Welcome to USMLE practice question #144! Today’s topic is hematology.
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A 42-year-old woman is admitted to the intensive care unit with fever, confusion, and hypotension. She was diagnosed with gram-negative sepsis secondary to a urinary tract infection. Physical examination reveals diffuse petechiae and ecchymoses, and oozing is noted from venipuncture sites. Laboratory studies show thrombocytopenia, elevated D-dimer, PT and PTT, and decreased fibrinogen. Which of the following best explains the underlying pathophysiology of her condition?
A) Depletion of antithrombin III leading to unopposed thrombin generation
B) Complement-mediated destruction of platelets causing consumptive coagulopathy
C) Activation of tissue factor by systemic inflammation leading to widespread fibrin formation
D) Impaired plasminogen activation resulting in excessive fibrin deposition
E) T-cell mediated cytokine release leading to suppression of megakaryopoiesis
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the underlying pathophysiology of her condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the problem, 2nd: Identify the underlying cause.
Step 3: Read the vignette carefully and ask yourself: “Based on the findings and my diagnosis, the underlying cause is ______________________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 42-year-old woman presents with disseminated intravascular coagulation (DIC), as evidenced by thrombocytopenia, elevated D-dimer, prolonged PT and PTT, and decreased fibrinogen. DIC is a complication of gram-negative sepsis, triggered by systemic inflammation and widespread activation of the coagulation cascade.
ANSWER CHOICES:
CHOICE A: Depletion of antithrombin III leading to unopposed thrombin generation
Explanation: Antithrombin III inhibits thrombin and other clotting factors. Depletion of antithrombin III can occur in DIC, contributing to hypercoagulability. However, while antithrombin depletion exacerbates DIC, it is not the primary initiating event.
CHOICE B: Complement-mediated destruction of platelets causing consumptive coagulopathy
Explanation: Complement activation can cause platelet destruction in conditions like thrombotic microangiopathies (e.g., atypical hemolytic uremic syndrome). Platelet consumption in DIC is not caused by complement-mediated destruction.
CHOICE C: Activation of tissue factor by systemic inflammation leading to widespread fibrin formation
Explanation: In sepsis-induced DIC, inflammatory cytokines (e.g., TNF-alpha, IL-1) stimulate endothelial cells and monocytes to express tissue factor (TF). TF activates the extrinsic coagulation pathway, leading to excessive thrombin generation, fibrin formation, and microvascular thrombosis. This triggers consumptive coagulopathy, resulting in bleeding due to depletion of platelets and clotting factors.
CHOICE D: Impaired plasminogen activation resulting in excessive fibrin deposition
Explanation: Impaired plasminogen activation reduces fibrinolysis, leading to excessive fibrin deposition. This occurs in conditions such as thrombotic thrombocytopenic purpura (TTP). In DIC, fibrinolysis is often increased (as evidenced by elevated D-dimer), not impaired.
CHOICE E: T-cell mediated cytokine release leading to suppression of megakaryopoiesis
Explanation: Cytokine-mediated suppression of megakaryopoiesis can cause thrombocytopenia in bone marrow disorders or chemotherapy-induced myelosuppression.
FINAL VERDICT…
CORRECT ANSWER: C) Activation of tissue factor by systemic inflammation leading to widespread fibrin formation
The underlying pathophysiology of DIC involves activation of tissue factor on endothelial cells and monocytes in response to inflammatory cytokines, leading to excessive thrombin generation, fibrin formation, and microvascular thrombosis. This results in consumptive coagulopathy, where clotting factors and platelets are depleted, causing both thrombosis and bleeding.
KEY CONCEPTS:
Pathophysiology of Disseminated Intravascular Coagulation (DIC):
Triggered by systemic inflammation (e.g., sepsis) or massive tissue injury.
Inflammatory cytokines induce tissue factor expression on endothelial cells and monocytes.
Tissue factor activates the extrinsic coagulation pathway → Excessive thrombin generation → Widespread fibrin formation.
Consumptive coagulopathy depletes clotting factors and platelets → Bleeding tendency.
Clinical Features of DIC:
Bleeding: Petechiae, ecchymoses, oozing from venipuncture sites.
Thrombosis: Microvascular clots causing organ dysfunction (e.g., renal failure).
Laboratory findings:
Thrombocytopenia.
Prolonged PT/PTT.
Elevated D-dimer (marker of fibrinolysis).
Low fibrinogen levels.
Management of DIC in Sepsis:
Treat underlying cause (e.g., antibiotics for gram-negative sepsis).
Supportive care:
Blood product replacement (e.g., platelets, fresh frozen plasma) for bleeding.
Heparin for thrombosis in select cases.
Monitor coagulation parameters closely.