Krafts Friday Thrombotic Disorder

Question 1

Lines of Zahn

Answer 1

looking at a blood clot on autopsy. If these lines exist, then the clot happened before death.

Question 2

Thrombosis Risk Factors

Answer 2

Endothelial damage –> atherosclerosis: hypertension, hyperlipidemia, obesity, smoking

Blood Stasis: immobilization, varicose veins, cardiac dysfunction

Hypercoagulability: trauma/surgery, carcinoma, estrogen/postpartum, thrombotic disorders

Question 3

Your patient has a thrombus……now what?

Answer 3

Get a good history: Risk factors, Family history

Order routine lab tests: INR, PTT, TT

Start to worry if: No obvious cause, Family history, Weird location, Recurrent, Patient is young, Miscarriages

Question 4

Thrombotic Disorders: names of disorders

Answer 4

Hereditary:
*Factor V Leiden*
ATIII deficiency
Protein C deficiency
Protein S deficiency
Factor II gene mutation
Homocysteinemia

Acquired
antiphospholipid Ab

Question 5

Factor V Leiden: things you must know

Answer 5

Most common cause of unexplained thromboses
Point mutation in factor V gene
Factor V can’t be turned off (You can turn it on…but you can’t turn it off!)
Need genetic testing for diagnosis

Question 6

What is Factor V Leiden?

Answer 6

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

Question 7

Factor V Leiden: PTT and INR are not helpful! Why?

Answer 7

You make the fibrin at the same rate, you just can’t shut it off. Goes no faster and no slower.

Need genetic testing!

Question 8

What is the risk of getting a clot with Factor V Leiden

Answer 8

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

Question 9

How common is factor V Leiden?

Answer 9

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

Question 10

How do you treat Factor V Leiden

Answer 10

DON’T…unless there is a thrombosis.
Then: give an anticoagulant for a while (Coumadin)

If there are multiple episodes (or other risk factors), give long-term anticoagulation.

Question 11

Antithrombin III Deficiency: things you must know

Answer 11

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

Question 12

What is antithrombin III

Answer 12

Natural anticoagulant
Inhibits IIa, VIIa, IXa, Xa, XIa
Potentiated by heparin so you can’t give them heparin to help

Question 13

What’s wrong with the ATIII gene in the ATIII deficiency

Answer 13

Mutated gene produces less ATIII
Rara avis (

Question 14

What’s the risk of getting a clot with ATIII deficiency

Answer 14

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

Question 15

Protein C deficiency and S Deficiencies: things to know

Answer 15

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 16

What is protein C

Answer 16

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

Question 17

What’s wrong with the protein C gene in protein C deficiency

Answer 17

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

Question 18

What’s the risk of getting a clot with protein C deficiency

Answer 18

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

Question 19

what is the first thing coumadin inhibits, why is it important

Answer 19

protein C is inhibited first so you actually have an increased change of thrombosis right away, especially if you have a defect

Question 20

Purpura Fulminans

Answer 20

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

Question 21

Protein S Deficiency

Answer 21

Über rara avis

Otherwise: same as protein C deficiency

Question 22

Factor II Gene Mutation: things you must know

Answer 22

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

Question 23

What’s wrong with the factor II gene when it is mutated

Answer 23

Mutated gene produces too much prothrombin!

Prothrombin itself is normal

5% of caucasians (rare in others)

Clot risk: 2 - 20 times normal

Question 24

Hyperhomocysteinemia: things you must know or you will die

Answer 24

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

Question 25

What is Homocysteine?

Answer 25

Amino acid Made from methionine Maintains myelin Converts dietary folate

Question 26

Homocysteinuria

Answer 26

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

Question 27

Homocysteinemia

Answer 27

Not so rare MTHFR gene mutation B12/folate deficiency

Question 28

What’s so bad about homocysteine?

Answer 28

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

Question 29

Heterozygous homocysteinemia

Answer 29

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

Question 30

Homocysteinemia in B12/folate deficiency

Answer 30

Less worrisome than heterozygous | …but watch out for other risk factors

Question 31

Antiphospholipid Antibodies: Things you must know

Answer 31

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

Question 32

What are antiphospholipid antibodies?

Answer 32

``` IgG antibodies against phospholipids Three variants: 1. anticardiolipin antibodies 2. lupus anticoagulants 3. antibodies against other molecules ```

Question 33

What do antiphospholipid antibodies do?

Answer 33

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 34

antiphospholipid antibodies do what in vivo an in vitro

Answer 34

Promote coagulation in vivo | Inhibit coagulation in vitro

Question 35

Who develops antiphospholipid antibodies

Answer 35

Children: Infection, Mild risk Adults: Autoimmune diseases, Moderate risk Elderly: Drugs, No risk

Question 36

Antiphospholipid Antibody Syndrome: what happens clinically

Answer 36

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

Question 37

How do you detect the antiphospholipid antibodies

Answer 37

1. Order a PTT. 2. If prolonged, order a PTT mixing study. If the PTT corrects…? then it was a factor problem If the PTT doesn’t correct…? there is something inhibitory in the blood 3. If normal, antibody may still be present! Order fancy tests.