© siemens 2013. all rights reserved. the clinical utility of d-dimer assays beth phillips mt,sh...
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© Siemens 2013. All rights reserved.
The Clinical Utility ofD-dimer Assays
Beth Phillips MT,SH (ASCP)
Zone Technical Application Specialist
Siemens Healthcare Diagnostics
© Siemens 2013. All rights reserved.Page 2
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
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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
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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
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Venous Thromboembolism Epidemiology
Yearly in the USA:
> 600,000 Deep Vein Thrombosis
~ 150,000 Pulmonary Embolism
Diagnostic Challenges with DVT/PE90% 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
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VENOUS THROMBOEMBOLISM
Venous Blood Clot Embolus
Venous Thromboembolic Disease
DVT
PE
Distinct clinical entities
Manifestation of the same disease
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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
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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
Deep Vein Thrombosis (DVT)
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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
Pulmonary Embolism (PE)
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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
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VTE Disease Predisposing Risk Factors
Clinical conditions
surgery, trauma, cancer
hormonal influences
Hereditary coagulapathies
Factor V Leiden
Protein C / S Deficiency
AT Deficiency
Prothrombin Gene Mutation
Acquired coagulapathies
Lupus Anticoagulant
Environment
air travel
smoking
age
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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
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DIAGNOSING DVT/PE
History and Exam DeterminesLow
ModerateHigh
Clinical Probability
Guides
Choice
Diagnostic Studies
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D-Dimer + Probability Score
“…DD testing has gained wide acceptance for ruling out the disease, at least in theoutpatient 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,eaixJournal of Thrombosis and Haemostasis, 2008, 6: 1059-1071
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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
Previous DVT documented +1
Collateral superficial veins (nonvaricose) +1
Alternative diagnosis (as likely or > that of DVT) -2
Wells Pre-test Probability of DVT
Score
>3 High probability
1 or 2 Moderate probability
<0 Low probability
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Clinical Parameter Score ScoreSuspected DVT 3.0Alternate Dx is less likely than PE 3.0Heart rate >100 1.5Immobilized or surgery in last 4 wk 1.5Previous DVT/PE 1.5Hemoptysis 1.0Malignancy (treated within 6 mo.) 1.0
Wells Pre-Test Probability of PE
Wells, PS et al. Thromb Haemost. 83: 416, 2000
Score Probability Risk
0 – 2 Low 3.6%3 – 6 Moderate 20.5%> 6 High 66.7%
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Implication of D-dimer
Thrombin
Fibrinogen Soluble Fibrin + FP A+B
FXIII
Fibrin Clot
Plasminogen Activators(tissue PA, urokinase PA, FXII, etc)
Plasmin Plasminogen
D-dimerD=D
D E D
Clot + Fibrinolysis = D-dimer formation
No Clot + Fibrinolysis = D-dimer formation
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Elevated D-dimer
DIC
Fibrinolytic therapy within 7 days
Malignancies
Aortic aneurysm, MI
Sepsis, severe infection, pneumonia
Trauma, surgery
Liver cirrhosis
Pregnancy or obstetric complication
Age
Hospitalized patients in general
Stress
Excessive exercise
Lipemic samples
Hemolyzed samples
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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
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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
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Goals of Diagnostic Studies
Provide reliable diagnosis
Shortest possible time
Least discomfort to patient
Reasonable cost
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PE / DVT Exclusion
D-dimer
Testing Algorithms
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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 PE
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Algorithm for DVT
Hirsh J, Lee AY How We Diagnose & Treat Deep Vein Thrombosis, Blood 2002; 99(9): 3102-3110
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Evaluating
D-dimer Results
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D-dimer vs. Imaging…Why Results Do Not Agree
Age of Clot
Time of Initial Symptoms
Size of Clot
Where Clot Located
Anticoagulants before Draw
Patient Age
Cancer
Previous Thrombosis
Pregnant
In-patient
Questions to Ask:
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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
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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 vs. Imaging…Why Results Do Not Agree
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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
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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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Questions