Thrombophilia

Question 1

Thrombophilia

Answer 1

A predisposition to form clots inappropriately

Question 2

acquired thrombophilia

Answer 2

Cancer – (Neoplasm induced coagulation activation)
Myeloproliferative (white cell) disorders – Cell surface tissue factor expression
Polycythaemia (red cell) – blood flow alteration
Thrombocytosis (platelets) – blood flow alteration + activation surface
Increase thrombotic risk x7

Heart failure
Recent MI/Stroke

Hyper-homocysteinaemia
Amino acid
Cysteine homologue
Biosythesis intermediary

Antiphospholipid syndrome (APS)
Antiphospholipid Auto-antibodies directed towards 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

Question 3

thrombophilia due to lifestyle

Answer 3

Pregnancy - (arterial 3-4x)(venous 4-5x)(2 per 1000 total)
Combined Oral Contraceptive Pill - (COCP) (3.5x relative risk)
Hormone replacement therapy (HRT) - (2.5x oral oestrogen)

Hormone release
Cellular activation

Obesity (? Independently. BMI>30 = 2x risk)
Trauma / Immobility

Surgery

Question 4

thrombophilia due to hereditary

Answer 4

Raised levels of procoagulants
reduced clearance
Inherited deficiency of natural anticoagulants

Question 5

Quantitative, actual amount (Type I.)

Answer 5

Monoclonal Ab. to specific factors

Microtitre plate assays (ELISA)

Attached to latex beads

Electrophoresis

How much is present but not if it works

Question 6

Qualitative, Does it work ? (Type II.)

Answer 6

Assay that requires the protein/protease to function
Clotting assays (envoke all of the pathway)
Chromogenic assays (functioning protein causes cleavage/colour change of a chromogenic substrate

Question 7

Antithrombin

Answer 7

Serine Protease Inhibitor (SERPIN)
Inactivation of Thrombin by 1:1 binding of active site serine
(also to a lesser extent IXa, Xa, XIa, XIIa )
Increased activity in presence of heparin like substances
- Dermatan sulphate from the endothelial
- Therapeutic heparin
Deficiencies Type I Quantitative (Immunological)
Type II Qualitative (Functional)
Autosomal dominant
Affected = 40-60% of normal levels
70% clot before age 50

Question 8

Protein C

Answer 8

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

Question 9

deficiency of protein C

Answer 9

Less severe than Antithrombin def.
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)

Question 10

Protein S

Answer 10

Co-factor to Protein C
65% bound to C4b-Binding protein (inactive)
35% unbound (active component)

		Free PS		Bound Protein S/C4b-BP

			Total Protein S (TPS)

Question 11

Factor FV Leiden

Answer 11

Single point mutation in FV
(Bertina, 1994) FactorV 1691 GA
Protects FactorV 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)

Question 12

Prothrombin G20210A

Answer 12

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

Question 13

Who to measure ?

Answer 13

British Society of Haematology guidelines 2001/10 (inherited)
Personal or family history of DVT/PE
Risk factors at that point (age, cancer, obesity, pill, immobility etc.)
Not during acute phase – Procoagulants  Anticoagulants 
Young person ? <50
Follow up counselling
Limited options to treat