AT III Deficiency

What kind of molecule is AT III?

• Serine Protease Inhibitor (Serpin)

• Vitamin K independent

What are serine protease inhibitors?

Main regulators of many serine proteases generated during activation of the clotting cascade

In the presence of Heparin, what does AT III act upon mainly?

Strong inhibitor of thrombin and factor Xa

What other clotting factors does AT III secondarily act on?

Factors:

• IX

• XIa

• XIIa

• VIIa

AT III prevalence

1:2000 to 1:5000 people

Is AT III deficiency a risk for women?

• Risk of thrombosis is particularly high in pregnancy

• Heparin prophylaxis is recommended throughout pregnancy & coumadin for 6 weeks postpartum

AT III importance in peds

Neonates are AT III deficient d/t underdeveloped livers and typically require a greater heparin loading dose

AT III Deficiency genetics

• Autosomal dominant

• Pt’s are generally heterozygous

• Causes AT III levels to be 40-60% less than normal

• Complete absence of AT III is thought to be incompatible w/ life (Homozygotes)

AT III Deficiency characteristics

Distinct thromboses in the:

• venous system (vena cava)

• Extremities

• Mesenteric

• renal

• hepatic

Inherited AT III Deficiency Type I

Low levels of circulating antithrombin

Inherited AT III Deficiency Type II

Antithrombin which does not function properly

High risk situations for a thrombosis

• Surgery

• Pregnancy

• Trauma

• Oral contraceptives

Acquired AT III Deficiency can be from:

• Pre-op heparin therapy

• DIC

• Hemolytic anemias

• Cancer/chemotherapy

• Systemic erythromatosus lupus

• Liver dz

• nephrotic syndrome

• Bone marrow transplants

What measures AT III Levels?

• Heparin cofactor assay of antithrombin activity

• Measures the ability of antithrombin to bind heparin & neutralize thrombin or Factor Xa

Normal concentration of AT III

0.12mg/mL

AT III MOA

• AT III acts by irreversibly binding to thrombin

• Neutralizes the effect of thrombin on fibrinogen

• Prevents clot formation

Heparin and AT III

• Heparin binds to AT III

• The rate of AT III-thrombin rxn is greatlly enhanced in the presence of heparin

• Heparin has no anticoagulant effect in AT III depleted plasma

Heparin Resistance guideline

ACT < 480 seconds after a bolus of 300 u/kg of Heparin (HLD)

Causes of heparin resistance

• Pre-op heparin therapy

• AT III < 60%

• Platelet count > 300,000 (plts bind heparin)

• DEC’d liver synthesis of AT III

• HIT

Strategies to combat heparin resistance

• Fresh Frozen Plasma (restores heparin effectiveness)

• Pooled AT III preparations (Thrombate)

• Recombinant AT III (ATryn)

• Whole Blood (but unlikely)

What is FFP?

• Plasma separated from erythrocytes & Platelets

• Contains all other procoagulants

1 unit of FFP is approximately how many mLs?

~200-250 mL

FFP matching

Compatibility for ABO antigens is desired, not required

FFP side effects

• allergic rxn

• transmission of dz (HIV, hepatitis, etc)

FFP characteristics

• High volume

• Slower (must be thawed in lab)

• small risk of TRALI, transfusion rxn

• Much cheaper

AT III concentrate characteristics

• very low volume (thus preferred 1st choice)

• Faster, reconstitured powder

• virtually no TRALI rxn risk

• Very expensive

Disseminated Intravascular Coagulation (DIC)

• Consumptive coagulopathy

• Activation of coagulation mechanisms

• Leads to formation of clots in blood vessels

• Clots consume the coagulation proteins & platelets

• Thus abnormal bleeding occurs since there no more factors left to do more clotting

DIC marker on labs

• ↑ PT

• ↑ PTT

• ↓ Fibrinogen

• ↑ Fibrin degradation products (FDP, FSP)

• Thrombocytopenia (low plts)