patients and ranged from 400 × 109/L to
1000 × 109/L. The mechanism behind this observed
increase in platelets was not discussed in this very preliminary study.
Other investigators have explored the mechanism of
vinca-induced thrombocytosis in animal models. In an
attempt to discover the possible mechanism of vinblastineinduced thrombocytosis in rats, Klener et al67 concluded
that vinblastine might increase megakaryocyte production,
resulting in peripheral thrombocytosis. Another hypothesis
was provided by Harris and Penington77 using low-dose
vincristine (0.1 mg/kg) on megakaryocyte colony-forming
cells and megakaryocyte ploidy in mice. This study found
that even low-dose vincristine produced a small, but significant, increase in platelets in mice. These authors postulated
that the significant toxic effects of vincristine on splenic
megakaryocytes activate a homeostatic feedback mechanism that releases thrombopoietin or other humoral factors
into the circulation, resulting in thrombocytosis.
There would appear to be convincing evidence that vinca
alkaloids can increase the production of platelets. However,
modest clinical data exist that this is a common finding in
patients being treated with vinca alkaloids.
Vinca Alkaloids
Neonatal Thrombocytosis
Vinca alkaloids are a commonly used class of cancer drugs.
There are 4 major vinca alkaloids in clinical use: vinblastine, vinorelbine, vincristine, and vindesine. Feliu et al45
reported 4 cases of marked thrombocytosis development
after treatment with vincristine and 6-mercaptopurine in
patients with chronic myeloid leukemia.4 In these cases, the
patients had normal platelet counts before starting the regimen. During a 3-month treatment course, the platelet counts
progressively increased and reached the maximum value of
greater than 1000 × 109/L, ranging from 1000 × 109/L to
2600 × 109/L. Interestingly, every one of these 4 patients
had smaller spleen sizes than normal; the investigators also
suspected that the smaller spleen size may account for
thrombocytosis in these patients because asplenia is a risk
Essential thrombocytosis is extremely rare in neonates78;
most cases of thrombocytosis are usually secondary or reactive.9,79,80 Maternal narcotic and nonnarcotic psychotropic
drug use have been reported as a cause of secondary thrombocytosis in infants.81,82 Nako et al83 reported a case of a
15-day-old female newborn whose mother was HIV positive and had been receiving methadone during pregnancy.
At 7 days of age, she presented with signs and symptoms of
methadone abstinence and was treated with chlorpromazine
for 15 days. Drug analysis of her urine was found to be
positive for methadone. She was HIV negative and had no
bacterial infection, and her platelet count was normal at the
time of hospital admission. However, platelets increased to
1049 × 109/L at 17 days of age and 1167 × 109/L at 23 days
533
Vo and Thompson
of age. The platelet count reduced progressively to 290 ×
109/L at 8 weeks and remained normal.
Chambers and Haslam82 reported 2 cases of neonatal
thrombocytosis associated with maternal narcotic abuse. A
male infant, of gestational age 31 weeks, developed a platelet count of 838 × 109/L in the third week of life and 919 ×
109/L by the sixth week. Other than the mother’s substance
abuse, she had no previous medical history. The baby had a
normal physical exam at birth; however, ultrasound examination showed persistent periventricular flare on the fourth
day of life and cystic degeneration at 6 months of age. The
child also developed spastic quadriplegia and was developmentally delayed. In the second case, a male infant, of gestational age 32 weeks, whose mother who was on methadone
maintenance program for heroin addiction, had a platelet
count that rose from 721 × 109/L at the end of the second
week to a peak of 969 × 109/L in the fourth week and at the
time of discharge. At 8 weeks of life, his platelet count was
still 818 × 109/L.
Nako et al83 reported a case of a male infant, of gestational age 35 weeks, whose mother was treated with nonnarcotic psychotropic drugs (haloperidol, biperiden,
promethazine, nitrazepam, and chlorpromazine) during
pregnancy. The infant’s platelet count at birth was 402 ×
109/L with possible neonatal drug withdrawal syndrome.
The platelet counts initially fell to 117 × 109/L on day 6
and then increased from 832 × 109/L on day 8 to a maximum of 1310 × 109/L on day 15. Dipyridamole 2 mg/kg/d
was used to prevent thrombotic complications and then
stopped on day 91 when the platelet count decreased to
820 × 109/L. No complications from thrombocytosis
occurred. After 3 months of age, the patient’s platelet
counts were normalized.
Burstein et al84 published a case series of 33 newborns
whose mothers were either on methadone maintenance or
abusing methadone during pregnancy.85 In all but 2 of these
mothers, other drugs of abuse were also used, such as diazepam, cocaine, heroin, morphine, amphetamine, and phenobarbital. All these infants had increased platelet counts
(average 550 ± 64 × 109/L) starting in the second week of
life, which persisted for more than 16 weeks. Of these 33
infants, 13 had thrombocytosis that persisted for more than
30 weeks of life. One of these infants had a platelet count
greater than 1000 × 109/L at 18 weeks of life. None of the
infants had a platelet count greater than 600 × 109/L after
40 weeks of life.
In these case reports and case series, thrombocytosis
developed at 2 to 3 weeks of life and persisted for about
16 weeks in the infants whose mothers had a history of
substance abuse. García-Algar et al48 and Burstein et al84
specifically pointed to methadone as the drug that was
responsible for neonatal thrombocytosis. However, only
the case reported by García-Algar et al provided the
infant’s blood sample, which was positive for methadone.
In the case series by Burstein et al, all the infants developed thrombocytosis by the second week of life. The
mothers of these infants were all taking methadone, but
also abused other drugs such as diazepam, cocaine, heroin,
morphine, amphetamine, and phenobarbital. It is likely
that any drug withdrawal syndrome experienced by the
neonate could cause a reactive thrombocytosis. Additional
studies are needed to fully elucidate the cause of this transient thrombocytosis seen in neonates.
Conclusion
Drug-induced thrombocytosis is an uncommon cause of
reactive thrombocytosis. Part of the differential diagnosis
of thrombocytosis is distinguishing reactive from essential
thrombocytosis. Pharmacists can play an important clinical role in determining the possibility of drug-induced
thrombocytosis and thereby avoiding a potential bone
marrow procedure in the diagnosis. LMWHs and neonatal
drug withdrawal have good evidence of a causal effect.
Epinephrine causes a modest, transient increase in platelets but is insufficient, in most cases, to meet the threshold
of thrombocytosis. Antibiotics have sufficient case report
evidence but are clouded by the overlapping acute-phase
reaction caused by infection. Likewise, gemcitabine has
clinical evidence but lacks a clear mechanism, and the rise
in platelets could be a rebound effect from chemotherapyinduced bone marrow suppression. Vinca alkaloids have
good mechanistic evidence but little clinical evidence.
All-trans retinoic acid, clozapine, and a host of other miscellaneous agents remain unproven as a cause of druginduced thrombocytosis.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
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