Thrombotic Disorders Flashcards
layers of thrombus if formed in life (vs. after death)
Lines of Zahn
Outcomes of thrombi
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
Thrombosis risk factors (3)
endothelial damage
Stasis
hypercoagulability
what leads to endothelial damage
atherosclerosis
what leads to stasiss
immobilization
varicose veins
cardiac dysfunction
what leads to hypercoagulability
trauma/surgery
carcinoma
estrogen/postpartum
thrombotic disorders
If patient has a thrombus
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
Factor V Leiden TYMK
Most common cause of unexplained thromboses
Point mutation in factor V gene
Factor V can’t be turned off
Need genetic testing for diagnosis
Underlying mutations in Factor V Leiden
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
How common is factor V leiden
Half of patients with unexplained
thromboses!
5% of Caucasians have it
VERY rare in non-Caucasians
Risk of getting a clot with factor V leiden
Heterozygotes: 7 times normal
Homozygotes: 80 times normal
Normal risk = 1-2 patients per 1000 (per year)
How do you diagnose factor V leiden
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
tx factor V leiden
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.
Antithrombin III Deficiency TYMK
ATIII is a natural anticoagulant
Potentiated by heparin
Lots of gene mutations exist
Very rare
What is ATIII?
Natural anticoagulant
Inhibits IIa, VIIa, IXa, Xa, XIa
Potentiated by heparin
What’s wrong with the ATIII gene?
Mutated gene produces less ATIII Rara avis (
ATIII risk of getting a clot
Homozygotes: can’t survive.
Heterozygotes: half get clots.
Heparin won’t work (obviously).
Antithrombin concentrates required.
Protein C and S deficiencies TYMK
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
what is protein c
Anticoagulant: inactivates Va and VIIIa
Fibrinolytic: promotes t-PA action
Anti-inflammatory: keeps cytokines low
whats wrong with protein C gene
Mutated gene produces less protein C
(or defective protein C)
Rara avis (dx protein C deficiency
Diagnosis: functional testing
risks with protein C def
Heterozygotes: 7 times normal clot risk
Unique risks:
Warfarin-induced skin necrosis
Purpura fulminans
Coumadin inhibits
II, VII, IX, and X
AND protein C and S
Purpura fulminans
Thrombotic state + vascular injury Net result: skin necrosis Associated with: protein C and S deficiency sepsis Treatment may include administering protein C
Warfarin induced skin necrosis
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
Protein S deficiency
VERY RARE
otherwise same as protein C def
Factor II gene mutation TYMK
Factor II = prothrombin
Mutated gene makes too much prothrombin
Prothrombin itself is normal
Rare in non-Caucasians
Gene mutaton in factor II gene
Mutated gene produces
too much prothrombin!
Prothrombin itself is normal
5% of caucasians (rare in others)
Clot risk: 2 - 20 times normalHyperhomocysteinemia TYMK
Homocysteine converts folate
Homocysteinuria = rare metabolic disorder
Too much homocysteine = thromboses
Homocysteinemia has many causes
Homocysteine
Amino acid
Made from methionine
Maintains myelin
Converts dietary folate
Homocysteinuria
Rare metabolic disorder
Deficient trans-sulphuration enzyme
↑ homocysteine in blood, urine
↑ thrombosis, premature atherosclerosis
homocysteine pathogenesis
Toxic to endothelium
Forms reactive oxygen species
Interferes with nitric oxide
NO is a vasodilater and an antithrombotic
homocysteinemia
Not so rare
MTHFR gene mutation
B12/folate deficiency
Heterozygous homocysteinemia
Inc. thrombosis, premature atherosclerosis
Risk of venous thrombosis: 2.5 x normal
Risk of arterial thrombosis: 10 x normal
Homocysteinemia in B12/folate def.
Less worrisome
…but watch out for other risk factors
antiphospholipid antibodies TYMK
Autoantibodies against phospholipids
Falsely prolong INR
May cause thromboses
Antiphospholipid syndrome is serious
antiphospholipid antibodies
IgG antibodies against phospholipids Three variants anticardiolipin antibodies lupus anticoagulants antibodies against other molecules
what do antiphospholipid abs do
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 testantiphospholipid abs = inhibitors?
Promote coagulation in vivo
Inhibit coagulation in vitro
Test results appear contradictory
Who develop anti-phos abs
Children Infection Mild risk Adults Autoimmune diseases Moderate risk Elderly Drugs No risk
anti-phos ab syndrome
Recurrent thrombosis Recurrent spontaneous abortions Increased risk of stroke Pulmonary hypertension Renal failure
How to detect anti-phos abs
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.
