Thrombotic Disorders

Question 1

layers of thrombus if formed in life (vs. after death)

Answer 1

Lines of Zahn

Question 2

Outcomes of thrombi

Answer 2

Degraded completely by body
Degraded partially
Could propagate in direction of blood flow (backwards towards heart)
Dislodged, flow in direction of blood flow that it can no longer fit through

Question 3

Thrombosis risk factors (3)

Answer 3

endothelial damage
Stasis
hypercoagulability

Question 4

what leads to endothelial damage

Answer 4

atherosclerosis

Question 5

what leads to stasiss

Answer 5

immobilization
varicose veins
cardiac dysfunction

Question 6

what leads to hypercoagulability

Answer 6

trauma/surgery
carcinoma
estrogen/postpartum
thrombotic disorders

Question 7

If patient has a thrombus

Answer 7

get a good history
order routine lab tests
start to worry if --> 
No obvious cause
Family history
Weird location (not in deep vein of leg)
Recurrent
Patient is young
Miscarriages

Question 8

Factor V Leiden TYMK

Answer 8

Most common cause of unexplained thromboses
Point mutation in factor V gene
Factor V can’t be turned off
Need genetic testing for diagnosis

Question 9

Underlying mutations in Factor V Leiden

Answer 9

A mutated factor V gene
Single point mutation
Discovered in Leiden, Netherlands

Produces abnormal factor V
Participates in the cascade
Can’t be cleaved by protein C
Can turn it on, but can’t turn it off

Question 10

How common is factor V leiden

Answer 10

Half of patients with unexplained
thromboses!
5% of Caucasians have it
VERY rare in non-Caucasians

Question 11

Risk of getting a clot with factor V leiden

Answer 11

Heterozygotes: 7 times normal
Homozygotes: 80 times normal
Normal risk = 1-2 patients per 1000 (per year)

Question 12

How do you diagnose factor V leiden

Answer 12

PTT and INR are not helpful because you can’t speed up clotting, factor V works just fine, just do more clotting than you should

Genetic testing

Question 13

tx factor V leiden

Answer 13

DON’T…unless there is a thrombosis.
Then: give an anticoagulant for a while.
If there are multiple episodes (or other risk factors), give long-term anticoagulation.

Question 14

Antithrombin III Deficiency TYMK

Answer 14

ATIII is a natural anticoagulant
Potentiated by heparin
Lots of gene mutations exist
Very rare

Question 15

What is ATIII?

Answer 15

Natural anticoagulant
Inhibits IIa, VIIa, IXa, Xa, XIa
Potentiated by heparin

Question 16

What’s wrong with the ATIII gene?

Answer 16

Mutated gene produces less ATIII
   Rara avis (

Question 17

ATIII risk of getting a clot

Answer 17

Homozygotes: can’t survive.
Heterozygotes: half get clots.
Heparin won’t work (obviously).
Antithrombin concentrates required.

Question 18

Protein C and S deficiencies TYMK

Answer 18

Proteins C and S are natural anticoagulants
C is also fibrinolytic and anti-inflammatory
Warfarin-induced skin necrosis
C deficiency rare; S deficiency super-rare

Question 19

what is protein c

Answer 19

Anticoagulant: inactivates Va and VIIIa
Fibrinolytic: promotes t-PA action
Anti-inflammatory: keeps cytokines low

Question 20

whats wrong with protein C gene

Answer 20

Mutated gene produces less protein C        
     (or defective protein C)
   Rara avis (

Question 21

dx protein C deficiency

Answer 21

Diagnosis: functional testing

Question 22

risks with protein C def

Answer 22

Heterozygotes: 7 times normal clot risk
Unique risks:
Warfarin-induced skin necrosis
Purpura fulminans

Question 23

Coumadin inhibits

Answer 23

II, VII, IX, and X

AND protein C and S

Question 24

Purpura fulminans

Answer 24

Thrombotic state + vascular injury
   Net result: skin necrosis
   Associated with: 
   protein C and S deficiency
   sepsis
   Treatment may include administering protein C

Question 25

Warfarin induced skin necrosis

Answer 25

Coumadin inhibits II, VII, IX, and X AND proteins C and S Protein C has a very short half life (shorter than 7 - will be the first thing to go down) If person is already deficient in Protein C and you inhibit this, people are hypercoagulable w/ coumadin d/t inhibition of protein C After a few days, factors will also be decreased and not at a risk for clotting Usually do coumadin and heparin for first few days

Question 26

Protein S deficiency

Answer 26

VERY RARE | otherwise same as protein C def

Question 27

Factor II gene mutation TYMK

Answer 27

Factor II = prothrombin Mutated gene makes too much prothrombin Prothrombin itself is normal Rare in non-Caucasians

Question 28

Gene mutaton in factor II gene

Answer 28

``` Mutated gene produces too much prothrombin! Prothrombin itself is normal 5% of caucasians (rare in others) Clot risk: 2 - 20 times normal ```

Question 29

Hyperhomocysteinemia TYMK

Answer 29

Homocysteine converts folate Homocysteinuria = rare metabolic disorder Too much homocysteine = thromboses Homocysteinemia has many causes

Question 30

Homocysteine

Answer 30

Amino acid Made from methionine Maintains myelin Converts dietary folate

Question 31

Homocysteinuria

Answer 31

Rare metabolic disorder Deficient trans-sulphuration enzyme ↑ homocysteine in blood, urine ↑ thrombosis, premature atherosclerosis

Question 32

homocysteine pathogenesis

Answer 32

Toxic to endothelium Forms reactive oxygen species Interferes with nitric oxide NO is a vasodilater and an antithrombotic

Question 33

homocysteinemia

Answer 33

Not so rare MTHFR gene mutation B12/folate deficiency

Question 34

Heterozygous homocysteinemia

Answer 34

Inc. thrombosis, premature atherosclerosis Risk of venous thrombosis: 2.5 x normal Risk of arterial thrombosis: 10 x normal

Question 35

Homocysteinemia in B12/folate def.

Answer 35

Less worrisome | …but watch out for other risk factors

Question 36

antiphospholipid antibodies TYMK

Answer 36

Autoantibodies against phospholipids Falsely prolong INR May cause thromboses Antiphospholipid syndrome is serious

Question 37

antiphospholipid antibodies

Answer 37

``` IgG antibodies against phospholipids Three variants anticardiolipin antibodies lupus anticoagulants antibodies against other molecules ```

Question 38

what do antiphospholipid abs do

Answer 38

``` Bind to phospholipids (in vivo and in vitro) Screw up coagulation tests: bind up PTT/PT reagent specimen can’t clot test result appears prolonged Screw up other tests: direct antiglobulin test syphilis test ```

Question 39

antiphospholipid abs = inhibitors?

Answer 39

Promote coagulation in vivo Inhibit coagulation in vitro Test results appear contradictory

Question 40

Who develop anti-phos abs

Answer 40

``` Children Infection Mild risk Adults Autoimmune diseases Moderate risk Elderly Drugs No risk ```

Question 41

anti-phos ab syndrome

Answer 41

``` Recurrent thrombosis Recurrent spontaneous abortions Increased risk of stroke Pulmonary hypertension Renal failure ```

Question 42

How to detect anti-phos abs

Answer 42

``` Order a PTT. If prolonged, order a PTT mixing study. If the PTT corrects…? If the PTT doesn’t correct…? If normal, antibody may still be present! Order fancy tests. ```