1303 - The Clinical Utility of D-Dimer Assays

The Clinical Utility of
D-dimer Assays
Beth Phillips MT,SH (ASCP)

Zone Technical Application Specialist
Siemens Healthcare Diagnostics
© Siemens 2013. All rights reserved.

Objectives:
 Define VTE as DVT and PE
 Identify D-dimer assays and the role they play in DVT/PE
 Explain Well’s pre-test probability scoring and clinical models
 Describe evaluation of D-dimer assay results
Page 2 © Siemens 2013. All rights reserved.

History of Fibrinolysis
 4th Century BC…Hippocratic school familiar with blood fluidity
 1687 (300 years later) Malpighi noted blood clotted & reliquidfied after death
 1893 Dastre coined term “fibrinolysis”
 1905 Morawitz concluded process was probably enzymatic
 1959 Sherry proved fibrinolysis due to activator converting plasminogen to

plasmin
 1960 five fragments of fibrinogen when treated with plasmin: A, B, C, D, & E
 1983 Greenberg measured “fibrin d-dimer” to differential FDP derived from

fibrinogen or fibrin

Use of D-Dimer
 30 years ago proposed as aid in suspect DVT
 mid 1990’s focus on use as aid in ruling out VTE
 DIC profile

Venous Thromboembolism Epidemiology
 Yearly in the USA:

> 600,000 Deep Vein Thrombosis
~ 150,000 Pulmonary Embolism
 Diagnostic Challenges with DVT/PE

90% of PE develop from DVT
PE mortality 18%-30% without treatment
VTE suspected…..15% - 25% actually positive
 Clinical suspicion has increased
 Prevalence has decreased, some statistics state only 10% of suspected

VTE are positive

VENOUS THROMBOEMBOLISM
Venous Thromboembolic Disease

DVT
PE
 Distinct clinical entities
 Manifestation of the same disease
Venous Blood Clot Embolus

VENOUS THROMBOEMBOLISM
 DVT-- thrombi form in deep veins of legs, pelvis or upper extremities
 PE -- thrombi embolize to pulmonary arteries
 elevate pulmonary vascular resistance

 heart failure
 cardiogenic shock
 impairment of gas exchange

Deep Vein Thrombosis (DVT)
 DVT may occur without obvious symptoms and may be difficult to detect
 Up to 50% of DVT incidents may produce minimal symptoms or are

completely "silent”
 85% are in the proximal venous system and 15% limited to the calf
 20% to 30% of calf thrombi extend proximally
 Symptoms:
• Pain, tenderness, or sudden swelling in the leg
• Discoloration or visibly large veins
• Skin that is warm to the touch

Pulmonary Embolism (PE)
 The highest incidence of recognized pulmonary embolism occurs in

hospitalized patients
 Approximately 10% of patients with diagnosed pulmonary embolism die within

the first 60 minutes
 Symptoms:
• Shortness of breath
• Anxiety or nervousness
• Rapid pulse
• Excessive sweating
• Sharp chest pain
• Cough that may produce a bloody discharge
• Very low blood pressure
• Fainting

WHY IDENTIFY PATIENTS WITH VTE
 Prevent mortality and morbidity associated with PE
 Anticoagulant therapy reduces risk of fatal outcome 15 fold
 Anticoagulant therapy related to high mortality and morbidity
 Justification for risk of bleeding
 Cost savings

VTE Disease Predisposing Risk Factors
 Clinical conditions  Environment

 surgery, trauma, cancer  air travel
 hormonal influences  smoking

 age
 Hereditary coagulapathies
 Factor V Leiden
 Protein C / S Deficiency
 AT Deficiency
 Prothrombin Gene Mutation
 Acquired coagulapathies
 Lupus Anticoagulant

Diagnostic Challenges with DVT/PE
 Only 15-25% of suspected VTE patients have disease

 DVT mortality rate of 21% in elderly
 PE mortality rate 30% without treatment
 90% of PE develops from DVT
 PE causes more deaths annually in the U.S. than
breast cancer, highway fatalities and AIDS combined

 Page 12 © Siemens 2013. All rights reserved.
DIAGNOSING DVT/PE
Clinical Probability
History and Exam Determines
Low
Moderate
High
Diagnostic Studies

D-Dimer + Probability Score
“…DD testing has gained wide acceptance for ruling out the disease, at least in the
outpatient population referred to the emergency department.”
“…ELISA DD assays and automated latex turbidimetric tests are associated with the
highest sensitivity and with virtually no interobserver variability.”
“…these tests should be used to rule out VTE only in non-high clinical probability
patients.”
D-Dimer for venous thromboembolism diagnosis: 20 years later; M. Righini, A. Perrier, P. De Mperloose amnd H. Bpima,eaix
Journal of Thrombosis and Haemostasis, 2008, 6: 1059-1071

Wells Pre-test Probability of DVT
Clinical Parameter Score Score
Active cancer (treatment ongoing, or within 6 months or palliative) +1
Paralysis or recent plaster immobilization of the lower extremities +1
Recently bedridden for >3 d or major surgery <4 wk +1
Localized tenderness along the distribution of the deep venous system +1
Entire leg swelling +1
Calf swelling >3 cm compared to the asymptomatic leg +1
Pitting edema (greater in the symptomatic leg) +1

Score
Previous DVT documented +1
>3 High probability
Collateral superficial veins (nonvaricose) 1 or 2 Moderate probability +1
Alternative diagnosis (as likely or > that of DVT) <0 Low probability -2

Wells Pre-Test Probability of PE
Clinical Parameter Score Score

Suspected DVT 3.0
Alternate Dx is less likely than PE 3.0
Heart rate >100 1.5
Immobilized or surgery in last 4 wk 1.5
Previous DVT/PE 1.5
Hemoptysis 1.0
Malignancy (treated within 6 mo.) 1.0
Score Probability Risk
0–2 Low 3.6%

3–6 Moderate 20.5%
>6 High 66.7%
Wells, PS et al. Thromb Haemost. 83: 416, 2000

Implication of D-dimer
Thrombin
Fibrinogen Soluble Fibrin + FP A+B

Plasminogen Activators
(tissue PA, urokinase PA, FXII, etc)
FXIII
Fibrin Clot Plasmin Plasminogen
DED D-dimer
D=D
Clot + Fibrinolysis = D-dimer formation

No Clot + Fibrinolysis =  D-dimer formation
Elevated D-dimer
 DIC  Age
 Fibrinolytic therapy within 7 days  Hospitalized patients in general
 Malignancies  Stress
 Aortic aneurysm, MI  Excessive exercise
 Sepsis, severe infection, pneumonia  Lipemic samples
 Hemolyzed samples
 Trauma, surgery
 Liver cirrhosis
 Pregnancy or obstetric complication

Why Differences in D-dimer Assays
 No D-dimer assay produces identical results to another D-dimer assay
 D-dimer antigen is not homogenous but a mixture of fragments & compounds

containing fragments of D & E of different molecular weight (HMW & LMW)
 D-dimer assays use different antibodies, buffers, measuring technique, standards

Comparability of D-Dimer Assays
 Facts that effect assay comparability

 No international standard for D-dimer
 Different reporting units: D-dimer units (DDU) & Fibrinogen Equivalent Units (FEU)
 Antibodies have different affinity to D-dimer compounds
 Different reagents & assay methodologies result in different interferences
and signals
 Conclusions
 Each manufacturer establishes its own standardization method
 Various assays have different performance characteristics
 Different standardizations typically result in different quantitative results
on the same patient

Goals of Diagnostic Studies
 Provide reliable diagnosis
 Shortest possible time
 Least discomfort to patient
 Reasonable cost

PE / DVT Exclusion
D-dimer
Testing Algorithms

Algorithm for PE
Low Clinical Probability of embolism
Highly sensitive D-dimer assay
Negative Positive
Diagnosis ruled out Ventilation-perfusion

scan or CT scan
. Fedullo, P, Tapson, V. The Evaluation of Suspected Pulmonary Embolism. N Engl J Med 2003:1247-56.

Algorithm for DVT
Hirsh J, Lee AY How We Diagnose & Treat Deep Vein Thrombosis, Blood 2002; 99(9): 3102-3110

Evaluating
D-dimer Results

D-dimer vs. Imaging…Why Results Do Not Agree
Questions to Ask:
 Age of Clot  Patient Age
 Time of Initial Symptoms  Cancer
 Size of Clot  Previous Thrombosis
 Where Clot Located  Pregnant
 Anticoagulants before Draw  In-patient

Normal D-dimer with Abnormal Scan
 Distal DVT
 Subsegmental / peripheral PE
 Presentation to ER > 7days after symptoms
 Size of clot, small clot may produce minimal D-dimer levels
 Anticoagulant therapy within 24 hours

D-dimer vs. Imaging…Why Results Do Not Agree
Age of Thrombus
Patients who report greater than 14 days duration of symptoms demonstrate
inactive fibrinolysis and D-dimer levels rapidly decrease, false negative
Size of Thrombus
Smaller thrombi produce minimal levels of D-dimer, false negative
Position of Thrombus
 Calf vein thrombi, false negative
 Sub-segmental PE, false negative
Anticoagulant Therapy
 Reduces fibrin formation
 D-dimer levels are reduced, false negative
 Do Not perform D-dimer on anticoagulated patients

D-dimer in Hospitalized Patients
 Hospitalized patients usually have on-going disease process

 D-dimer levels can be elevated in these patients due to disease state
 Patients may be tested, but will likely have elevated levels in absence of clot
 DO NOT perform D-dimer on hospitalized patients for DVT/PE rule-out
 Utilize imaging methods for DVT/PE rule-out
 D-dimer is used for DIC in hospitalized patients
 Do not use hospitalized patients in a normal reference range study

Summary for Clinical Utility of D-dimer Assay
 Negative D-dimer with low pre-test probability can exclude VTE
 D-dimer is cost effective, saving thousands of dollars in health care cost
 D-Dimer test results should always be used in conjunction with the patient’s
medical history, pre-test probability scoring and clinical presentation.

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The Clinical Utility of

Beth Phillips MT,SH (ASCP)

© Siemens 2013. All rights reserved.

 Define VTE as DVT and PE

 Identify D-dimer assays and the role they play in DVT/PE

 Explain Well’s pre-test probability scoring and clinical models

 Describe evaluation of D-dimer assay results

Page 2 © Siemens 2013. All rights reserved.

 4th Century BC…Hippocratic school familiar with blood fluidity

 1893 Dastre coined term “fibrinolysis”

 1905 Morawitz concluded process was probably enzymatic

 1959 Sherry proved fibrinolysis due to activator converting plasminogen to

 1960 five fragments of fibrinogen when treated with plasmin: A, B, C, D, & E

 1983 Greenberg measured “fibrin d-dimer” to differential FDP derived from

Page 3 © Siemens 2013. All rights reserved.

 30 years ago proposed as aid in suspect DVT

 mid 1990’s focus on use as aid in ruling out VTE

Page 4 © Siemens 2013. All rights reserved.

 Yearly in the USA:

 Diagnostic Challenges with DVT/PE

 Clinical suspicion has increased

 Prevalence has decreased, some statistics state only 10% of suspected

Page 5 © Siemens 2013. All rights reserved.

Venous Thromboembolic Disease

Venous Blood Clot Embolus

 DVT-- thrombi form in deep veins of legs, pelvis or upper extremities

 PE -- thrombi embolize to pulmonary arteries

 elevate pulmonary vascular resistance

Page 7 © Siemens 2013. All rights reserved.

 Up to 50% of DVT incidents may produce minimal symptoms or are

• Pain, tenderness, or sudden swelling in the leg

• Discoloration or visibly large veins

• Skin that is warm to the touch

Page 8 © Siemens 2013. All rights reserved.

 The highest incidence of recognized pulmonary embolism occurs in

 Approximately 10% of patients with diagnosed pulmonary embolism die within

Page 9 © Siemens 2013. All rights reserved.

 Prevent mortality and morbidity associated with PE

 Anticoagulant therapy reduces risk of fatal outcome 15 fold

 Anticoagulant therapy related to high mortality and morbidity

 Justification for risk of bleeding

Page 10 © Siemens 2013. All rights reserved.

 Clinical conditions  Environment

 hormonal influences  smoking

Page 11 © Siemens 2013. All rights reserved.

 Only 15-25% of suspected VTE patients have disease

Page 13 © Siemens 2013. All rights reserved.

Page 14 © Siemens 2013. All rights reserved.

Clinical Parameter Score Score

Active cancer (treatment ongoing, or within 6 months or palliative) +1

Paralysis or recent plaster immobilization of the lower extremities +1

Recently bedridden for >3 d or major surgery <4 wk +1

Localized tenderness along the distribution of the deep venous system +1

Entire leg swelling +1

Calf swelling >3 cm compared to the asymptomatic leg +1

Pitting edema (greater in the symptomatic leg) +1

Page 15 © Siemens 2013. All rights reserved.

Clinical Parameter Score Score

Score Probability Risk

0–2 Low 3.6%

Wells, PS et al. Thromb Haemost. 83: 416, 2000

Page 16 © Siemens 2013. All rights reserved.

Fibrinogen Soluble Fibrin + FP A+B

Fibrin Clot Plasmin Plasminogen