NotSoFriendly Skies A discussion of Economy Class Syndrome Are you at Risk

1
Not-So-Friendly SkiesA discussion of Economy
Class SyndromeAre you at Risk?

• PRESENTED BY
• David Schaffner, Ph.D.,MT(ASCP)
• Scientific Affairs Manager, Beckman Coulter, Inc.
• AND
• Jennifer J. Kiblinger
• Technical Affairs Manager, DiaPharma Group, Inc.

2
Introduction
3
Economy Class Syndrome

• A 28-year old woman arrives at Londons Heathrow
  Airport
• Collapses on the way to Baggage Claim
• Died before reaching the hospital

What happened?
4
Economy Class Syndrome

• Autopsy revealed a blood clot in the lung
• Economy Class Syndrome
• Medical condition called Venous Thromboembolism

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(No Transcript)
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Economy Class Syndrome
Tokyo Japans first survey of What is being
called economy class syndrome found that 25
passengers Have died of the condition at
Tokyos Narita airport in the past eight years,
a figure likely to put pressure on Airlines to
find solutions.
7
Economy Class Syndrome
London British Airways said on Tuesday it will
give passengers warning leaflets about the risks
of potentially fatal blood clots on long haul
flights. A spokesman said leaflets would be put
in ticket jackets for all long haul flights,
warning passengers that sitting for long periods
may cause circulation to become sluggish,
increasing the risk of health problems like blood
clots.
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Objectives

• How blood clots are formed
• Some basic science
• Acquired and inherited clotting diseases
• Risk assessment
• Diagnosis and treatment of clotting diseases
• Lab tests
• Prevention
• Simple steps to help prevent ECS

9
Basic Coagulation
10
Coagulation Basics
The process of blood clotting and then the
subsequent dissolution of the clot is termed
hemostasis.
11
Thrombosis

• If the clotting system is activated
• Or the fibrinolytic system in inhibited
• A hypercoagulable state exists that leads to
  abnormal clot formation

12
Losing that balance
13
Thrombogenesis

• Arterial thrombi
• platelet aggregates bound together by fibrin
  strands (white clots)
• Venous thrombi
• Consist mainly of fibrin and RBCs (red clots)

14
Virchows Triad
15
Vascular Injury

• Trauma
• Surgical manipulation
• Prior thrombosis
• Atherosclerosis

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(No Transcript)
17
Blood Hypercoagulability

• Increased procoagulants
• Decrease in inhibitors
• Impaired fibrinolysis

Hypercoag- ulability
18
Blood Hypercoagulability
19
Stasis

• Immobility
• Post-op state, debility, coma
• Economy Class Syndrome
• Pressure
• catheter, tumor obstruction
• Increased viscosity
• Polycythemia
• Dehydration
• EPO

Stasis
20
Thrombotic Disease
21
The Extent of Thrombotic Disease Annually in the
U.S.

• 1.5 million MIs
• Mortality of 30 (450,000)
• 500,000 CVAs
• Mortality of 30 (150,000)
• 2 million DVTs
• 200,000 deaths from PE

22
Venous Thromboembolism

• Third most common cardiovascular disease
• Significant morbidity and mortality
• VTE includes
• Deep Venous Thrombosis (DVT)
• Pulmonary Embolism (PE)

23
Deep Vein Thrombosis

• Blood clot of lower leg or thigh
• Approximately 1 per 1,000 people affected by DVT
• Hospitalization for 5 to 7 days
• 50 of patients with DVT are asymptomatic

24
Pulmonary Embolism

• Dislodged blood clot entering the pulmonary
  circulation
• Accounts for 5-10 of all hospital deaths
• 80 of patients die within the first 2 hours

25
Laboratory Tests to Diagnose VTE

• Due to the high prevalence of DVT and PE, and in
  order to prevent the morbidity and mortality
  associated with such diseases, a reliable and
  rapid diagnosis of these conditions is required.

26
Laboratory Tests to Diagnose VTE

• The current standard methods for the diagnosis of
  DVT (contrast venography) and PE (pulmonary
  angiography) are invasive, costly tests
  associated with high risks to the patients.
• Several non-invasive tests have been developed
  for the diagnosis of both DVT (impedance
  plethysmography, doppler ultrasound,) and PE
  (lung scanning)
• These procedures provide lower risk, but none has
  been able to achieve the sensitivity and
  specificity of the standard methods.
• They are still expensive and not always available
  (i.e. nights and weekends).

27
Laboratory Tests to Diagnose VTE D-Dimer

• D-Dimer, a measure of fibrin degradation
  products, is the final product formed during the
  fibrinolysis process by plasmin
• Degradation of Factor XIIIa cross-linked fibrin
  (XDP).
• Utility is in its Negative Predictive Value
• Elevated levels of D-Dimer are indicative of
  on-going fibrinolysis
• Found in pathological conditions such as deep
  vein thrombosis (DVT), pulmonary embolism (PE)
  and disseminated intravascular coagulation (DIC).
• D-Dimer levels also rise during the normal
  pregnancy and very high levels are associated
  with complications.

28
Thrombophilia

• Tendency to develop thrombosis
• Can be acquired or inherited or both
• Manifested as venous thromboembolism (VTE)
• Multi-hit theory

29
Hereditary Acquired Risk Factors

• There are several well-established risk factors
  and corresponding assays to test for them
• Most of these risk factors can be hereditary or
  acquired

30
Hereditary Acquired Risk Factors

• Inherited Risk Factors
• APC resistance-Factor V Leiden
• AT deficiency
• Protein C deficiency
• Protein S deficiency
• Prothrombin Mutation
• Dysfibrinogenemia (rare)

• Acquired Risk Factors
• Age
• Malignancy
• Immobilization
• Trauma, Post-op
• Pregnancy
• Estrogen use
• Antiphospholipid Antiboides
• Long distance flights
• Hematologic Diseases

• Inherited or Acquired Risk Factors
• Hyperhomocystenemia
• Elevated levels of FVIII, IX,XI

31
Genetic risk factors in unselectedthrombosis
patients
32
Laboratory Evaluation of Thrombotic Risk

• Laboratory Screening for thrombophilia is
  appropriate only in certain circumstances, as it
  is cost-prohibitive.
• There is no global assay currently available to
  determine thrombotic risk, so a panel of assays
  is performed.

33
Laboratory Evaluation of Thrombotic Risk

• What is the role of the coag lab in evaluating
  patients with thrombosis?
• Laboratory personnel have an important role in
  discussing with clinicians
• Diagnostic tests available
• Which assays are optimal and appropriate
• Sample collection timing

34
Laboratory Evaluation of Thrombotic Risk

• The quality of blood sample is of major
  importance
• Evacuated tubes with 3.2 trisodium citrate
  should be used for blood draws
• An improperly drawn sample may be activated,
  interfering with measured levels of coagulation
  factors
• Samples drawn from lines may contain heparin,
  interfering with clotting assays

35
Laboratory Evaluation of Thrombotic Risk

• Types of Assays
• Functional Activity Assays
• Clotting
• Chromogenic
• Immunological / Antigenic Assays
• ELISA
• LIA

36
Chromogenic vs. Clotting Assays

• In general, chromogenic assays are more specific,
  accurate, and precise generally less susceptible
  to pre-analytical variables
• Clot-based assays are typically fast and less
  expensive
• Clot-based assays are subject to interference by
  other coagulation factor levels, heparin,
  warfarin, other anticoagulants, as well as the
  presence of lupus anticoagulant
• Both clotting and chromogenic assays can
  typically be put on automated analyzers

37
What is a Chromogenic Assay?

• Chromogenic substrate peptide that reacts with
  proteolytic enzymes, thus forming color
• Labeled with a chromophore that gives off a color
  when hydrolyzed by specific enzyme

38
Chromogenic Assay General Principle
Activator
Zymogen
Enzyme
Enzyme
PNA
PNA

Peptide
Peptide
(Substrate)
Yellow color develops
39
Chemical structure
Prothrombin, the natural substrate of FXa, is
cleaved by FXa at two positions, each proceeded
by the same four amino acid sequence. FXa
activity can be determined by the chromogenic
substrate S-2222 which is composed of the same
amino acids coupled to a chromophore
40
Chemical structure
Blocking group
Chromophore
Residues
41
Laboratory Evaluation of Thrombotic Risk
42
Anticoagulation Pathways - Antithrombin
FX
TF FVIIa
Prothrombin
TFPI
PL
FXa
Va
Heparin (cofactor)
Thrombin
Antithrombin III
43
Antithrombin, Protein C, Protein S Deficiencies

• Loss-of-Function Abnormalities
• Deficiencies of AT, PC, and PS are most commonly
  seen in the heterozygous state
• Levels are about 30 60 of normal
• Risk potential of each of these deficiencies is
  10 25 fold
• Individuals with AT, PC, or PS deficiencies
  typically have a thrombotic event at a fairly
  young age

44
Antithrombin

• Major inhibitor of blood coagulation
• Inhibits thrombin (F IIa),
• FXa and IXa, XIa and XIIa
• Heparin binds to AT

45
Antithrombin, Protein C, Protein S Deficiencies

• Type I Decreased Activity, Decreased Antigen
• Type 2 Decreased Activity, Normal Antigen

46
Antithrombin assays
ACTIVITY
IMMUNOLOGICAL measures only type I deficiency
Clotting Plasma samples require
defibrination Slow assay, high variability
Chromogenic Good precision, simple to use
FXa The most used assay reccommended by
ISTH Better diagnotic accuracy
FIIa Influenced by heparin cofactor II, (no
accurate determination in patients receiving
heparin therapy) and by thrombin inhibitors.
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FVIIIa
FVa
FIIa
FIXa
FX/Xa
FII
APC
Protein S
48
Protein C Deficiency
Normal Type I Type II

• 
  

PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
Absent molecules
Variant molecules
Normal antigen and normal activity
Reduced antigen and reduced activity Functional
antigenic assays will detect
Normal antigen but reduced activity Functional
assay will detect Antigenic assay will NOT detect
49
Protein C Assays - Chromogenic assays

• Chromogenic assays use specific PC activator
  (Protac) to activate Protein C
• Preferred method since subject to fewer
  pre-analytical variables
• Measure also non-carboxilated forms of protein C
  over-estimate the true level of protein C in OAC
  treated patients.
• When plasma samples from patients on
  streptokinase therapy, suffering from DIC or
  receiving oral contraceptives are tested a blank
  should be measured since these plasma may to some
  extent cleave the chromogenic substrate
• Detect abnormalities of PC activation and
  abnormalities of the enzymatic active site. Do
  not detect defects in binding of FVa and FVIIIa
  or inability to bind Protein S or phospholipid
  (minority of patients)

50
Protein C Assays - Chromogenic assays

• Simple and rapid
• Excellent accuracy and precision
• Adapted to a broad range of instruments
• No interference from heparin

51
Protein C assays Clotting assays

• Clotting assays are based on the ability of APC
  to prolong the aPTT clotting time
• Clotting assays are influenced by APC Resistance.
• APC-R will shorten the clotting time
• High levels of FVIII results in under estimation
  of the PC level. FVIII levels 250 will shorten
  the clotting time.
• Presence of lupus inhibitor results in over
  estimation of the protein C level.The lupus
  anticoagulant will inhibit the phospholipid in
  the APTT reagent and prolong the clotting time.

52
Protein S

• Vitamin K dependent protein
• Acts as a cofactor to Protein C
• Expresses some anticoagulant activity independent
  of APC
• Circulates in plasma in the free or bound by
  C4bBP
• Free Protein S is the functionally active form of
  the protein

53
Type I
and
Type III

appear to be different phenotypic expressions
of the same genotype
54
Protein S Assays

• Functional protein S can be measured with
  clot-based assays or by measuring free protein S
  antigen levels with an immunological assay
• Total protein S antigen can also be measured
  using immunological assays
• APTT based Protein S activity assays, like
  Protein C assays, may show interference by
  elevated FVIII levels as well as the presence of
  lupus anticoagulant
• Clotting assay therefore not recommended better
  to perform Free Protein S Antigen assay for
  thrombophilia screening purposes

55
APC Resistance

• Common in the general population
• Most common cause of hereditary thrombophilia
• Can be hereditary or acquired
• APC Resistance alone is not a significant risk
  factor. Having APC Resistance combined with other
  risk factors, however, greatly increases risk of
  thrombosis

56
ANTICOAGULANT RESPONSE TO APC
Seconds
APC resistance phenotype A poor anticoagulant
response to activated protein C (APC).
100
Normal
80
APC resistant
60
Clot time
40
20
nM
20
40
60
80
100
APC concentration
57
INACTIVATION OF NORMAL FVa
A
P
C

c
l
e
a
v
a
g
e

s
i
t
e
s
6
7
9
5
0
6
3
0
6
2
C
a
F
V
a

h
e
a
v
y

c
h
a
i
n
F
V
a

l
i
g
h
t

c
h
a
i
n
58
INACTIVATION OF MUTANT FVaQ506

• FV Leiden Mutation
• Accounts for approx. 90 of APC Resistance
• Prevalent in about 2 13 of general population
• Accounts for about 20 60 of VTE cases
• Heterozygotes for FV Leiden have 2 5 fold
  increased thrombotic risk

A
P
C

c
l
e
a
v
a
g
e

s
i
t
e
s
6
7
9
3
0
6
2
C
a
F
V
a

h
e
a
v
y

c
h
a
i
n
F
V
a

l
i
g
h
t

c
h
a
i
n
Mutation results in a 10-fold lower inactivation
rate of FVa
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GENETIC AND ACQUIRED RISKS
Genetic risk factors APC resistance (FVQ506,
FV Leiden) Acquired risk factors Surgery,
Pregnancy and Oral Contraceptive Pills / Patch
60
F.V Leiden and Risk Factors for DVT
61
APTT-based APC Resistance Assays
1 vol. Prediluted Plasma
V DEF Plasma
Sample Plasma



Incubate 5 min. 37C
1 vol. APTT


1 vol. APC/CaCl2
1 vol. CaCl2
Record time for clot formation
62
APC RESISTANCE INTEPRETATION OF RESULTS

• APC- ratio
• APC Resistance is indicated when the APC ratio is
  below or equal to the calculated cut-off value.
• APC R V ratio below the calculated cut-off is due
  to presence of the factor VQ506 mutation

Clot time APC/CaCl2
Clot time CaCl2
63
APTT-based APC Resistance Assays

• Benefit
• Offers genotypic information for clinical
  decision-making
• Utility
• For factor VQ506 mutation screening
• Features
• Unsurpassed sensitivity for the factor VQ506
  mutation and close to 100 specificity
• Applicable to anticoagulant treated patients
• Economical alternative to genetic testing

64
APC Resistance
Clear discrimination between normals,
heterozygotes, and homozygotes is achieved with
the APTT-based screening assay.
65
Algorithm for APC R Testing
66
Prothrombin G20210A mutation

• Prevalence in normal population approximately 3
• G ? A translation at nucleotide 20210 in
  prothrombin gene
• Leads to an increase in Factor II (prothrombin)
  levels
• Increased risk of venous thrombosis
• DNA analysis can confirm the presence of the gene
  mutation

67
Hyperhomocysteinemia

• Homocysteine an amino acid metabolite central to
  the formation of methionine cysteine
• Conversion of homocysteine to either metabolite
  dependent on a number of enzymes, including
  methylene tetrahydrofolate reductase (MTHFR)
• Cofactors folic acid, vitamins B12 and B6
• Mutations in MTHFR may be associated with
  hyperhomocysteinemia
• Elevated homocysteine is a risk factor for
  cardiovascular disease
• Increased risk of coronary heart disease, stroke
  and recurrent VTE
• Homocysteine can be measured by enzyme
  immunoassay (EIA) or HPLC new assays are coming
  out for use on chemistry analyzers
• Must separate serum or plasma from cells within
  an hour of sample collection, as RBCs will
  continue to secrete homocysteine

68
Hyperhomocysteinemia

• Premature vascular disease
• Thromboembolic disease at an early age
• Arterial and venous thromboembolism
• M.I.
• DVT
• Graded risk factor
• 40 for every 5 ?mol/L

69
Hyperhomocysteinemia

• Congenital
• Deficiency of metabolic enzymes
• 11 of the population
• Acquired
• Poor dietary intake of folic acid and B12
• Effectively treated by dietary supplementation

70
Elevated Factor VIII

• FVIII activity 1.5 IU/mL results in 5-6-fold
  higher risk for DVT, especially recurrent DVT,
  than FVIII activity
• Confirmation of risk not associated with acute
  phase response
• Elevated FVIII persistent over time
• Familial trait observed no explanation so far

71
Measuring Elevated Factor VIII

• Chromogenic assay has been recommended as the
  optimal assay for measuring elevated FVIII levels
• Chromogenic assay precision is typically better
  than that of one-stage clotting assay at high
  FVIII levels
• No interference from heparin, direct thrombin
  inhibitors, or lupus anticoagulant
• Assay is automatable

72
FVIII MonitoringAlso important for bleeding
disordersMeasuring Factor VIII in Hemophilia
Patients
73
Methods for Determination of Factor VIII activity

• One-stage clotting assay
• Two-stage clotting assay
• Chromogenic assay

74
One-stage Clotting Assay

• Principle
• APTT based assay
• Diluted sample
• FVIII Def. Plasma
• PL, Ca2, Surface
• activator
• time for clot formation

• Most widely used method
• Cheap, rapid and simple
• but..........
• Accuracy and precision influenced by a large
  number of variables
• Sensitive to pre-activation of the coagulation
  cascade
• Over estimation in assessment of FVIII
  concentrates potency
• Requires considerable amount of FVIII deficient
  plasma

75
Two-stage Clotting Assay

• Principle
• Stage 1
• FIXa Ca2 Phospholipids
• FX FXa FVIII
• FXa
• Ca2, FV
  Complex
• Phospholipids
• Stage 2
• Complex
• Prothrombin Thrombin
• Fibrinogen Thrombin

• Less variation than one-stage assay
• No need of FVIII-deficient plasma
• In the past, it was the method of choice by the
  British and European Pharmacopoeia..........
• ......It has been replaced by the chromogenic
  method

76
FVIII Assays

• One stage clotting assays give different results
  from two-stage clotting and chromogenic assays
• The difference between methods is more pronounced
  for products of higher purity
• The discrepancies, sometimes up to 25 -50,
  create problems when determining therapeutic
  dosages
• One-stage assays give under-estimation of FVIII
  levels therefore may treat patients with more
  FVIII than needed
• Though not dangerous to patient, very costly and
  unnecessary

77
FVIII Assays

• Chromogenic assay is useful for measuring
  elevated FVIII as well as FVIII treatment in
  hemophilia patients

78
Lupus Anticoagulant / Anti-Phospholipid Syndrome
(APS)

• Auto-antibodies against phospholipids or
  Phospholipid-binding proteins
• Also known as Lupus Anticoagulant
• Excessive clotting in vivo, Anticoagulant in
  vitro
• Frequency of APS Ab in the general population
  approximately 1-10
• Major risk factor for venous thrombosis
• Presence of antiphospholipid antibodies increases
  risk 9-fold
• Thrombotic event in about 30 of patients with aPS

79
Anti-Phospholipid Syndrome- Laboratory Assays

• Diagnosis of a definite syndrome meet at least
  one clinical and one laboratory criteria.
• Clinical criteria
• Occurrence of thrombotic event venous or
  arterial
• Recurrent miscarriage, fetal death, or premature
  birth
• Laboratory criteria
• Lupus anticoagulant
• Prolonged APTT, DRVVT assays
• Anti-cardiolipin Antibodies IgG or IgM
• Perform testing on two or more occasions, 6 weeks
  apart
• Can also perform panel including anti-b2-GPI
  anti-Prothrombin

80
Treatment of DVT

• Once DVT is diagnosed, Unfractionated Heparin or
  Low Molecular Weight Heparin is administered,
  followed by an oral anticoagulant drug such as
  warfarin (trade name Coumadin)
• New anticoagulant drugs such as direct thrombin
  inhibitors and FXa inhibitors are also available.

81
Anticoagulants

• Heparin
• Unfractionated
• Low Molecular Weight

• Oral Anticoagulants
• Warfarin

• Direct thrombin inhibitors
• Hirudin

82
Heparin

• Heparin is a biological material derived from
  porcine intestine or bovine lung.
• Heparin catalyzes the inhibitory reaction of
  antithrombin to bind and inhibit FIXa, FXIa,
  FXIIa, and especially FIIa FXa.
• Binds specifically to a pentasaccharide chain in
  heparin
• induces a conformational change in antithrombin,
  accelerating the enzyme inhibtion.
• Risks bleeding, thrombocytopenia, osteoporosis

83
Thrombin inhibition catalysed by heparin
P
AT
H
P
AT
R
H
R
IIa
IIa
P
P
AT
H
AT
H
R
R
IIa
IIa
84
FXa inhibition catalysed by heparin
P
AT
H
P
AT
R
H
R
Xa
Xa
P
P
AT
H
AT
H
R
R
Xa
Xa
85
Heparin Monitoring Unfractionated Heparin (UFH)

• UFH is administered by I.V.
• UFH is typically monitored with an APTT test
• Ideally, the therapeutic range of APTTs for each
  reagent (1.5 2.5) should correspond to anti-Xa
  activity of 0.3 0.7 U/ml

86
Heparin Monitoring LMW Heparin

• Low Molecular Weight Heparin (LMWH) has been
  shown as effective as UFH in preventing recurrent
  VTE and cause less bleeding
• Generally LMWH does not need monitoring
• When monitoring is required, a chromogenic
  anti-Xa assay is required

87
UF heparin versus LMW Heparin

• Elimination primarily through cellular uptake
• Bioavailability 30
• Half-life 1 3 hours
• Accelerates primarily the inhibition of thrombin
  and FXa
• Can be measured by APTT assays

• Elimination mainly through a renal mechanism
• Bioavailability 90
• Half-life 4 hours
• Accelerates primarily the inhibition of FXa
• Cannot be measured by APTT assays

88
Heparin Monitoring
Anti-Xa chromogenic is considered the most
accurate method
89
Long Term Therapy

• Warfarin (Coumadin), a coumarin derivative, is
  the most commonly used oral anticoagulant (OAC)
  in the US
• Warfarin is a vitamin K antagonist - Impairs the
  generation of active vitamin K, decreasing the
  amounts of vitamin K dependent coagulation
  factors (FII, FVII, FIX, FX)
• Depending on factors such as age, risk factors,
  recurrence, etc., warfarin may be continued for
  anywhere from 1 month to lifelong

90
Monitoring Warfarin Therapy is a Balancing Act!
91
Warfarin Monitoring

• Why monitor? Need to balance proper
  anticoagulation without bleeding risk.
• Monitored with PT, expressed as INR
• INR Patient PT / Mean Normal PTISI
• Where ISI international sensitivity index,
  assigned by each thromboplastin manufacturer
• Warfarin is given orally and titrated to achieve
  an INR of typically 2.0 3.0

92
Warfarin Monitoring Chromogenic Factor X Assay

• Lupus anticoagulants may produce prolonged
  prothrombin times, which result in an INR that
  does not accurately reflect the level of
  anticoagulation
• The chromogenic Factor X assay may be used to
  more accurately monitor warfarin therapy in
  patients with LA
• The therapeutic range must be determined by each
  lab, but is in the general range of 20 40,
  corresponding to an INR of about 2.0 3.5.

93
New Anticoagulants

• Limitations of traditional anticoagulants, both
  with heparin and warfarin, have prompted the
  development of new agents

94
Heparin-Induced Thrombocytopenia (HIT)

• (HIT) is a potentially serious, immune-mediated
  complication of heparin therapy that is strongly
  associated with subsequent venous and arterial
  thrombosis.
• Administration of all heparin LMWH and UFH) must
  be discontinued
• However, patients may still require
  anticoagulation for prevention and treatment of
  thromboembolic events.

95
Anticoagulant Drugs

• FXa Inhibitors
• Parenteral synthetic pentasaccharide analogs
• Fondaparinux (Arixtra)
• Synthetic and highly selective inhibitor of FXa
• Acts as cofactor to AT
• Administered by subcutaneous injection
• Absolute bioavailability of 100

96
Anticoagulant Drugs

• FXa Inhibitors
• Parenteral synthetic pentasaccharide analogs
• Danaparoid (Orgaran)
• LMW mixture of heparinoids (glycosaminoglycans,
  GAGs) acts as cofactor to AT
• Anticoagulation effect is predominantly mediated
  by inhibition of FXa
• Also has some anti-IIa effects
• Fast acting, generally predictable dose response

97
Anticoagulant Drugs

• Direct Thrombin Inhibitors (DTIs)
• Hirudin
• Argatroban
• Bivalirudin
• Ximelagatran

98
Anticoagulant Drugs

• Direct Thrombin Inhibitors
• Lepirudin (recombinant hirudin Refludan)
• recombinant hirudin, a derivative of the saliva
  of the medicinal leech Hirudo medicinalis
• Refludan was the first direct thrombin inhibitor
  (DTI) to be approved by the FDA for
  anticoagulation in patients with (HIT)
• Can be monitored with ECT, APTT, TT, chromogenic
  anti-IIa.

99
Anticoagulant Drugs

• Direct Thrombin Inhibitors
• Argatroban is a synthetic direct thrombin
  inhibitor indicated as an anticoagulant for
  prophylaxis or treatment of thrombosis in
  patients with heparin-induced thrombocytopenia
  (HIT)
• Active against both free and clot-bound thrombin
• May increase the PT must be taken into
  consideration when converting to warfarin therapy
• Chromogenic Factor X assay may be useful for
  monitoring warfarin in these cases.
• Argatroban is typically monitored by APTT, but
  other methods like the ECT and the chromogenic
  anti-IIa assay may be more accurate.

100
Anticoagulant Drugs

• Direct Thrombin Inhibitors
• Bivalirudin
• Synthetic polypeptide hirudin analog that
  interacts with the thrombin active site to
  reversibly inhibit thrombin
• Alternative to heparin
• Administered parenterally
• Short half life
• Monitored by Activated Clotting Time (ACT)

101
Anticoagulant Drugs

• Direct Thrombin Inhibitors
• Ximelagatran oral anticoagulant
• Studies have shown similar efficacy and bleeding
  risk to warfarin
• Does not need monitoring
• Was not FDA approved more studies needed to
  assess liver failure risk

102
Anticoagulant Drugs

• Monitoring Direct Thrombin Inhibitors
• No clear, established method
• aPTT commonly used, but has poor linearity
  reproducibility
• Ecarin Clotting Time (ECT) shows better linearity
  and more accurately reflects plasma concentration
  of DTIs
• Not widely available no FDA cleared assay kit on
  market
• Chromogenic anti-IIa measures specifically the
  inhibition of thrombin

103
So What Happened?

• Known Facts
• PE
• Long flight
• Just engaged
• Vacation in Australia
• Suppositions
• Genetic risk factor(s)
• Oral contraceptives
• Dehydration

104
What do you think?

• Known Facts
• PE
• Desert
• Confined space
• Born in Minnesota
• Suppositions
• Genetic risk factor(s)
• Stasis
• Dehydration
• Stress

105
Prevention
106
Know Your Risk

• Identify inherited risk factors
• Family history
• Previous episodes
• Laboratory screening
• Remove or diminish acquired factors
• Contraceptive choice
• Lifestyle changes

107
Prevention of ECS

• Book exit,bulkhead or aisle seat
• Get up once per hour
• Remain hydrated
• Exercise calf muscles while seated
• Avoid constrictive clothing (knee-highs)
• Consult physician if at risk
• Anticoagulant
• Compression hose

108
Prevention
109
Prevention
110
Summary

• Economy Class Syndrome is Venous Thromboembolic
  disease
• VTE is a result of thrombophilia
• Thrombophilia may be inherited or acquired
• Thrombophilia may be treated with anticoagulants
  and/or prevented in some circumstances

111
Conclusion

• If patients who are at risk for developing
  pathologic blood clots can be identified early,
  appropriate measures may be undertaken to
  decrease the incidence and severity of thrombotic
  events.
• But

112
Conclusion
A little red wine
A piece of chocolate
Doesnt hurt either!
113
Thank you

• David Schaffner, Ph.D.,MT(ASCP)
• Scientific Affairs Manager, Beckman Coulter, Inc.
• dfschaffner_at_beckman.com
• AND
• Jennifer J. Kiblinger
• Technical Affairs Manager, DiaPharma Group, Inc.
• jkiblinger_at_diapharma.com