What is the next step to investigate a prolonged activated partial thromboplastin time (APTT) with a normal thrombin time and no evidence of heparin use?

Investigation of Prolonged APTT in a Patient with Normal PT and Platelet Count

The next step in investigating this patient's markedly prolonged APTT (125.9 seconds) with normal PT and platelet count should be to mix the patient's plasma with normal plasma and repeat the APTT test. 1, 2

Rationale for Mixing Study

When faced with an isolated prolonged APTT (with normal PT and platelet count), a mixing study is the essential first-line investigation to differentiate between:

1. Factor deficiency: The prolonged APTT normalizes when mixed with normal plasma (which supplies the missing factors)
2. Inhibitor presence: The prolonged APTT remains abnormal even after mixing with normal plasma

This patient's laboratory profile shows:

• Normal platelet count (256 x 10³/μL)
• Normal PT (11.6 seconds)
• Markedly prolonged APTT (125.9 seconds)
• Normal thrombin time (as stated in the question)

Mixing Test Procedure

The mixing test involves:

• Combining equal parts (1:1) of patient plasma with normal pooled plasma
• No preincubation is required when performing the test within 30 minutes 1
• Repeating the APTT on this mixture
• Comparing the result to reference ranges

Interpretation of Mixing Test Results

If the APTT normalizes (corrects):

• Suggests factor deficiency (such as hemophilia A or B)
• Further testing would include specific factor assays to identify which factor is deficient (typically factors VIII, IX, XI, or XII) 3

If the APTT remains prolonged (doesn't correct):

• Suggests the presence of an inhibitor
• Most commonly a lupus anticoagulant or specific factor inhibitor
• Further confirmatory testing would be required 1, 4

Why Other Options Are Not Appropriate First Steps

1. Neutralizing heparin and repeating APTT: Not indicated as the first step since there's no history of heparin use mentioned, and the thrombin time is normal (which would typically be prolonged with heparin) 5

2. D-dimer test: Not useful for determining the cause of a prolonged APTT; it's primarily used to rule out thrombosis

3. Factor IX assay: Premature to test for specific factor deficiencies before determining whether the abnormality is due to a deficiency or an inhibitor 4

Important Clinical Considerations

• Despite the markedly prolonged APTT, the patient denies abnormal bleeding symptoms, which is more consistent with an inhibitor (particularly lupus anticoagulant) than with a severe factor deficiency 6

• Lupus anticoagulants paradoxically increase thrombotic risk despite prolonging clotting tests in vitro 5

• If the mixing study suggests an inhibitor, further testing should include lupus anticoagulant-specific assays as recommended by the International Society on Thrombosis and Haemostasis 1

The mixing study is a simple but crucial diagnostic step that will guide all subsequent investigations and ultimately inform proper clinical management of this patient with an unexplained prolonged APTT.