What are the possible causes of thrombocytosis in a patient recently treated for Klebsiella septicemia with IV ceftriaxone (Ceftriaxone) followed by oral Augmentin (Amoxicillin-Clavulanate) with normal hemoglobin (Hb) and total white blood cell count (TWBC)?

Thrombocytosis Following Klebsiella Septicemia Treatment

The thrombocytosis in this patient is most likely a reactive (secondary) thrombocytosis representing the recovery phase from sepsis and infection, which typically peaks in the second to third week after acute illness and requires no specific treatment beyond monitoring. 1, 2

Most Likely Cause: Post-Infectious Reactive Thrombocytosis

Recovery from sepsis and infection is the primary driver of thrombocytosis in this clinical context. The timeline is characteristic—thrombocytosis typically does not occur until the second week of illness, peaking in the third week (mean platelet count ~700,000/mm³) and normalizing by 4-6 weeks after onset. 3 This patient is approximately 2 weeks post-treatment initiation, placing him squarely in the expected window for reactive thrombocytosis.

Key Supporting Evidence:

• Normal hemoglobin and white blood cell count argue strongly against primary myeloproliferative disease and indicate resolution of the acute infectious process 3, 1
• Infections, particularly acute bacterial infections like Klebsiella septicemia, are well-established causes of secondary thrombocytosis 1
• The platelet count elevation represents an acute-phase reaction with increased thrombopoietin production during recovery from inflammation 3

Drug-Induced Thrombocytosis (Less Likely but Possible)

Both ceftriaxone and amoxicillin-clavulanate (Augmentin) have documented associations with thrombocytosis, though the evidence is limited and confounded by underlying infection. 4, 5, 6

Specific Drug Considerations:

• Amoxicillin-clavulanate (Augmentin): The FDA label explicitly states "thrombocytosis was noted in less than 1% of patients treated with amoxicillin and clavulanate potassium" 4
• Ceftriaxone in combination with fluoroquinolones: A 2019 case report documented thrombocytosis with ceftriaxone and ciprofloxacin combination (Naranjo score of 5, indicating "probable" causation) 5
• Beta-lactam antibiotics generally: The data are difficult to interpret because the acute-phase reaction from infection itself can cause thrombocytosis, making drug causation uncertain 6

The temporal relationship matters: If thrombocytosis developed or worsened specifically during oral Augmentin therapy (after IV ceftriaxone), drug-induced thrombocytosis becomes more plausible. However, this would still be secondary thrombocytosis and self-limited. 2

Other Potential Contributing Factors

Iron Deficiency (Check if Present):

• Iron deficiency can cause secondary thrombocytosis and should be excluded with iron studies 1, 2
• If present, iron replacement will normalize both hemoglobin and platelet count 2

Tissue Damage/Inflammation:

• Any tissue damage from the septic episode itself can trigger reactive thrombocytosis 1
• The normal WBC count suggests inflammation has largely resolved 3

What to Rule Out (Low Probability but Important)

Primary myeloproliferative neoplasms are unlikely given the clinical context but should be excluded if thrombocytosis persists beyond 4-6 weeks: 1, 2

• Essential thrombocythemia: Requires sustained platelet count ≥450 × 10⁹/L, JAK2V617F mutation testing, and bone marrow showing megakaryocyte proliferation 1
• Polycythemia vera: Would typically show elevated hemoglobin (which is normal in this patient) 3, 1
• Chronic myeloid leukemia or primary myelofibrosis: Would show other cell line abnormalities on peripheral smear 1

Recommended Management Algorithm

Immediate Actions:

1. Obtain peripheral blood smear to evaluate for other cell line abnormalities that would suggest primary myeloproliferative disease 1
2. Check iron studies (ferritin, iron, TIBC) to exclude iron deficiency as a contributing factor 2
3. Review medication timing to assess temporal relationship between antibiotic administration and thrombocytosis onset 5

If Platelet Count <600,000/mm³:

• No specific treatment required 2
• No antiplatelet therapy indicated unless other cardiovascular indications exist 1, 2
• Recheck platelet count in 2-4 weeks to confirm downward trend 2

If Platelet Count ≥600,000/mm³ or Persists Beyond 4-6 Weeks:

• Order JAK2V617F mutation testing to exclude essential thrombocythemia and polycythemia vera 2
• Consider hematology referral if mutation positive or if thrombocytosis persists/worsens 2
• Bone marrow biopsy indicated only if clonal disorder cannot be excluded by clinical assessment and mutation testing 2

Monitoring Strategy:

• Expect normalization within 4-6 weeks of infection resolution 3
• If platelet count normalizes, no further hematologic workup needed 2
• If thrombocytosis persists beyond 6 weeks, repeat JAK2V617F testing and consider bone marrow evaluation 2

Critical Pitfalls to Avoid

Do not initiate antiplatelet therapy or cytoreductive treatment for reactive thrombocytosis. Secondary thrombocytosis is generally benign and self-limited when the underlying cause resolves, with venous thrombosis only occurring when additional risk factors are present. 1 Treatment of the underlying condition (which has already been completed with antibiotics) is the primary approach. 1

Do not overlook the possibility of masked polycythemia vera if iron deficiency is present. Iron deficiency must be excluded by trial of iron replacement therapy before diagnosing essential thrombocythemia, as occult polycythemia vera may be masked. 1

Do not assume drug causation without considering the infection itself. The acute-phase reaction from Klebsiella septicemia is a more likely explanation than drug-induced thrombocytosis, particularly given the characteristic timing. 3, 6