What are the next steps in managing a patient with concerns about factor V, factor VIII, and protein S deficiency, who has normal Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), Thyroid-Stimulating Hormone (TSH), Prothrombin Time/International Normalized Ratio (PT/INR), and activated Partial Thromboplastin Time (aPTT) levels, but low iron stores indicated by a ferritin level of 13, suggestive of iron deficiency?

Management of Low Ferritin with Normal Coagulation Studies

Start oral iron supplementation immediately with ferrous sulfate 65 mg elemental iron daily (or alternate-day dosing) to restore depleted iron stores, and screen for celiac disease with tissue transglutaminase antibodies. 1, 2

Understanding the Clinical Picture

Your patient's ferritin of 13 ng/mL is definitively diagnostic of absolute iron deficiency (threshold <15 μg/L has 99% specificity), while the normal PT/INR and aPTT effectively rule out clinically significant deficiencies of factors V, VIII, and protein S. 1, 2

Why the Coagulation Studies Are Reassuring

• Normal PT/INR excludes factor V and factor VII deficiency, as these factors are required for the extrinsic pathway and would prolong PT if significantly deficient 3, 4, 5
• Normal aPTT excludes factor VIII deficiency, which would prolong aPTT due to its role in the intrinsic pathway 6
• Protein S deficiency causes thrombosis (not bleeding) and would not be detected by routine coagulation studies—it requires specific protein S antigen/activity assays only if there is a personal or family history of clotting 1
• Combined factor V and VIII deficiency is extremely rare (1:1,000), presents with mild-moderate bleeding symptoms, and would show prolonged PT and aPTT—not normal studies 6, 7

Immediate Treatment Protocol

Iron Supplementation

• Initiate ferrous sulfate 324 mg tablets (65 mg elemental iron) once daily, taken on an empty stomach for optimal absorption 1, 8
• Alternate-day dosing (60-65 mg every other day) may improve absorption and reduce GI side effects compared to daily dosing 2
• If GI symptoms occur (constipation, nausea, diarrhea), take with meals or switch to alternate-day dosing 2
• Continue iron supplementation for 3 months after hemoglobin normalizes to fully replenish iron stores 1

Essential Screening Tests

• Screen for celiac disease with tissue transglutaminase antibodies (tTG), as it is present in 3-5% of iron deficiency cases and causes treatment failure if missed 2
• Test for H. pylori non-invasively (stool antigen or urea breath test), as it can impair iron absorption 2

Investigation Strategy

For Premenopausal Women

• GI evaluation is conditional, not mandatory, unless specific red flags are present 2
• Assess menstrual blood loss history thoroughly, as heavy menses are the most common cause in this population 2
• If young with heavy menses, negative celiac/H. pylori testing, and no GI symptoms, empiric iron supplementation alone is reasonable 2

Reserve Bidirectional Endoscopy For:

• Age ≥50 years (higher GI malignancy risk) 2
• GI symptoms (abdominal pain, change in bowel habits, blood in stool) 2
• Positive celiac or H. pylori testing requiring confirmation 2
• Failure to respond to adequate oral iron therapy after 8-10 weeks 1, 2
• Strong family history of colorectal cancer 2

Follow-Up and Monitoring

• Repeat CBC and ferritin at 8-10 weeks to assess treatment response 1, 2
• Expected hemoglobin rise ≥10 g/L within 2 weeks, with full correction by 3-4 weeks (2 g/dL increase) 1, 2
• Target ferritin >100 ng/mL to restore iron stores and prevent recurrence 2
• If no improvement after 8-10 weeks, consider malabsorption (celiac disease, IBD), non-compliance, ongoing blood loss, or need for IV iron 1, 2

Long-Term Management

• For recurrent low ferritin (menstruating females, vegetarians, athletes), screen ferritin every 6-12 months 2
• Do not continue daily iron supplementation once ferritin normalizes, as this is potentially harmful 2

Common Pitfalls to Avoid

• Do not perform extensive coagulation factor testing (factor V, VIII, protein S assays) when PT/INR and aPTT are normal—these screening tests are sufficient to exclude clinically significant deficiencies 1
• Do not assume normal hemoglobin excludes iron deficiency—ferritin <15 μg/L represents Stage 1 iron deficiency where stores are depleted before anemia develops 2
• Do not overlook celiac disease, which can cause persistent iron deficiency despite supplementation 2
• Do not order protein S testing without a thrombotic history—protein S deficiency causes clotting, not bleeding, and is irrelevant to this presentation 1