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2.2 Haematology > Thrombophilia > Flashcards

Thrombophilia Flashcards

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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
Write about thrombosis before age 25 years
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
26
What are the three different antithrombin deficiency types
Type I Type II Type III
27
Write about Type 1 antithrombin deficiency
Low antithrombin functional activity Quantitative reduction in antigen and function Major gene deletions and point mutations
28
Write about type II antithrombin deficiency
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
29
Write about antithrombin deficiency treatment
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%
30
Write about the protein C pathway
The protein C pathway regulates coagulation on phospholipid surfaces It limits the procoagulant activity of FVa and FVIIa
31
What are the components of the protein C pathway
Protein C (PC) Activated protein C (APC) Protein S (PS) Thrombomodulin (TM) Thrombin (FIIa) Endothelial protein C receptor (EPCR)
32
How does increased generation of thrombin affect the protein C pathway
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
33
What activates protein C pathway
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
34
Write about protein C deficiency (5)
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
Write about type I protein C deficiency
Quantitative defect Characterised by the parallel reductions of functional and immunological protein C
36
Write about type II protein C deficiency
Qualitative defeect Functional level is significantly lower than the immunological protein C level
37
How is protein C deficiency treated (4)
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
Write about protein S
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
Write about the action of protein S (4)
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
What are the three types of protein S deficiency
Type I, II, III It has been suggested that type I and type III defects are phenotypic variants of the same genetic disorder
41
Write about type I Protein S deficiency (3)
Quantitative deficiency resulting in reduced production of structurally normal protein Deficiency in total and free PS Variety of mutations
42
Write about type II deficiency
Qualitative defect Missense mutations
43
Write about type III deficiency
Qualitative deficiency with reduced free PS antigen and normal total PS antigen Missense mutations
44
Write about protein S deficiency in women
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
What might reduce protein S levels (4)
Warfarin therapy Antiphospholipid syndrome DIC Liver disease
46
Write about factor V Leiden and APCR (4)
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
What is APCR
APCR is defined as an impaired plasma anticoagulant response to APC added in vitro
48
Write about APCR and the FVL mutation
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
Write about the FVL mutation FVR 506Q
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
What are some acquired thrombosis risk factors
Smoking OCP Recent Surgery
51
What strongly enhances factor V Leiden
Oral contraceptives
52
Write about the prothrombin gene
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
Write about mutations in the prothrombin gene
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
What are the five main BSH guidelines
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
When should you not do a thrombophilia screen? (4)
Reason for thrombosis known such as central venous catheter Upper Limb Thrombosis Hospital acquired thrombosis Retinal vein occlusion
56
What are three acquired venous thromboembolism causes
Environmental Iatrogenic Disease related
57
What four environmental factors might caused venous thromboembolism
Age Pregnancy and post-partum Immobility Dehydration
58
What three iatrogenic factors can cause acquired venous thromboembolism
Postoperative immobilisation Indwelling venous devices Pharmacological (COCP, HRT, Tamoxifen, chemotherapy)
59
What four fisease related factors might cause acquired venous thromboembolism
Antiphospholipid syndrome Malignancy and inflammatory states Intravenous drug users Thrombotic thrombocytopenic purpurra
60
What are some other names for antiphospholipid syndrome
Hughes Syndrome Sticky Blood Syndrome
61
What is antiphospholipid syndrome
Acquired autoimmune clinical syndrome with features of thrombosis (venous, arterial and micro-vascular) and/or pregnancy complications and failure
62
What can antiphospholipid syndrome cause
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
What are the two types of APS
Primary APS Secondary APS
64
What is primary APS
Arterial occlusion Venous thrombosis Recurrent miscarriage Sterile endocarditis
65
What is secondary APS
SLE RA SS Temporal arthritis
66
What are antiphospholipid antibodies
A heterogenous family of antibodies that react with proteins which bind to negatively charged phospholipids B2 - GPI most reactive
67
How do we investigate PAS
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
What antibodies are used in the investigation of APS
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
What is lupus anticoagulant
Recognised as a strong risk factor for thromboembolic events and pregnancy morbidity LA tests are sensitive to antibodies to B2GPI and Prothrombin
70
What does the presence of anti-phospholipid antibody mean
They slow clot formation prolonging clotting time, impairment of the assembly of the prothrombinase complex
71
How should you select patients for APS testing
Do not test randomly on patients, patient should have significant probability of having APS, Unexplained prolonged APTT Low, moderate or high probability
72
What would put someone at low risk for APS
VTE, arterial thrombosis in older patient
73
What would put someone at moderate risk of APS
Abnormal APTT in asymptomatic patient Recurrent early pregnancy loss Provoked VTE
74
What would put someone at risk for APS testing
Unprovoked VTE Unusual thrombosis Late pregnancy loss Thrombosis in patients with auto-immune diseae
75
What are anticardiolipin antibodies
The most sensitive test for APS diagnosis ELISA test Test is not influenced by warfarin and heparins Low, moderate or high aCL
76
What are anti-B2-glycoprotein-I antibodies
Detected using ELISA and are included in the classification criteria There is no standardisation for this methodology
77
What are some diagnostic criteria for lupus anticoagulant
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
What are two tests used to detect lupus anticoagulant
Dilute Russell viper venom time Sensitive APTT with reduced phospholipid and silica as activator
79
Write about the lupus anticaogulant screen
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
Write about the use of APTT with Sillica as the activator
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
What is needed for the laboratory diagnosis of APS
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
What is needed for diagnosis of acquired thrombophilia
Increased factor VIII levels Hyperhomocysteinaemia attributable to non genetic causes Elevated fibrinogen levels Fulfils at least one clinical and one laboratory criteria
83
What are some criteria for diagnosis of APS
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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