D-Dimer

SAYED NOUR

History
D-dimer was originally

described in the 1970s, and found its diagnostic application in the 1990s.

 The usefulness of D-dimer testing as a

diagnostic tool lies in its negative predictive value, and research has established its high sensitivity, but low specificity. Testing products can correctly identify D-dimer elevation, but they don't identify why D-dimer is elevated.

 Coagulation, the formation of a blood clot or thrombus, occurs when the proteins of the "coagulation cascade" are activated, either by contact with damaged blood vessel wall (intrinsic pathway) or by activation of factor VII by tissue activating factors. Both pathways lead to the generation of thrombin, an enzyme that turns the soluble blood protein fibrinogen into fibrin, which aggregates into proteofibrils. Another thrombin-generated enzyme, factor XIII, then crosslinks the fibrin proteofibrils at the D fragment site, leading to the formation of an insoluble gel which serves as a scaffold for blood

clot formation.[

D-dimer production (from Wakai et al, 2003)

 The circulating enzyme plasmin,

the main enzyme of fibrinolysis, cleaves the fibrin gel in a number of places. The resultant fragments, "high molecular weight polymers",are digested several times more by plasmin to lead to intermediate and then to small polymers (fibrin degradation products or FDPs). The cross-link between two D fragments remains intact, however, and these are exposed on the surface when the fibrin fragments are sufficiently digested. The typical D-dimer containing fragment contains two D domains and one E domain of the original fibrinogen molecule

 D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated, for instans because of the presence of thrombosis or disseminated intravascular coagulation. The D-dimer assay depends on the binding of a monoclonal antibody to a particular epitope on the D-dimer fragment. Several detection kits are commercially available; all of them rely on a

different monoclonal antibody against D-dimer. For some of these, the area of the D-dimer to which the antibody binds is known. The binding of the antibody is then measured quantitatively by one of various laboratory methods

 Indications D-dimer testing is of clinical use when there is a

suspicion of deep venous thrombosis (DVT), pulmonary embolism (PE) or disseminated intravascular coagulation (DIC). It is under investigation in the diagnosis of aortic dissection. For DVT and PE, there are various scoring systems that are used to determine the a priori clinical probability of these diseases; the bestknown were introduced by Wells et al. (2003).

 For a very high score, or pretest probability, a

D-dimer will make little difference and anticoagulant therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.

 For a moderate or low score, or pretest

probability:
A negative D-dimer test will virtually rule out

thromboembolism: the degree to which the Ddimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in the clinical setting: most available D-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%

If the D-dimer reads high, then further testing (ultrasound of the leg veins or lung scintigraphy or CT scanning) is required to confirm the presence of thrombus.
Anticoagulant therapy may be started at this

point or withheld until further tests confirm the diagnosis, depending on the clinical situation.

 In some hospitals, they are measured by

laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high probability.

Test properties
Various kits have a 93-95% sensitivity

and about 25%-50% specificity in the diagnosis of thrombotic disease. False positive readings can be due to various causes: liver disease, high rheumatoid factor, inflammation, malignancy, trauma, pregnancy, recent surgery as well as advanced age.

 False negative readings can occur if the sample is

taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension. Likelihood ratios are derived from sensitivity and specificity to adjust pretest probability. In interpretation of the d-dimer, for patients over age 50 a value of ageX10 may be abnormal.[

 D-dimer tests are ordered, along with other

laboratory tests and imaging scans, to help rule out the presence of a thrombus. Some of the conditions that the d-dimer test is used to help rule out include: Deep vein thrombosis (DVT) Pulmonary embolism (PE) Strokes

 This test may be used to determine if

further testing is necessary to help diagnose diseases and conditions that cause hypercoagulability, a tendency to clot inappropriately. A D-dimer level may be used to help diagnose disseminated intravascular coagulation (DIC) and to monitor the effectiveness of DIC treatment.

 D-dimer is especially useful when the

doctor thinks that something other than DVT or PE is causing the symptoms. It is a quick, non-invasive way for the doctor to help rule out abnormal or excess clotting.

 When a person has symptoms of DIC, such as

bleeding gums, nausea, vomiting, severe muscle and abdominal pain, seizures, and decreased urine output, a D-dimer test may be ordered, along with a PT, PTT, fibrinogen, and platelet count to help diagnose the condition. D-dimer may also be ordered at intervals when a patient is undergoing treatment for DIC to help monitor its progress.

What does the test result mean?

A normal or negative D-dimer result means that it is most likely that the person tested does not have an acute condition or disease that is causing abnormal clot formation and breakdown. Most doctors agree that a negative D-dimer is most valid and useful when the test is done on people who are considered to be at low to intermediate risk for thrombosis. The test is used to help rule out clotting as the cause of symptoms.

 A positive D-dimer result may indicate the

presence of an abnormally high level of fibrin degradation products. It tells the doctor that there may be significant blood clot (thrombus) formation and breakdown in the body, but it does not tell the location or cause. It may be due to, for example, a venous thromboembolism (VTE) or DIC. Typically, the D-dimer level is very elevated in DIC.

 However, an elevated D-dimer does not always

indicate the presence of a clot because a number of other factors can cause an increased level. Elevated levels may be seen in conditions in which fibrin is formed and then broken down, such as recent surgery, trauma, infection, heart disease, and some cancers or conditions in which fibrin is not cleared normally, such as liver disease. Therefore, D-dimer is typically not used to rule out VTE in hospitalized patients (inpatient setting).

 Pregnancy is also a condition in which

fibrin is formed and broken down and may result in an elevated D-dimer level. However, if DIC is suspected in a woman who is pregnant or is in the immediate postpartum period, then the D-dimer test may be used, along with a PT, PTT, fibrinogen, and platelet count to help diagnose her condition. If the woman has DIC, her D-dimer level will be very elevated.

 D-dimer is recommended as an adjunct test. It should not be the only test used to diagnose a disease or condition. Both increased and normal D-dimer levels may require followup and can lead to further

testing. When used to monitor DIC treatment, decreasing levels indicate that treatment is effective while increasing levels may indicate that treatment is not working.

Is there anything else I should know?

D-dimer concentrations may rise in

the elderly, and false positives may be seen with high levels of rheumatoid factor, a protein seen in patients with rheumatoid arthritis. Substances such as high triglycerides, lipemia, and bilirubin can also cause false positives as can hemolysis caused by improper sample collection and handling.

 There are several different methods of

testing for D-dimer. Most of the D-dimer tests that yield quantitative results are done in a hospital lab, while those that yield qualitative or semi-quantitative results are performed at the patient's bedside (point of care).

 In healthy patients, procoagulant and

anticoagulant factors in the clotting cascade are in fine balance. Any change in the balance could place a patient at risk for VTE or bleeding. A recent study found that at certain levels, procoagulant and anticoagulant factors are grouped together in the coagulation cascade.

 Investigators believe the discovery of

hereditarily high levels of certain coagulation factors is associated with increased risk of VTE, and regulatory genes may be located outside clotting factor genes that control protein levels affecting the coagulation cascade. At certain levels, researchers theorize that these regulatory proteins cause grouping together, or clustering, of procoagulant and anticoagulant factors.

 Procoagulant vitamin K-dependent factors,

factor XI, and factor XII were found to cluster together. Factor V and factor VIII were found to cluster with fibrinogen and D-dimer; factor XIII remained independent. The anticoagulant factors protein C, protein S, and antithrombin also clustered together.

 Hospitalized patients
If D-dimer can be used as a rule-out tool

for VTE in outpatients, why isn't it used more often in the inpatient setting? Some studies have examined the use of D-dimer in the inpatient population, and the consensus is that D-dimer isn't a reliable rule-out tool for VTE in this population.

 One study cautioned against the

use of D-dimer testing on inpatients due to the high rate of false-positive results in patients with active disease processes such as pneumonia, heart failure, and malignancy.

 Researchers further described the possibility of a false-negative result in patients receiving anticoagulation prophylaxis or therapy and in those patients for whom duration of symptoms is unknown or subacute. Their research showed D-dimer levels had little reliability as a rule-out tool in determining which patients did or didn't have VTE if patients met the following criteria: * they'd been hospitalized for more than 3 days * they were over age 60 * they had had high C-reactive protein levels.

 Researchers did document a relationship

between D-dimer and C-reactive protein, supporting a connection between inflammation and thrombosis. For every quartile in which C-reactive protein rises, there's a correlational rise in D-dimer. The higher the two rise, the less reliable Ddimer's negative predictive value becomes. This correlation implies that as inflammation progresses, the likelihood of thromboembolism increases.

D-dimer in the ICU

Proinflammatory states in critically ill

hospitalized patients lead to elevated D-dimer levels via cytokine activation of the coagulation cascade and corresponding inhibition of fibrinolysis. Although D-dimer hasn't been shown to be an effective resource to rule out VTE in hospitalized patients, given the correlation of D-dimer to protein C and the inflammatory response, researchers are examining whether D-dimer could be used as a prognostic tool for mortality in the emergency department or intensive care unit (ICU), where activation of the inflammatory response is prominent.

 Virchow's triad and the subsequent

activation of the clotting cascade through physiologic activity, such as the inflammatory process, can result in microthrombi, which has been implicated in sepsis, ARDS, and multisystem organ failure.

 Sepsis mortality is directly related to the number

and severity of organs affected. Many studies show coagulation abnormalities emerging before symptom onset in sepsis or shock and baseline elevation of D-dimer levels soon after the onset of the first organ system to be affected.10 One study defined baseline D-dimer as the Ddimer level the day of admission to the ICU, and the first day of severe sepsis as, "the first calendar day after the onset of the first sepsis-induced organ dysfunction. Researchers also correlated the degree of abnormal baseline D-dimer to 28-day mortality. Changes in PT and D-dimer were related to 28-day mortality.

 Researchers who evaluated a rapid assay

D-dimer test sought to draw a parallel between D-dimer levels and poor outcomes in the critically ill by comparing Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score

(SAPS) scores.

 Their findings show an association

between D-dimer levels 24 hours after admission to an ICU and the 48-hour APACHE II and SAPS scores. Significant correlation was discovered between the 48-hour D-dimer level and the 48-hour APACHE II, SAPS, and the organ system failure index. This relationship demonstrates that the value of using D-dimer to predict clinical severity is seen 48 hours after admission to the ICU.

 Surprisingly, neither the 24-hour nor

the 48-hour D-dimer level predicted in-hospital mortality, whereas APACHE II, SAPS, and the organ system failure index did predict mortality. However, the D-dimer level was capable of predicting the magnitude of organ failure.

 Therefore, the investigators suggest

that D-dimer be used to predict general clinical severity of the critically ill patient. A particularly interesting point of the study is that the investigators included surgical patients, in whom D-dimer is expected to be elevated postoperatively

 The aim of treatment for microembolism is to

limit the degree of the inflammatory response, resolve or prevent further embolization, and prevent or repair as much end organ damage as possible. The PROWESS study, which documents the efficacy of using recombinant human activated protein C to treat severe sepsis, also documents lower D-dimer levels achieved by means of treatment with activated protein C, which correlated to improved survival.

What's normal?
Though multiple tests are available on

the market, no gold standard in which to compare results exists, so there's no "normal" value for D-dimer. With multiple products available designed to measure D-dimer levels, practitioners must be familiar with the test they're using and the respective manufacturerrecommended parameters.

 Tests can be quantitative and reported in

numerical units of measure, such as nanograms per milliliter, or they can be nonquantitative, which are reported as positive or negative values. Quantitative tests provide recommended cutoff levels for positive results and units of measure such as nanograms per milliliter, milligrams per liter of fibrinogen equivalent units (FEUs), or D-dimer units. Units of measure aren't interchangeable between testing products, as each product will have its own parameters.

 Nonquantitative or semi-quantitative tests rely on reader interpretation and can vary from

technician to technician. For example, one study used two types of Ddimer testing products to evaluate the efficacy of D-dimer testing on inpatients versus outpatients. Although they were both measured in milligrams per liter of FEU, one product reported positive results as greater than 1.0 mg/L and the other reported positive results as greater than 4.0 mg/L.

 Though each testing kit

reported positive results quantitative results in milligrams per liter, each retained its own cutoff value for a positive result. Past that positive value, the exact number wasn't reported.

Q1. What are

d-dimers?
D-dimers are specific cross-linked fibrin

derivatives that are the product of plasminmediated fibrinolytic degradation. They are an excellent marker of fibrinolytic activity.

Q2. When is the d-dimer test indicated?

The D-dimer assay can be used as a rule out test in the emergency department when the pre-test probability of venous thromboembolism (VTE) is low. The pre-test probability is best assessed using a clinical prediction guide (CPG), such as the Wells criteria or the revised Geneva score for pulmonary embolism (PE) and the Wells criteria for deep vein thrombosis (DVT).

For instance, a negative D-dimer test result when using a highly sensitive assay can rule out VTE using the Wells clinical prediction guides if: Low/intermediate probability of PE (score 0 to 6) Wells criteria for PE DVT unlikely (score 0 or 1) Wells criteria for DVT

Click!

Wells Criteria for Pulmonary Embolism / PE

Calculates Wells' Score for risk of PE.

Clinical Signs and Symptoms of DVT? PE Is #1 Diagnosis, or Equally Likely Heart Rate > 100? Immobilization at least 3 days, or Surgery in the Previous 4 weeks Previous, objectively diagnosed PE or DVT? Hemoptysis? Malignancy w/ Treatment within 6 mo, or palliative? Patient has none of these

Yes +3 Yes +3 Yes +1.5 Yes +1.5 Yes +1.5 Yes +1 Yes +1

Score

Click!

Wells Criteria for DVT

Yes +1

Active cancer?

Bedridden recently >3 days or Yes +1 major surgery within four weeks? Calf swelling >3cm compared to the other leg? Collateral (nonvaricose) superficial veins present? Entire leg swollen? Localized tenderness along the deep venous system? Pitting edema, greater in the symptomatic leg? Yes +1 Yes +1 Yes +1 Yes +1 Yes +1

Paralysis, paresis, or recent plaster immobilization of the lower extremity

Previously documented DVT? Alternative diagnosis to DVT as likely or more likely? Patient has none of these Score

Yes +1 Yes +1 Yes -2

points

The D-dimer assay can also be used to help diagnose fibrinolytic disorders such as venom-induced consumptive coagulopathy (VICC) and disseminated intravascular coagulation (DIC).

The D-dimer assay can also be used to help diagnose fibrinolytic disorders such as venom-induced consumptive coagulopathy (VICC) and disseminated intravascular coagulation (DIC).

How to use the D-dimer assay in the Emergency Department. Note that highly sensitive D-dimer assays can be used to rule out PE in patients with low or intermediate Wells scores (0 to 6), less sensitive assays should only be used for low Wells scores (0 to 2).

Q1. What is the PERC rule?

PERC = Pulmonary Embolism Rule-out Criteria

Pulmonary embolism can be ruled out clinically if none of the 8 PERC criteria are present in a patient with a low pretest probability of PE (e.g. Wells PE CPG score of <3) that is consistent with the gestalt of an experienced physician:

age < 50 years pulse < 100 beats min SaO2 >or= 95% no hemoptysis no estrogen use no surgery/trauma requiring hospitalization within 4 weeks no prior venous thromboembolism (VTE) no unilateral leg swelling

Cant remember all of this? Try this mnemonic suggested by the guys at Keeping Up in Emergency Medicine to remember which patients the PERC rule cant be used on: HAD CLOTS Hormone, Age >50, DVT/PE history, Coughing blood, Leg swelling, O2 >95%, Tachycardia 100+, Surgery/trauma <28 d Alternatively why waste valuable brain space? Use @grahamwalkers MDCalc.comonline and/or download Tschopp and Pfiffners MedCalc for free onto your smart phone.

Q2. In which patients may the PERC rule be unreliable? Answer and interpretation Kline et al (2004), the creators of the PERC rule, chose 1.8% as the point of equipoise between (1) the benefits and risks of further investigations for PE, and (2) the benefits and risks of not investigating further.

The original PERC rule study by Kine et al (2004) excluded patients with these characteristics: patients in whom shortness of breath is not the most important, or equally most important, presenting complaint cancer thrombophilia strong family history of thrombophilia beta blockers that may mask tachycardia patients with transient tachycardia patients with amputations patients who are massively obese and in whom leg swelling cannot be reliably ascertained with baseline hypoxemia in whom a pulse oximetry reading <95% is long-standing

However, since the derivation study there has been two validation studies. One of the validation studies (Kline et al, 2008) was a multi-center study that included patients with a primary complaint of shortness of breath or chest pain. Thus, I think that the PERC rule can be safely applied to patients with chest pain as the primary complaint.

Q3. What does this mean?

Equipoise is reached when the risk-benefit ratio of one course of action is balanced by the risk-benefit ratio of an alternative course of action. When deciding to investigate further for PE, this point is reached when the pre-test probability of PE is 1.8%. Kline et al (2004) calculated this number based on a formula that incorporated the risks from CT angiography: cancer from radiation exposure anaphylaxis or severe pulmonary edema requiring intubation requiring hemodialysis from the dye as well as the risk of death from missing a PE (dened as a 20% risk reduction for detected vs. missed). So, to use the PERC rule you have to choose the right patient to apply it too, and then accept a miss rate of 1.8%.

According to Carpenter et al (2008), the negative likelihood ratio for the PERC rule is 0.17 (95%CI 0.110.25).

Q4. What is the maximum pre-test probability of VTE such that the post-test probability (after correctly applying the PERC rule) is 1.8% or less?

There are a few way of working this out. 1. Use the Fagan nomogram (the link is to an interactive version click here for an old-school non-interactive version) 2. Do the math Step a. convert post-test probability to post-test odds post-test odds = probability / (1 probability) = 0.018 / 0.982 = 0.018 Step b. Divide post-test odds by the negative likelihood ratio to get pre-test odds pre-test odds = post-test odds / LR = 0.018 / 0.17 = 0.106 Step c. Convert pre-test odds to pre-test probability pre-test probability = odds / (1 + odds) = 0.106 / 1.106 = 0.096 Thus the PERC rule can be applied to patients with a pre-test probability ofabout 10% (this decreases to about 7% if a negative likelihood ratio of 0.25 is used, which is the upper limit of the 95% confidence interval) 3. Back calculate an estimate using MedCalc on your smart phone. Note that when using the Wells criteria for PE, low risk (score 0 or 1) is a probability of 1.3% and moderate risk (score 2 to 6) is a probability of 16.2%. Thus the PERC can be safely applied to low risk patients, but not moderate risk patients when using the Wells criteria for PE.

Q5. Is inappropriate use of the D-dimer assay a problem in medicine?

Yes! As an example consider the paper by Durieux et al (2001). This describes a single centre prospective study of 168 patients to analyze D-dimer usage after an educational intervention to implement guidelines for the diagnosis of PE. Despite the intervention 20% of the D-dimer requests were inappropriate and 45% of those with a positive Ddimer test had no imaging procedures performed. Whether it is being used appropriately or not, over half of D-dimer positive tests are false positives. Hence there is a definite need for something like the PERC rule.

Q6. What problems can arise from inappropriate use of the D-dimer test?

Problems from over-use of the D-dimer test include: Unnecessary cost of D-dimer test Unnecessary delays in investigation, management or disposition Unnecessary further imaging (if PERC rule would have prevented a false-positive D-dimer result from being obtained)
Radiation exposure from CTPA or CT venography Risk of contrast nephropathy Diversion of focus away from other more likely causes

Problems from under-use of the D-dimer test include: Unnecessary further imaging (if negative D- dimer would have precluded further investigation)
Radiation exposure from CTPA or CT venography Risk of contrast nephropathy

Missed diagnosis of venous thromboembolism resulting in morbidity and mortality

Q7. What should you do if a patient has a positive D-dimer test, but on reflection the investigation was not indicated for example, the patient meets the PERC rule criteria, which is consistent with a senior clinicians gestalt, but a D-dimer test has already been performed?

This is what I suggest: Ignore the result with respect to assessing VTE risk (go back and use the Wells criteria for PE!). Consider the other possible causes of an elevated D-dimer and manage as indicated (this may include no further action).

Q3. Can the d-dimer test be used to rule out thoracic aortic dissection?

No The systematic review of 10 studies by Sutherland et al (2008) showed that Ddimer cannot be used as a sole screening tool for acute aortic dissection. Problems with the studies include: 4 of the 10 studies had sensitivities <95%, and 3 of the 5 studies with sensitivities of 100% had the lower limit of the 9% confidence interval <85%. Thus the sensitivty of the D-dimer is insufficient for ruling out a must not miss diagnosis like acute aortic dissection inclusion bias and poorly defined inclusion criteria poorly defined duration of symptoms prior to performing the D-dimer test (up to 120 hours) the studies do not assess how clinical suspicion or other investigations affected the use of the D-dimer test heterogeneity of D-dimer assays used and the cut-off values used the non-specificity of the D-dimer test might lead to excessive imaging use of the D-dimer in high risk cases may delay definitive imaging and treatment

Q4. can the d-dimer test be used to rule atrial thrombus in a patient with atrial fibrillation, thus allowing safe cardioversion?

No early studies are promising but the test is not yet ready for prime-time for this use. A Best Bets review (updated in 2007) suggests that a negative D-dimer test may be able to rival echocardiography in ruling out an atrial thrombus in atrial fibrilation (negative predictive value ~98%), thus allowing cardioversion to be safely performed in the emergency department without the need for further investigation. However many of the studies included were in Japanese and only the English language abstracts were appraised. A large welldesigned study is needed to confirm these promising findings.

Q5. What situations may result in a false negative D-dimer assay when investigating for possible venous thromboembolic disease?

VTE can occur in the presence of a negative Ddimer test D-dimer assays can only be used to rule out VTE if the pre-test probability is sufficiently low. Negative results in the presence of VTE can occur if: there is a small clot load (eg. small calf only DVTs) the thrombus has matured over time the patient has defective fibrinolysis (which can contribute to thrombus formation in the first place)

Q6. What non- pathological conditions are associated with elevated D-dimer titres?

Non-pathological conditions associated with elevated D-dimer titres include: Age (healthy elderly people) Cigarette smoking Functional impairment Post-operatively Pregnancy Race (e.g. African Americans)

Q7. What pathological conditions are associated with elevated D-dimer titres?

Pathological conditions associated with elevated D-dimer titres include Acute coronary syndromes Acute upper gastrointestinal haemorrhage Aortic dissection Arterial or venous thromboembolism Atrial fibrillation Consumptive coagulopathy DIC, VICC Infection Malignancy Pre-eclampsia Sickle cell disease Stroke Superficial thrombophlebitis Trauma

Q8. Can the d-dimer assay be used to rule out VTE in an elderly patient?

Yes, with caveats. The D-dimer assay is more likely to give a positive result in the elderly, limiting the usefulness of the test. However, if the Ddimer is negative it can still be used to rule out VTE in elderly patients with low pre-test probabilities. A recent retrospective study by Douma et al (2010) suggests that higher cutoffs might be safely used in patients over 55 years of age.

Q9. Can the d-dimer assay be used to rule out VTE in a pregnant patient?

Yes, with caveats. As in the elderly, the D-dimer test result is more likely to be positive. The D-dimer result is nearly always positive in the third trimester, and less so the earlier the pregnancy. A negative D-dimer test in a patient with a low pre-test probability still rules out VTE.

Q10. Are there different types of d-dimer assays? Does it matter?

There are many different D-dimer assays (qualitative and quantitative) available. Different types of assay are not standardized and have varying sensitivities and specificities, but they generally have high sensitivity and negative predictive value for the presence of thrombus in patients with low pre-test probabilities. Furthermore, different laboratories may use different cut-offs for what constitutes a positive or negative result. The performance characteristics of the available D- dimer assay can affect its use in clinical decision making.

I am most familiar with the HemosIL DD HS assay, which is a rapid highly sensitive second-generation latex agglutination D-dimer assay. This has similar performance characteristic to the best performing ELISA assays, unlike first-generation latex agglutination assays. The published data for the HemosIL DD HS assays performance characteristics (using a cut-off of 230 ng/mL) are: Sensitivity: 100% (95%CI 95.4-100%) Negative predictive value: 100% (95%CI 96.5-100%) Specificity: 46.8% (95%CI 40.1-53.6%)

It turns out that the patient is a lawyer. He has a sore right calf and additional symptoms consistent with a mild panic attack. He wants to know what the meaning and significance of a positive or negative D-dimer test.

Q11. What will you say?

Two options one is better than the other: Forget about the D-dimer test. Lets stick in you in a scanner and irradiate the hell out of you. Hopefully youll eventually die of cancer, you goddam ambulance chaser!

or, perhaps say something that encapsulates this information: The D-dimer test is a marker of blood clotting activity and is not diagnostic of VTE. When used appropriately the D-dimer test helps rule out VTE if the test is negative and the chance of the patient having a VTE is relatively low. If the D-dimer test is positive further investigation may or may not be necessary depending on the likely cause of the elevated Ddimer result, of which there are many.

Diagnosis of VTE is based on probabilities and balances the risks of further investigation against the risk of missing the diagnosis. No investigation can reduce the chance of having VTE to absolute zero. D-dimer negative patients can still develop VTE and should be advised to return if symptoms worsen or new symptoms develop (e.g. worsening of leg pain and swelling, shortness of breath, chest pain or collapse).

Does this patient have pulmonary embolism?

Pre-test Probability
Definition Pretest Probability is defined as the probability of the target disorder before a diagnostic test result is known. It represents the probability that a specific patient, say a middle-aged man, with a specific past history, say hypertension and cigarette smoking, who presents to a specific clinical setting, like Accident and Emergency, with a specific symptom complex, say retrosternal chest pressure, dyspnoea and diaphoresis, has a specific diagnosis, such as acute myocardial infarction.

Application
The pretest probability is especially useful for four things: interpreting the results of a diagnostic test, selecting one or more diagnostic tests choosing whether to start therapy: * a) without further testing (treatment threshold); * b) while awaiting further testing; deciding whether it's worth testing at all (test threshold)

Calculation The probability of the target disorder, usually abbreviated P(D+), can be calculated as the proportion of patients with the target disorder, out of all the patients with the symptoms(s), both those with and without the disorder: P(D+) = D+ / (D+ + D-) where D+ indicates the number of patients with target disorder, D- indicates the number of patients without target disorder, and P(D+) is the probability of the target disorder.

Example: A group of investigators in North America studied the underlying diseases found in patients presenting to a primary care setting with persistent dizziness. They studied a total of 100 dizzy patients, finding 16 had dizziness from psychiatric conditions. Thus, 16 / 100, or 16 per cent, is the estimate of of disease probability for psychiatric conditions from this study.

So, if this information proves valid and applicable to your practice, if IF one of your patients presents to a primary care setting with persistent dizziness, the P(D+) of a psychiatric cause might be estimated at 16 per cent.