Each week, Osmosis shares a USMLE® Step 1-style practice question to test your knowledge of medical topics. Today’s case involves a 25-year-old woman with breathing difficulties and chest pain. Labs show an elevated d-dimer. Purified protein C is added to the patient’s plasma and causes no change in the lab values. Can you figure it out?
A 25-year-old Caucasian woman presents to the emergency department due to difficulty breathing. Two hours ago, she suddenly felt chest pain accompanied by dyspnea. The patient denies any recent trauma, and she does not smoke or use illicit drugs. She is sexually active with her partner and uses condoms for contraception. The patient’s temperature is 37.1°C (98.8°F), pulse is 75/min, and blood pressure is 118/73 mmHg. On physical examination, the patient appears distressed. Heart sounds are normal and the lungs are clear to auscultation. Labs show an elevated d-dimer. PT and PTT are 12 and 10 seconds, respectively. Purified protein C is added to the patient’s plasma and causes no change in the lab values. Which of the following is the most likely diagnosis?
A. Protein S deficiency
B. Prothrombin gene mutation
C. Antiphospholipid syndrome
D. Antithrombin deficiency
E. Factor V Leiden deficiency Scroll down to find the answer!
→ Reinforce your understanding with more self-assessment items on Osmosis Prime.
The correct answer to today’s USMLE® Step 1 Question is…
E. Factor V Leiden deficiency
Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect answer explanations
The incorrect answers to today’s USMLE® Step 1 Question are…
A. Protein S deficiency
Incorrect: Protein S is a vitamin K-dependent protein that serves as a cofactor for activated protein C to inactivate the procoagulant factors Va and VIIIa, thereby reducing thrombin generation. Protein S also functions as a cofactor for activated protein C in augmenting fibrinolysis. Deficiency of protein S may occur due to mutations and leads to hypercoagulability, resulting in pulmonary embolism. Although protein S deficiency is difficult to distinguish from factor V Leiden deficiency, the former is far rarer and therefore less likely.
B. Prothrombin gene mutation
Incorrect: Prothrombin, also known as factor II, is the precursor of thrombin, the end product of the coagulation cascade. Thrombin’s main role is to proteolytically cleave fibrinogen to fibrin, which in turn crosslinks to form a fibrin clot. It also interacts with other hemostatic components. The G20210A point mutation in the prothrombin gene results in a gain-of-function of prothrombin that leads to hypercoagulability. However, the failure to change PTT after adding purified protein C favors another diagnosis.
C. Antiphospholipid syndrome
Incorrect: Antiphospholipid syndrome (APS) refers to an autoimmune condition characterized by venous and/or arterial thrombosis due to the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I antibodies). It is most commonly associated with systemic lupus erythematosus (SLE). Patients with APS often show prolonged PTT. In contrast, this patient shows no features of SLE and has reduced PTT.
D. Antithrombin deficiency
Incorrect: Antithrombin (AT, previously called AT III) deficiency may be acquired or inherited in an autosomal dominant fashion with variable penetration. Antithrombin is a natural anticoagulant that inhibits thrombin (factor IIa), factor Xa, and other factors in the coagulation cascade. A variety of mutations have been recognized. AT has no direct effect on the PT, PTT, or thrombin time. Instead, it diminishes the increase in PTT following heparin administration. This phenomenon exists since heparin, an indirect inhibitor of thrombin and factor Xa, requires functional AT to be effective.
Main explanation
This young patient who has no acquired risk factors for hypercoagulability (e.g., smoking, OCP use) is presenting with a pulmonary embolism, raising concerns for a hereditary cause. Factor V Leiden is the most common inherited hypercoagulability disorder in Caucasians with venous thromboembolism (VTE). Patients may be homozygous or heterozygous.heterozygous.

Factor V is a procoagulant clotting factor that is synthesized as an inactive form and activated by thrombin at the wound site. Activated factor V then functions as a cofactor in the production of more thrombin from prothrombin. However, thrombin also halts its own production via a negative feedback loop. It does so by activating protein C (aPC), a protease that deactivates factor Va and factor VIIIa, thereby reducing thrombin production.production.

Factor V Leiden deficiency is caused by a single point mutation in the factor V gene in which guanine is switched to adenine. The corresponding mRNA codon forms a polypeptide chain in which arginine is replaced by glutamine at position Arg506. Consequently, the cleavage site is altered and factor V can no longer be degraded by protein C.
Patients are at increased risk for venous or arterial thromboembolism, MI, stroke, and obstetric complications. Laboratory testing often shows shortened or normal PTT. Diagnosis can be made via functional assay by demonstrating failure to prolong PTT with the addition of purified protein C (protein C resistance). Definitive diagnosis is made via genetic testing.
Major takeaway
Factor V Leiden is an autosomal dominant condition and is the most common cause of inherited hypercoagulability in Caucasians. Point mutations alter the cleavage site of factor V at locus Arg506, resulting in factor V that is resistant to degradation by protein C.
References
_________________________
Want more USMLE® Step 1 practice questions? Try Osmosis today! Access your free trial and find out why millions of current and future clinicians and caregivers love learning with us.

The United States Medical Licensing Examination (USMLE®) is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). Osmosis is not affiliated with NBME nor FSMB.
Leave a Reply