Antithrombin III deficiency

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. This causes excessive clot formation, and the clots can get lodged in small vessels that nourish different organs and tissues, causing strokes.

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.