© siemens 2013. all rights reserved. the clinical utility of d-dimer assays beth phillips mt,sh...

© Siemens 2013. All rights reserved.

The Clinical Utility ofD-dimer Assays

Beth Phillips MT,SH (ASCP)

Zone Technical Application Specialist

Siemens Healthcare Diagnostics


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


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/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


VENOUS THROMBOEMBOLISM

Venous Blood Clot Embolus

Venous Thromboembolic Disease

DVT

PE

Distinct clinical entities

Manifestation of the same disease


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


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)


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)


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

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


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


DIAGNOSING DVT/PE

History and Exam DeterminesLow

ModerateHigh

Clinical Probability

Guides

Choice

Diagnostic Studies


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


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


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%


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


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


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


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


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

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:


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


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


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.


Questions

© siemens 2013. all rights reserved. the clinical utility of d-dimer assays beth phillips mt,sh...

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