AssessmentsAntithrombin III deficiency
Antithrombin III deficiency
USMLE® Step 1 style questions USMLE
A 46-year-old woman comes to the clinic complaining that her wedding ring no longer fits on her finger. On inspection, there is marked edema, particularly in the periorbital region and lower extremities. Of note, she has had no recent infections, and no blood in her urine. The lab results are shown below.
A diagnosis of nephrotic syndrome is made and an ultrasound reveals ascites and a clot in the left renal vein, suggesting a loss of a particular anticoagulant in the urine. Which of the following factors does this natural anticoagulant typically inactivate?
Antithrombin III is an anticoagulant protein which is made by the liver.
So antithrombin III deficiency is when a genetic mutation makes antithrombin III either deficient or defective.
Antithrombin III deficiency presents as a hemostasis disorder.
Hemostasis is the process where blood flow is stopped after there’s damage to a blood vessel, and it has two steps.
Primary hemostasis involves the formation of a platelet plug at the site of injury, and secondary hemostasis involves the coagulation cascade, where several clotting factors come into play to form a fibrin mesh over the platelet plug to reinforce it - forming a blood clot.
Hemostasis can be both stimulated, and inhibited by several factors.
In the first category, there’s thrombin, or factor II, which accelerates hemostasis by increasing platelet activation, and cleaving several factors involved in secondary hemostasis to their active form.
On the other hand, the most important factor that inhibits hemostasis is antithrombin III.
Antithrombin III binds excess thrombin and factor X from secondary hemostasis, and also inhibits coagulation factors VII, IX, XI and XII - which are also key players in secondary hemostasis.
So, antithrombin helps regulate clot formation, preventing clots from growing too large and blocking blood flow to tissues supplied by the vessel.
It also prevents clots from getting so big that small parts of the growing clot break off in the form of emboli.
Finally, the anticoagulant properties of antithrombin III can also be enhanced by an anticoagulant medication called heparin - which binds to antithrombin and increases its affinity for its target proteins.
So, the two major consequences of antithrombin III deficiency are increased risk of thrombosis and insensitivity to heparin.
Antithrombin deficiencies can be acquired, or genetic.
Acquired deficiencies are more common, and result from impaired production of antithrombin III due to liver disease, or protein losses such as nephrotic syndrome, or disseminated intravascular coagulation or DIC. With DIC, clots form all over the body from trauma, sepsis, or medications, and this depletes both pro-coagulant and anticoagulant factors, so severe bleeding ensues.
Genetic causes occur via an autosomal dominant inheritance pattern and they are further divided into type I and type II disease. With type I, there is a quantitative defect, so the person doesn’t make enough Antithrombin III.
In type II disease, there is a qualitative defect with Antithrombin III - so while enough of it is produced, the mutation leads to a structurally abnormal protein, that doesn’t fold properly, and, therefore, can’t do its job right.
Most people with antithrombin III deficiency present with a venous thromboembolism. Most commonly a clot forms in the deep veins of the leg and then travels to other parts of the body like the heart of the brain, causing strokes, or the lungs, causing pulmonary embolism.
Clots that form in the arteries, called arterial thromboembolisms can occur as well, but they occur less frequently than venous thromboembolism in patients with antithrombin III deficiency. Heparin insensitivity can be seen when individuals don’t respond to heparin that is given for blood clots.