A 28-year-old man with a history of recurrent thrombosis (deep vein thrombosis at age 24, pulmonary embolism at age 27) presents for hypercoagulability workup. Which of the following is NOT associated with inherited thrombophilia?

## Inherited vs. Acquired Thrombophilia: Distinguishing the Mechanisms **Key Point:** Inherited thrombophilias are due to genetic defects in coagulation factors, anticoagulant proteins, or fibrinolytic factors. Elevated lipoprotein(a) [Lp(a)] is an ACQUIRED risk factor for thrombosis, not an inherited thrombophilia—it is associated with impaired fibrinolysis and atherothrombotic disease, not primary hypercoagulability. ### The Five Major Inherited Thrombophilias | Defect | Mechanism | Inheritance | Relative Risk | |--------|-----------|-------------|---------------| | **Factor V Leiden** | Resistance to activated protein C (APC); point mutation at factor V cleavage site | Autosomal dominant | 3–8× (heterozygous); 50–80× (homozygous) | | **Prothrombin G20210A** | Increased factor II (prothrombin) levels | Autosomal dominant | 2–3× | | **Antithrombin III deficiency** | Reduced inhibition of thrombin, IIa, IXa, Xa, XIa | Autosomal dominant | 5–10× | | **Protein C deficiency** | Reduced inactivation of factors Va and VIIIa | Autosomal dominant | 5–10× | | **Protein S deficiency** | Reduced cofactor for protein C | Autosomal dominant | 5–10× | **High-Yield:** Factor V Leiden is the MOST common inherited thrombophilia in Caucasians (~5% prevalence); prothrombin G20210A is the second most common (~2% prevalence). Both are autosomal dominant. ### Why Lipoprotein(a) Is NOT an Inherited Thrombophilia **Clinical Pearl:** Lp(a) is a lipoprotein particle structurally similar to LDL, with an additional apolipoprotein(a) moiety. Elevated Lp(a) levels are: - **Genetically influenced** (heritable component ~70%), but NOT a single-gene disorder - Associated with impaired fibrinolysis (apolipoprotein(a) resembles plasminogen, competing for fibrin binding) - A risk factor for atherothrombotic disease (MI, stroke), NOT primary hypercoagulability - Classified as an **acquired/multifactorial** cardiovascular risk factor, not a Mendelian inherited thrombophilia **Warning:** Do not confuse "heritable" (runs in families) with "inherited thrombophilia" (single-gene defect causing hypercoagulability). Lp(a) is heritable but is NOT classified among the five major inherited thrombophilias. ### Diagnostic Approach to Hypercoagulability ```mermaid flowchart TD A[Recurrent VTE or arterial thrombosis]:::outcome --> B{Clinical suspicion for thrombophilia?}:::decision B -->|Yes| C[Screen for inherited thrombophilia]:::action C --> D[Factor V Leiden mutation]:::action C --> E[Prothrombin G20210A]:::action C --> F[Antithrombin III level]:::action C --> G[Protein C and S levels]:::action B -->|No or acquired risk factors| H[Assess for acquired thrombophilia]:::action H --> I[Antiphospholipid syndrome]:::outcome H --> J[Elevated Lp(a], hematologic malignancy, immobility]:::outcome ``` **Mnemonic: FAPPS** — Five major inherited thrombophilias: - **F**actor V Leiden - **A**ntithrombin III deficiency - **P**rothrombin G20210A - **P**rotein C deficiency - **P**rotein S deficiency ### Summary: Inherited vs. Acquired Thrombophilia | Category | Examples | Mechanism | |----------|----------|----------| | **Inherited** | Factor V Leiden, Prothrombin G20210A, Antithrombin III deficiency, Protein C/S deficiency | Single-gene defects; Mendelian inheritance | | **Acquired** | Antiphospholipid syndrome, Lp(a) elevation, malignancy, immobility, surgery | Environmental or multifactorial; develops over time | [cite:Harrison 21e Ch 139]