A 38-year-old woman presents to the emergency department with acute onset dyspnea, pleuritic chest pain, and hemoptysis. She has been on oral contraceptives for 5 years. Vital signs: HR 110/min, BP 130/85 mmHg, RR 28/min, SpO₂ 88% on room air. D-dimer is markedly elevated at 2.8 μg/mL. CT pulmonary angiography shows multiple segmental and subsegmental pulmonary emboli bilaterally. Leg examination reveals mild swelling of the left calf. What is the most likely underlying thrombophilic state in this patient?

Explanation

## Clinical Presentation & Context This patient presents with acute pulmonary embolism (PE) with bilateral segmental involvement and evidence of deep vein thrombosis (DVT) in the left calf. The critical context is her 5-year history of oral contraceptive use, which is a major acquired risk factor for venous thromboembolism (VTE). ## Why Factor V Leiden (Activated Protein C Resistance) is Correct **High-Yield:** Factor V Leiden is the most common inherited thrombophilia, present in 3–7% of Caucasian populations and up to 20% of VTE patients. It accounts for approximately 40–50% of familial thrombophilia cases. **Key Point:** Factor V Leiden causes resistance to activated protein C (APC), a natural anticoagulant. The mutant Factor V cannot be cleaved efficiently by APC, leading to unopposed thrombin generation and a prothrombotic state. **Clinical Pearl:** The combination of oral contraceptives + Factor V Leiden creates a **synergistic prothrombotic effect**. OCPs increase factors II, VII, IX, and X while decreasing protein S, amplifying the thrombotic risk in carriers of Factor V Leiden. This patient's presentation—young, female, on OCPs, with bilateral PE and DVT—is the classic high-risk scenario for this mutation. ## Mechanism & Pathophysiology ```mermaid flowchart TD A[Factor V Leiden mutation]:::outcome --> B[Abnormal Factor Va produced] B --> C[Resistant to APC cleavage]:::outcome C --> D[Unopposed thrombin generation] D --> E[Hypercoagulable state] E --> F[VTE risk, especially with OCPs]:::urgent G[Oral contraceptives]:::action --> H[↓ Protein S, ↑ Factors II VII IX X] H --> I[Additive prothrombotic effect]:::urgent F -.-> I ``` ## Comparison of Inherited Thrombophilias | Feature | Factor V Leiden | Protein C Deficiency | Antithrombin III Deficiency | Prothrombin G20210A | |---------|-----------------|----------------------|------------------------------|---------------------| | **Prevalence** | 3–7% (Caucasians) | 0.2–0.4% | 0.02–0.1% | 1–2% | | **Mechanism** | APC resistance | ↓ Natural anticoagulant | ↓ Thrombin inhibitor | ↑ Prothrombin levels | | **VTE Risk (homozygous)** | 10–80× | 10–15× | 10–25× | 3–4× | | **Typical Age at VTE** | 30–40 years | 20–30 years | 20–30 years | 30–40 years | | **Superficial Thrombophlebitis** | Rare | Yes | Yes | Rare | | **Neonatal purpura** | No | Yes (homozygous) | No | No | | **OCP/HRT Interaction** | **Marked increase** | Moderate | Moderate | Mild | **Key Point:** This patient's age (38), female sex, OCP use, and acute bilateral PE with DVT fit the classic presentation of Factor V Leiden in a woman using hormonal contraception. ## Diagnostic Confirmation **High-Yield:** Factor V Leiden is diagnosed by: 1. **Activated Protein C Resistance (APCR) assay** — screening test; prolonged aPTT ratio after APC addition 2. **Genetic testing** — DNA sequencing for the Factor V G1691A mutation (definitive) 3. **Thrombin generation assay** — research tool, not routine In this acute VTE setting, anticoagulation is initiated immediately; thrombophilia workup is deferred until after acute phase resolution and cessation of anticoagulation (which can falsely normalize protein C/S levels). ## Management Implications **Clinical Pearl:** Patients with Factor V Leiden and VTE require: - Immediate anticoagulation (LMWH, UFH, or DOAC) - **Cessation of OCPs** — absolute contraindication - Consideration of extended anticoagulation (beyond 3 months) if unprovoked VTE - Counseling on VTE risk with future hormonal therapy - Family screening if homozygous or recurrent thrombosis [cite:Harrison 21e Ch 111]