Antithrombin III deficiency

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Introduction0:00–0:24

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.

Pathophysiology0:24–2:22

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.

Causes2:22–3:26

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 or the brain, causing strokes; or the lungs, causing pulmonary embolism.

Symptoms3:26–3:26

Symptoms3:26–4:07

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. Antithrombin III deficiency can be suspected based on a family history of deep vein thrombosis or DVT and based on lab values, especially the partial thromboplastin time, or PTT, before and after heparin administration.

Diagnosis4:07–5:29

PTT reflects how long it takes for coagulation factors used in secondary hemostasis to activate and lead to clot formation.
And normally, after heparin is given, it binds to antithrombin III and causes it to inactivate thrombin and factor X, prolonging the PTT.
So with antithrombin III deficiency, the PTT doesn’t change, or it doesn’t prolong as much as it should, after heparin administration.
Diagnosis can be confirmed with a functional assay for plasma antithrombin activity called the antithrombin-heparin cofactor assay or AT-heparin cofactor assay.
During this test, the ability of heparin to inhibit thrombin or factor Xa gets measured. Antithrombin III deficiency is diagnosed when antithrombin activity is less than 80% of the normal range in AT-heparin cofactor assay.
Genetic testing for this disorder is still being researched and is not routinely available. Treatment is necessary when individuals develop a clot, and anticoagulant therapy can be done with a direct thrombin inhibitor like argatroban or a direct factor Xa inhibitor like rivaroxaban.

Treatment5:29–6:47

Additionally, prophylactic anticoagulation with warfarin or the above medications can be used in high-risk settings such as during surgery.
For secondary prophylaxis, meaning preventing the recurrence of deep vein thrombosis, warfarin or low molecular weight heparin can be used - and the latter is preferred during pregnancy.
And even though heparin, or its low molecular weight counterpart, is not as effective as other anticoagulant drugs used with antithrombin III deficiency, it’s the only one that doesn’t cross the placenta, so it doesn’t have any negative effects on the fetus.
So it is given in the hope that it can prolong the PTT just enough to have an anticoagulant effect. On the other hand, warfarin is contraindicated during pregnancy because it can cross the placenta and cause congenital malformations in the fetus or even death!
In addition, many of these people benefit from replacement antithrombin III either via recombinant antithrombin III or from plasma transfusions, and is indicated for patients with antithrombin III deficiency who are not controlled with oral anticoagulants.All right, as a quick recap, antithrombin III deficiency refers to a coagulation disorder where this protein becomes deficient or defective due to genetic mutations, or it can be acquired.

Review6:47–7:28

The most common presentation is the development of a venous thromboembolism. Treatment involves the use of a direct thrombin inhibitor or direct factor Xa inhibitors.
Prophylactic treatment is useful during