131 Hereditary Thrombophilia Flashcards
Examples of acquired thrombophilia
Antiphospholipid syndrome, cancer, surgery, strict immobilization, pregnancy and the postpartum period, and the use of estrogen-containing medication, such as oral contraceptives and hormone replacement therapy
TRUE OR FALSE
Hereditary thrombophilia has mean age at time of a first thrombosis being approximately 10 years lower than in the general population, the majority of patients with thrombophilia have the first episode later in life.
TRUE
Hereditary thrombophilia has mean age at time of a first thrombosis being approximately 10 years lower than in the general population, the majority of patients with thrombophilia have the first episode later in life.
TRUE OR FALSE
Hereditary thrombophilia is a major risk factor for arterial cardiovascular disease.
FALSE
Hereditary thrombophilia is not a major risk factor for arterial cardiovascular disease.
TRUE OR FALSE
Most hereditary thrombophilias are also modestly associated with pregnancy-related disorders
TRUE
Most hereditary thrombophilias are also modestly associated with pregnancy-related disorders
Such as recurrent miscarriage; stillbirth; intrauterine growth retardation; preeclampsia; and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome of pregnancy, although for later pregnancy complications, this association is controversial
The genetic basis for activated protein C (APC) resistance
Single point mutation in the factor V gene
Factor V Leiden
Common Hereditary Thrombophilia among the general population
Elevated FVIII:c levels
Common Hereditary Thrombophilia among Patients with VTE
Elevated FVIII:c levels (25%)
Factor V Leiden (21%)
Types of antithrombin and protein C deficiency
- Type I: both antigen and activity are reduced
- Type II: antigen levels are normal, but one or more functional defects in the molecule lead to a decreased activity
- Type IIa: defect is located in the thrombin binding domain (ie, the reactive site)
- Type IIb: defect is located in the heparin binding domain
- Type IIc: pleiotropic group of mutations
Interestingly, patients with type IIb deficiency seem to have a significantly lower risk of VTE than other types.
Two forms of protein S
- Free protein S (∼40–50%): functions as a cofactor for APC
- Protein S bound to complement component C4b-binding protein
Types of Protein S deficiency
- Type I deficiency: total and free antigen levels and activity are all reduced
- Type II deficiency: total and free antigen are normal, but activity is reduced
- Type III deficiency: activity and free antigen are reduced, but total antigen is low to normal
TRUE OR FALSE
Most laboratory panels now only test the activity of antithrombin, protein C, or protein S and thereby do not distinguish between different types of deficiencies.
TRUE
Most laboratory panels now only test the activity of antithrombin, protein C, or protein S and thereby do not distinguish between different types of deficiencies.
TRUE OR FALSE
Homozygous type I deficiency has never been described in humans and is believed to be incompatible with life.
TRUE
Homozygous type I deficiency has never been described in humans and is believed to be incompatible with life.
Homozygous protein C and protein S deficiencies are also very rare and are associated with neonatal purpura fulminans and massive thrombosis.
In the general population, the prevalence of the deficiencies of the natural anticoagulants combined is approximately ____%
1%
The most common hereditary thrombophilia
Factor V Leiden mutation
Factor V Leiden is very rare among Asians and Africans but has a high prevalence (∼5%) among whites
Underlying genetic defect in Factor V Leiden disease
Single G-to-A substitution in the gene of factor V at nucleotide position 1691
Resulting in an amino acid change from arginine (Arg) to glutamine (Gln) at position 506, the first cleavage site of factor Va for APC
The high prevalence of factor V Leiden suggests an evolutionary benefit such as:
- Reduced peripartum and menstrual blood loss in affected female carriers
- Increased sperm counts and a shorter conception time in affected male and female carriers
TRUE OR FALSE
Unlike factor V Leiden, the prothrombin G20210A mutation is found largely in Asians.
FALSE
Like factor V Leiden, the prothrombin G20210A mutation is found largely in white.
____________ is the most common familial, albeit not monogenetic, thrombophilia with an estimated population attributable risk of 15%
Increased level of FVIII
Most of coagulation FVIII circulates in complex with
vWF
Conditions/factors have been associated with high FVIII levels
Increasing age, high body mass index, diabetes mellitus, and hypertriglyceridemia
High FVIII levels are part of acute-phase reactions and sustained increases are observed during pregnancy, surgery, chronic inflammation, malignancy, liver disease, hyperthyroidism, renal disease.
TRUE OR FALSE
Increased FVIII levels in patients with VTE are usually not influenced by acute-phase reactions.
TRUE
Increased FVIII levels in patients with VTE are usually not influenced by acute-phase reactions
The association between high FVIII levels and venous thrombosis is well established.
Tests not affected by various factors during testing
Examples
- Use of VKAs, which reduces the levels of anticoagulant factors protein C and protein S
- Pregnancy: reduces free protein S levels and increases APC resistance and FVIII levels
Factor V Leiden
Prothrombin G20210A
Enzymes involved in homocysteine metabolism are dependent on what vitamins
Vitamin B6, folic acid, and vitamin B12
Deficiencies lead to hyperhomocysteinemia
Common genetic cause of mild hyperhomocysteinemia
Polymorphism in the enzyme methylenetetrahydrofolate reductase (MTHFR), c.C677T
Leads to an alanine to valine substitution at position 222 resulting in a variant enzyme with reduced activity and increased thermolability
The prevalence is 10% to 20% in whites and 10% in Asians, but it is rare in Africans.
Other conditions are associated with hyperhomocysteinemia
Renal failure, hypothyroidism, smoking, excessive coffee consumption, inflammatory bowel disease, psoriasis, and rheumatoid arthritis
Severe hyperhomocysteinemia (plasma levels >100 μmol/L)
A rare autosomal recessive disorder clearly associated with vascular occlusive disease
Homocystinuria
TRUE OR FALSE
Homocysteine lowering by B vitamins reduce the incidence of recurrent events both in patients with VTE as well as in patients with arterial cardiovascular disease
FALSE
Homocysteine lowering by B vitamins did not reduce the incidence of recurrent events both in patients with VTE as well as in patients with arterial cardiovascular disease
As a result of these studies, homocysteine testing (either its levels of polymorphisms) as part of a thrombophilia panel has been largely abandoned.
TRUE OR FALSE
For deficiencies of the natural anticoagulants as well as for elevated FVIII levels, repeated testing should be performed to exclude spuriously abnormal tests.
TRUE
For deficiencies of the natural anticoagulants as well as for elevated FVIII levels, repeated testing should be performed to exclude spuriously abnormal tests.
Most known is the use of VKAs, which reduces the levels of anticoagulant factors protein C and protein S, which can thereby mimic severe deficiencies.
Another example is pregnancy, which reduces free protein S levels and increases APC resistance and FVIII levels.
TRUE OR FALSE
Genetic testing for deficiencies of the natural anticoagulants is not performed because of the large number of known mutations.
TRUE
Genetic testing for deficiencies of the natural anticoagulants is not performed because of the large number of known mutations.
TRUE OR FALSE
Individuals heterozygotes for the prothrombin G20210A or factor V Leiden mutations are at higher risk for VTE than homozygous.
FALSE
Individuals homozygous for the prothrombin G20210A or factor V Leiden mutations are at higher risk for VTE than heterozygotes.
Likewise, patients with combined thrombophilic disorders have a higher risk of VTE than those with a single defect.
Hereditary thrombophilia no association/no consistent association with arterial thrombosis
- Antithrombin deficiency
- Protein C deficiency
- Protein S deficiency
TRUE OR FALSE
Regardless of thrombophilia, the absolute risk of a recurrent episode is much higher than the risk of a first episode of VTE.
TRUE
Regardless of thrombophilia, the absolute risk of a recurrent episode is much higher than the risk of a first episode of VTE.
The most important determinant of recurrence is the
Presence of transient clinical risk factors during the time of the first episode
After an unprovoked first episode of VTE, the risk of recurrence is approximately ___% in the first year after cessation of anticoagulation and approximately ___% per year thereafter.
10%
5%
Other determinants for recurrence of VTE
- Male sex
- Proximal (vs distal) DVT
- Elevated D-dimer levels after stopping anticoagulation
GENERAL CONSIDERATIONS OF THROMBOPHILIA TESTING
- First, an obvious disadvantage of testing for thrombophilia is the high cost.
- Second, although the psychological impact and consequences of knowing that one is a carrier of a (genetic) thrombophilic defect are considered limited, a qualitative study described several negative effects of both psychological and social origins.
- Third, the most compelling argument against testing is the potential false reassurance that may arise from a negative thrombophilia test for individuals who come from families with a thrombotic tendency.
The 2018 American Society of Hematology guidelines recommends postpartum thrombosis prophylaxis in women with:
- Antithrombin
- Protein C, or protein S deficiency
- Family history of VTE
The 2018 American Society of Hematology guidelines recommends antepartum and postpartum prophylaxis in women with:
- Antithrombin deficiency and a family history of VTE
- Homozygous for factor V Leiden or prothrombin mutation
- Those who have combined thrombophilias
Thrombophilia testing is most often considered in patients with VTE, particularly if
- Young
- Recurrent episodes
- Thrombosis at unusual sites
- Positive family history for the disease
TRUE OR FALSE
The association between hereditary thrombophilia and arterial cardiovascular disease is questionable or at least much weaker than for VTE.
TRUE
The association between hereditary thrombophilia and arterial cardiovascular disease is questionable or at least much weaker than for VTE.
The association is stronger in patients with events before the age of 55 years.
Thrombophilia testing in asymptomatic relatives may be useful in
- Families with antithrombin, protein C, or protein S deficiency or
- For siblings of patients who are homozygous for factor V Leiden and is limited to women who intend to become pregnant or who would like to use oral contraceptives
Still, testing for thrombophilia serves only a limited purpose and should not be performed on a routine basis.
