Journal Reading

A Shortened
Activated Partial Thromboplastin Time
is Associated With
The Risk Of Venous Thromboembolism
( by The American Society Of Hematology )

Blood, 1 December 2004.

Volume 104,Number 12

VTE ( Venous Thromboembolism ) estimated = 1 : 1000 / year

The causes not always identified
Hipercoagulability triggers VTE : alter balance of hemostasis
Due to :
- Defective naturally anticoagulant mechanisms
- Heigtened levels of procoagulant factor
( VIII, IX, XI, II and Fibrinogen )
The Classical intrinsic
Common Pathways of blood coagulation

= XI, IX and VIII

= II and Fibrinogen

Cummulatively explored by the global coagulation test

APTT ( Activated Partial Thromboplastin Time )

A shortened APTT

Reflect the procoagulant imbalance

Increased levels of coagulation factors

Increased risk of VTE

Patient and Control Subject

Collected : Januari 1998 June 2003
The Thrombosis Center (University and IRCCS Maggiore
Hospital, Milano, Italy)
Thrombophilia testing.
DVT : Ultrasonography / venography
Pulmonary embolism : ventilation/perfusion scan
Cerebral V. thrombosis : contrast CT or MRI
Excluded from the study :
- Underwent standard anticoagulant treatment
- Still on anticoagulants at the time of the visit
- Neoplastic diseases.
- Other conditions potentially affecting the APTT
antiphospholipid antibodies,liver disease, pregnancy
- Recent thrombosis (in the last 3 months)

Study Population
: 605 patients and 1290 controls

Laboratory investigation
Blood : vacuum tubes ( 3.8% trisodium citrate 9 :1)
Plasma measurement
- Antithrombin
- Protein C
- Protein S.
- Mutations Factor V G1691A (factor V Leiden)
- Prothrombin G20210A genes
- Antiphospholipid antibodies
(lupus anticoagulants & anticardiolipin antibodies)
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Results APTT
a ratio of test to reference coagulation times
( using as reference a normal plasma tested in
parallel with plasmas)
Definition the shorter the APTT
if result of test plasmas smaller than ratio
The normal plasma used as reference was prepared by pooling
equal portions of fresh plasmas from the blood of 30 donors
(15 males and females)
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Factor VIII measured as clotting activity on fresh plasmas by

the one-stage APTT- based assay
uses :
- APTT reagent (Synthasil; Instrumentation Laboratory)
- The factor VIlI deficient plasma (Instrumentation
Laboratory) in combination with the Electra MLA
(Instrumentation Laboratory) automated photooptical coagulometer
Results expressed as IU/dL
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Statistical Analysis
Continuous variables : medians and ranges
Nonparametric Mann-Whitney U test
Differences between median values of the APTT ratios or factor
VIII levels in patients and controls
Nonparametric Spearman test.
Correlation between factor VIII levels and APTT ratios
p values of 0.05 or less statistically significant
We considered as risk factors :
APTT ratio < The fifth percentile
Factor VIII level > the ninety-fifth percentile of the
distribution found in control population

RESULT
The main characteristics of patients with venous
thromboembolism and control subjects

The median time elapsed from thrombosis to blood sampling

was 10 months (range: 3 to 79 months)
Median value of the test-to-reference APTT ratio
0.97 (range: 0.75 to 1.41) for patients
1.00 (range: 0.72 to 1.33) for controls (P < .001)
The APTT ratio coresponding to the fifth percentile of the
distribution in controls was 0.87
An APTT ratio smaller than the cut-off value
: 66 of 605 patients (11%)
63 of the 1290 controls (5% by definition)
Odds ratio for VTE of 2.4 (95% CI: 1.7 to 3.6)

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Association between decreasing APTT ratio and the occurrence of

VTE, patients were stratified into 4 categories according to the 11
APTT ratio
In particular, 14 of 605 patients and 9 of 1290 controls had an APTT
ratio 0.80, Odds ratio for VTE of 4.6 (95% CI: 1.8 to 11.8)

Table 3. Relative risk of venous thromboembolism according to the APTT ratio

using as cut off value the fifth percentile of the distribution of value in controls

APTT Ratio *

Patient
N = 193

Controls
N = 259

Odds ratio
( 95 % CI )

Odds ratio
( 95 % CI )

0.87
< 0.87

165
28

243
16

1
2,7
( 1.4-5.3 )

1
2.1
(1.0-4.2 )

The analysis represented in the table refers to the patients and controls for whom factor
VIII levels and blood group were available
* Test to- reference coagulation time
Adjust for age, sex, and presence of inherited thrombophilia
Adjust for age, sex, and presence of inherited thrombophilia, factor VIII level greater
than 171 IU/dl ( > 95 % of the distribution of the value in controls ) and blood group

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Discussion
Several case-control studies of single coagulation factors
measured as antigen or functional activity plasmatic
hypercoagulability
Risk factor of VTE
APTT test suitable candidate to reflect globally the
procoagulant imbalance
Resulting from increased levels of the single
coagulation factors

Risk Factors of VTE

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In this study
Patients APTT ratio smaller than 0.87
2- to 3-fold increased relative risk of VTE
Patients with the smallest APTT ratios (equal or smaller than
0.80) compared with those with the greatest ratio (> 1.00)
Relative risk of VTE was increased 5-fold.
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These results are biologically plausible

because shortened APTTs have been associated with
high levels of biochemical markers of thrombin
generation and fibrin deposition

Poor prognosis for thrombosis and mortality

in patients admitted over time to a general
medical center
15

APTT is a global test responsive to the plasma levels of

coagulation
- Factors of the contact ( factor XII, prekallikrein,
HMWK)
- Intrinsic (factor XI, VIII, IX)
- Common pathways of blood coagulation(factor X, V,
II and fibrinogen)
Elevated levels of some of these coagulation factors
(XI, IX, VIII, II, and fibrinogen)

Risk factors of VTE.

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This study has the following limitations

1. Patients were tested after their thrombotic episodes and
therefore a direct causal effect of the hypercoagulability
detected by the shortened APTT cannot be established,
even if the conditions known to affect the test (lupus
anticoagulant, recent thrombosis, liver disease, and
pregnancy) were excluded
2. The role played by high levels of coagulation factors
other than factor VIII. already identified as independent
risk factors of VTE (factor XI, IX, II and fibrinogen),
in shortening the APTT could not be evaluated.
3. Results have not been confirmed using other
commercial reagents for the APTT test
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The Procoagulant imbalance

: Detected by a shortened APTT

Increased Risk of VTE

Low cost and simplicity
Suitable to be evaluated in prospective
studies
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CRITICAL APPRAISAL
General

Description
What Kind Of Design ?
Who Is The Target Population And
Sample ?
How To Get The Sample ?
What Is The Independent Variable ?
What Is The Dependent Variable ?
What Is The Major Result Of The Study ?
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 Internal

Validity Noncausal Relationship :

Bias Factor
Precipitaty Factor
Probability Factor
Internal Validity Causal Relationship
Time
Doses
Result Being Consistently
Biologically Plausible
External Validity
Result For Large Population

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