Antithrombin Deficiency

Question 1

what does antithrombin do?

Answer 1

AT is an enzyme inhibitor that plays a key role in regulation of the coagulation pathway

1. inhibits thrombin (factor IIa)
2. acts on activated factors VIIa, IXa, Xa, and XIa to inhibit the coagulation cascade

Question 2

what’s the inheritance of AT deficiencies?

Answer 2

inherited or acquired

Question 3

what do AT deficiencies cause?

Answer 3

individuals with AT deficiency are prone to developing thrombotic episodes

aka too much clotting

Question 4

what causes acquired AT deficiency?

Answer 4

may be caused by any condition that results in:

1. decreased AT production
2. increased AT consumption
3. loss of AT

Question 5

where is AT synthesized?

Answer 5

liver

Question 6

what would decrease AT production?

Answer 6

since AT is synthesized in the liver, liver disease (think cirrhosis) would decrease AT production

Question 7

what would increase AT consumption?

Answer 7

• acute thrombosis
• surgery
• trauma

Question 8

what would cause a loss of AT?

Answer 8

Nephrotic syndromes are associated with urinary loss of AT

Question 9

what causes hereditary AT deficiency?

Answer 9

genetic mutations in the antithrombin gene

various types of mutations at different locations in the antithrombin gene may lead to AT deficiency

Question 10

what’s the inheritance pattern of AT deficiency?

Answer 10

autosomal dominant

Question 11

what are the types of mutations that can cause AT deficiency?

Answer 11

type I

type II

Question 12

what is type I mutation that causes AT deficiency?

Answer 12

the mutation causes a complete loss of the mutant antithrombin

results in significantly reduced level of circulating antithrombin

can happen with a nonsense mutation at the AT gene

**only heterozygous forms are observed in type I, as homozygous type I are fatal in utero

Question 13

what is a nonsense mutation?

Answer 13

a single nucleotide change (point mutation) leads to a premature stop codon

this results in an incomplete protein that is truncated

Question 14

what is type II mutation that causes AT deficiency?

Answer 14

functionally defective antithrombin that is otherwise synthesized in normal levels

typically due to a mutation that results in a single amino acid substitution at one of the reactive sites

Question 15

what does AT deficiency cause?

Answer 15

whether it is type I or type II, the deficiency in antithrombin leads to a hypercoagulable state

AT deficiency is one of the main inherited thrombophilia

Question 16

what is inherited thrombophilia?

Answer 16

hereditary conditions that result in a hypercoagulable state due to a genetic defect in component in the coagulation cascade

Question 17

defects in which components of the coagulation cascade can cause inherited thrombophilia?

Answer 17

AT deficiency

factor V Leiden

prothrombin G20210A

protein C deficiency

protein S deficiency

Question 18

What is the difference between type I and type II antithrombin deficiency?

Answer 18

Type I: Reduced level of circulating antithrombin

Type II: Relatively normal level of antithrombin, but they are
functionally defective

1 is less than 2, so antithrombin levels are lower in type I

Question 19

what are the two key clinical characteristics of AT deficiency?

Answer 19

1. increased risk of thrombosis

2. heparin resistance (heparin is a blood thinner)

Question 20

where does thrombosis happen in the body if there’s an AT deficiency?

Answer 20

typically manifests on the venous side

arterial thrombosis is less common

most common sites of thrombosis are the deep veins in the leg (deep vein thrombosis)

Question 21

what are the less common sites of thrombosis?

Answer 21

• hepatic veins
• renal veins
• retinal veins
• inferior vena cava

Question 22

which risk factors increase the risk of thrombosis?

Answer 22

thrombotic episodes in AT deficiency may happen spontaneously, which means that there was no other identifiable trigger for thrombosis

BUT acquired risk factors such as pregnancy, trauma, and oral contraceptive use increase the risk of thrombosis in individuals with AT deficiency

Question 23

what is deep vein thrombosis?

Answer 23

DVT

the presence of thrombus in deep veins, most commonly in the leg

if left untreated, particularly in the proximal leg, the thrombus can embolize and obstruct pulmonary arteries, causing potentially life threatening pulmonary embolism (PE)

Question 24

What type of thrombosis is characteristic of AT deficiency?

Answer 24

Venous thrombosis, such as DVT

Question 25

what does heparin do?

Answer 25

heparin is an anticoagulant so it would reduce clotting and thrombin activity

heparin binds to antithrombin and induces a conformational change that increases the affinity for thrombin and factor X

this dramatically increases the inactivating ability of antithrombin and promotes anticoagulation

increased heparin = increased AT activity = decreased thrombin activity = decreased clotting

Question 26

why is there heparin resistance in AT deficiency?

Answer 26

increased heparin = increased AT activity = decreased thrombin activity = decreased clotting

if there’s an AT deficiency then you need higher doses of heparin to get the same level of anticoagulation

Question 27

What is heparin’s mechanism of action?

Answer 27

1. Heparin binds to antithrombin
2. Induces conformational changes in antithrombin
3. Increases antithrombin’s ability to inactivate thrombin and factor Xa
4. Promotes anticoagulation

Question 28

when do you test for AT deficiency?

Answer 28

it’s super rare so you only test for it if there’s a high clinical suspicion for inherited thrombophilia or signs of heparin resistance

Question 29

Arrange the following hereditary thrombotic disorders in the order of prevalence starting with most common:
Antithrombin deficiency, Factor V Leiden, Protein C deficiency, Protein S deficiency, Prothrombin G20210A

Answer 29

1. Factor V Leiden
2. Prothrombin G20210A
3. Protein C deficiency
4. Protein S deficiency
5. Antithrombin deficiency

Question 30

what are the steps to test for AT deficiency?

Answer 30

1. heparin cofactor assay to measure AT activity

then, once decreased AT activity is established:
2. immunoassays like ELISAs

Question 31

what does a heparin cofactor assay do?

Answer 31

measures the level of antithrombin activity in the plasma

the assay essentially measures how fast heparin is able to inactivate thrombin or factor Xa

Since heparin works by binding to AT, defective AT would significantly hinder the action of heparin

impaired inactivation rate by heparin would indicate reduced AT activity

Question 32

what does an immunoassay do?

Answer 32

once decreased AT activity is established, measure the level of antithrombin antigen in the plasma

this determines the level of circulating antithrombin, which allows us to distinguish between type I and type II AT deficiency

type I is defined as less than 50% of normal AT antigen level while type II usually has normal AT antigen levels

Question 33

what is the level of circulation AT in type I AT deficiency?

Answer 33

type I is defined as less than 50% of normal AT antigen level

Question 34

what is the level of circulation AT in type II AT deficiency?

Answer 34

type II AT deficiency typically has normal AT antigen levels

Question 35

35-year-old woman with family history of thrombotic disorder presents with recurrent DVTs. What is the most likely clinical manifestation in a case of antithrombin deficiency?

Answer 35

Budd-Chiari syndrome

venous thrombosis is more common than arterial thrombosis in AT deficiency

Budd-Chiari syndrome is induced by obstruction of the hepatic vein, and is characterized by abdominal pain, hepatomegaly, and abdominal pain

Question 36

what disease are associated with arterial thrombosis?

Answer 36

Amaurosis fugax

ischemic colitis

recurrent fetal loss

stroke

Question 37

Which thrombotic disorders has the highest prevalence in the general US population?

Answer 37

Factor V Leiden

Question 38

The patient discloses that her family has been known to have AT deficiency. Given this information, which of the following test should be used for AT testing?

Answer 38

Heparin cofactor assay

Heparin cofactor assay is the first step in diagnosing AT deficiency.

the impaired inactivation rate by heparin would indicate reduced AT activity

AT antigen level can then be determined to differentiate between type I and type II deficiency

Question 39

The assay shows markedly reduced antithrombin activity and antigen level assay shows that the level of antithrombin is 40% of normal value. Which type of antithrombin gene mutation is most likely to be responsible for this finding?

Answer 39

nonsense mutation

reduction in both antithrombin activity level and antigen level is consistent with type I AT deficiency

nonsense mutation places a premature stop codon which would result in reduced synthesis of antithrombin