Related Subjects:
|Thrombophilia testing
|Antiphospholipid syndrome
|Protein C Deficiency
|Protein S Deficiency
|Prothrombin 20210A mutation
|Factor V Leiden Deficiency
|Antithrombin III deficiency (AT3)
|Cerebral Venous Sinus thrombosis
|Budd-Chiari syndrome
About
- The term thrombophilia means an inherited or acquired predisposition to venous thromboembolism. Thrombophilia screening is mainly for those who suffer from venous thrombosis. It is expensive and much of it is inappropriate. Patient selection is key.
- Diagnosing heritable thrombophilia will rarely alter a patient's management. As a predictor of risk, it is appreciated that individual risk is affected by multiple genetic and environmental factors which will be different even amongst first degree relatives.
- More likely to find inherited causes in younger patients with no obvious precipitant of a DVT or PE
| Effect | Factors | Effect of loss of function |
|---|
| Procoagulants | Factor II, V, VIII, IX, XI | Propensity to Bleeding |
| Anticoagulants | Antithrombin, Protein C, S, Z | Propensity to Thrombosis |
Clinical Indications for screening
- Patients under 40 with unexplained VTE
- Family history of VTE in relative less than 40
- Venous thrombosis with no obvious precipitating cause or at a relatively young age. Presently this is advised below the age of 50.
- Women with a history of recurrent miscarriages should be screened for the lupus anticoagulant
- Under 60 years with VTE in unusual site e.g. cerebral venous sinus thrombosis, portal vein thrombosis, mesenteric, subclavian.
- Arterial thrombosis (Stroke/Definite TIA) where there is no other obvious cause in those under 40: anticardiolipin and lupus anticoagulant
Investigations
- Lupus anti-coagulant
- Anti-phospholipid antibody
- Protein C deficiency
- Protein S deficiency
- Anti-thrombin deficiency
- Factor V Leiden
- Prothrombin 20210A mutation
- 3' prothrombin UTR variant
- JAK2 mutation
Inherited Thrombophilic Conditions
| Condition | Details |
|---|
| Antithrombin is a major inhibitor of blood coagulation and is essential for
effective Heparin therapy. It inhibits the coagulation proteases including IIa,
IXa, Xa and XIa. |
Antithrombin deficiency is very rare (prevalence 0.02%)
but has a high risk of venous thrombosis (5-10x relative risk (RR) for first VTE).
|
|
Protein C is a vitamin K-dependent protein made by the liver. It
is a natural anticoagulant. It is converted to activated protein
C (APC) by thrombin. APC inactivates factors Va and VIIIa.
|
Protein C deficiency is rare (prevalence
0.2%). There is variable increased thrombotic risk
(4-6x RR for first VTE).
|
|
Protein S is a vitamin K-dependent protein made by the liver. It
is the co-factor for the anticoagulant activity of APC. It circulates in a free form (40%) or bound to the acute phase C4b-binding protein (60%).
Only the free form is functional and only this is measured in the thrombophilia screen.
|
Protein S deficiency is rare (prevalence 0.03-0.13%) and is associated
with a variable increased thrombotic risk (1-10x RR for first VTE)
|
|
Factor V Leiden mutation and APC Resistance Assay (
APCR) If a patient's plasma does not produce the appropriate anticoagulant response to APC, this is termed
APC Resistance.
|
The most common cause for this is the
Factor V Leiden mutation (FVL) produces a factor V molecule that is resistant to cleavage by APC. FVL is identified using PCR techno
logy. PCR testing is carried out on all samples that have a reduced APCR
or have a family history of FVL. FVL is the most prevalent thrombotic risk factor known in the Caucasian population (around 5%). Heterozygotes have a modest increase in Guidelines for Thrombophilia Testing the risk of thrombosis (3-5x RR for first VTE). Homozygotes are much less
common but have a much higher thrombotic risk (80x
RR).
|
| Name | Frequency |
|---|
| Factor V Leiden mutation | 3-7% |
| Prothrombin gene mutation | 1-2% |
| Antithrombin deficiency | 3 |
| Protein C deficiency | 0.3% |
| Protein S deficiency | 0.1% |
Acquired and Inherited Prothrombotic states
- Factor V Leiden mutation: A mutation of one of the clotting factors is seen in 5% of the normal population. The mutation makes it less vulnerable to breakdown by Protein C and so increased factor V activity and clots
- Prothrombin 20210A gene mutation: seen in 2 %. There is elevated prothrombin levels and 3 times increase risk of thrombosis
- Protein C or S deficiency: Skin necrosis with Warfarin. Protein C cleaves factor V and so reduces clotting. Its deficiency therefore increases clotting.
- Antithrombin III deficiency: Heterozygous x 4 risk of VTE Homo - No survival. Those with Antithrombin III deficiency are relatively resistant to Heparin as Heparin usually acts via its effect on ATIII. Can also be acquired after trauma or surgery, pregnancy and nephrotic syndrome
- Pregnancy and Oral contraceptive usage
- Paroxysmal nocturnal haemoglobinuria (PNH)
- Polycythemia vera and essential thrombocythemia: elevated erythrocyte mass or platelet count, splenomegaly, and bone marrow hypercellularity. The risk of thrombosis is highest in patients over the age of 60 and in those with a previous history of thrombosis
- Hyperhomocysteinemia - Increased risk of arterial thrombosis and MI or stroke. Treat with Folate, B6 and B12
- Heparin-induced thrombocytopenia (HIT)
- Malignancies: migratory superficial thrombophlebitis (Trousseau syndrome), VTE, DIC, or ischemic stroke. Trousseau syndrome and VTE usually associated with carcinomas of the pancreas, lung, prostate, breast, uterus, stomach, and colon. DIC with adenocarcinomas or acute leukaemias. Cardioembolic stroke in cancer patients often arises from nonbacterial thrombotic endocarditis.
- Antiphospholipid syndrome: acquired disorder with arterial and venous thrombosis. Fetal loss in pregnancy are associated with autoantibodies directed toward phospholipids or phospholipid-binding proteins.
Who to screen
| Who to test
|
|
Arterial thrombosis
|
Arterial thrombosis is a multi-factorial condition with different risk factors to venous thrombosis. No firmly established
increased risk for arterial cardiovascular diseases
by heritable thrombophilia
exists. Treatment and secondary prevention should be in relation to established cardiovascular risk facts. Testing for heritable thrombophilia is NOT recommended.
However antiphospholipid syndrome may present with
arterial thrombosis and should be tested for if this occurs at a young age,
particularly in the absence of other risk factors
|
|
|
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Children
|
Children have a very low thrombotic risk and should
not normally be tested. Any possible need for thrombophilia screening in a
the child should first be discussed with a Consultant Haematologist or Paediatrician
|
|
Thrombophilia testing - check local laboratory values
|
|
Antithrombin activity
|
80-118% or 0.8-1.2 IU/ml
|
1 citrate (blue-capped) tube
|
|
Protein C activity
|
70-143% or 0.7-1.4 IU/ml
|
1 citrate (blue-capped) tube
|
|
Protein S (free) level
|
55-118% or 0.7-1.0 IU/ml
|
1 citrate (blue-capped) tube
|
|
Factor V Leiden
|
Reported as normal, abnormal (heterozygote), abnormal (homozygote)
|
1 EDTA (purple-capped) tube
|
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Prothrombin G20210A
|
Reported as normal, abnormal (heterozygote), abnormal (homozygote)
|
1 EDTA (purple-capped) tube
|
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Lupus anticoagulant and Anticardiolipin
|
LA: Reported in an interpretive
manner
ACLA: normal range 0 -17 u/ml. Cardiolipin Antibodies:
11 - 20 Indeterminate, 21 - 80 Low/Med Positive >80 Strong Positive
Persistent antibodies for >12 weeks and clinical features of an APS
are required for a diagnosis of an antiphospholipid syndrome.
|
2 x citrate (blue-capped) tube and 1 x clotted tube (gold-capped)
|
Full thrombophilia screen test Take
- 2 x 3.2ml citrate (blue-capped) tube (must be filled to the correct level)
- 5mls EDTA (purple-capped)
- 1x clotted tube (gold-capped)
Thrombophilia screen in Venous thrombosis or Paradoxical embolism
- Measure levels
- Antithrombin
- Protein C levels
- Protein S levels
- Gene mutation testing
- Prothrombin 20210A
- Factor V Leiden
- Antibodies
- Lupus anticoagulant
- Anticardiolipin antibodies
- Plasma total homocysteine
Thrombophilia screen in Arterial thrombosis
- Lupus anticoagulant
- Anticardiolipin antibodies
- Plasma total homocysteine
- If under 50 check for thrombophilia
- Measure levels
- Antithrombin levels
- Protein C levels
- Protein S levels
- Gene mutation testing
- Prothrombin 20210A
- Factor V Leiden
Interpretation
- Sample requirements: 2 * 3.2mL citrate (blue-capped) tube, 5mls of blood in EDTA (lilac capped) tubes, 1 * EDTA sample tube (lilac-capped), 1 * Clotted sample tube no anticoagulant (mustard-capped). NB Citrate sample tubes must be filled to the correct level.
- Anti-thrombin 0.8-1.2 IU/ml : Not reliable in patients receiving Heparin or low-molecular weight Heparin.
- Protein C 0.7-1.4 IU/ml: Not reliable in patients receiving Warfarin or in the acute period following a thrombotic event
- Protein S total 0.7-1. IU/mL: Not reliable in patients receiving Warfarin or in the acute period following a thrombotic event
- APC resistance ratio Ratios of greater than 2.5
- Factor V Leiden - reported as normal, abnormal (heterozygous) or abnormal (homozygous)
- Prothrombin gene mutation reported as normal, abnormal (heterozygous) or abnormal (homozygous)
- Lupus anticoagulant - depends upon an analysis of a series of clotting assays and would always be reported in an interpretive manner
- Anticardiolipin antibodies: Standardized immunoassays for immunoglobulin G or immuno- globulin M antibodies that recognize bovine cardiolipin in a molecular complex with alpha 2-glycoprotein I.