What is antithrombin deficiency?
Antithrombin deficiency is a condition where a natural anti-clotting agent in the blood, known as antithrombin III, is either deficient or dysfunctional. It can be inherited or may be acquired in life. The condition can lead to serious complications when clots form in the circulation and block the blood flow to crucial organs. Death is possible. Antithrombin deficiency is a fairly common blood clotting disorder occurring in about 1 in 2,000 to 5,000 people. It can affect both men and women equally.
Function of Antithrombin
Blood clotting (coagulation) is an essential mechanism by which the body can ‘plug’ any point of blood loss from arteries or veins. It ensures that the compromised blood vessel does not lose large amounts of blood that can affect health or even lead to death. In order to do this, various inactive enzymes and clotting components are constantly circulating in the bloodstream. The moment it is activated it can immediately start clotting at the affected site and plug the leak.
However, the body has several fail safe mechanisms to ensure that these components of blood clotting are not prematurely activated. Should a clot form in an otherwise uncompromised blood vessel, it can block the normal flow of blood and lead to tissue death in the affected area. This can at times be fatal. A single clotting enzyme or component on its own cannot cause the formation of a clot. Instead several enzymes need to activate each other and eventually activate the actual clotting material for a clot to form. This is a multi-step process known as the coagulation cascade.
In addition, there are certain substances which can help break down clots and prevent clotting from happening. These substances are anti-clotting agents, known as anticoagulants. Antithrombin III is an anticoagulant. It blocks several of the clotting enzymes from becoming activated and is meant to prevent a premature or unnecesary blood clot from forming. Antithrombin is not extremely efficient and becomes more potent when it works synergistically with heparin, another natural anticoagulant.
What happens in antithrombin deficiency?
Thrombin is one of the final components of the coagulation cascade. It is known as prothrombin (previously thrombinogen) in its inactive form. Despite its name, antithrombin does not only inhibit thrombin. Antithrombin actually blocks several clotting enzymes. It primarily blocks clotting factors Xa, IXa and IIa (thrombin). Antithrombin also has an impact on XIIa, XIa and the complex of factors VIIa and III (tissue factor). Clotting enzymes are constantly getting activated in the bloodstream to plug tiny holes that form in daily life, as a result of vessel wall damage, substances that affect the coagulability of blood and with slow movement of blood flow.
Imbalance between clotting and anti-clotting
However, the presence of anticoagulants like antithrombin ensures that the activated clotting enzymes do not create clots at various sites in the circulation. Normally the balance between the activated clotting factors and anticoagulants are such that blood flow continues smoothly and clots do not obstruct blood vessels. However, in antithrombin deficiency the person is at risk of having blood clots form within the blood vessels. Antithrombin may not be completely deficient for the manifestations of antithrombin deficiency to arise. Even just half the normal antithrombin levels are sufficient to lead to abnormal clotting.
Dangers of antithrombin deficiency
Clots can block blood supply to the brain, heart, lungs and even the bowels among various other organs. This can lead to tissue death, organ dysfunction and even lead to death of a person. Therefore a patient may need antithrombin replacement but there is added risk with blood products as the patient may contract HIV, viral hepatitis and other blood-borne infections. Therefore a person with antithrombin deficiency is not only at risk of blockages in the blood supply but also of infections, some of which are incurable, during the course of treatment for the condition.
Types of Antithrombin Deficiency
There are two types of antithrombin deficiency – type I and type II.
In type of antithrombin deficiency, there is an insufficient amount of otherwise normally acting antithrombin in circulation. The balance in terms of quantity is therefore in the favor of the activated clotting factors.
With type II antithrombin deficiency, the quantity of antithrombin is normal but it does not function as it should. The dysfunctional antithrombin can therefore not act against activated clotting factors.
Signs and Symptoms
The symptoms seen in antithrombin deficiency largely depends on the site of clot formation (thrombosis). A blood clot (thrombus) is more likely to occur in the venous system (veins that carry away deoxygenated blood back to the heart) rather than in arteries. The symptoms of antithrombin deficiency may therefore include blockages of blood vessels at the following sites.
Deep vein thrombosis (DVT) presents as :
- Swelling of the legs, usually only the affected leg.
- Pain in the leg and thigh worsened with movement.
- Discoloration of the skin on the affected leg.
Pulmonary embolism (PE) presents as :
- Difficulty breathing (dyspnea).
- Chest pain.
- Coughing, which may be bloody sputum.
Central nervous system
- Slurred speech.
- Blurred vision, double vision or blindness.
- Difficulty understanding the speech of others.
- Weakness in the face muscles, arms and/or legs.
- Tingling and numbness of the face, arms and/or legs.
- Poor coordination.
- Dizziness or fainting.
- Abdominal pain and cramping.
- Abdominal bloating.
- Bowel urgency.
- Bloody stools – fresh blood in the feces.
Causes of Antithrombin Deficiency
Antithrombin deficiency can be inherited or acquired. Inherited cases are usually present from birth and are due to genetic defects that are passed from parents to the child. Only one copy of the mutated gene is needed to lead to inherited antithrombin deficiency. A person will have the condition for life in these cases and need to be treated on an ongoing basis.
Acquired antithrombin deficiency develops during life even though there is no inherited genetic defect. It may develop secondary to several possible diseases. These conditions may include :
- Acute respiratory distress syndrome (ARDS)
- Bone marrow transplantation
- Disseminated intravascular coagulation (DIC)
- Kidney disease
- Liver disease
- Sepsis (commonly referred to as blood poisoning)
Certain medication and therapeutic procedures may also be the cause of antithrombin deficiency (iatrogenic causes). Not all patients using these drugs or undergoing these procedures may be affected.
- Estrogen replacement and oral contraceptives
- Heparin injections
- Chemotherapy using asparaginase
- Following transfusion of blood (acute hemolytic transfusion reactions)
It is also possible for antithrombin levels to be lower than normal in some stages of life despite the lack of a disease.
- Pregnancy (particularly third trimester)
- At birth (newborns naturally have lower antithrombin levels which increase within the first month of life)
Tests and Diagnosis
Two important tests are conducted to diagnose antithrombin deficiency :
- Antithrombin activity where the ability of antithrombin to neutralize clotting factors like thrombin are tested. It indicates whether the antithrombin is functioning normally or not.
- Antithrombin antigen to assess the amount of antithrombin within the sample. It indicates whether there is sufficient antithrombin or not.
Genetic testing is rarely done except for screening purposes.
- Type I antithrombin deficiency : Both activity and antigen is decreased. The lower than normal antithrombin activity is due to insufficient amounts of otherwise normal antithrombin.
- Type II antithrombin deficiency : Activity is decreased but antigen is within normal levels.
Treatment of Antithrombin Deficiency
Heparin and warfarin may be used in acute cases where a clot has formed or the risk of a clot forming is high. These anitcoagulants may be used for short periods of up to a few months at a time. Long term use of anticoagulants is usually not considered but if needed then warfarin may be used. However, it increases the risk of a major hemorrhage which can be fatal.
Antithrombin concentrates may be needed in certain patients where anticoagulants are contraindicated. It also increase the effectiveness of anticoagulant medication. Replacement therapy is mainly considered when a patient is pregnant or soon to undergo major surgery. Antithrombin supplementation may also be considered in cancer patients, where the patient is in shock or with sepsis.