Transcript D-dimer in Hospitalized Patients

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
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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/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
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VENOUS THROMBOEMBOLISM
Venous Thromboembolic Disease
DVT
PE
 Distinct clinical entities
 Manifestation of the same disease
Venous Blood Clot
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Embolus
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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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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
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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:
•
•
•
•
•
•
•
•
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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
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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
 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
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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
Determines
Clinical Probability
Low
Moderate
High
Diagnostic Studies
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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
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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
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Wells Pre-Test Probability of PE
Clinical Parameter Score
Suspected DVT
Alternate Dx is less likely than PE
Heart rate >100
Immobilized or surgery in last 4 wk
Previous DVT/PE
Hemoptysis
Malignancy (treated within 6 mo.)
Score
3.0
3.0
1.5
1.5
1.5
1.0
1.0
Score
Probability
Risk
0–2
3–6
>6
Low
Moderate
High
3.6%
20.5%
66.7%
Wells, PS et al. Thromb Haemost. 83: 416, 2000
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Implication of D-dimer
Thrombin
Fibrinogen
Soluble Fibrin + FP A+B
Plasminogen Activators
(tissue PA, urokinase PA, FXII, etc)
FXIII
Fibrin Clot
DED
Plasmin
Plasminogen
D-dimer
D=D
Clot + Fibrinolysis = D-dimer formation
No Clot + Fibrinolysis =  D-dimer formation
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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
 Trauma, surgery
 Hemolyzed samples
 Liver cirrhosis
 Pregnancy or obstetric complication
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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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Algorithm for PE
Low Clinical Probability of embolism
Highly sensitive D-dimer assay
Negative
Diagnosis ruled out
Positive
Ventilation-perfusion
scan or CT scan
. Fedullo, P, Tapson, V. The Evaluation of Suspected Pulmonary Embolism. N Engl J Med 2003:1247-56.
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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
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
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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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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
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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
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