L.16 Thrombophilia

Question 2

What is thrombophilia?

Answer 2

Disorders of the haemostatic system which are likely to predispose to thrombosis

Can be hereditary or acquired

Question 3

Which deficiencies are associated with familial thrombosis?

Answer 3

Deficiencies in Protein C and protein S

These deficiencies increase the risk of thrombosis

Question 4

What occurs during arterial thrombosis?

Answer 4

A blood clot forms unintentionally and obstructs an artery or an embolus breaks off and lodges in the heart or brain, causing tissue death

Risk factors include hypercholesterolaemia, hypertension, smoking, obesity, diabetes

Question 5

What is venous thromboembolism?

Answer 5

A condition that causes ~3 million deaths/year worldwide

Includes DVT and pulmonary embolism

Question 6

What is DVT?

Answer 6

When a thrombus forms in a deep vein in the leg/pelvis either partially or fully blocking the flow of blood

Deep vein thrombosis can lead to serious complications if untreated

Question 7

What happens during a pulmonary embolism (PE)?

Answer 7

Occurs when a DVT or part of it breaks off and travels through the bloodstream to the heart and lung, blocking a vessel and interrupting blood supply

Can be life-threatening

Question 8

What causes venous thromboembolism?

Answer 8

When activation of blood coagulation exceeds the ability of anticoagulants/inhibitors and the fibrinolytic system to prevent the formation of fibrin

This imbalance leads to thrombus formation

Question 9

What is the risk of below knee DVT?

Answer 9

Unlikely to cause acute complications

Generally considered less severe than above knee DVT

Question 10

What can an above knee DVT lead to?

Answer 10

Pulmonary embolism (PE), which is life-threatening and leads to shortness of breath and chest pain

Prompt treatment is crucial to prevent complications

Question 11

What type of disease is venous thrombosis?

Answer 11

A multi-causal disease involving gene-environment interactions

Both hereditary and acquired factors play a role

Question 12

What are high-risk factors for venous thromboembolism?

Answer 12

• Surgery
• Trauma
• Hip/Leg fracture

These factors significantly increase the risk of thrombus formation

Question 13

What are moderate risk factors for venous thromboembolism?

Answer 13

• Atherosclerosis
• Acquired thrombophilia
• Hereditary thrombophilia
• Malignancy

These conditions can contribute to thrombus risk

Question 14

What are weak risk factors for venous thromboembolism?

Answer 14

• Inflammation
• Immobility
• Obesity

These factors are less significant but still relevant

Question 15

What are the three anticoagulant protein deficiencies associated with venous thrombosis?

Answer 15

Antithrombin, Protein C, Protein S

These deficiencies can lead to an increased risk of thromboembolic events.

Question 16

Name two genetic defects associated with an increased risk of thrombosis.

Answer 16

Factor V Leiden mutation, Prothrombin gene mutation

These mutations can predispose individuals to venous thromboembolism.

Question 17

What percentage of patients presenting with a spontaneous thromboembolic event under 40 years of age have hereditary thrombosis?

Answer 17

Over 50%

This indicates a significant genetic contribution to early-onset thromboembolic events.

Question 18

What are the three requirements for the formation of a clot in venous thromboembolism (VTE)?

Answer 18

• Vessel wall injury causing platelet activation
• Venous stasis
• Localized trapped activated coagulation factors

These factors contribute to the pathophysiology of VTE.

Question 19

What is Antithrombin and where is it produced?

Answer 19

A serine protease inhibitor produced in the liver

It plays a crucial role in regulating coagulation.

Question 20

What percentage of inhibition in coagulation is Antithrombin responsible for?

Answer 20

80%

This highlights its importance in the coagulation cascade.

Question 21

What are the primary targets of Antithrombin?

Answer 21

• FIIa
• FXa
• FIXa
• FXI
• TF-FVIIa

These targets are key factors in the coagulation pathway.

Question 22

How does Antithrombin inhibit coagulation factors?

Answer 22

Forms a stable covalent complex with its substrate and is rapidly cleared from circulation

This mechanism is essential for its role in preventing excessive coagulation.

Question 23

Does Antithrombin inhibit free or bound coagulation factors more easily?

Answer 23

Free FIIa and FXa

This property allows Antithrombin to act as a scavenger in the circulation.

Question 24

By how much is the rate of activity of Antithrombin enhanced by heparin?

Answer 24

1000X

Heparin significantly increases the effectiveness of Antithrombin.

Question 25

What is the relationship between antithrombin deficiency and the severity compared to Protein C or Protein S deficiencies?

Answer 25

AT deficiency is more severe than PC or PS deficiencies ## Footnote Family studies suggest this severity difference.

Question 26

At what age do the majority of patients with antithrombin deficiency experience thrombosis?

Answer 26

Before age 25 years

Question 27

How many mutations have been reported for antithrombin deficiency?

Answer 27

More than 250 mutations

Question 28

Is homozygosity common in antithrombin deficiency?

Answer 28

Rare

Question 29

What are the two types of antithrombin deficiency?

Answer 29

* Type I deficiency * Type II deficiency

Question 30

What characterizes Type I antithrombin deficiency?

Answer 30

Quantitative reduction in antigen and function

Question 31

What causes Type I antithrombin deficiency?

Answer 31

Major gene deletions and point mutations

Question 32

What characterizes Type II antithrombin deficiency?

Answer 32

Qualitative defect with abnormal AT protein

Question 33

What is a reactive site defect in Type II deficiency?

Answer 33

Reduced ability to inhibit thrombin or FXa with or without heparin

Question 34

What is a heparin binding site defect in Type II deficiency?

Answer 34

Reduced ability to bind and be activated by heparin

Question 35

What is a pleiotropic effect in the context of antithrombin deficiency?

Answer 35

Mutations produce multiple effects on the structure-function relationship of the molecule

Question 36

What causes the qualitative defect in Type II antithrombin deficiency?

Answer 36

Single base substitutions in the coding regions

Question 37

What is a common treatment for antithrombin deficiency?

Answer 37

* Warfarin * Low molecular weight heparin or unfractionated heparin

Question 38

In some cases, what additional treatments may be considered for antithrombin deficiency?

Answer 38

* Antithrombin concentrates * LMWH therapy

Question 39

What is the aim for the INR in antithrombin deficiency treatment?

Answer 39

2.0 - 3.0

Question 40

What initial antithrombin activity percentage is targeted in treatment?

Answer 40

Over 120%

Question 41

What is the goal for maintaining antithrombin activity after initial treatment?

Answer 41

80%

Question 42

What does the protein C pathway regulate?

Answer 42

Coagulation on phospholipid surfaces

Question 43

What does the protein C pathway limit?

Answer 43

Procoagulant activity of FVa and FVIIIa

Question 44

What happens to thrombin affinity when its generation increases?

Answer 44

Increased affinity for thrombomodulin (TM) on the endothelial cell surface

Question 45

What does the FIIa-TM complex prevent?

Answer 45

Binding of FIIa to procoagulant substrates and activated platelets

Question 46

What does the FIIa-TM complex alter?

Answer 46

Substrate specificity of FIIa allowing activation of Protein C

Question 47

How does TM bound FIIa affect its inhibition?

Answer 47

Increases susceptibility to inhibition by Antithrombin

Question 48

What type of inheritance is associated with Protein C deficiency?

Answer 48

Autosomal dominant inheritance

Question 49

What is the relative risk for thrombosis in Protein C deficiency?

Answer 49

10-fold

Question 50

What characterizes Type I deficiency of Protein C?

Answer 50

Quantitative defect characterized by parallel reductions of functional protein C

Question 51

What characterizes Type II deficiency of Protein C?

Answer 51

Qualitative defect characterized by significantly lower functional levels

Question 52

In which conditions are reduced levels of Protein C found?

Answer 52

Warfarin therapy, DIC, liver disease

Question 53

What is the typical activity level of adult heterozygous Protein C deficiency patients?

Answer 53

60% activity

Question 54

What are the primary treatments for Protein C deficiency?

Answer 54

* Heparin or LMWH * Warfarin after achieving therapeutic anticoagulation

Question 55

What is the target INR for patients treated with warfarin for Protein C deficiency?

Answer 55

2.5

Question 56

What type of protein is Protein S?

Answer 56

Vitamin K dependent glycoprotein

Question 57

What role does Protein S play in the activation of FVa and FVIIIa?

Answer 57

Non-enzymatic cofactor for Activated Protein C-mediated activation

Question 58

What percentage of total plasma Protein S is complexed with C4b-binding protein?

Answer 58

60%

Question 59

What percentage of total plasma Protein S remains free and active?

Answer 59

40%

Question 60

What is the mechanism of action of free Protein S?

Answer 60

Binds strongly to negatively charged phospholipids and forms a Ca2+ dependent complex with activated protein C

Question 61

What does the APC/PS complex inactivate?

Answer 61

FVa

Question 62

What is required for the regulation of FVIIIa?

Answer 62

APC/FV/PS complex

Question 63

What characterizes Type I deficiency of Protein S?

Answer 63

Quantitative deficiency resulting in reduced production of structurally normal protein

Question 64

What characterizes Type II deficiency of Protein S?

Answer 64

Qualitative defect

Question 65

What characterizes Type III deficiency of Protein S?

Answer 65

Qualitative deficiency with reduced free PS antigen and normal total PS antigen

Question 66

What has been suggested about Type I and Type III defects in Protein S deficiency?

Answer 66

They are phenotypic variants of the same genetic disorder

Question 67

What are the biological sex differences in levels?

Answer 67

Lower levels in females ## Footnote Separate reference range for male/female

Question 68

What happens to factor levels during pregnancy?

Answer 68

Level falls progressively during pregnancy

Question 69

What effect does Warfarin therapy have on factor levels?

Answer 69

Reduced in Warfarin therapy

Question 70

List conditions that reduce factor levels.

Answer 70

* Antiphospholipid syndrome * DIC * Liver disease

Question 71

Where is the gene for Factor V located?

Answer 71

On chromosome 1

Question 72

What is FVa required for?

Answer 72

Activation of FII by FXa in the prothrombinase complex

Question 73

How is Factor Va inactivated?

Answer 73

Cleaved and inactivated by APC and PS to produce FVi

Question 74

What mutation affects Factor V's resistance to cleavage?

Answer 74

Mutation in the gene for FV results in production of FV that is resistant to cleavage by APC

Question 75

Define APCR.

Answer 75

Impaired plasma anticoagulant response to APC added in vitro

Question 76

What is the effect of the mutant FV Leiden on procoagulant activity?

Answer 76

Normal procoagulant activity but impaired response to APC

Question 77

What is the specific G to A base substitution in the FV gene?

Answer 77

At base 1691 results in R506Q (Arginine to Glutamine) in Factor V protein

Question 78

What percentage of patients present with first VTE episode due to FV Leiden?

Answer 78

15%

Question 79

What is the increased risk for heterozygous carriers of FV Leiden?

Answer 79

3-8 fold increased risk (90-95%)

Question 80

What is the increased risk for homozygous carriers of FV Leiden?

Answer 80

80 fold increased risk (5-10%)

Question 81

List acquired thrombosis risk factors that increase FV Leiden risk.

Answer 81

* Smoking * OCP * Recent surgery

Question 82

How does the use of oral contraceptives affect Factor V Leiden?

Answer 82

The effect is strongly enhanced by use of oral contraceptives

Question 83

Where is the prothrombin gene located?

Answer 83

On chromosome 11

Question 84

What type of protein is prothrombin and where is it produced?

Answer 84

Vitamin K dependent protein produced in liver

Question 85

What base substitution in the prothrombin gene leads to increased risk of venous thrombosis?

Answer 85

G to A base substitution at base 20210

Question 86

What is the relative risk of venous thrombosis for heterozygotes of the prothrombin mutation?

Answer 86

2 fold in heterozygotes

Question 87

What is known about the risk for homozygotes of the prothrombin mutation?

Answer 87

Risk for homozygotes is unknown although asymptomatic homozygotes have been described

Question 88

What percentage of patients with heterozygous FVL are also heterozygous for the prothrombin mutation?

Answer 88

15-40%

Question 89

What do BSH guidelines state about results predicting recurrence of thrombotic episodes?

Answer 89

Results don’t predict likelihood of recurrence of thrombotic episode

Question 90

In which patients are thrombophilia screenings indicated according to BSH guidelines?

Answer 90

Patients with first time thrombotic episode under the age of 40, family history of unprovoked thrombotic events, and three or more early pregnancy losses

Question 91

When should testing for thrombophilia be carried out?

Answer 91

Testing should only be carried out when testing is going to influence treatment

Question 92

When should a thrombophilia screen not be performed?

Answer 92

When the reason for thrombosis is known (e.g., central venous catheter), upper limb thrombosis, hospital-acquired thrombosis, or retinal vein occlusion

Question 93

What are the components of a thrombophilia screen?

Answer 93

* PT APTT * Antithrombin (AT) * Protein C (PC) * Protein S (PS) * Activated Protein C Resistance (APCR) * Factor VIII * Fibrinogen * Anticardiolipin * Beta 2 Glycoprotein * Lupus anticoagulant * Genetic tests for Factor V Leiden and Prothrombin G20210A mutation

Question 94

What other tests may be used in conjunction with thrombophilia screening?

Answer 94

* D-dimer * Ultrasound test * Further imaging techniques

Question 95

What environmental factors contribute to acquired venous thromboembolism?

Answer 95

* Age * Pregnancy and post-partum * Immobility * Dehydration

Question 96

What iatrogenic factors are associated with acquired venous thromboembolism?

Answer 96

* Postoperative immobilisation * Indwelling venous devices * Pharmacological (COCP, HRT, Tamoxifen, chemotherapy)

Question 97

What disease-related factors can lead to acquired venous thromboembolism?

Answer 97

* Antiphospholipid Syndrome * Malignancy and Inflammatory states * Intravenous drug users * Thrombotic thrombocytopenic purpura

Question 98

What is Antiphospholipid Syndrome (APS)?

Answer 98

Acquired autoimmune clinical syndrome with features of thrombosis and/or pregnancy complications.

Question 99

List the types of thrombosis associated with Antiphospholipid Syndrome.

Answer 99

* Venous thrombosis * Arterial thrombosis * Microvascular thrombosis

Question 100

What is the potentially lethal form of microvascular thrombosis in APS known as?

Answer 100

Catastrophic antiphospholipid syndrome (CAPS)

Question 101

Differentiate between primary and secondary Antiphospholipid Syndrome.

Answer 101

Primary APS involves arterial occlusion, venous thrombosis, recurrent miscarriage, sterile endocarditis. Secondary APS is associated with conditions like SLE, RA, SS, Temporal Arthritis.

Question 102

What are Antiphospholipid Antibodies?

Answer 102

A heterogeneous family of antibodies that react with proteins binding to negatively charged phospholipids.

Question 103

Which antiphospholipid antibody is most reactive?

Answer 103

β2-Glycoprotein I (β2-GPI)

Question 104

What are the types of antiphospholipid antibodies detected in APS?

Answer 104

* Lupus Anticoagulant (LA) * Anticardiolipin antibody (aCL) (IgG/IgM) * Anti-β2-Glycoprotein I antibody (β2-GPI) (IgG/IgM)

Question 105

Why is the presence of Lupus Anticoagulant significant?

Answer 105

Recognised as a strong risk factor for thromboembolic events and pregnancy morbidity.

Question 106

What effect do antiphospholipid antibodies have on clot formation?

Answer 106

They slow clot formation, prolonging the clotting time and impairing the assembly of the prothrombinase complex.

Question 107

What are the indications for patient selection for APS testing?

Answer 107

* Unprovoked VTE * Unusual thrombosis * Late pregnancy loss * Thrombosis in patients with autoimmune disease

Question 108

True or False: Random testing for APS is recommended.

Answer 108

False

Question 109

What is the most sensitive test for APS diagnosis?

Answer 109

Anticardiolipin Antibodies (aCL)

Question 110

What testing method is used for detecting Anticardiolipin Antibodies?

Answer 110

ELISA

Question 111

Does the Anticardiolipin test get influenced by warfarin and heparins?

Answer 111

No

Question 112

How are aCL titres classified?

Answer 112

* Low (< 40) * Moderate (40 to 80) * High (> 80)

Question 113

How are Anti-β2-glycoprotein-I Antibodies detected?

Answer 113

Using ELISA

Question 114

What activates Factor X in the Lupus Anticoagulant Screen?

Answer 114

Russell’s Viper Venom (RVV)

Question 115

What does Lupus Anticoagulant do in the context of clot formation?

Answer 115

Prolongs the DRVVT by binding to the phospholipid and preventing the action of RVV.

Question 116

What is measured in the Lupus Anticoagulant Screen?

Answer 116

DRVVT in the presence of low dose and high dose phospholipid.

Question 117

How is the final result of the Lupus Anticoagulant Screen expressed?

Answer 117

As a ratio of both clot times.