Family Medicine Board Review · Case-Based · Difficult Level

Thrombocytosis — Clinical Vignette MCQs

Board-style cases built from the thrombocytosis summary — reactive vs. primary recognition, the evaluation algorithm, ET risk stratification logic, treatment thresholds, and the MPN comparison table. Tap "Reveal Answer" on each, then read the pearl.

10 Questions ●●●● Difficult Single Best Answer

Q1Platelet Count ≠ Etiology●●●● Very Hard

A 68-year-old man recovering from pneumonia has a platelet count of 720 × 10⁹/L. A colleague states this markedly elevated count strongly suggests a primary myeloproliferative process rather than a reactive one, since "reactive thrombocytosis doesn't get that high." Is this reasoning valid?

A. Yes — platelet counts above 700 are diagnostic of essential thrombocythemia
B. No — no specific platelet count can reliably predict reactive versus primary cause; his recent infection is a plausible reactive explanation regardless of the count's magnitude
C. Yes — reactive thrombocytosis is capped at 450
D. No, but only because his age makes ET impossible
E. Yes — bone marrow biopsy is unnecessary once a count exceeds 700 regardless of clinical context

Reveal Answer

Correct answer: B

There is no specific platelet count threshold that reliably distinguishes reactive from primary thrombocytosis. A recent infection (pneumonia) is a well-recognized reactive cause, and even quite high platelet counts can be reactive. The magnitude of elevation alone should not be used to presume an MPN.

Why the others are wrong A/C — no such diagnostic or capping threshold exists; both reactive and primary thrombocytosis can span a wide range of platelet counts. D — age alone doesn't make ET impossible; his age would actually be relevant to ET risk stratification if ET were eventually diagnosed, not to excluding it outright. E — bone marrow biopsy decisions are driven by clinical suspicion (worrisome smear findings, MPN symptoms, unexplained persistence), not by an absolute platelet count cutoff.

Exam Pearl Repeat this to yourself: "no specific platelet count predicts reactive vs. primary." Use clinical context (recent illness/surgery, smear morphology, systemic symptoms) instead of the raw number to guide your differential.

Q2Blood Smear Interpretation●●●●● Extreme

A 45-year-old woman with persistent thrombocytosis has a peripheral blood smear reviewed. The pathologist notes unusually large platelets. What is the most appropriate interpretation of this finding?

A. Large platelets suggest a reactive process and no further workup is needed
B. Large platelets may suggest an underlying myeloproliferative neoplasm, warranting further evaluation
C. Large platelets are a normal, nonspecific finding with no diagnostic value
D. Large platelets confirm iron deficiency as the cause
E. Large platelets specifically diagnose chronic myeloid leukemia

Reveal Answer

Correct answer: B

On peripheral smear, large platelets may suggest an underlying myeloproliferative neoplasm (primary thrombocytosis), while younger (smaller) platelets might indicate a reactive process. This finding should prompt further evaluation (mutation testing, possible hematology referral), not reassurance.

Why the others are wrong A — this reverses the correct interpretation; large platelets point toward MPN, not reactive causes. C — platelet size on smear is specifically informative in this evaluation framework, not nonspecific. D — iron deficiency isn't diagnosed by platelet size; ferritin testing addresses that question separately. E — large platelets are a nonspecific MPN clue, not diagnostic of CML specifically, which requires BCR-ABL1/Philadelphia chromosome confirmation.

Exam Pearl Smear platelet size cheat sheet: large platelets → think MPN (primary); young/smaller platelets → think reactive process. This is a simple but frequently tested pattern-recognition fact.

Q3Ferritin Pathway●●●●● Extreme

A 29-year-old woman with heavy menstrual bleeding has persistent thrombocytosis, no worrisome smear findings, and no features suggestive of MPN. Serum ferritin returns at 8 ng/mL. What is the most appropriate next step?

A. Refer directly to hematology for bone marrow biopsy
B. Replete iron and reassess platelet count in 1–2 months
C. Start hydroxyurea empirically
D. Order JAK2, CALR, and MPL testing before any other intervention
E. No action needed; ferritin of 8 is a normal, reassuring value

Reveal Answer

Correct answer: B

With no worrisome smear findings and no MPN features, a ferritin <15 ng/mL (hers is 8) points to iron deficiency as the likely driver of reactive thrombocytosis — consistent with her heavy menstrual bleeding. The appropriate step is to replete iron and reassess in 1–2 months; if thrombocytosis resolves, no further workup is needed.

Why the others are wrong A — hematology referral for bone marrow biopsy is reserved for MPN-suspicious findings or unresolved/unexplained cases, not this straightforward iron-deficiency-driven picture. C — hydroxyurea is an ET treatment, not appropriate before even confirming a primary process, and clearly premature here. D — mutation testing is pursued when MPN is suspected (which isn't the case here, per the algorithm) or after the iron-repletion pathway fails to resolve the thrombocytosis. E — a ferritin of 8 ng/mL is below the 15 ng/mL threshold and should be treated as iron deficient, not reassuring.

Exam Pearl Ferritin <15 ng/mL → iron repletion → reassess platelets in 1–2 months. Resolved thrombocytosis after iron repletion needs no further workup; if unresolved, refer to hematology.

Q4ET Risk Stratification Grid●●●●● Extreme

A 58-year-old woman is newly diagnosed with essential thrombocythemia. She is JAK2 V617F positive, has no history of thrombosis, and is 58 years old. What is her risk category?

A. High-risk, because she is JAK2 positive
B. Low-risk — age ≤60, JAK2 V617F positive, and no history of thrombosis
C. Intermediate-risk, because JAK2 positivity always raises risk regardless of age
D. Very low-risk, since she has no thrombosis history
E. Cannot be determined without bone marrow biopsy results

Reveal Answer

Correct answer: B

The ET risk grid is defined by age (≤60 vs. >60), JAK2 status, and thrombosis history. She is age ≤60, JAK2 V617F positive, with no history of thrombosis — this specific combination defines low-risk disease. JAK2 positivity only pushes her into the high-risk category if combined with age >60 (or if she has a thrombosis history, which trumps everything).

Why the others are wrong A — JAK2 positivity alone at age ≤60 without thrombosis is low-risk, not high-risk; high-risk specifically requires either a thrombosis history OR (age >60 AND JAK2+). C — JAK2 positivity does not universally raise risk regardless of age; the age cutoff of 60 is central to the grid. D — very low-risk requires JAK2 negative status (plus age ≤60, no thrombosis); she is JAK2 positive, which makes her low-risk, not very low-risk. E — this risk stratification is based on clinical/genetic criteria already given; bone marrow biopsy isn't required to assign risk category.

Exam Pearl Build the mental 2×2 grid: age ≤60 + JAK2(+) = low-risk; age ≤60 + JAK2(−) = very low-risk; age >60 + JAK2(−) = intermediate-risk; age >60 + JAK2(+) = high-risk. A history of thrombosis automatically overrides all of this and makes the patient high-risk regardless of age/JAK2 status.

Q5ET Risk Stratification Grid — Flip●●●●● Extreme

A 64-year-old man with ET has no history of thrombosis and tests negative for JAK2 mutation. What is his risk category, and how does it differ from a 64-year-old JAK2-positive patient with the same thrombosis history?

A. He is high-risk, identical to a JAK2-positive patient of the same age
B. He is intermediate-risk (age >60, no JAK2 mutation, no thrombosis history), while the JAK2-positive patient of the same age would be classified as high-risk
C. He is very low-risk since he lacks JAK2 mutation entirely
D. Both patients are classified identically regardless of JAK2 status once age exceeds 60
E. He is low-risk, and JAK2 status doesn't affect risk category after age 60

Reveal Answer

Correct answer: B

Age >60 with no JAK2 mutation and no thrombosis history = intermediate-risk. In contrast, age >60 with JAK2 V617F positivity meets the definition of high-risk disease. This directly illustrates how JAK2 status changes the risk category specifically in patients older than 60.

Why the others are wrong A — the two patients are NOT classified identically; JAK2 status is the differentiating factor at this age. C — very low-risk requires age ≤60, not >60; his age alone excludes this category regardless of JAK2 status. D — JAK2 status does matter after age 60, distinguishing intermediate-risk (JAK2−) from high-risk (JAK2+). E — "low-risk" specifically requires age ≤60; this doesn't apply to him, and the premise that JAK2 doesn't matter after 60 is incorrect.

Exam Pearl At age >60, JAK2 status is the swing factor between intermediate-risk (JAK2−) and high-risk (JAK2+) — a frequently tested "compare two similar patients" style question.

Q6Reactive Thrombocytosis Treatment●●●○ Hard

A 50-year-old man recovering from a recent surgery has reactive thrombocytosis (platelet count 610 × 10⁹/L) with no history of thrombosis. His surgeon asks whether prophylactic aspirin should be started to reduce thrombotic risk given the elevated platelet count. What is the most appropriate response?

A. Yes, empirical aspirin should be started in all patients with reactive thrombocytosis
B. No — there is no benefit to empirical aspirin in reactive thrombocytosis without a thrombotic event; if thrombosis occurs, it should be managed according to the nature of that event
C. Yes, but only hydroxyurea should be used instead of aspirin
D. No, and platelet count should never be rechecked in this setting
E. Yes, anticoagulation (not aspirin) should be started empirically

Reveal Answer

Correct answer: B

In reactive thrombocytosis, there is no benefit to empirical aspirin for thrombosis prevention. If a thrombotic event does occur, it should be managed according to the specific nature of that event, rather than reflexively adding prophylactic antiplatelet therapy based on the platelet count alone.

Why the others are wrong A — this directly contradicts the specific "no benefit" teaching for reactive thrombocytosis (contrasted with ET, where aspirin has an established role). C — hydroxyurea is an ET/MPN-directed cytoreductive agent, not indicated in reactive thrombocytosis. D — repeat CBC to confirm/monitor the platelet count is part of standard evaluation; "never recheck" is inappropriate. E — empirical anticoagulation isn't indicated either, absent an actual thrombotic event.

Exam Pearl Reactive thrombocytosis: no empirical aspirin. This is a specific, testable contrast against essential thrombocythemia, where aspirin plays a central prophylactic role across almost all risk categories.

Q7ET Treatment — Age/Pregnancy Split●●●●● Extreme

A 27-year-old woman with high-risk essential thrombocythemia (history of thrombosis) is planning to become pregnant within the next year. What is the most appropriate cytoreductive agent to pair with aspirin, and why?

A. Hydroxyurea, since it is first-line for all high-risk ET patients
B. Interferon-alfa, since she is under age 40 with potential for pregnancy, and hydroxyurea carries teratogenic risk
C. No cytoreductive therapy should be used in any woman of reproductive age
D. Busulfan, as the standard choice in reproductive-age women
E. Anticoagulation alone, without any cytoreductive agent, regardless of thrombosis history

Reveal Answer

Correct answer: B

In high-risk ET, patients age <40 or with potential for pregnancy should be started on aspirin + interferon-alfa rather than hydroxyurea, given hydroxyurea's teratogenic potential. She meets both criteria (age 27, pregnancy potential), making interferon-alfa the appropriate cytoreductive pairing with aspirin.

Why the others are wrong A — hydroxyurea is specifically reserved for high-risk patients age ≥40 who are not pregnant/without pregnancy potential; it's not universally first-line across all high-risk ET patients. C — cytoreductive therapy is still indicated in high-risk disease; interferon-alfa is simply the pregnancy-safer alternative rather than omitting therapy altogether. D — busulfan isn't described as the standard reproductive-age choice in this framework; interferon-alfa is. E — since she has high-risk disease (history of thrombosis), cytoreductive therapy plus aspirin (and anticoagulation if applicable given prior thrombosis) is indicated, not anticoagulation in isolation.

Exam Pearl High-risk ET cytoreductive choice mirrors PV logic exactly: age ≥40 and not pregnant → hydroxyurea; age <40 or pregnancy potential → interferon-alfa. Add aspirin BID for prior arterial thrombosis, and anticoagulation for prior thrombosis in general.

Q8ET Treatment — Arterial Thrombosis Add-On●●●● Very Hard

A 55-year-old man with high-risk ET (started on aspirin and hydroxyurea) has a new episode of transient ischemic attack, consistent with an arterial thrombotic event. What adjustment to his antiplatelet regimen is most appropriate?

A. Discontinue aspirin entirely given the new event
B. Increase aspirin to twice-daily dosing (BID) given the prior arterial thrombosis
C. No change to his regimen is needed
D. Switch aspirin to clopidogrel monotherapy as the described standard approach
E. Add hydroxyurea, since he is not already on it

Reveal Answer

Correct answer: B

In high-risk ET, if there is a prior arterial thrombosis, the recommendation is to add aspirin BID (increase to twice-daily dosing). Separately, if there is prior thrombosis in general (arterial or venous), an anticoagulant should also be added.

Why the others are wrong A — discontinuing aspirin after a thrombotic event is the opposite of the correct response; intensifying antiplatelet therapy (BID dosing) is indicated instead. C — a new arterial thrombotic event specifically requires regimen adjustment (aspirin BID) per the described approach. D — clopidogrel monotherapy isn't the described standard adjustment in this framework; aspirin BID is. E — he is already on hydroxyurea per the vignette; the adjustment needed relates to his antiplatelet dosing given the new arterial event, not adding an agent he's already taking.

Exam Pearl High-risk ET treatment escalation: prior arterial thrombosis → add aspirin BID; prior thrombosis (any type) → add anticoagulant. These are separate, specific triggers worth memorizing individually.

Q9MPN Comparison — Pattern Recognition●●●●● Extreme

A 62-year-old man presents with an extremely elevated platelet count, normal hematocrit, normal white blood cell count, minimal splenomegaly, and no hepatomegaly. Genetic testing shows a CALR mutation. Which myeloproliferative neoplasm is most consistent with this profile?

A. Chronic myeloid leukemia
B. Polycythemia vera
C. Idiopathic (primary) myelofibrosis
D. Essential thrombocythemia
E. Acute myeloid leukemia

Reveal Answer

Correct answer: D

This profile — markedly elevated platelets (↑↑↑), normal hematocrit and WBC, minimal splenomegaly (+), and no hepatomegaly (−) — matches essential thrombocythemia most closely among the MPNs. ET is also associated with CALR mutations in roughly 30% of cases (shared with IMF, but ET's minimal organomegaly and normal other cell lines point away from IMF here).

Why the others are wrong A — CML shows markedly elevated WBC and significant splenomegaly (+++), and is defined by bcr-abl, not CALR. B — PV shows markedly elevated hematocrit (↑↑), which is normal here, and is defined by JAK2 (96%), not primarily CALR. C — IMF shows marked marrow fibrosis (+++) and prominent hepatosplenomegaly (+++), which contrasts with this patient's minimal organomegaly. E — AML is an acute leukemia, not an MPN, and doesn't fit this chronic, isolated thrombocytosis picture.

Exam Pearl Use the comparison table as a process-of-elimination tool: ET = platelets way up, everything else roughly normal, minimal organomegaly/fibrosis. This "isolated thrombocytosis with otherwise unremarkable counts and exam" pattern is the ET signature versus its MPN relatives.

Q10Family History & Referral Logic●●●●● Extreme

A 40-year-old woman has persistent thrombocytosis with no worrisome smear findings, no MPN-suggestive features, and a normal ferritin (45 ng/mL). She reports that her mother and sister both have unexplained lifelong elevated platelet counts. What is the most appropriate next step per the evaluation algorithm?

A. No further evaluation needed since her ferritin is normal
B. Given the family history of unexplained thrombocytosis (not accounted for by infection, inflammation, or splenectomy), referral to hematology is appropriate
C. Start empirical hydroxyurea given the family history
D. Reassure her that family history is irrelevant to this evaluation
E. Order only a repeat ferritin in 6 months with no other action

Reveal Answer

Correct answer: B

Once ferritin is normal (ruling out iron deficiency as the driver), the algorithm asks whether there is a family history of unexplained thrombocytosis or whether infection, inflammation, or splenectomy can account for the finding. Since neither of the latter apply and there is a notable family history, this should prompt referral to hematology for further evaluation (e.g., to consider hereditary thrombocytosis syndromes or an underlying MPN).

Why the others are wrong A — a normal ferritin alone doesn't end the evaluation; the algorithm specifically continues to the family history/infection-inflammation branch next. C — empirical hydroxyurea is inappropriate without an established diagnosis; referral and further workup come first. D — family history is specifically incorporated into this branch of the evaluation algorithm and should not be dismissed. E — simply repeating ferritin doesn't address the family history question the algorithm specifically raises next.

Exam Pearl After the ferritin branch: if ferritin is normal, ask whether infection/inflammation/splenectomy explains the thrombocytosis. If yes → no further workup. If no (and/or there's a family history of unexplained thrombocytosis) → refer to hematology.