4.4 Thrombosis Flashcards
CBS (cystathionine beta synthase)
- how is related to hemostasis disorders?
- mech
- CBS deficiency: causes homocysteinemia/homocysteinuria
- increased risk of thrombosis from high homocysteine, which damages endothelium
- homocysteine is normally converted by CBS to cystathione for degradation.
Vit B12/Folate deficiency
- effect on hemostasis
- mech
- increased risk of thrombosis from high homocysteine, which damages endothelium
- lack of either means homocysteine is not methylated into methionine
Prothrombin 20210A
- leads to hypercoagulable state.
- mutation in prothrombin leads to increased expression, leading to excessive thrombin, cross linking more fibrinogen.
Thrombosis can be caused by endothelial damage. What conditions cause this damage (3)
- atherosclerosis
- vasculitis
- high levels of homocysteine
Pt using oral contraceptives.
-why increased risk for thrombosis?
Estrogen increases production of coag factors.
You see a pt who has recurring DVTs, is mentally retarded, has poor vision, and has long slender fingers.
Think what?
CBS deficiency homocysteinuria
- thrombosis
- mental retardation
- lens dislocation
- long slender fingers
Factor V Leiden
- leads to hypercoagulable state.
- mutated Factor 5 leads to excessive Factor 5. Mutation makes F.5 lack cleavage site for protein C and S deactivation.
Virchow Triad
- 3 risk factors of thrombosis:
1. Abnormal blood flow
2. Endothelial damage
3. Hypercoagulable state–excessive procoagulants or defective anticoagulants
Antiphospholipid antibodies -examples
-example of acquired hypercoag, leads to increased risk of thromboses -Acquired Ab against phospholipid complexes -ex: 1. “lupus anticoagulant”– it is not an anticoagulant, although it paradoxically increases PTT (lab test artifact) and is associated with SLE 2. anti-cardiolipin Ab
Pt with thrombosis that you treat with heparin, but no change in PTT.
- Suspect what?
- If so, how to induce anticoagulated state?
Possible ATIII deficiency.
-If so, use warfarin, along with temporary high dose heparin to prevent warfarin skin necrosis (there may still be existing ATIII to be activated).
CBS deficiency:
-clinical presentation (4)
homocysteinemia/homocystenuria
- vessel thrombosis
- mental retardation
- lens dislocation
- long slender fingers
1/4 die before age 30 from thrombosis complications.
Protein C or S deficiency
- what does this cause
- what is there increased risk of?
- leads to hypercoagulable state.
- Protein C and S are anticoagulants, normally inactivate F.5, F.8
- increased risk of warfarin skin necrosis (acute loss of protein C,S from warfarin can induce thrombosis of skin vessels)
ATIII deficiency
- mech
- what lab test is changed?
- leads to hypercoagulable state.
- ATIII is an anticoagulant activated by heparin that inactivates thrombin and coag factors.
- PTT does not rise when heparin is given, b/c there is no ATIII to bind to.
Pts with genetic hypercoagulable state
-classic presentation
- DVTs (possibly recurrent) at a young age.
- usu in leg, but also hepatitic and cerebral veins
How to distinguish thrombus from postmortem clot?
Histology of thrombus:
- Lines of Zahn (alternating layers of platelets/fibrin and RBCs)
- attachment to vessel wall
What do endothelial cell secrete to prevent thrombosis? (4)
- Endothelial cells secrete:
1. PGI2/NO–both vasodilate and inhibit platelet aggregation
2. HLM (heparin-like molecules)–activate ATIII, which inactivates thrombin and coag factors
3. tPA, activating plasmin (remember: it cleaves fibrin and serum fibrinogen, destroys coag factors, and blocks platelet agg)
4. thrombomodulin (modulates thombin to activate protein C, which inactivates factors 5,8)
Thrombosis from Abnormal blood flow
-example disorders
- DVT from lack of movement
- AFib
- Aneurysm
How do oral contraceptives affect hemostasis?
-Estrogen increases production of coag factors, leading to increased risk of thrombosis
warfarin skin necrosis
- what is it
- what condition has an increased risk of this?
- Skin necrosis can occur from clotting when using warfarin. (paradoxical)
- Warfarin inactivates Vit K, inactivating 2,7,9,10,C,S. C and S (anticoags) are inactivated first, creating a window of hypercoagulable state, which can lead to thrombosis, esp in the skin. Prevent this by giving heparin with warfarin.
- increased risk in Protein C or S deficiency
homocysteine
- how is it related to hemostasis disorders
- mech
- specific disorders (3)
- high levels cause endothelial damage, increasing risk of thrombosis
- THF becomes methylated, donating the methyl to Vit B12, which donates to homocysteine, creating methionine. Also, homocysteine is normally converted by CBS to cystathione for degradation.
1,2. Vit B12/Folate deficiency
-lack of either means homocysteine is not methylated into methionine
- CBS (cystathionine beta synthase) deficiency
thrombomodulin
- made from where
- what does it do?
- secreted by endothelium
- modulates thrombin to activate Protein C, which inactivates Factors 5, 8. Therefore, inhibits clotting.
Pt with a DVT.
How to start thinking about your differential?
Think Vichow’s triad:
- blood stasis
- immobilization, AFib, aneurysm, etc - endothelial damage
- atherosclerosis, vasculitis, homocysteinemia - hypercoag state
- oral contraceptives
- genetic: Factor 5 leiden, Protein C/S deficiency, ATIII deficiency, prothrombin 20210A
Thrombosis can be caused by a hypercoagulable state. What conditions cause this?(5)
-which is most common?
-excessive procoagulants or defective anticoagulants
Genetic:
- Protein C or S deficiency–lack of anticoags
- Factor 5 Leiden–mutated in F.5 cleavage site for deactivation by proteins C and S
- Prothrombin 20210A–mutation in prothrombin that increases its expression
- ATIII deficiency–lack of anticoag
Non-genetic:
5. Oral contraceptives–estrogen increases production of coag factors
Factor 5 Leiden is most common.
