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2.2 Haematology > Thrombophilia > Flashcards

Thrombophilia Flashcards

1
Q

What is thrombophilia

A

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

Hereditary or acquired

Heritable thrombophilia is an inherited tendency for venous thrombosis (DVT with or without PE)

Relates to an increase risk of venous thrombosis and may be asymptomatic

Can occur as a result of genetic factors, acquired changes in the clotting mechanism or more commonly an interaction between genetic and acquired factors

First described deficiency of anti-thrombin as a risk factor for thrombosis

Deficiencies of protein C and Protein S have since been found to be associated with familial thrombosis

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2
Q

What is Heritable thrombophila

A

Heritable thrombophilia is an inherited tendency for venous thrombosis (DVT with or without PE)

Relates to an increase risk of venous thrombosis and may be asymptomatic

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3
Q

What can cause thrombophilia

A

Can occur as a result of genetic factors, acquired changes in the clotting mechanism or more commonly an interaction between genetic and acquired factors

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4
Q

What deficiencies are associated with thrombophilia

A

First described deficiency of anti-thrombin as a risk factor for thrombosis

Deficiencies of protein C and Protein S have since been found to be associated with familial thrombosis

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5
Q

What initiates thrombosis

A

Rupture of the plaque, exposing material to subendothelium in the blood

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6
Q

What does thrombosis cause

A

Platelet plasma coagulation factor activation which results in fibrin formation

The end result is a thrombus that can obstruct the artery or an embolus breaks off and lodges in the heart or brain, causing tissue death

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7
Q

What are the risk factors for thrombosis

A

Hypercholesterolemia
Hypertension
Smoking
Physical inactivity
Obesity
Diabetes
Inflammatory processes related to artherosclerosis

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8
Q

What is deep vein thrombosis

A

A blood clot that forms in a deep vein of the leg or pelvis either partially or totally blocking the flow of blood

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9
Q

What is pulmonary embolism

A

Deep vein thrombosis (blood clot) or part of it, breaks off from the vein

The break away clot travels through the bloodstream to the heart and migrates towards the lung

The clot blocks a vessel in the lung interupting blood supply

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10
Q

What is venous thrombosis

A

Occurs when activation of blood coagulation exceeds ability of the anticoagulant/inhibitors and fibrinolytic system to prevent the formation of fibrin

Post thrombotic syndrome can result in significant morbidity

Venous thrombosis is a multi-causal disease i.e. gene-environment interactions

Case fatality ranges from 1 to 5%, incidence and fatality are age dependent

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11
Q

How frequent is venous thrombosis

A

1.17 per 1000 per year

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12
Q

How frequent is DVT

A

0.48 per 1000 population/year

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13
Q

How frequent is pulmonary embolism

A

0.69 per 1000 population/year

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14
Q

Write about DVT

A

Unlikely to cause acute complications

Above knee DVT could cause PE within the lungs, life threatening>shortness of breath and chest pain

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15
Q

What causes thrombosis

A

Inherited defects
Acquired factors
Multiple defects

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16
Q

What are the eight main risk factors for thrombosis

A

Atherosclerosis
Acquired thrombophilia
Surgery trauma
Estrogens
Malignancy
Inflammation
Immobility
Hereditary thrombophilia

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17
Q

What are the five strongest risk factors for thrombosis

A

Hip or leg fracture
Hip or knee replacement
Major General surgery
Major trauma
Spinal Cord Injury

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18
Q

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

A

Antithrombin
Protein C
Protein S

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19
Q

What are the genetic defects associated with venous thrombosis?

A

Factor V Leiden
Prothrombin gene mutation

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20
Q

How does the clot form in VTE
(5)

A

Local venous stasis is necessary

Increased turbulence of blood around valves

Endothelial damage causing platelet activation

Localised trapped activated coagulation factors

Low shear rates of blood flow

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21
Q

What causes vascular wall injury

A

Trauma or surgery
Venepuncture
Chemical irritation
Heart valve disease or replacement
Artherosclerosis
Indwelling catheters

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22
Q

What causes circulatory stasis

A

Atrial fibrillation
Left ventricular dysnfuction
Immobility or paralysis
Venous insufficiency or varicose veins
Venous obstruction from tumour, obesity or pregnancy

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23
Q

Write about antithrombin

A

Serine protease inhibitor produced in the liver

Most potent serine protease in coagulation

Responsible for 80% of inhibition that takes place

It’s primary targets are FIIa, FXa, FIXa (FXIa and TF-FVIIa)

It inhibits free FIIa and FXa more easily than that bound in complexes: acts as a scavenger

Antithrombin forms a stable covalent complex with its substrate is then rapidly cleared from the circulation

It’s rate of activity is enhanced 1000x by heparin

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24
Q

Write about antithrombin deficiency

A

More thrombogenic that PC or PS deficiency

Family studies suggest that AT deficiency is more severe than PC or PS

Majority of patients experience thrombosis before age 25 years

More than 250 mutations have been reported. Homozygosity is rare

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25
Q

Write about thrombosis before age 25 years

A

Slightly lower in pre-menopausal women than in men of similar age

Lower in COCP use than in non COCP use

Low levels in patients on heparin and in patients with current thrombosis

Significant decreases in DIC, liver diseases, nephrotic syndrome

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26
Q

What are the three different antithrombin deficiency types

A

Type I
Type II
Type III

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27
Q

Write about Type 1 antithrombin deficiency

A

Low antithrombin functional activity
Quantitative reduction in antigen and function
Major gene deletions and point mutations

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28
Q

Write about type II antithrombin deficiency

A

Reduced antithrombin functional activity

Qualitative defect with abnormal AT protein

Reactive site defect - reduced ability to inhibit thrombin or FXa with or without heparin

Heparin binding site defect - reduced ability to bind and be activated by heparin

Pleiotropic effect where mutations produce multiple effects on the structure-function relationship of the molecule

Results from single base substitutions in the coding regions

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29
Q

Write about antithrombin deficiency treatment

A

Warfarin
Low molecular weight heparin or unfractionated heparin
In some cases antithrombin concentrates and LMWH therapy may be considered
LMWH therapy with regulated dose of warfarin
INR aim 2.0-3.0
Aim is to initially get antithrombin activity over 120% and then maintain activity at 80%

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30
Q

Write about the protein C pathway

A

The protein C pathway regulates coagulation on phospholipid surfaces

It limits the procoagulant activity of FVa and FVIIa

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31
Q

What are the components of the protein C pathway

A

Protein C (PC)
Activated protein C (APC)
Protein S (PS)
Thrombomodulin (TM)
Thrombin (FIIa)
Endothelial protein C receptor (EPCR)

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32
Q

How does increased generation of thrombin affect the protein C pathway

A

Increased generation of thrombin results in increased affinity for thrombomodulin on the endothelial cell surface

FIIa-TM complex prevents binding of FIIa to procoagulant substrates and activated platelets

FIIa-TM complex alters substrate specificity of FIIa allowing activation of PC

TM bound FIIa increases its susceptibility to inhibition by AT

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33
Q

What activates protein C pathway

A

Activated by the FIIa-TM complex on the surface of the endothelial cells

The inhibitory effects of Protein C are facilitated by the cofactor Protein S

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34
Q

Write about protein C deficiency
(5)

A

Autosomal dominant inheritence

Relative risk for thrombosis is 10 fold

Type 1 and Type II, Type 1 is more common

Reduced level in Warfarin therapy, DIC, liver disease

Adult heterozygous protein C deficiency patient normally have 60% activity

35
Q

Write about type I protein C deficiency

A

Quantitative defect
Characterised by the parallel reductions of functional and immunological protein C

36
Q

Write about type II protein C deficiency

A

Qualitative defeect
Functional level is significantly lower than the immunological protein C level

37
Q

How is protein C deficiency treated
(4)

A

LMWH or heparin

Once the therapeutic anticoagulation has been achieved with these patients, warfarin can be introduced

Target INR of 3.5 (2.0-3.0)

Side effects of high doses of warfarin treatment is warfarin necrosis

38
Q

Write about protein S

A

Vitamin K dependent glycoprotein produced in liver, endothelial cells and megakaryocytes

PS is a non-enzymatic cofactor for APC-mediated inactivation of FVa and FVIIIa

60% of the total plasma PS is complexed with C4b-binding protein (C4bBP) and has no cofactor activity, 40% is free PS remains uncomplexed and is the active moiety

The bioavailability of PS is linked to the concentration of C4bBP and acts as an important regulatory protein in the APC pathway

39
Q

Write about the action of protein S
(4)

A

Free PS binds strongly to negatively charged phospholipids on the surface of activated platelets

It forms a Ca++ dependent complex with APC

APC/PS complex will inactivate FVa

Regulation of FVIIIa requires APC/FV/PS

40
Q

What are the three types of protein S deficiency

A

Type I, II, III

It has been suggested that type I and type III defects are phenotypic variants of the same genetic disorder

41
Q

Write about type I Protein S deficiency
(3)

A

Quantitative deficiency resulting in reduced production of structurally normal protein

Deficiency in total and free PS

Variety of mutations

42
Q

Write about type II deficiency

A

Qualitative defect
Missense mutations

43
Q

Write about type III deficiency

A

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

Missense mutations

44
Q

Write about protein S deficiency in women

A

Lower levels in women
Separate reference range for male/female
Level falls progressively during pregnancy
Reduced levels in women using estrogen containing OCP or HRT

45
Q

What might reduce protein S levels
(4)

A

Warfarin therapy

Antiphospholipid syndrome

DIC

Liver disease

46
Q

Write about factor V Leiden and APCR
(4)

A

The gene for FV is on chromosome 1

FVa is required for the activation of FII by FXa in the prothrombinase complex

Factor Va is cleaved and inactivated by APC and PS to produce FVi

A mutation in gene for F5 results in production of factor V that is resistant to cleavage by APC

47
Q

What is APCR

A

APCR is defined as an impaired plasma anticoagulant response to APC added in vitro

48
Q

Write about APCR and the FVL mutation

A

APC resistance co-segregated with thrombosis in families with familial VTE

Mutant FV Leiden has normal procoagulant activity but impaired response to APC

The mutation was first identified in 1994

In the FV gene there is a G (guanine) to A (adenine) base substitution

This results in the amino acid exchange from Arginine to Glutamine at position 506 in the factor V protein

49
Q

Write about the FVL mutation FVR 506Q

A

5% of Caucasians

More common in Northern Europeans than in south

15% of patients presenting with first VTE episode

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

Homozygous carriers 80 fold increased risk (5-10%)

Acquired thrombosis risk factors

The effect of factor V Leiden is strongly enhanced by use or oral contraceptives

50
Q

What are some acquired thrombosis risk factors

A

Smoking
OCP
Recent Surgery

51
Q

What strongly enhances factor V Leiden

A

Oral contraceptives

52
Q

Write about the prothrombin gene

A

Chromosome 11

Vitamin K dependent protein produced in the liver

Guanine to adenine base substitution at base 20210 of the prothrombin gene

Elevated plasma prothrombin levels and increased risk of venous thrombosis

53
Q

Write about mutations in the prothrombin gene

A

Prevalence in northern europe is 3% and in 4% of patients with first VTE episode

Relative risk is 2 fold in heterozygotes. Risk for homozygotes is unkown although asymptomatic homozygotes have been described (mild defect)

15-40% of patients with heterozygous FVL are also heterozygous for prothrombin mutation

54
Q

What are the five main BSH guidelines

A

Results don’t predict likelihood of recurrence of thrombotic episode

Indicated for patients with first time thrombotic episode under the age of 40

Family history of unprovoked thrombotic events

Indicated for patients with three or more early pregnancy loses

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

55
Q

When should you not do a thrombophilia screen?
(4)

A

Reason for thrombosis known such as central venous catheter

Upper Limb Thrombosis

Hospital acquired thrombosis

Retinal vein occlusion

56
Q

What are three acquired venous thromboembolism causes

A

Environmental
Iatrogenic
Disease related

57
Q

What four environmental factors might caused venous thromboembolism

A

Age
Pregnancy and post-partum
Immobility
Dehydration

58
Q

What three iatrogenic factors can cause acquired venous thromboembolism

A

Postoperative immobilisation

Indwelling venous devices

Pharmacological (COCP, HRT, Tamoxifen, chemotherapy)

59
Q

What four fisease related factors might cause acquired venous thromboembolism

A

Antiphospholipid syndrome
Malignancy and inflammatory states
Intravenous drug users
Thrombotic thrombocytopenic purpurra

60
Q

What are some other names for antiphospholipid syndrome

A

Hughes Syndrome
Sticky Blood Syndrome

61
Q

What is antiphospholipid syndrome

A

Acquired autoimmune clinical syndrome with features of thrombosis (venous, arterial and micro-vascular) and/or pregnancy complications and failure

62
Q

What can antiphospholipid syndrome cause

A

Venonus thrombosis -> lower limb DVT +/- PE

Arterial thrombosis -> cerebral vasculature: TIA, stroke

Microvascular thrombosis is least common but can present at the potential lethal catastrophic antiphospholipid syndrome

63
Q

What are the two types of APS

A

Primary APS
Secondary APS

64
Q

What is primary APS

A

Arterial occlusion
Venous thrombosis
Recurrent miscarriage
Sterile endocarditis

65
Q

What is secondary APS

A

SLE
RA
SS
Temporal arthritis

66
Q

What are antiphospholipid antibodies

A

A heterogenous family of antibodies that react with proteins which bind to negatively charged phospholipids

B2 - GPI most reactive

67
Q

How do we investigate PAS

A

Persistent laboratory detection of antibodies, 12 weeks apart

Rules out the possibility of a transient positivity of antiphospholipid antibodies induced by infections or drugs

68
Q

What antibodies are used in the investigation of APS

A

Antibodies directed against proteins that have the property of binding to negative charged phospholipids

Lupus Anticoagulant (LA)
Anticardiolipin antibody (aCL) (IgG, IgM)
Anti-B2-Glycoprotein I antibody

69
Q

What is lupus anticoagulant

A

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

LA tests are sensitive to antibodies to B2GPI and Prothrombin

70
Q

What does the presence of anti-phospholipid antibody mean

A

They slow clot formation prolonging clotting time, impairment of the assembly of the prothrombinase complex

71
Q

How should you select patients for APS testing

A

Do not test randomly on patients, patient should have significant probability of having APS, Unexplained prolonged APTT

Low, moderate or high probability

72
Q

What would put someone at low risk for APS

A

VTE, arterial thrombosis in older patient

73
Q

What would put someone at moderate risk of APS

A

Abnormal APTT in asymptomatic patient
Recurrent early pregnancy loss
Provoked VTE

74
Q

What would put someone at risk for APS testing

A

Unprovoked VTE
Unusual thrombosis
Late pregnancy loss
Thrombosis in patients with auto-immune diseae

75
Q

What are anticardiolipin antibodies

A

The most sensitive test for APS diagnosis
ELISA test
Test is not influenced by warfarin and heparins

Low, moderate or high aCL

76
Q

What are anti-B2-glycoprotein-I antibodies

A

Detected using ELISA and are included in the classification criteria

There is no standardisation for this methodology

77
Q

What are some diagnostic criteria for lupus anticoagulant

A

Prolongation of phospholipid dependent coagulation test
Demonstration of an inhibitor
Confirmation of phospholipid dependent nature of the inhibitor
Perform 2 screening tests based on different principles, no single test is sufficiently sensitive to LA
Risk of false positives if more than 2 tests used
Some methods are unsuitable for testing when the patient is on warfarin or heparin
Guidelines issued by ISTH, BSH and CLSI

78
Q

What are two tests used to detect lupus anticoagulant

A

Dilute Russell viper venom time
Sensitive APTT with reduced phospholipid and silica as activator

79
Q

Write about the lupus anticaogulant screen

A

Positive DRVVT ratio is > 1.2

Russell’s Viper Venom activates factor X leading to a clot formation in the presence of FV, prothrombin, phospholipid and Ca++

LA prolongs the DRVVT by binding to the phospholipid and preventing the action of RVV

DRVVT is measured in presence of low dose and high dose phospholipid

The final result is expressed as a ratio of both clot times

The excess phospholipid will neutralise the LA and normalise the DRVVT

This gives the tests it’s specificity

80
Q

Write about the use of APTT with Sillica as the activator

A

Use reagent with low concentration of phospholipid
Use a combination of two reagents
- Low concentration of phospholipid
- High concentration of phospholipid

Calculate ratio of Silica time of patient results to normal plasma for both reagents and then overall ratio for both phospholipid reagent

Improve specificity for LA

A ratio < 1.16 is normal

81
Q

What is needed for the laboratory diagnosis of APS

A

DRVVT positive
SCT postitive
Interpretation - Lupus Anticoagulant detected
In order to fulfil laboratory criteria for APS a positive result on two occasions more than 12 weeks apart must be obtained

82
Q

What is needed for diagnosis of acquired thrombophilia

A

Increased factor VIII levels

Hyperhomocysteinaemia attributable to non genetic causes

Elevated fibrinogen levels

Fulfils at least one clinical and one laboratory criteria

83
Q

What are some criteria for diagnosis of APS

A

LA: persistence in positivty on two or more occasions at least 12 weeks apart

Coagulation test:
- Lupus anticoagulant

Immunology test:
- Anti-Cardiolipin antibody
- B-GPI antibody

2.2 Haematology (38 decks)

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