What could be the cause of consistently elevated platelet counts and how can I investigate potential underlying conditions such as myeloproliferative neoplasms or other platelet disorders?

Investigation of Persistently Elevated Platelets with Pregnancy Complications

You should undergo immediate testing for myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia (ET), given your 6-year history of elevated platelets combined with severe preeclampsia, IUGR at 28 weeks, and miscarriage—all recognized complications of MPN in pregnancy. 1

Immediate Diagnostic Workup

First-Line Testing for MPN

JAK2 V617F mutation testing is the single most important initial test, as it is 100% specific for myeloproliferative disease and is present in the majority of ET patients. 1 This mutation testing should be performed on peripheral blood granulocytes and can be done immediately without waiting for other results. 1

• Complete blood count with differential to assess all cell lines, not just platelets—look specifically for leukocytosis (white blood cells >11 × 10⁹/L), which increases thrombotic risk by 60% in ET patients. 1
• Peripheral blood smear examination to evaluate platelet morphology, size variation, and assess for other cell abnormalities that might suggest specific disorders. 1, 2
• If JAK2 V617F is negative, proceed to CALR (calreticulin) mutation testing, as CALR-mutated ET patients have lower thrombotic risk but still require diagnosis. 1

Risk Stratification Based on Your History

Your clinical presentation places you in the high-risk category for MPN-related pregnancy complications based on established criteria: 1

• Severe preeclampsia at 28 weeks with IUGR meets the definition of premature delivery due to placental insufficiency
• One miscarriage (though the threshold is typically ≥3 consecutive miscarriages for highest risk classification)
• The timing of platelet elevation coinciding with your first pregnancy is consistent with MPN presentation in women of childbearing age

Additional Specialized Testing

If JAK2 and CALR Are Negative

• Bone marrow biopsy with evaluation for dystrophic megakaryocyte clusters, which are diagnostic of ET even when molecular markers are absent. 1
• MPL (thrombopoietin receptor) mutation testing to complete the MPN mutation panel. 1

Excluding Other Causes

Iron deficiency must be ruled out, as it commonly causes reactive thrombocytosis—check serum ferritin, iron studies, and assess for any chronic blood loss. 1

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to exclude inflammatory/reactive causes of elevated platelets
• Peripheral blood flow cytometry using antibodies against GPIIb/IIIa (CD41), GPIIIa (CD61), GPIb (CD42b), and GPIb/IX (CD42a) to evaluate for inherited platelet disorders. 1, 2

Genetic Considerations

MPN-Associated Genes

The primary genetic mutations causing persistently elevated platelets in MPNs are: 1

• JAK2 V617F (most common—found in ~60% of ET patients)
• CALR mutations (exon 9 insertions/deletions—found in ~25% of ET patients)
• MPL mutations (W515L/K—found in ~3% of ET patients)

These are acquired somatic mutations, not inherited, meaning they developed in your bone marrow cells and are not passed from parents or to children through germline DNA. 1

Inherited Platelet Disorders (Less Likely Given Your Presentation)

If MPN testing is negative, consider inherited causes: 1, 2

• Familial thrombocytosis (rare autosomal dominant conditions with mutations in TPO or MPL genes)
• Storage pool disorders affecting platelet granules
• Platelet receptor defects (though these typically present with bleeding, not thrombosis)

Cancer Risk Assessment

Your concern about cancer is valid but requires context: 3

• ET itself is a chronic blood cancer (a myeloproliferative neoplasm), but it is typically slow-growing with near-normal life expectancy when properly managed
• The risk of transformation to acute leukemia in ET is approximately 1-3% over 10-15 years, significantly lower than other MPNs
• Long-term hydroxyurea therapy (a common ET treatment) does carry increased risk of secondary leukemia and skin cancer, but this is relevant only if you require this treatment in the future. 3

Critical Pitfalls to Avoid

Do not dismiss elevated platelets as "reactive" without thorough MPN workup, especially given your pregnancy complications—the combination of thrombocytosis with severe preeclampsia and IUGR is highly suggestive of underlying MPN. 1

• Platelet counts often decline during pregnancy in MPN patients (by up to 43% from baseline to delivery), so your current platelet count may underestimate the severity if measured during or shortly after pregnancy. 1
• The postpartum period carries 4-6 fold increased VTE risk—if you have MPN, this risk is compounded and requires specific monitoring for 6 weeks postpartum. 1

Next Steps After Diagnosis

If MPN is confirmed, you will need: 1

• Cardiovascular risk factor assessment (hypertension, diabetes, smoking status)—these contribute additional points to your thrombotic risk score
• Discussion about future pregnancy planning, as management requires stopping certain medications (hydroxyurea, anagrelide) with adequate washout and potentially using interferon-alpha if cytoreductive therapy is needed
• Aspirin therapy consideration based on your JAK2 mutation status and cardiovascular risk factors (though aspirin should be avoided if extreme thrombocytosis >1,000/μL with acquired von Willebrand syndrome). 4

Consult a hematologist specializing in MPNs immediately to coordinate this workup and interpret results in the context of your pregnancy history and future reproductive plans. 1