Elevated Platelets and Ferritin: Diagnostic Work-Up and Management
Immediate Priority: Rule Out Hemophagocytic Lymphohistiocytosis (HLH)
When an adult presents with thrombocytosis and elevated ferritin, the first critical step is to determine the ferritin level and assess for HLH, a life-threatening condition that requires urgent recognition. 1
Ferritin-Based Risk Stratification
- Ferritin >10,000 μg/L is 90% sensitive and 96% specific for HLH in adults and should trigger immediate HLH evaluation 1, 2
- Ferritin 7,000–10,000 μg/L warrants strong suspicion for HLH, particularly if accompanied by fever, cytopenias, or splenomegaly 1
- Ferritin <10,000 μg/L makes HLH less likely but does not exclude it if other clinical features are present 1
HLH Diagnostic Criteria (HLH-2004)
Diagnose HLH if 5 of 8 criteria are met 1:
- Fever
- Splenomegaly
- Cytopenias affecting ≥2 lineages (hemoglobin <90 g/L, platelets <100 × 10⁹/L, neutrophils <1.0 × 10⁹/L)
- Hypertriglyceridemia (≥3.0 mmol/L) and/or hypofibrinogenemia (≤1.5 g/L)
- Hemophagocytosis in bone marrow, spleen, or lymph nodes
- Low or absent NK cell activity
- Ferritin ≥500 μg/L
- Soluble CD25 (IL-2 receptor) ≥2,400 U/mL
Critical caveat: Your patient has thrombocytosis, not thrombocytopenia, which argues strongly against HLH. However, if ferritin is extremely elevated (>10,000 μg/L), still evaluate for HLH because the diagnostic criteria can be met without all features present 1.
Step 1: Measure Transferrin Saturation to Differentiate Iron Overload from Secondary Causes
The single most important test is fasting transferrin saturation (TS), which must be measured simultaneously with ferritin to distinguish true iron overload from inflammatory hyperferritinemia. 3, 4
Interpretation Algorithm
| TS Result | Clinical Significance | Next Step |
|---|---|---|
| TS ≥45% | Suspect primary iron overload (hereditary hemochromatosis or other iron-overload disorder) | Order HFE genetic testing for C282Y and H63D mutations [3,4] |
| TS <45% | Iron overload excluded with >90% certainty; secondary causes predominate | Evaluate for inflammation, liver disease, malignancy, infection [3,4] |
Do not proceed with HFE genetic testing if TS <45%, as over 90% of elevated ferritin cases are caused by non-iron-overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome 3.
Step 2: Evaluate for Secondary Causes When TS <45%
Most Common Etiologies of Hyperferritinemia with Thrombocytosis
Based on large retrospective studies, the most frequent causes are 5, 6:
- Malignancy (most common overall) – particularly hematologic malignancies, solid tumors, lymphomas 5, 6, 7
- Liver disease – alcoholic liver disease, viral hepatitis (B/C), NAFLD, hepatocellular injury 3, 6
- Infection – bacterial, viral, or fungal infections 5, 6
- Inflammatory conditions – rheumatologic diseases, inflammatory bowel disease 3, 8
- Chronic kidney disease 6
Thrombocytosis specifically suggests: reactive thrombocytosis from inflammation, infection, malignancy, or iron deficiency (paradoxically, iron deficiency can coexist with elevated ferritin in inflammatory states) 7.
Essential Laboratory Panel
- Complete blood count with differential – assess for anemia, leukocytosis, or other cytopenias 3
- Comprehensive metabolic panel – ALT, AST, alkaline phosphatase, bilirubin, albumin, creatinine 3, 4
- Inflammatory markers – CRP and ESR 3, 4
- Lactate dehydrogenase (LDH) – elevated in hemolysis, malignancy, tissue necrosis 3
- Peripheral blood smear – evaluate for abnormal cells, schistocytes, or hematologic malignancy 3
Additional Testing Based on Clinical Context
- Hepatitis B surface antigen and hepatitis C antibody if liver enzymes are elevated 3
- Abdominal ultrasound to evaluate for fatty liver, hepatomegaly, splenomegaly, or cirrhotic features 3
- Tissue transglutaminase (TTG) antibodies if unexplained iron deficiency coexists with elevated ferritin 3
- Serum protein electrophoresis (SPEP) if multiple myeloma is suspected 3
- JAK2 mutation testing if polycythemia vera is suspected (look for aquagenic pruritus, elevated hemoglobin/hematocrit) 3
Step 3: Evaluate for Specific High-Risk Conditions
Adult-Onset Still's Disease (AOSD)
If ferritin rises above 4,000–5,000 μg/L with persistent fever, measure glycosylated ferritin fraction. 3, 8
- Glycosylated ferritin <20% is 93% specific for AOSD when combined with 5-fold ferritin elevation 1, 3
- Mean ferritin in AOSD is approximately 11,000–14,000 μg/L 1, 8
Malignancy-Associated HLH
In adults, malignancies (particularly T-cell/NK-cell lymphomas and B-cell lymphomas) are a major trigger for HLH 1:
- 35% T-cell or NK-cell lymphomas
- 32% B-cell lymphomas
- 6% leukemias
- 6% Hodgkin lymphoma
A meticulous search for occult malignancy should be continued despite ongoing HLH treatment. 1
Thrombocytopenia vs. Thrombocytosis Context
- Thrombocytopenia (platelet count <150 × 10⁹/L) is strongly associated with hyperferritinemia, particularly in hematologic diseases 7
- Thrombocytosis (your patient's presentation) suggests reactive thrombocytosis from inflammation, infection, or malignancy rather than HLH 7
- Patients with chronic blood transfusions are more susceptible to thrombocytopenia (93% vs. 69%) 7
Step 4: Risk Stratification by Ferritin Level
| Ferritin Range | Clinical Implication | Action Required |
|---|---|---|
| <1,000 μg/L | Low risk of organ damage; 94% negative predictive value for advanced fibrosis [3,4] | Evaluate secondary causes; no liver biopsy needed if TS <45% and liver enzymes normal [3,4] |
| 1,000–10,000 μg/L | Increased risk of advanced fibrosis/cirrhosis if iron overload present; in C282Y homozygotes, ferritin >1,000 μg/L + elevated ALT + platelets <200,000/μL predicts cirrhosis in 80% [3,4] | Consider liver biopsy if TS ≥45% and abnormal liver tests [3,4] |
| >10,000 μg/L | Rarely represents simple iron overload; mandates urgent specialist referral for life-threatening conditions (HLH, AOSD, severe inflammatory syndromes) [3,2] | Immediate hematology/rheumatology consultation [3,2] |
Step 5: Management Based on Underlying Cause
If TS ≥45% and C282Y Homozygosity Confirmed (Hereditary Hemochromatosis)
Initiate therapeutic phlebotomy with a target ferritin of 50–100 μg/L. 4
- Remove 500 mL blood weekly or biweekly 4
- Check hemoglobin/hematocrit before each phlebotomy; allow hemoglobin to fall no more than 20% from baseline 4
- Check ferritin every 10–12 phlebotomies 4
- Once target ferritin achieved, continue maintenance phlebotomy every 2–4 months 4
- Screen all first-degree relatives with TS, ferritin, and HFE genetic testing 4
If TS <45% (Secondary Hyperferritinemia)
Treat the underlying condition, not the elevated ferritin. 3, 4
- NAFLD/metabolic syndrome: Weight loss, metabolic control, avoid alcohol 3, 4
- Inflammatory conditions: Disease-specific anti-inflammatory therapy 3
- Malignancy: Oncologic treatment 3
- Infection: Antimicrobial therapy 3
- Chronic kidney disease with anemia: Consider IV iron if ferritin 500–1,200 μg/L with TS <25% and on erythropoiesis-stimulating agents 3, 4
Do not perform phlebotomy or iron chelation unless TS ≥45%. 3, 4
Critical Pitfalls to Avoid
- Never use ferritin alone to diagnose iron overload – TS must be measured simultaneously 3, 4
- Do not assume iron overload when TS <45% – in the general population, iron overload is NOT the most common cause of elevated ferritin 3
- Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 3, 4
- Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 3
- Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload – evaluate urgently for HLH, AOSD, or malignancy 3, 2
- Do not delay HLH evaluation if ferritin >10,000 μg/L, even if thrombocytosis is present 1, 2
When to Refer to Specialist
Immediate referral to hematology/rheumatology if: 3, 4
- Ferritin >10,000 μg/L (regardless of other findings)
- Ferritin >1,000 μg/L with elevated bilirubin
- Confirmed TS ≥45% on repeat testing
- Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly)
- Confirmed C282Y homozygosity requiring therapeutic phlebotomy
- Suspicion for HLH, AOSD, or malignancy-associated hyperferritinemia