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WINTER 2016
Inside this issue
CASE STUDY
•Thrombosis in
Pregnancy
•Idarucizumab and the
lab in patients bleeding
on Dabigatran
CLINICAL TRIAL
•The Environmental
Determinants of Lupus
Flares study (EDOLF)
THERAPEUTIC DRUG
MONITORING
CHANGES
Incorporating:
•
•
•
•
•
Northern NSW
Hunter New England
Mid North Coast
Central Coast
Northern Sydney
FROM THE DIRECTOR
A CASE FOR CHANGE?
“Would you tell me please, which way I ought to go from
here?” said Alice.
“That depends a good deal on where you
want to get to,” said the Cat.
“I don’t much care where…”
said Alice.
“Then, it doesn’t matter
which way you go,” said
the Cat.
Lewis Carroll:
Alice’s Adventures in Wonderland
I have often wondered
why I was so pleased by
Lewis Carroll’s “Alice”
stories, but so uninterested
in the “heroine”. The
uniqueness, vibrancy and range
of characters in these stories was
astonishing. The peculiarity of the
environment in which they existed was fascinating. The
laws of physics were irrelevant and an alternate universe;
one of the “multiverses” was created. In that world the
rules of engagement and conduct were novel and
sometimes whimsical. “Sentence first – verdict afterwards.”
They often had draconian consequences. “Off with
her head!”
The Alice novels are, to me, early “fantasy” and “science
fiction” genre; a mixture of Game of Thrones and Star
Wars. Not that I have ever read any of these novels!
Alice seemed so insipid. Things happened to Alice by
happenstance. The outcomes were fortuitous but Alice, to
me, never apeared in control. Her destiny never appeared
to be a consequence of active decision making.
“Take care of the sense, and the sounds will take care
of themselves.”
When she returns to the real world it is bland and staid and
static compared to the world “through the looking glass”.
To some of you, the realm we now inhabit in pathology may
seem like Alice’s fantasy world, populated by Madhatters,
Doormice, Cheshire Cats and White Rabbits or,
unfortunately, Knaves and Queen of Hearts! The pressure
for change in our world is powerful. It is a conflation of
social, political, technical and financial imperatives. There
are many pressures upon people in our communities and we
are committed to assisting them.
Pathology North is very aware of the environment in which
we work and, unlike Alice, we do know “where we want to
go”. We are, therefore, continually intiating new rules of
engagement to move in the right direction, to shape our
destiny and to deliver a service that is mandated by our
clients, customers and patients. Being a part of NSW Health
Pathology assists us in improving the services required by
the Local Health Districts, the community and the
private sector.
It is important to note however, one thing that will not
change is our commitment to our community. We will
continue to bulk bill for pathology services wherever
Commonwealth MBS funding arrangements allow. We will
continue our service to the entire NSW Health community
and we appreciate your support in delivering this goal.
Dr. Stephen Braye
Director, Pathology North
Front Cover:Benicar Tindall, Technical Officer (Grafton Laboratory) working in the
haematology department. She is about to spread a blood film so it can
be stained for her to examine under the microscope.
2
DR BRYONY ROSS,
MBBS, FRACP, FRCPA
Staff Specialist Haematologist
Dr Ross specialises in Paediatric
Haematology and Oncology and
Laboratory Haematology
therapy are switched to LMWH prior to 6 weeks
gestation. The direct oral anticoagulants (DOACs) are
not recommended for use in pregnancy or lactation (e.g.
rivaroxaban, apixaban, dabigatran).
Which patients require anticoagulation in
pregnancy?
Antepartum
Postpartum
anticoagulation anticoagulation
[email protected]
Thrombosis in Pregnancy
Rose is a 32 year old G2P1 who presents to her regular
GP after a positive urine pregnancy test at home. She
unfortunately developed a DVT at 36 weeks gestation
in her last pregnancy. She was initially treated with low
molecular weight heparin (LMWH) and converted to
warfarin at approximately 6 weeks post-partum. She
completed a total of 6 months of anticoagulation and
has presented today as she recalls being told that she
would likely require treatment with anticoagulants in
subsequent pregnancies.
What are the changes in haemostasis seen in a
normal pregnancy?
Normal pregnancy is a prothrombotic state. This protects
the mother from excessive bleeding at the time of
delivery and placental separation BUT it also increases
the risk of venous thromboembolism during pregnancy
and post-partum.
Changes to haemostasis during pregnancy include:
• The anticoagulant protein S decreases
•Procoagulant factors (fibrinogen, Factors II, VII, VIII,
X, XII, and XIII) increase by 20 – 200%
• Von Willebrand Factor increases
• Activity of fibrinolytic inhibitors increase
The net effect is an increase in the tendency for
thrombus formation and extension, particularly in the
post-partum period. Normalisation of coagulation
parameters and factor levels varies, but normally these
return to baseline by 6-8 weeks post-partum.
However, there are also other multiple acquired risk
factors for venous thrombosis in pregnancy that need
to be considered, including increasing age, obesity,
smoking, dehydration due to hyperemesis as well as
many chronic medical conditions.
Which anticoagulants can be used in pregnancy?
Low molecular weight heparins (for example enoxaparin)
are the most commonly used anticoagulants in
pregnancy (LMWH). Vitamin K antagonists
(VKA - e.g. Warfarin) are contraindicated
in pregnancy. It is suggested
that women on long
term VKA
Previous VTE
• single episode
of VTE with
transient risk
factor,
• not associated
with pregnancy
or oestrogen
✗
Previous VTE
✓
• unprovoked VTE
(prophylactic
• pregnancy or
or intermediate
oestrogendose)
related VTE
✓
(prophylactic or
intermediate
dose)
✓
(prophylactic
or intermediate
dose)
Long term VKA
prior to pregnancy
✓
(treatment
dose LMWH)
✓
(treatment
dose LMWH)
Increased risk of
VTE after caesarean
section
✗
✓
(prophylactic
dose)
✗
✓
(prophylactic or
intermediate
dose)
Homozygous
Factor V Leiden or
Prothrombin
20210A mutation
• no personal hx of
VTE
• no family hx of
VTE
Homozygous
Factor V Leiden or
Prothrombin
✓
20210A mutation
(prophylactic or
• no personal hx of intermediate
dose)
VTE
• with family hx of
VTE
All other
thrombophilias
• no personal hx of
VTE
• no family hx of
VTE
✓
(prophylactic or
intermediate
dose)
✗
✗
All other
thrombophilias
• no personal hx of
VTE
• with family hx of
VTE
✗
✓
(prophylactic or
intermediate
dose)
Antiphospholipid
antibody syndrome
• with hx of 3 or
more pregnancy
losses
✓
(prophylactic
LMWH and
aspirin)
✓
(prophylactic
LMWH and
aspirin)
3
Prophylactic or intermediate dose depends on the LMWH
heparin used (for example with enoxaparin prophylactic
dose = 40mg daily; intermediate dose = 40mg BD). For
women with mechanical heart valves, treatment dose
anticoagulation is required – please seek specialist advice.
It is best that these patients be cared for during their
pregnancy by a multidisciplinary team experienced
in the care of patients with thrombotic disorders. A
comprehensive anticoagulation plan for pregnancy,
labour and delivery should be formulated. Consider
referral to a centre with a maternal-foetal medicine and
haematology services.
Should I be testing pregnant women for inherited
thrombophilias?
The association between a diagnosis of an inherited
thrombophilia and pregnancy morbidity is weak:
PROFESSOR
CHRISTOPHER WARD
BMedSc, MBCHB, PhD, FRACP,
FRCPA
Haematologist
Prof Ward is the current Head of
the Department of Haematology
and Transfusion Medicine at Royal
North Shore Hospital and the
Director of Research. His primary clinical and laboratory
expertise is in coagulation disorders, and he oversees the
diagnostic investigation of platelet function disorders
at Pathology North. His research interests include
hypercoagulable states and novel anticoagulants, platelet
disorders and heparin-induced thrombocytopenia.
He is Past President of the Australasian Society on
Thrombosis and Haemostasis and represents Australia
on the Executive Council of the Asia-Pacific Society on
Thrombosis and Haemostasis. Prof Ward has conducted
several clinical trials at Royal North Shore Hospital using
novel anticoagulants and thrombopoietin receptor
agonists and contributes to local and national guidelines
on these therapies.
[email protected]
DR CATHERINE TANG
Dr Tang is an Advanced Trainee in
Haematology at Royal North Shore
Hospital in Sydney. [email protected].
gov.au
4
•The laboratory tests are imprecise (particularly in
the setting of pregnancy when normal ranges
are incomplete, and the physiologic changes of
pregnancy can interfere with interpretation)
•The tests that are available do not comprehensively
assess the genetic framework of thrombophilia
•Both laboratory abnormalities and pregnancy
morbidity are common, so inevitably with increased
investigation, abnormalities are frequently found
Based on the current evidence, we would not
recommend thrombophilia testing in pregnancy.
What happened to our patient?
Rose was treated with prophylactic LMWH (enoxaparin
40mg daily) throughout her pregnancy and for 6 weeks
post-partum. She delivered a beautiful baby boy with no
complications.
Idarucizumab and the lab
in patients bleeding on
Dabigatran
A 93 year-old woman was admitted to the Emergency
Department with severe per-rectal bleeding resulting
in haemodynamic instability. Her past medical history
included atrial fibrillation resulting in significant embolic
events, and prior nephrectomy with a reduced GFR
of approximately 43mL/min. She was on Dabigatran
110mg BD, last taken 10 hours prior to her presentation.
Her coagulation profile on admission demonstrated a
markedly deranged Thrombin Time >120.0s (15-19.0s),
Prothrombin Time 29.9s (11-15.0s) and Activated Partial
Thromboplastin Time 69.5 (24-36.0s). A dilute thrombin
time (dTT) was measured using the Hemoclot Assay
which was significantly prolonged at 103s correlating to
a Dabigatran level of 534ng/mL.
The patient was then given the reversal agent
Idarucizumab as part of the REVERSE-AD trial with
immediate normalisation of her dTT (below detection
limit <35s) and haemodynamic status (See Table 1).
Discussion
There has been increasing use of direct oral
anticoagulants (DOACs) in management of conditions
such as atrial fibrillation within the community. Of
concern are elderly patients who, across multiple
studies, have been shown to have an increased risk of
gastrointestinal bleeding on DOACs versus warfarin1.
The monitoring of these DOACs is not routinely required,
however guidelines have been developed to use standard
coagulation assays to determine anticoagulant effect2
Recently, Idarucizumab has been approved as a
reversal agent for Dabigatran in emergent settings.
Idarucizumab is a monoclonal antibody which binds
to both free and thrombin-bound dabigatran at
high affinity to neutralize the anticoagulant effect of
Dabigatran3. The advent of Idarucizumab necessitates
appropriate assays to determine the anticoagulant effect
of Dabigatran in emergent settings to direct appropriate
use of this reversal agent.
Prior pharmacokinetic and pharmacodynamics
correlation studies in the initial development of
Dabigatran have demonstrated the deficiencies of
standard coagulation assays in determining levels of
Dabigatran4. The PT is often insensitive with only
modest elevation even at high plasma concentrations
of Dabigatran; the aPTT demonstrates a curvilinear
response that flattens at higher concentrations whilst the
TT is too sensitive with results often exceeding the upper
limit of the coagulometer. The dTT has been found to
demonstrate a linear dose response curve to plasma
concentrations of Dabigatran. (See figure)
Whilst there is still no defined “therapeutic range” for
Dabigatran the preliminary data of the REVERSE-AD
trial suggests that there are a significant percentage
of patients who present with significant bleeding
but actually have low levels of Dabigatran on board
compared to the 10-90th percentile of patients
enrolled in the RE-LY trial3,5. Therefore early use of
dTT to identify patients who have significant plasma
levels of Dabigatran could help direct the rationale of
Idarucizumab. Additional research to define dabigatran
levels associated with haemorrhagic vs thrombotic events
would further improve the clinical utility of dTT assays.
Table 1: Results of coagulation tests and clinical status
of patient pre and post Idarucizumab
Timepoint
PT(s) APTT (s) TCT (s) dTT (s)
References:
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB,
Deenadayalu N, Ezekowitz MD, et al. Comparison of
the efficacy and safety of new oral anticoagulants with
warfarin in patients with atrial fibrillation: a meta-analysis
of randomised trials. Lancet. 2014;383(9921):955-62.
Tran H, Joseph J, Young, L, McRae S, Curnow J, Nandurkar
H, Wood P and McLintock C. New oral anticoagulants:
a practical guide on prescription, laboratory testing
and peri-procedural / bleeding management. Internal
Medicine Journal. 2014; 44(6):525-36
Pollack CV, Jr., Reilly PA, Eikelboom J, Glund S, Verhamme
P, Bernstein RA, et al. Idarucizumab for Dabigatran
Reversal. The New England journal of medicine.
2015;373(6):511-20.
Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The
pharmacokinetics, pharmacodynamics and tolerability
of dabigatran etexilate, a new oral direct thrombin
inhibitor, in healthy male subjects. British journal of clinical
pharmacology. 2007;64(3):292-303.
Lehr T, Haertter S, Liesenfeld KH, Staab A, Clemens A,
Reilly PA, et al. Dabigatran etexilate in atrial fibrillation
patients with severe renal impairment: dose identification
using pharmacokinetic modeling and simulation. Journal
of clinical pharmacology. 2012;52(9):1373-8.
Dabigatran
(ng/mL)
Clinical Notes
Presentation
29.9
69.5
>120
103
533.99
PR Bleed, on DABI
Just prior to Rx
29.7
71.2
>120
98
445.6
Bleed; pre reversal agent
After 1 vial
16.1
26.6
16.7
<35
0.0
post reversal agent Dose 1
After 2 vial
16.4
28.1
18.4
<35
0.0
post reversal agent Dose 2
st
nd
Figure 1: R
elative performance of available clotting assays to determine Dabigatran
concentration
5
MARLINE SQUANCE
Cert Path., Cert Bio Tech., Dip BioMed, CT (ASC), CT (IAC), B. Env Sc (Health) Hons., PhD.
Ms Squance is the Chief Executive Officer of the Autoimmune Resource and Research Centre
(ARRC) based in the Hunter. The centre offers education, resources and support services as
well as access to innovative research projects for people living with autoimmune illnesses
in particular Lupus, Scleroderma, Sjogren’s and associated illnesses of Pulmonary Arterial
Hypertension and Raynauds Phenomenon. ARRC works closely with Specialists and staff of
Pathology North and has a patient resource office within our Newcastle building.
Marline has degrees in Biomedical Science, Diagnostic Cytology and Environmental Science/
Environmental Health. Marline has worked both internationally and nationally in Health for over 30 years. Marline
began her career in 1983 as a Cytotechnologist in the Anatomical Pathology Department of the Royal Newcastle
Hospital. She worked for 10 years in this department before leaving to work and live in Canada and also in
Switzerland. Upon her return to Newcastle, Marline returned to Cytology with work in local pathology services
before moving to research and project management positions with local General Practice network groups and also
the NSW Cancer Council.
After a brief meeting with A/Professor Glenn Reeves (Immunology) in 2005, Marline returned to Hunter Area
Pathology as a research coordinator of studies related to coeliac disease, scleroderma and lupus. Under the
supervision of A/Prof Reeves, she took on the management role of ARRC and also completed her doctorate which
investigated environmental determinants of lupus flares.
The Environmental Determinants of Lupus Flares study (EDOLF)
The Environmental Determinants of Lupus Flares study (EDOLF) investigated the relationships between common
environmental agents found indoors and self-reported symptom flare days (SRF) in 101 Australian female lupus
patients as compared to 41 age matched healthy controls. The study was retrospective and employed mixed
methods examining differences in lifestyle behaviours and agent exposure with personal product use.
The study showed that the Australian population was similar to other Caucasian populations, with the average
number of flares reported to be 29.9 SRF days, with 6.8 discrete flares for the study year. Flare symptoms were
consistent with other population profiles published, however the EDOLF Australian population also reported
gastrointestinal issues (13.9%) and shortness of breath (9.9%) as common symptoms.
Commonly published flare triggers of UV radiation, infection and stress were confirmed, with the addition of new
potential triggers: temperature & weather changes, work, and cleaning chemicals. Use of personal care products for
home cleaning, personal hygiene and lifestyle activities, resulted in significant increased risk associations for bath oil
(IRR 1.008, CI 1.00-1.02) and significant reduced SRF risk for cleansing beauty products (IRR 0.999, CI 0.998-0.999)
and a combined makeup group (foundation and sunscreen) (OR 0.998: CI 0.997–1.0). A flare day reduction of
0.15% was calculated for each day of combined makeup group product use.
In comparison to control participants, the SLE group showed significant difference in 25(OH)D deficiency (p=0.02),
and 25(OH)D levels (means-control 74nmol/L (29.5ng/ml); SLE 58nmol/L (23.1ng/ml), p=0.04). Reduced levels of
25(OH)D were associated with expression of serological autoimmunity (ANA titres of 1:80) with odds ratios (OR) for
ANA-positivity declining by 36% of the baseline OR for every two-fold rise in 25(OH)D level. A significant association
could not be found between levels of 25(OH)D and SRF.
Significant associations were found for Finnish Job Exposure Matrix (FINJEM) occupational exposure classes; manual
handling burden (p=0.02, IRR 1.01); iron (p=0.00, IRR 1.37); wood dust (p=0.00, IRR 3.34); and asbestos (p=0.03,
IRR 2.48), indicating that participating in occupations such as nursing, teaching and specialist labouring could pose
an increased risk to SLE patients.
6
Analysis of lifestyle factors indicates that the EDOLF SLE participants, as compared to the control participants, had
reduced levels of QOL on VAS scales, lower levels of physical activity but similar dietary variables. SLE participants
also used significantly more whole medical system CAM (p=0.0301). SLE patients commonly used therapies
suchas acupuncture, hydrotherapy, massage and dietary supplements including vitamin D and anti-inflammatory
homeopathic medications such as fish oils.
The retrospective design of the EDOLF study may have resulted in a number of study limitations including
misclassification and recall bias; however a number of data validation steps were incorporated to limit bias influences
on reported results. One considerable limitation of the retrospective EDOLF study design was that establishment of
firm causal relationships was not possible. Therefore, reported results can only infer potential significant relationships
and health effects.
In conclusion, the EDOLF study provides insight into the patient SLE experience particularly perceived flare symptoms,
triggers and management strategies. Each year, the average SLE patient experiences 30 days of symptom flares
which are commonly self-managed with no extra physician assistance. The study also identified that everyday
behaviours and exposures in day-to-day life activities, including both home and work environments, could potentially
trigger exacerbation of SLE symptoms. In addition, the use of UV protective products, whilst potentially reducing
symptom exacerbation and flare days, may paradoxically influence serum 25(OH)D in a group of patients with a
higher incidence of deficiency and insufficiency as compared to the general population.
Importantly, the EDOLF study provides insight into future research directions that will better inform appropriate
protective measures that people living with SLE can adopt to reduce adverse health impacts and improve life
potential and quality.
List of publications to date
1. The lived experience of lupus flares: features, triggers and management in an Australian female cohort.
Journal: International Journal of Chronic Diseases
Authors: Marline Squance, Glenn EM Reeves, Howard Bridgman.
www.hindawi.com/journals/ijcd/2014/816729/
2. Exploring lifetime occupational exposure and SLE flare: a patient focussed pilot study.
Journal: Lupus, Science & Medicine
Authors: Marline Squance, Maya Guest, Glenn Reeves, John Attia, Howard Bridgman
www.lupus.bmj.com/content/1/1/e000023
3. Vitamin D levels are associated with expression of SLE, but not flare.
Journal: International Journal of Rheumatology
Authors: Marline Squance, Glenn Reeves, Huy Tran
www.hindawi.com/journals/ijr/2014/362834/
4. Self-reported Lupus flare: associations with everyday home and personal product exposure.
Journal: Toxicology Reports
Authors: Marline Squance, Glenn Reeves, John Attia, Howard Bridgman, Maya Guest
www.sciencedirect.com/science/article/pii/S2214750015300044
5. Patient reported lupus flare: exploring associations with foundation makeup and sunscreen use.
Journal: Journal of Cosmetics, Dermatological Sciences and Applications
Authors: Marline Squance, Glenn Reeves, and John Attia
www.scirp.org/journal/PaperDownload.aspx?paperID=52242
For more information about EDOLF email: [email protected]
For more information about ARRC and its services www.autoimmune.org.au
or [email protected]
7
CHANGE OF UNITS FOR THERAPEUTIC DRUG MONITORING
As part of a national harmonization initiative, Pathology North will be changing the reporting of therapeutic drugs to
mass units as of 4th July 2016.
The use of mass units follows recommendations from the Royal Australasian College of Physicians, The Royal College
of Pathologists of Australasia, the Australasian Association of Clinical Biochemistry and the Australasian Society for
Clinical and Experimental Toxicology as published in Med J Aust, 2013; 198 (7): 368-369 (www.mja.com.au). This
aligns drug concentration measurements with the units used for drug dosing and with the major English language
sources of information on drug efficacy, metabolism and toxicity. The aim is for therapeutic drug measurements from
all laboratories in Australia to be in the standardised units to avoid clinical errors.
In general the use of mass units (e.g. mg/L or ug/L) will apply, with the following exceptions:
•
•
•
•
•
Methotrexate in umol/L
Lithium in mmol/L (as these are currently fully harmonised in these units)
Iron in umol/L
Free thyroxine (fT4) in pmol/L
Vitamin D (25-Hydroxy Vitamin D) in nmol/L
These are examples of drugs which are also endogenous substances where the current units are retained.
Results in the new mass units will be reported in parallel with the old units for a transitional period of at least 12
months. During this dual reporting period, on the printed and eMR laboratory report, two sets of results will be
shown for each unit of measurement of the drug in question; e.g.:
•
•
Paracetamol (mg/L) 10
Paracetamol (umol/L) 66
PLEASE ENSURE THAT THE CORRECT UNIT IS USED IN THE PARACETAMOL
NOMOGRAM (Available at: Med J Aust 2015; 203: 215-218. doi:10.5694/mja15.00614.)
Drug results will be marked with a footnote for a period of time to alert users to the change.
On the 4th July 2016, this change over may delay Therapeutic Drug reports for up to four hours. Pathology North
staff apologises for the inconvenience.
For further information, or for clinical enquiries, please contact the following Pathology North staff:
Northern Sydney
and Central Coast
Peter Ward, Royal North Shore Hospital Tel: 9926 4142
Email: [email protected]
Newcastle/Hunter
and Taree region
Dr A Caswell, John Hunter Hospital Tel: 4921 4401
Email: [email protected]
New England
Don Clausen, Tamworth Base Hospital Tel: 6767 7813
Email: [email protected]
Mid North Coast
Dileep Kumar, Coffs Harbour Hospital Tel: 6656 7509
Email: [email protected]
Northern NSW
Lyndall Palmer, Lismore Base Hospital Tel: 6620 2915
Email: [email protected]
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