Thrombophilia: A congenital or acquired predisposition to thrombosis.
Causes of thrombophilia
Inherited:
An inherited abnormality of one of the plasma proteins listed below:
* Factor V Leiden homozygous individuals have an 80 X risk of Venous
Thromboembolism (VTE).
Acquired Risk factors for thrombosis
Causes of thrombophilia
Inherited:
An inherited abnormality of one of the plasma proteins listed below:
* Factor V Leiden homozygous individuals have an 80 X risk of Venous
Thromboembolism (VTE).
Acquired Risk factors for thrombosis
Risk factors for arterial thrombosis include:
Hypertension
Smoking
Diabetes
Polycythaemia
Lupus anticoagulant
Risk factors for venous thrombosis include:
Conditions causing stasis e.g. advanced age, cardiac failure, oedema, nephritic syndrome, obesity, trauma, long distance travel, immobility, post-operative, pelvic obstruction, myocardial infarct, central venous catheter
Altered blood constituents that is acquired in oestrogen therapy, contraceptive pill, malignancy, pregnancy, antiphospholid syndrome, raised plasma homocysteine, or raised factors VIII, IX or XI.
Polycythaemia and thrombocythaemia.
Pathogenesis is multifactorial and relates to elevated levels of procoagulant, depressed levels of inhibitor proteins and physical factors (e.g. stasis, surgery).
What is thrombophilia screen used for?
It is used to investigate the cause of thrombophilia.
Who should be referred for a thrombophilia screen?
Patients with have the following:
- Spontaneous thrombosis, particularly at a young age, or associated with pregnancy
- Thrombosis at an unusual site e.g. sagittal sinus thrombosis
- Recurrent thrombosis
- Thrombosis in those with a VTE and a first degree relative with a history of VTE.
What is screened for in the patient’s blood sample?
Activated Protein C Resistance (APCR)
The APCR test is a sensitive screening test for Factor V mutations which may lead to an increased risk of thrombosis. APCR is the most common known hereditary predisposition to venous thrombosis. Activated protein C normally degrades activated factors V and VIII by proteolytic change to inhibit coagulation. Individuals with APCR have a mutated Factor V, which is resistant to degradation by activated Protein C.
Protein CHypertension
Smoking
Diabetes
Polycythaemia
Lupus anticoagulant
Risk factors for venous thrombosis include:
Conditions causing stasis e.g. advanced age, cardiac failure, oedema, nephritic syndrome, obesity, trauma, long distance travel, immobility, post-operative, pelvic obstruction, myocardial infarct, central venous catheter
Altered blood constituents that is acquired in oestrogen therapy, contraceptive pill, malignancy, pregnancy, antiphospholid syndrome, raised plasma homocysteine, or raised factors VIII, IX or XI.
Polycythaemia and thrombocythaemia.
Pathogenesis is multifactorial and relates to elevated levels of procoagulant, depressed levels of inhibitor proteins and physical factors (e.g. stasis, surgery).
What is thrombophilia screen used for?
It is used to investigate the cause of thrombophilia.
Who should be referred for a thrombophilia screen?
Patients with have the following:
- Spontaneous thrombosis, particularly at a young age, or associated with pregnancy
- Thrombosis at an unusual site e.g. sagittal sinus thrombosis
- Recurrent thrombosis
- Thrombosis in those with a VTE and a first degree relative with a history of VTE.
What is screened for in the patient’s blood sample?
Activated Protein C Resistance (APCR)
The APCR test is a sensitive screening test for Factor V mutations which may lead to an increased risk of thrombosis. APCR is the most common known hereditary predisposition to venous thrombosis. Activated protein C normally degrades activated factors V and VIII by proteolytic change to inhibit coagulation. Individuals with APCR have a mutated Factor V, which is resistant to degradation by activated Protein C.
Heterozygous protein C deficiency increases the risk for venous thrombosis sevenfold. It is more likely to be of relevance in young (<>
Protein S
Protein S is a cofactor for activated Protein C mediated degradation of the coagulation factors Va and VIIIa.
Protein S is a cofactor for activated Protein C mediated degradation of the coagulation factors Va and VIIIa.
Antithrombin
Antithrombin is a powerful physiological coagulation inhibitor, which inhibits the activity of thrombin and factor Xa and to a lesser degree on factors IXa, XIa and XIIa and Kallikrein.
Antithrombin is a powerful physiological coagulation inhibitor, which inhibits the activity of thrombin and factor Xa and to a lesser degree on factors IXa, XIa and XIIa and Kallikrein.
Factor V Leiden and Prothombin Gene Mutation Testing
The Factor V Leiden mutation has been identified as a major cause of familial venous thrombosis and is inherited in an autosomal dominant fashion. Heterozygosity is associated with an 8-fold increased risk of venous thrombosis and homozygosity with an 80-100-fold increased risk.
The prothrombin mutation (G20210A) is linked to increased prothombin levels. It is inherited independently from the Leiden mutation in an autosomal dominant fashion and is associated with an approximate 3-fold increased risk of venous thrombosis.
The Factor V Leiden mutation has been identified as a major cause of familial venous thrombosis and is inherited in an autosomal dominant fashion. Heterozygosity is associated with an 8-fold increased risk of venous thrombosis and homozygosity with an 80-100-fold increased risk.
The prothrombin mutation (G20210A) is linked to increased prothombin levels. It is inherited independently from the Leiden mutation in an autosomal dominant fashion and is associated with an approximate 3-fold increased risk of venous thrombosis.
Antiphospholipid Antibodies
Antiphospholipid antibodies are a family of autoantibodies that recognise various phospholipids and/or phospholipid-binding proteins. This antibody family includes lupus anticoagulants, anticardiolipin antibodies and anti-beta2-glycoprotein I antibodies. All confer an increased risk of thromboembolic .
Antiphospholipid antibodies are a family of autoantibodies that recognise various phospholipids and/or phospholipid-binding proteins. This antibody family includes lupus anticoagulants, anticardiolipin antibodies and anti-beta2-glycoprotein I antibodies. All confer an increased risk of thromboembolic .
The diagnosis of Antiphospholipid syndrome, which can occur in isolation, or in association with other systemic autoimmune disease, such as SLE, is made using clinical and laboratory criteria.
Clinical criteria
1. Thrombosis -arterial, venous or small vessel
2. Complications of pregnancy -recurrent miscarriage in the first trimester of pregnancy, foetal death in the 2nd or 3rd trimesters of pregnancy, and premature birth.
1. Thrombosis -arterial, venous or small vessel
2. Complications of pregnancy -recurrent miscarriage in the first trimester of pregnancy, foetal death in the 2nd or 3rd trimesters of pregnancy, and premature birth.
Laboratory criteria
1. Lupus anticoagulant detected on 2 or more occasions, at least 6 weeks apart.
2. Moderate or high levels of anticardiolipin antibodies detected on 2 or more occasions, at least 6 weeks apart.
1. Lupus anticoagulant detected on 2 or more occasions, at least 6 weeks apart.
2. Moderate or high levels of anticardiolipin antibodies detected on 2 or more occasions, at least 6 weeks apart.
To make a defintive diagnosis of antiphospholipid syndrome, patients must meet at least one of the clinical AND one of the laboratory criteria.
Important points to take note of before doing a thrombophilia screen:
- Patient needs to know nature and limitation of tests. Important to know what advice should be given if an abnormality is identified.
- Laboratory tests may be affected by other medical conditions and medication e.g. liver disease, pregnancy, anti-coagulants.
- Identification of a laboratory thrombophilic abnormality will not usually affect immediate treatment but may be of value in preventing further thrombosis and in counselling other family members so as to reduce their risk of a thrombosis.
- A person who develops spontaneous DVT may have a normal thrombophilia screen. This does not imply that the patient is normal and that the patient has no increased risk of thrombosis in the future or in the family member. There may be heritable defects that have yet to be discovered.
- As the clinical interpretation of a thrombophilia screen will depend upon each patient's circumstances it is sensible for patients to be referred to a specialist who has experience in counselling and testing such individuals and families (rather than just taking a blood sample and requesting thrombophilia investigations).
Sources:
Haematology at a Glance, 2nd Edition, Mehta & Hoffbrand
British Heart Foundation, Thrombophilia Factfile 02/2002, http://www.bhsoc.org/bhf_factfiles/bhf_factfile_feb_2002.pdf
Guidelines for Thrombophilia Screening in Patients Taking Oral Contraceptives,
http://www.gp-training.net/protocol/cardiovascular/thrombo.htm
ACT Pathology: Investigations for Thrombophilia
http://www.actpathology.act.gov.au/c/ap?a=da&amp;did=1008510&pid=1059373329&sid=
Important points to take note of before doing a thrombophilia screen:
- Patient needs to know nature and limitation of tests. Important to know what advice should be given if an abnormality is identified.
- Laboratory tests may be affected by other medical conditions and medication e.g. liver disease, pregnancy, anti-coagulants.
- Identification of a laboratory thrombophilic abnormality will not usually affect immediate treatment but may be of value in preventing further thrombosis and in counselling other family members so as to reduce their risk of a thrombosis.
- A person who develops spontaneous DVT may have a normal thrombophilia screen. This does not imply that the patient is normal and that the patient has no increased risk of thrombosis in the future or in the family member. There may be heritable defects that have yet to be discovered.
- As the clinical interpretation of a thrombophilia screen will depend upon each patient's circumstances it is sensible for patients to be referred to a specialist who has experience in counselling and testing such individuals and families (rather than just taking a blood sample and requesting thrombophilia investigations).
Sources:
Haematology at a Glance, 2nd Edition, Mehta & Hoffbrand
British Heart Foundation, Thrombophilia Factfile 02/2002, http://www.bhsoc.org/bhf_factfiles/bhf_factfile_feb_2002.pdf
Guidelines for Thrombophilia Screening in Patients Taking Oral Contraceptives,
http://www.gp-training.net/protocol/cardiovascular/thrombo.htm
ACT Pathology: Investigations for Thrombophilia
http://www.actpathology.act.gov.au/c/ap?a=da&amp;did=1008510&pid=1059373329&sid=
Contributed by John Lee
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