Coagulation Inhibitors, Thrombotic Disorders, and Anticoagulant Therapy

Question 1

Physiological inhibitor

Answer 1

• natural anticoagulants
• provide balance between thrombosis and hemorrhage
• slow activation of coag factors (suppress thrombin formation)
• assist in keeping clot formation localized (prevent excess thrombosis)
• deficiencies = increased clotting

Question 2

mechanisms of regulating coagulation

Answer 2

• local processes = fluid blood restricts clot formation
• cellular processes = macrophages remove activated coag factors
• intact blood vessel and endothelial surface = inert to coag factors and PLTs
• physiological inhibitors = substances that inactivate coag factors

Question 3

physiological inhibitors

Answer 3

• natural anticoagulant
• provide a balance between thrombosis and hemorrhage
• slow activation of coag factors; suppress thrombin formation
• assist in keeping clot formation localized; prevent excess thrombosis
• defs => increase clotting

Question 4

serine protease inhibitors

Answer 4

serpins

• antithrombin = inhibits factors IXa, Xa, XIa, XIIa, thrombin, kallikrein
• heparin cofactor II = inhibits thrombin

activity of both are enhanced by heparin; physiologic or therapeutic

Question 5

tissue factor pathway inhibitor

Answer 5

TWO Steps:

1. TFPI binds to Xa to directly inactivate it
2. TFPI bound to Xa inactivates TF:VIIa
   - feedback inhibition: activated hen coagulation is initiated; specifically when factor X -> Xa; TFPI inactivates Xa and then TFPI:Xa complex inactivate TF:VIIa complex
   - inhibits extrinsic pathway

Question 6

protein C

Answer 6

• vitamin K dependent zymogen
• activated when thrombin binds to thrombomodulin on endothelial cell surface (thrombin shifts from procoag to anticoag role)
• thrombin:thrombomodulin complex activates protein C (APC)
• serine protease - degrades Va, VIIIa;enhances fibrinolysis

Question 7

protein S

Answer 7

• vitamin K-dependent cofactor
• 2 forms = bound to C4b-binding protein
• free = heps protein C inhibit
• enhances action of APC

Question 8

inappropriate formation of PLT or fibrin clots that obstruct blood vessels

Answer 8

thrombosis

• venous or arterial
• can cause ischemia and necrosis

Question 9

thrombophilia

Answer 9

hypercoagulability

- increased clots formed

Question 10

causes of thrombotic disorders

Answer 10

• release of prothrombic molecules
• suppression of antithrombotic substances
• inappropriate PLT activation
• uncontrolled coag system activation
• uncontrolled fibrinolysis suppression

Question 11

activated protein C resistance

Answer 11

• most common mechanism: mutation in the factor V gene AKA factor V leiden
• amino acid substitution causes factor V to be resistant to APC
• factor Va remains active => increased thrombin production
• homozygous mutations = increased risk of thrombosis (3x for heterozygotes)
• APC inhibitors (autoantibody)
• protein S deficiency

Question 12

prothrombin G20210A mtuation

Answer 12

• mutation in prothrombin gene: increased prothrombin production and activity; increased risk of thrombosis
• sub of guanine to adenine at nucleotide base position 20210

Question 13

antithrombin deficiency

Answer 13

• can’t turn off serine protease

- inherited and acquired = liver, DIC, pregnancy, prolonged use of heparin, oral contraceptives

Question 14

protein C and S def

Answer 14

• usually acquired
• warfarin/Coumadin therapy
• DIC
• liver disease
• vit K deficiency
• pregnancy, oral contraceptive use

Question 15

hyperhomocysteinemia

Answer 15

• increased levels of homocysteine
• increased risk of venous thrombosis and atherosclerotic vascular disease
• causes
  > vit B12 and folate def, and/or vit B6
  > mutation in methylene tetrahydrofolate reductase (MTHFR)

Question 16

acquired thrombophilia

Answer 16

• antiphospholipid antibodies (Lupus anticoagulant)

- heparin-induced thrombocytopenia (HIT)

Question 17

heparin-induced thrombocytopenia

Answer 17

• Ab-mediated cause of thrombosis
  > Ab against PLT factor 4+heparin complex
• double hit mechanism
  > PLTs removed in the spleen = thrombocytopenia; sudden decrease in PLT count (within 5 days after starting heparin)
  > immune complex can activate PLTs = thrombosis

decrease PLTs but increased thrombosis

Question 18

anithrombotic therapies: drugs to treat and prevent thrombosis

Answer 18

• anticoags: reduce thrombin formation and suppress coagulation
• anti-platelet drugs: suppress PLT activation
• fibrinolytics: disperse existing clots

effective dose range is narrow*

Question 19

warfarin (Coumadin)

Answer 19

• oral
• mode of action: vit K antagonist (interferes with vit K dependent factor production); blocks y-carboxylation of glutamic acid residues by vit K
• factors still produced but can’t bind Ca 2+ and PF3
• monitoring = PT
• treatment for overdose = bolus of vit K, factor concentrates for emergency bleeding

Question 20

heparin therapy

Answer 20

• unfractionated (larger)
• IV or subcutaneous
• mode of action: catalyst for antithrombin, AT alone is a weak serin protease inhibitor, heparin increases efficiency and rate of AT action
• speed is immediate
• aPTT to monitor or chromogenic anti-Xa assay (more preferred); also monitor PLT counts to ensure no drop
• discontinue drug if overdose or protamine sulfate for neutralization

Question 21

low molecular weight heparin therapy

Answer 21

• less thrombin activation, but same Xa inactivation
• subcutaneous injection
• 90% less risk of HIT in patients who have never been exposed to heparin
• cannot use aPTT to monitor bc insensitive to LMWH
• multi-use anti-Xa assay
• *more expensive!**