Understanding the scientific
literature
(Reading and evaluation of a research paper)
Prof David Lane
Department of Haematology
Hammersmith Hospital Campus
d.lane@imperial.ac.uk
Our paper is:
Risk factors and recurrence rate of
primary deep vein thrombosis of the
upper extremities. Martinelli et al,
Circulation 2004; 110: 566-570
(This is given to you initially without the Title and
Abstract. The Abstract will be given out at the end)
Aims of the paper are:
1. Investigate the role of risk factors
(thrombophilia, transient) in upper
extremity DVT.
2. To evaluate recurrence rate after a
period of antcoagulant therapy.
It uses a case control study design.
Haemostasis is a fine balance between
procoagulant and anticoagulant activities
Inadequate procoagulant/excessive
anticoagulant function - bleeding
Lo Pro Coag
Hi Anti Coag
Thrombosis
Bleeding
Haemostasis is a fine balance between
procoagulant and anticoagulant activities
Excessive procoagulant/inadequate
anticoagulant function - thrombosis
Lo Anti Coag
Hi Pro Coag
Thrombosis
Bleeding
TF/FVIIa
End Stage Blood
Coagulation
FIXa
+
FVIII
FVIIIa
FX
FXa
+
FV
FVa
Prothrombin
Thrombin
Procoagulant
Fibrinogen
Fibrin
Coagulation Inhibitory
Mechanisms
1. Antithrombin (+heparin or heparan
sulphate)
2. Protein C anticoagulation pathway
3. Tissue factor pathway inhibitor
1 & 2 are of know clinical importance!
3 is important physiologically, but of uncertain
clinical importance!
Coagulation Regulation
By Antithrombin
FIXa
FXa-Antithrombin
Complex
+
FVIII
FVIIIa
FX
Anticoagulant
FXa
+
FV
FVa
Antithrombin
+ Heparin or EC
Heparan Sulphate
Anticoagulant
Prothrombin
Thrombin
Thrombin-Antithrombin
Complex
Procoagulant
Fibrinogen
Fibrin
Coagulation Regulation
by Activated Protein C
FIXa
+
FVIII
FVIIIa
FX
FVIIIi
FXa
+
FV
FVa
Prothrombin
FVi
Thrombin
Procoagulant
Protein S
Protein Ca
(APC)
Protein C/EPCR
Anticoagulant
Fibrinogen
Fibrin
Thrombomodulin
Factor Va
APC cleavage sites in FVa
Model of factor Va
Pellequer et al Thromb Haemost 2000;84,849
Inactivation of Factor Va By APC
Arg506
“Rapid” cleavage
Results in FVa with intermediate
(25%-40%) co-factor activity
BIPHASIC
INACTIVATION
Arg306
“Slow” cleavage
Completely abolishes
FVa activity
Factor V Leiden (Arg506Gln)
FV Leiden (Arg506Gln)
-mutation/polymorhism present in ~5% of white Caucasians
-associated with “APC-resistance”
-most prevalent genetic thrombophiliac factor in people of European
descent
Arg506Gln
Arg->Gln substitution prevents proteolysis by APC at 506 site.
FVa is therefore only partially inactivated
Organisation of Prothrombin Gene
chromosome 11p11-q12
~21kb
Leader
+ Gla
I II
Kringles
V VII
Catalytic domain
X
5’
(Degan & Davie Biochemistry 26 6165, 1987
Poort et al Blood 88 3698 1997)
XIV
3’
20210 G/A,
increases prothrombin
levels, increase risk of
DVT
Some risk factors for venous
thromboembolism
Genetic (thrombophilia) risk factors
Antithrombin deficiency*
Protein C deficiency*
Protein S deficiency*
Factor V Leiden*
Prothrombin G20210A*
Acquired/acquired risk factors
Hyperhomocysteinemia*
Antiphospholipid antibodies
Transient risk factors
Oral contraceptives*
Travel
Surgery
HRT
Pregnancy
*of interest today
Venous Thrombosis is Multi-Causal Arising from Interacting Genetic
and Acquired Risk Factors
after Rosendaal, 1998
Risk
Transient acquired
risk
Cumulative risk
Thrombotic
threshold
Risk from “ageing”
Genetic risk 2
Genetic risk 1
Age
Odds Ratio
Odds of an event
Number of events/number of non events
Odds ratio
Odds in treated or exposed group/odds in
control group
Odds Ratio
In a week
90/100 men have drunk beer
Odds 90/10
20/100 women have drunk beer
Odds 20/80
Odds Ratio 90/10 = 36
20/80
95% Confidence Interval (CI)
A 95% confidence interval is an interval generated by
a process that is correct 95% of the time. It gives a
measure of confidence to the mean.
If 95% CI crosses unity, result not “statistically”
significant!
Compare OR (95% CI)
3.3 (1.6-7.0)
With
3.2 (0.8-12.3)
(taken from Table 1 of paper)
Relative Risk
Relative risk is another common measure of risk.
RR= Probability of event in exposed group
Probability of event in non exposed group
RR is actually very similar to Odds Ratio, especially
when the probabilities are small.
In Clinical Studies, the Odds Ratio is favoured for
case control studies and retrospective studies.
Relative Risk is used in randomised controlled trials
and cohort studies.
Example of OR calculation:
Factor V Leiden
10/105 = 3.35
22/775
(The adjusted results in last column are to be focussed on)
Example of OR calculation:
Compare results in last and first lines
5/35
3/191
= 9.09
(Results in final column, adjusted for age, are the ones to focus on)
Kaplan Meier plots and Hazard
Ratios
Kaplan Meier plots show survival (often
expressed as % or as fraction of 1.00) over
time
Hazard ratio is broadly similar to Relative
Risk. It is useful when the risk varies over
time. The term is often used in connection
with the Kaplan Meier survival plot (over
time). If the overall RR of an event is half
in one group, then HR is 0.5.
Prob of no recurrence at 5 years:
Without thrombophilia 93%
With thrombophilia 80%
The adjusted Hazard Ratio for recurrence of upper limb DVT
in patients with compared to those without thrombophilia
is 2.7 (95% CI 0.7-9.8): note this is not significant!
Task: In 60 minutes write a 250-350 word abstract of
the article.
Divide the article into the following sections (section
headings not to be included in the word count):
Background
Methods & Participants
Results
Conclusions
Execution: Include size of study in Methods, and
important findings in Results, expressed in quantitative
terms.