Thrombophilia Diagnosis Wk 3 Flashcards
What is thrombophilia
A predisposition to form clots inappropriately
Virchow’s triad
Arterial thrombosis (stroke/MI)
Alterations to normal blood flow
Injuries to the vascular endothelial Alterations to the constitution of the blood e. (hypercoagulability)
Venous thrombosis (DVT/PE)
Constant balance consists on these three factors
Acquired x environmental x inherited
Between coagulation and anticoagulation
Acquired factors (cell based)
- Cancer (neoplasm induced coagulation activation )
• myeloproliferative (white cell) disorders - cell surface tissue factors expression
• polycythaemia (red cell) - blood flow alteration
• thrombocytosis (platelets) - blood flow alteration + activation surface
• increase thrombotic risk X7 - heart failure
- recent MI/stroke
Polycythaemia
Red cell
Myeloproliferative
White cell disorders
Thrombocytosis
Platelets
Acquired factors (plasma based)
-Hyper-homocysteinaemia
Amino acid
Cysteine homologue
Biosynthesis intermediary
Impaired breakdown
(Homocysteine Cystathionine)
Impaired remethylation (recycle)
(Homocysteine Methionine)
Can be acquired or inherited
(often dietry, B6,B12, Folic acid)
(MTHFR gene polymorph C677T and A1298C)
1969 McCully Atherscelerosis / Arterial thrombosis
Endothelial cell damage
1996 Den Heijer x4 risk of Thrombosis
Mild Hyperhomocysteinaemia 5 to 7 % population
Antiphospholipid syndrome (APS)
Alterations to the constitution of the blood (hypercoagulability)
^ auto-antibodies directed to platelet components required for coagulation pathway
• Cell membrane component Phosphatidylserine
• Cell protein component b2-GPI
• Primary or secondary to other auto-immune
(ie Rheumatoid/SLE)
• Ability to cause arterial and venous thrombosis
• Recurrent pregnancy loss
• Mostly acquired, can be inherited
Lifestyle / environmental
- Pregnancy
- combined oral contraceptive pill
- hormone replacement therapy
- obesity (bmi>30=2x risk)
- trauma / immobility
- surgery
Hereditary - raised levels of procuagulants
Which to measure
Hereditary reduced clearance
Hereditary - inherited deficiency of natural anticoagulants
Direct inhibition - direct binding
Negative feedback loops - via the action of others
Anticoagulant or procoagulant
Thrombin → powerful procoagulant enzyme
powerful initiator of anticoagulation
How to measure - quantitative, actual amount - monoclonal Ab. To specific factors
• Microtitre plate assays(ELISA)
• attached to latex beads
• electrophoresis - how much present
Measure - qualitative
- Assay requires protein/protease to function
• clotting assays (invoke pathway top to bottom)
• chromogenic assays (functioning protein causes cleavage/colour change of chromogenic substrate)
Doesn’t need standardisation
Intrinsic pathway
Common pathway
Antithrombin
- Serine protease inhibitor SERPIN
-Inactivation of thrombin by 1:1 binding of active site serine - increased activity in presence of heparin like substances:
- Dermatan sulphate from the endothelial
- Therapeutic heparin
Deficiencies Type I Quantitative (Immunological)
Type II Qualitative (Functional)
Antithrombin (1965, Egeberg et al.)
- Autosomal dominant affected = 40 - 60% of normal levels
- 70% clot before age 50
- 1995 Tait et al. 10,000 blood donors
Intrinsic pathway
Common pathway
Protein C
Vitamin k dependent glycoprotein
- synthesized in the liver
- converted to activated protein C ( APC) by thrombin/ thrombomodulin cleavage
- requires co-factor protein S for full function
- Inactivates FVIIIa and FVa by cleavage at specific sites
- autosomal dominant inheritance
Deficiency of protein C
-Less severe than antithrombin deficiency.
Type I. (Quantitative) more common than Type II. (Qualitative)
0.2-0.3% prevalence in normal population (Tait et al. 1995)
3% of all first time clots (DVT/PE)
10-15x more likely to have clot (DVT/PE)
Protein S
Co-factor to Protein C
65% bound to C4b-Binding protein (inactive)
35% unbound (active component)
Type I. def (Quantitative FPS)
Type II. def (Qualitative FPS)
? Type III. def (Low FPS, Normal Total PS)
Protein S
More difficult to measure
Lower in Women than Men
Decreased during pregnancy and Oestrogen therapies (HRT/COCP)
Prevalance ? 3% of all first time clots (DVT/PE )
? 1-2% of normal population
Limited risk factor ? x2
Differing effects depending on mutation/family
? Interactions with other factors
Limited explanation of risk of thrombosis (10%)
(1993, Dahlback et al.) Resistance to Activated Protein C (APC) in approx 50% of patients presenting with unexplained thrombosis
Natural anticoagulation negative feedback loop
Factor FV Leiden
Single point mutation in FV
Factor V 1691 GA (Bertina, 1994)
Protects Factor V from degradation by APC
Autosomal dominant
Heterozygotes 3-8x risk of thrombosis
Homozygotes 80x risk of thrombosis
3-15% of normal population have mutation (asymptomatic)
Prothrombin G20210A
Mutation causes raised level of prothrombin FII _ hyperprothrombinaemia
Increase Thrombin generation
2% of normal population (het)
6% of those with thrombosis (Poort et al. 1996)
Risk x0-3 (mild)
Cumulative risk ?
+ COCP = x15 risk of clot
Inherited Thrombophilia
Antithrombin def 1 in 3,000
Protein C def 1 in 300
Protein S def 1 in 300
Factor V Leiden mutation 1 in 20
Prothrombin G20210A mutation 1 in 50-100
Who do you measure?
Personal, family history of DVT/PE
Risk factors
<50
Is testing worthwhile?
