Family Medicine Board Review · Hematology · Source: Thrombocytosis Notes 2026
Thrombocytosis: High-Yield Board Summary
Reactive vs. primary causes, the stepwise evaluation algorithm, essential thrombocythemia risk stratification and treatment, and the CML/PV/IMF/ET side-by-side comparison.
Definition
Thrombocytosis = platelet count ≥ 450 × 10⁹/L.
Causes
1. Reactive Thrombocytosis
- Anemia, blood loss, hemolysis
- Infection: viral, bacterial, TB, fungal
- Malignancy
- Rheumatological diseases
- IBD, celiac disease
- Post-splenectomy
2. Primary Thrombocytosis
- Myeloproliferative neoplasm — e.g., essential thrombocythemia, where patients have a gene mutation (e.g., JAK2)
- Often associated with vasomotor symptoms: flushing, erythromelalgia
Board trap: reactive thrombocytosis is by far the more common category in practice — always screen for anemia, infection, inflammation, and malignancy before jumping to a primary/MPN workup.
History & Examination
History
- Recent trauma or surgery
- Prior splenectomy
- Findings suggesting infection or inflammation
- History of bleeding (menorrhagia, GI) or iron deficiency
- History of arterial and/or venous thrombosis
- Medications
- Smoking and alcohol consumption
- Prior diagnosis of a chronic hematologic disorder
- Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy
Examination
- Evidence of cutaneous or mucosal bleeding/bruising
- Lymphadenopathy
- Hepatosplenomegaly
- Findings suggestive of arterial or venous thrombosis
Evaluation of Elevated Platelets
To All Patients
- Repeat CBC — confirm the high platelet count; no specific platelet count can reliably predict reactive vs. primary cause
- Blood smear — large platelets might suggest MPN; younger platelets might indicate a reactive process
- Serum ferritin
Specific/Targeted Tests
- Inflammatory markers (ESR, CRP) — if history suggestive
- Bone marrow biopsy — if suspecting essential thrombocythemia, polycythemia vera, primary myelofibrosis, or chronic myeloid leukemia
Board trap: platelet count magnitude alone cannot distinguish reactive from primary thrombocytosis — very high counts can still be reactive, and moderate counts can still be MPN-driven. Don't anchor on the number; use the smear, history, and targeted testing instead.
Evaluation Algorithm — Persistent Thrombocytosis
Start: Persistent thrombocytosis noted
↓
Worrisome findings on blood smear? Yes → refer to hematology directly
↓ (No)
Findings suggest MPN? (vasomotor symptoms, constitutional symptoms, unusual thromboses, splenomegaly)
↓
If Yes: Test peripheral blood for JAK2, CALR, MPL, BCR-ABL1 (or refer to hematology) → mutation detected → refer to hematology; not detected → if continued suspicion of MPN → refer to hematology; if not → proceed to ferritin pathway
If No: Check ferritin <15 ng/mL? → Yes → replete iron, reassess in 1–2 months (resolved → no further workup; not resolved → refer to hematology). No → assess family history of unexplained thrombocytosis and whether infection/inflammation/splenectomy explains it → if accounted for → no further workup; if not → refer to hematology
Exam pearl: a ferritin <15 ng/mL in the setting of thrombocytosis should prompt iron repletion first, with reassessment in 1–2 months — reactive thrombocytosis from iron deficiency often resolves with treatment of the underlying deficiency, avoiding unnecessary hematology referral.
Risk Stratification for Essential Thrombocythemia (ET)
High-Risk Disease
History of thrombosis, OR age >60 with JAK2 V617F
Low-Risk Disease
Age ≤60, JAK2 V617F present, and no history of thrombosis
Very Low-Risk Disease
Age ≤60, no JAK2 mutation, and no history of thrombosis
Board trap: notice that JAK2 status flips the risk direction depending on age — JAK2(+) at age ≤60 = low-risk, but JAK2(+) plus age >60 = high-risk, while JAK2(−) at age >60 without thrombosis is only intermediate-risk (not high). Build this 2×2 grid mentally: age (≤60 vs. >60) × JAK2 status, plus thrombosis history as the automatic high-risk trump card.
Treatment
1. Reactive Thrombocythemia
- Asymptomatic patient with a known reactive cause who responded to needed treatment → no further evaluation or management required
- Persistent/worsening thrombocytosis, or platelet count not improving with treatment → consider other contributing factors; referral to hematology may be helpful
- Thrombosis: no need for empirical aspirin, as there is no benefit; if thrombosis is present, manage according to the nature of the thrombotic event
Board trap: unlike ET, reactive thrombocytosis does not benefit from empirical aspirin — this is a key distinguishing management point tested against ET's aspirin-centric approach below.
2. Essential Thrombocythemia (ET)
| Risk Group | Treatment |
|---|
| High-risk |
Age ≥40 and not pregnant → aspirin + hydroxyurea
Age <40 or potential for pregnancy → aspirin + interferon-alfa
If prior arterial thrombosis → add aspirin BID
If prior thrombosis (in general) → add anticoagulant
|
| Intermediate-risk | Low-dose aspirin alone, or low-dose aspirin + hydroxyurea |
| Low-risk | Aspirin alone |
| Very low-risk | Either observation or low-dose aspirin |
Exam pearl: in high-risk ET, the choice between hydroxyurea vs. interferon-alfa hinges on age/pregnancy potential (age ≥40 and not pregnant → hydroxyurea; <40 or pregnancy potential → interferon-alfa) — the exact same logic pattern tested in polycythemia vera.
MPN Comparison Table
| CML | PV | IMF | ET |
|---|
| Hct | N/↓ | ↑↑ | ↓/N | N |
| WBC | ↑↑ | ↑ | ↑/↓ | N |
| Plt | ↑/↓ | ↑ | ↑/↓ | ↑↑↑ |
| Marrow Fibrosis | ± | ± | +++ | ± |
| Splenomegaly | +++ | ++ | +++ | + |
| Hepatomegaly | + | ++ | +++ | − |
| Genetic Association | bcr-abl mut. (95+%) | JAK2 mut. (96%) | JAK2 mut. (~50%), CALR mut. (~30%) | JAK2 mut. (~50%), CALR mut. (~30%) |
CML = chronic myeloid leukemia; ET = essential thrombocythemia; IMF = idiopathic myelofibrosis; PV = polycythemia vera; CALR = calreticulin
Board trap: ET has the highest platelet elevation (↑↑↑) but the LEAST marrow fibrosis and hepatosplenomegaly of the four — IMF is the mirror opposite, with the most fibrosis/organomegaly but more variable (not uniformly elevated) counts. Use this table to instantly cross off wrong MPN answers based on which lab/exam finding is most dominant in the vignette.
Genetic pearl: bcr-abl = CML (essentially always positive, ~95%+); JAK2 = PV (96%, nearly universal); JAK2/CALR mutations are shared between IMF and ET (~50% JAK2, ~30% CALR in both) — so genetic testing alone doesn't distinguish IMF from ET; marrow fibrosis and organomegaly do.