131 Hereditary Thrombophilia

Question 1

Examples of acquired thrombophilia

Answer 1

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

Question 2

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.

Answer 2

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.

Question 3

TRUE OR FALSE

Hereditary thrombophilia is a major risk factor for arterial cardiovascular disease.

Answer 3

FALSE

Hereditary thrombophilia is not a major risk factor for arterial cardiovascular disease.

Question 4

TRUE OR FALSE

Most hereditary thrombophilias are also modestly associated with pregnancy-related disorders

Answer 4

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

Question 5

The genetic basis for activated protein C (APC) resistance

Answer 5

Single point mutation in the factor V gene
Factor V Leiden

Question 6

Common Hereditary Thrombophilia among the general population

Answer 6

Elevated FVIII:c levels

Question 7

Common Hereditary Thrombophilia among Patients with VTE

Answer 7

Elevated FVIII:c levels (25%)
Factor V Leiden (21%)

Question 8

Types of antithrombin and protein C deficiency

Answer 8

• 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.

Question 9

Two forms of protein S

Answer 9

• Free protein S (∼40–50%): functions as a cofactor for APC
• Protein S bound to complement component C4b-binding protein

Question 10

Types of Protein S deficiency

Answer 10

• 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

Question 11

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.

Answer 11

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.

Question 12

TRUE OR FALSE

Homozygous type I deficiency has never been described in humans and is believed to be incompatible with life.

Answer 12

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.

Question 13

In the general population, the prevalence of the deficiencies of the natural anticoagulants combined is approximately ____%

Answer 13

1%

Question 14

The most common hereditary thrombophilia

Answer 14

Factor V Leiden mutation

Factor V Leiden is very rare among Asians and Africans but has a high prevalence (∼5%) among whites

Question 15

Underlying genetic defect in Factor V Leiden disease

Answer 15

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

Question 16

The high prevalence of factor V Leiden suggests an evolutionary benefit such as:

Answer 16

• Reduced peripartum and menstrual blood loss in affected female carriers
• Increased sperm counts and a shorter conception time in affected male and female carriers

Question 17

TRUE OR FALSE

Unlike factor V Leiden, the prothrombin G20210A mutation is found largely in Asians.

Answer 17

FALSE

Like factor V Leiden, the prothrombin G20210A mutation is found largely in white.

Question 18

____________ is the most common familial, albeit not monogenetic, thrombophilia with an estimated population attributable risk of 15%

Answer 18

Increased level of FVIII

Question 19

Most of coagulation FVIII circulates in complex with

Answer 19

vWF

Question 20

Conditions/factors have been associated with high FVIII levels

Answer 20

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.

Question 21

TRUE OR FALSE

Increased FVIII levels in patients with VTE are usually not influenced by acute-phase reactions.

Answer 21

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.

Question 22

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

Answer 22

Factor V Leiden
Prothrombin G20210A

Question 23

Enzymes involved in homocysteine metabolism are dependent on what vitamins

Answer 23

Vitamin B6, folic acid, and vitamin B12

Deficiencies lead to hyperhomocysteinemia

Question 24

Common genetic cause of mild hyperhomocysteinemia

Answer 24

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.

Question 25

Other conditions are associated with hyperhomocysteinemia

Answer 25

Renal failure, hypothyroidism, smoking, excessive coffee consumption, inflammatory bowel disease, psoriasis, and rheumatoid arthritis

Question 26

Severe hyperhomocysteinemia (plasma levels >100 μmol/L) A rare autosomal recessive disorder clearly associated with **vascular occlusive disease**

Answer 26

Homocystinuria

Question 27

# 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

Answer 27

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 ## Footnote As a result of these studies, homocysteine testing (either its levels of polymorphisms) as part of a thrombophilia panel has been largely abandoned.

Question 28

# 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.

Answer 28

TRUE For **deficiencies of the natural anticoagulants** as well as for **elevated FVIII levels**, **repeated testing** should be performed to exclude spuriously abnormal tests. ## Footnote 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**.

Question 29

# TRUE OR FALSE Genetic testing for deficiencies of the natural anticoagulants is not performed because of the large number of known mutations.

Answer 29

TRUE Genetic testing for deficiencies of the natural anticoagulants is **not performed** because of the large number of known mutations.

Question 30

# TRUE OR FALSE Individuals heterozygotes for the prothrombin G20210A or factor V Leiden mutations are at higher risk for VTE than homozygous.

Answer 30

FALSE Individuals **homozygous** for the prothrombin G20210A or factor V Leiden mutations are at **higher** risk for VTE than heterozygotes. ## Footnote Likewise, patients with **combined** thrombophilic disorders have a **higher** risk of VTE than those with a single defect.

Question 31

Hereditary thrombophilia no association/no consistent association with arterial thrombosis

Answer 31

* Antithrombin deficiency * Protein C deficiency * Protein S deficiency

Question 32

# 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.

Answer 32

TRUE Regardless of thrombophilia, **the absolute risk of a recurrent episode is much higher than the risk of a first episode of VTE.**

Question 33

The most important determinant of recurrence is the

Answer 33

Presence of transient clinical risk factors during the time of the first episode

Question 34

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.

Answer 34

10% 5%

Question 35

Other determinants for recurrence of VTE

Answer 35

* Male sex * Proximal (vs distal) DVT * Elevated D-dimer levels after stopping anticoagulation

Question 36

GENERAL CONSIDERATIONS OF THROMBOPHILIA TESTING

Answer 36

* 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.

Question 37

The 2018 American Society of Hematology guidelines recommends **postpartum thrombosis prophylaxis** in women with:

Answer 37

* Antithrombin * Protein C, or protein S deficiency * Family history of VTE

Question 38

The 2018 American Society of Hematology guidelines recommends **antepartum and postpartum prophylaxis** in women with:

Answer 38

* Antithrombin deficiency and a family history of VTE * Homozygous for factor V Leiden or prothrombin mutation * Those who have combined thrombophilias

Question 39

Thrombophilia testing is most often considered in patients with VTE, particularly if

Answer 39

* Young * Recurrent episodes * Thrombosis at unusual sites * Positive family history for the disease

Question 40

# TRUE OR FALSE The association between hereditary thrombophilia and arterial cardiovascular disease is questionable or at least much weaker than for VTE.

Answer 40

TRUE The association between hereditary thrombophilia and arterial cardiovascular disease is questionable or at least much weaker than for VTE. ## Footnote The association is **stronger** in patients with **events before the age of 55 years.**

Question 41

Thrombophilia testing in **asymptomatic relatives** may be useful in

Answer 41

* 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 ## Footnote **Still, testing for thrombophilia serves only a limited purpose and should not be performed on a routine basis.**