Thrombotic Disorders - Krafts Flashcards
1
Q
What kind of blood flow increases the risk of thrombi?
A
Turbulent flow!
- aneurysms
2
Q
What does a thrombus look like microscopically?
A
- organized cells
- fibroblasts
- some trapped inflammatory cells
- small white spaces
- can use elastin stain to tell where clot ends and vessel wall begins
3
Q
What happens to a blood vessel after a thrombus forms?
A
- Thrombus can propagate itself
- add to itself in the direction of blood flow
- Body able to resolve clot entirely
- endogenous tPA breaks down fibrin
- everything washes away
- Part of thrombus breaks off and travels up to the next vessel and gets stuck
- usually end up in small vessels of lung (PE)
- Blood vessel can re-canalize to allow blood flow through, but thrombi remain present
4
Q
What is the first arm of Virchow’s Triad of thrombosis risk factors?
A
- Endothelial damage (anything that disrupts endothelium)
- atherosclerosis
- hypertension
- hyperlipidemia
- obesity
- smoking
- atherosclerosis
5
Q
What is the second arm of Virchow’s Triad of thrombosis risk factors?
A
- Stasis
- immobilization (bed ridden)
- varicose veins
- cardiac dysfunction
6
Q
What is the third arm of Virchow’s Triad of thrombosis risk factors?
A
- Hypercoagulability
- trauma/surgery
- carcinoma
- adenocarcinomas have mucin that kicks of the coag cascade
- estrogen/postpartum
- thrombotic disorders
7
Q
What do you do if your patient has a clot?
A
- Get a good history
- risk factors
- family Hx
- Order routine lab tests
- INR, PTT, TT
- Start to worry if:
- no obvious cause
- family Hx
- weird location (anywhere but deep veins of the leg)
- recurrent (1+)
- patient is young
- miscarriages
8
Q
What are the 6 Hereditary Thrombotic Disorders?
A
- Factor V Leiden
- ATIII deficiency
- Protein C deficiency
- Protein S deficiency
- Factor II gene mutation
- Homocyteinemia
9
Q
What characterizes Factor V Leiden?
A
- Most common cause of unexplained thromboses
- Point mutation in factor V gene
- Factor V can’t be turned off
- Need genetic testing for diagnosis
10
Q
What is Factor V Leiden pathogenesis?
A
- A mutated factor V gene
- single point mutation
- discovered in Leiden, Netherlands
- Produces abnromal factor V
- participates in the cascade normally
- can’t be cleaved by protein C (due to change in structure)
11
Q
How common is factor V Leiden?
A
- Half of patients with unexplained thromboses!
- 5% of Caucasians have it
- VERY rare in non-Caucasians
12
Q
What is the risk of getting a clot with Factor V Leidan mutation?
A
- Heterozygotes: 7x normal
- Homozygotes: 80x normal
- Normal risk = 1-2 patients per 1000 (per year)
13
Q
How do you diagnose Factor V Leiden?
A
- Need genetic testing (PCR test for it)
- PTT and INR are not helpful
- pt can make fibrin at same rate
- normal coags
- do not measure ability to stop coag
- PTT and INR are not helpful
14
Q
How do you treat Factor V Leiden?
A
- DON’T TREAT… unless there is a thrombosis
- Then: given an anticoagulant for a while
- If there are multiple episodes OR other risk factors
- give Long-Term anticoagulation
15
Q
What characterizes Antithrombin III Deficiency?
A
- AT III is a natural anticoagulant
- Potentiated by heparin
- Lots of gene mutations exist
- Very rare
16
Q
What is antithrombin III?
A
- Natural anticoagulant
- Inhibits IIa, VIIa, IXa, Xa, XIa
- Potentiated by heparin
17
Q
What is wrong with the ATIII gene in ATIII Deficiency?
A
- Mutated gene produces less ATIII
- Rara avis (<1%)
- Lots of different mutations described
- Can’t do genetic testing!
18
Q
What’s the risk of getting a clot with ATIII Deficiency?
A
- Homozygotes: can’t survive
- Heterozygotes: half get clots
- Heparin won’t work
- Antithrombin concentrates required
- need all three anticoags (Protein S & C)
19
Q
What characterizes Protein C and S Defieciencies?
A
- 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
20
Q
What is Protein C?
A
- Anticoagulant: inactivates Va and VIIIa
- Fibrinolytic: promotes t-PA action
- Anti-inflammatory: keeps cytokines low
21
Q
What is wrong with protein C gene in Protein C Deficiency?
A
- Mutated gene produces less protein C
- or defective protein C
- Rara avis (<1%)
- Lots of mutations described
- Diagnosis: functional testing
22
Q
What is the risk of getting a clot with Protein C Deficiency?
A
- Heterozygotes: 7x normal
- Unique risks:
- Warfarin-induced skin necrosis
- Purpura fulminans
- lesions of bleeding into skin
23
Q
When does Purpura Fulminans occur? Net result? Associated with?
A
- Thrombotic state + vascular injury
- Net result: skin necrosis
- Associated with:
- protein C and S deficiency
- sepsis
24
Q
What is the treatment for purpura fulminans?
A
- HARD TO TREAT
- Usually in the setting of sepsis
- May include administering protein C
25
What characterizes Factor II Gene Mutation?
* Factor II = prothrombin
* Mutated gene makes too much prothrombin
* Prothrombin itself is normal
* Rare in non-Caucasians
26
What's wrong with the factor II gene? Result of mutation?
* Mutated gene produces too much prothrombin!
* Prothrombin itself is normal
* 5% of caucasians (rare in others)
* Clot risk: 2-20x normal
27
What characterizes Hyperhomocysteinemia?
* Homocysteine converts folate
* Homocysteinuria = rare metabolic disorder
* Too much homocysteine = thrombosis
* Homocysteinemia has many causes
28
What is Homocysteine?
* Amino acid
* Made from methionine
* Maintains myelin
* Converts dietary folate
29
What is homocystein**uria**?
* rare metabolic disorder
* deficient trans-sulphuration enzyme
* increased homocysteine in blood, urine
* increased thrombosis, premature atherosclerosis
30
What is homocystein**emia**?
* Not so rare
* MTHFR gene mutation
* B12/folate deficiency
31
Why is a build up of homocysteine bad?
* Toxic to endothelium
* forms ROS
* Interferes with nitric oxide
* NO is a vasodilater and an antithrombotic
32
What is the risk of clotting in Homocysteinemia?
* Heterozygous homocysteinemia
* increased risk of thrombosis
* premature atherosclerosis
* Risk of venous thrombosis: 2.5x normal
* Risk of arterial thrombosis: 10x normal
* Homocysteinemia in B12/folate deficiency
* Less worrisome
* but watch out for other risk factors
33
What characterizes Antiphospholipid Antibodies?
* Autoantibodies against phospholipids
* Falsely prolong INR
* May cause thromboses
* Antiphospholipid syndrome serious
* multi-organ involvement
34
What are antiphospholipid antibodies?
* IgG antibodies against phospholipids
* Three variants
* anticardiolipin antibodies
* lupus anticoagulants
* antibodies against other molecules
35
What do antiphospholipids antibodies do?
* Bind to phospholipids (in vivo and in vitro)
* Screw up coagulation tests:
* bind up PTT/PT reagent
* specimen can't clot
* test appears prolonged
* Screw up other tests:
* direct antiglobulin test
* syphilis test
36
Who develops antiphospholipid antibodies?
* Children
* infection
* mild risk
* Adults
* autoimmune diseases
* moderate risk
* Elderly
* drugs
* no risk
37
What is the effect of antiphospholipid antibodies *in vivo* vs. *in vitro*?
* *in vivo*
* promote coagulation
* *in vitro*
* inhibit coagulation
38
What are the clinical findings in Antiphospholipid Antibody Syndrome?
* Recurrent thrombosis
* Recurrent spontaneous abortions
* Increased risk of stroke
* Pulmonary hypertension
* Renal failure
39
How do you detect antiphospholipid antibodies?
* Order a PTT
* If prolonged, order a PTT mixing study
* If the PTT corrects → something was missing in patient's blood (factor)
* If the PTT doesn't correct→ something in the patient's blood inhibited normal coagulation
* If normal, antibody may still be present
* order fancy tests
