A 21-year-old woman comes to the physician because of a 1-day history of right leg pain. The pain is worse while walking and improves when resting. Eight months ago, she was diagnosed with a pulmonary embolism and was started on warfarin. Anticoagulant therapy was discontinued two months ago. Her mother had systemic lupus erythematosus. On examination, her right calf is diffusely erythematous, swollen, and tender. Cardiopulmonary examination shows no abnormalities. On duplex ultrasonography, the right popliteal vein is not compressible. Laboratory studies show an elevated serum level of D-dimer and insensitivity to activated protein C. Further evaluation of this patient is most likely to show which of the following?

Mutation of coagulation factor V

Elevated coagulation factor VIII levels

A 3-week-old boy is brought to the pediatrician by his parents for a circumcision. The circumcision was uncomplicated; however, after a few hours, the diaper contained blood, and the bleeding has not subsided. A complete blood count was ordered, which was significant for a platelet count of 70,000/mm3. On peripheral blood smear, the following was noted (figure A). The prothrombin time was 12 seconds, partial thromboplastin time was 32 seconds, and bleeding time was 13 minutes. On platelet aggregation studies, there was no response with ristocetin. This result was not corrected with the addition of normal plasma. There was a normal aggregation response with the addition of ADP. Which of the following is most likely true of this patient's underlying disease?

Adding epinephrine would not lead to platelet aggregation

A 12-year-old boy is brought by his mother to the emergency room because of a swollen, hot, and tender knee that he sustained after falling on his way home. He has never had a swollen joint before; however, he has had frequent nosebleeds throughout his life. His mother is worried because they live with her parents who are currently on blood thinners. Every morning she puts the blood thinner pill in the boy's grandfather's milk and was concerned that she may have switched it this morning. Family history reveals a number of uncles who have had bleeding disorders; however, the mother does not know the exact disorder suffered by these relatives. A hematologic panel reveals the following findings: Bleeding time: Increased Prothrombin time: 12 seconds Partial thromboplastin time (PTT): 55 seconds PTT after factor mixing study: 37 seconds Which of the following most likely explains the abnormal partial thromboplastin time in this patient?

Activation of inhibitory factors

A 35-year-old woman presents to her primary care physician for recurrent deep venous thrombosis (DVT) of her left lower extremity. She is a vegetarian and often struggles to maintain an adequate intake of non-animal based protein. She currently smokes 1 pack of cigarettes per day, drinks a glass of wine per day, and currently denies any illicit drug use, although she endorses a history of heroin use (injection). Her past medical history is significant for 4 prior admissions for lower extremity swelling and pain that resulted in diagnoses of deep venous thrombosis. Her vital signs include: temperature, 36.7°C (98.0°F); blood pressure, 126/74 mm Hg; heart rate, 87/min; and respiratory rate, 16/min. On physical examination, her pulses are bounding, the patient's complexion is pale, breath sounds are clear, and heart sounds are normal. The spleen is mildly enlarged. She is admitted for DVT treatment and a full hypercoagulability workup. Which of the following is the best initial management for this patient?

Begin warfarin, target INR 2.5–3.5

Consult IR for IVC filter placement

Begin warfarin, target INR 2.0–3.0

A 61-year-old man presents to the emergency room with a painful, swollen left leg. He states that his symptoms began that morning after a long flight from Australia. He denies shortness of breath, chest pain, or cough. On review of systems, he notes that he has been constipated recently and had several episodes of bright red blood per rectum. He has not noticed any weight loss, fevers, or night sweats. He has a past medical history of a deep vein thrombosis 4 years ago during a hospitalization for community acquired pneumonia and was treated with warfarin for 3 months afterward. He also has chronic hepatitis C from previous intravenous drug use. The patient has a 30 pack-year smoking history and has never had a colonoscopy. His father is 84-years-old and has chronic kidney disease from diabetes, and his mother passed away from a massive pulmonary embolus when pregnant with his younger sister. In the emergency room, his temperature is 98.7°F (37.1°C), blood pressure is 142/85 mm/Hg, pulse is 79/min, and respirations are 14/min. On exam, he is in no acute distress. His left calf is larger in caliber than the right calf which is red and tender to palpation. Dorsiflexion of the foot worsens the pain. His abdomen is soft, nontender, and nondistended without hepatomegaly. The remainder of the physical exam is unremarkable. Labs are shown below: Hemoglobin: 13.0 g/dL Leukocyte count: 6,000/mm^3 Platelets: 160,000/mm^3 Aspartate aminotransferase: 15 U/L Alanine aminotransferase: 19 U/L Alkaline phosphatase: 81 IU/L Hepatitis C antibody: reactive Hepatitis C titer: 0 copies/mL Which of the following is the most likely cause of this patient’s condition?

Resistance of factor V to inactivation by protein C

Loss of antithrombin III in urine

A 24-year-old woman comes to the physician because of pain and swelling of her left leg over the past 24 hours. The pain is worse while walking and improves when resting. Seven months ago, she was diagnosed with a pulmonary embolism and was started on warfarin. Anticoagulant therapy was discontinued 1 month ago. Her sister has systemic lupus erythematosus. The patient does not smoke. She currently takes no medications. Her temperature is 37.8°C (100°F), pulse is 78/min, and blood pressure is 123/72 mm Hg. On physical examination, the left calf is diffusely erythematous, swollen, and tender. Dorsal flexion of the left foot elicits pain. Cardiopulmonary examination shows no abnormalities. On duplex ultrasonography, the left popliteal vein is not compressible. Laboratory studies show an elevated serum concentration of D-dimer and insensitivity to activated protein C. Further examination is most likely to show which of the following?

Mutation of coagulation factor V

Elevated levels of homocysteine

A 48-year-old man comes to the emergency department because of sudden right flank pain that began 3 hours ago. He also noticed blood in his urine. Over the past two weeks, he has developed progressive lower extremity swelling and a 4-kg (9-lb) weight gain. Examination shows bilateral 2+ pitting edema of the lower extremities. Urinalysis with dipstick shows 4+ protein, positive glucose, and multiple red cell and fatty casts. Abdominal CT shows a large right kidney with abundant collateral vessels and a filling defect in the right renal vein. Which of the following is the most likely underlying cause of this patient's symptoms?

Malignant erythropoietin production

Increased lipoprotein synthesis

A 28-year-old woman at 36 weeks gestation presents with severe headache, epigastric pain, and visual disturbances. Her blood pressure is 160/110 mmHg. Laboratory studies show a hematocrit of 32%, leukocyte count of 9,400/mm³, and platelet count of 96,000/mm³. Serum studies reveal an aspartate aminotransferase of 94 U/L and an alanine aminotransferase of 92 U/L. Which of the following is the most likely cause of this patient's condition?

Overactivation of the coagulation pathway

Thrombotic obstruction of hepatic veins

Sequestration of platelets in the spleen

Embolism of amniotic fluid into maternal circulation

Viral reactivation and replication

Hypercoagulable states for USMLE Step 2 CK: High-Yield Internal Medicine Lessons

Virchow's Triad - The Clotting Culprits

📌 SHE: Stasis, Hypercoagulability, Endothelial injury.

Stasis: Disrupted blood flow (e.g., immobilization, atrial fibrillation, venous insufficiency).
Endothelial Injury: Vessel wall damage (e.g., surgery, trauma, catheters, atherosclerosis).
Hypercoagulability: Pro-thrombotic state, either inherited or acquired.
- Inherited: Factor V Leiden, Prothrombin gene mutation.
- Acquired: Malignancy, pregnancy, OCPs (estrogen), sepsis.

⭐ Factor V Leiden is the most common inherited thrombophilia in Caucasian populations.

Inherited Thrombophilias - Bad Blood by Birth

General Presentation: Suspect in patients < 50 years with unprovoked thrombosis, recurrent venous thromboembolism (VTE), or a significant family history. Most are autosomal dominant.
Factor V Leiden (FVL)
- Pathophysiology: A specific gene mutation makes Factor V resistant to cleavage and inactivation by Activated Protein C (APC).
- Diagnosis: APC resistance assay, confirmed with genetic testing.
- ⭐ Factor V Leiden is the most common inherited thrombophilia in Caucasian populations, significantly increasing the risk for DVT and PE.
Prothrombin Gene Mutation (G20210A)
- Pathophysiology: Mutation leads to increased prothrombin levels, promoting excess thrombin generation.
Protein C or S Deficiency
- Pathophysiology: Reduced levels of these natural vitamin K-dependent anticoagulants.
- ⚠️ Warning: Can lead to warfarin-induced skin necrosis; always bridge with heparin.
Antithrombin Deficiency
- Pathophysiology: Lack of antithrombin impairs the inactivation of thrombin and Factor Xa.
- 💡 Pearl: Patients may show heparin resistance as heparin's anticoagulant effect depends on antithrombin.

Protein C pathway and its role in coagulation regulation

Acquired Hypercoagulable States - Clots on the Go

Antiphospholipid Syndrome (APS): Autoantibodies against phospholipid-binding proteins.
- Clinical: Venous/arterial thrombosis, recurrent fetal loss.
- Labs: Anticardiolipin Ab, Anti-β2 glycoprotein-I Ab, Lupus Anticoagulant.
⭐ Paradoxically, Lupus Anticoagulant can prolong the aPTT in vitro but causes thrombosis in vivo.
Malignancy: Procoagulants from tumors (e.g., pancreatic, lung adenocarcinoma).
- Presents as Trousseau's syndrome (migratory superficial thrombophlebitis).
Nephrotic Syndrome: Urinary loss of anticoagulant proteins (Antithrombin III).
- Leads to ↑ risk of DVT, PE, and especially renal vein thrombosis.
Pregnancy & OCPs: ↑ Estrogen → ↑ clotting factors, ↓ Protein S.
Immobilization / Post-Op: Stasis + endothelial injury (Virchow's Triad).
Myeloproliferative Neoplasms: (e.g., Polycythemia Vera) ↑ viscosity & platelet activation.
Heparin-Induced Thrombocytopenia (HIT): IgG antibodies against heparin-platelet factor 4 (PF4) complexes.

Antiphospholipid Syndrome: Two-Hit Mechanism of Thrombosis

Workup & Management - Spot & Stop the Clot

Initial Workup: Algorithm-driven based on pre-test probability.

Acute Management:
- Immediate anticoagulation: DOACs (Apixaban, Rivaroxaban) or LMWH/UFH.
- IVC filter only if anticoagulation is absolutely contraindicated.
Long-Term Therapy:
- DOACs are first-line over Warfarin.
- Duration: 3-6 months for provoked VTE; consider lifelong for unprovoked/recurrent cases.

⭐ Factor V Leiden is the most common inherited thrombophilia in Caucasians, causing resistance to activated Protein C.

Algorithm for Diagnosis of PE in Outpatients

High‑Yield Points - ⚡ Biggest Takeaways

Factor V Leiden is the most common inherited thrombophilia, causing resistance to activated Protein C.

Prothrombin gene mutation is the second most common, leading to ↑ prothrombin levels and venous clots.

In Antithrombin III deficiency, heparin is less effective as it requires antithrombin to work.

Protein C or S deficiency carries a risk for warfarin-induced skin necrosis.

Antiphospholipid syndrome presents with thrombosis, recurrent pregnancy loss, and a paradoxically prolonged aPTT.

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