Article, Hematology

Proper observation of patient-related factors is an important determinant in the use of the D-dimer test for exclusion of venous thromboembolism in the ED


Proper observation of patient-related factors is an important determinant in the use of the D-dimer test for exclusion of venous thromboembolism in the ED

To the Editor,

Recently, Ray et al [1] reported on the accuracy of the rapid quantitative D-dimer assay that is performed on the bioMe’rieux VIDAS system. In their outpatient population with a venous thromboembolism prevalence of 28%, the reported sensitivity (78%) and specificity (41%) resulted in a too low negative predictive value (NPV) of 84%. The specificity is in agreement with that reported by previous studies, but the sensitivity is clearly at odds [2]. A recent meta-analysis concluded that a negative result with the VIDAS D-dimer test is considered as diagnostically useful as a normal lung scan or negative duplex ultrasound [2]. Furthermore, the VIDAS assay is among the most frequently used D-dimer tests in prospective outcome studies that have demonstrated the safety of VTE exclusion based on a negative result [3].

Fortunately, Ray et al provide a detailed analysis of the characteristics of the patients with a false-negative D-dimer. Although this study was not powered to draw statistically valid conclusions on the association of clinical factors with false negatives, a number of patterns emerge that are corroborated by previous reports. The main lesson from the study by Ray et al is that D-dimer cannot be indiscriminately used for VTE exclusion in suspected outpatients and needs to be interpreted in the Clinical context of the patient.

First, the current prevailing expert opinion is that D-dimer cannot be used as a stand-alone test for VTE exclusion and needs to be combined with an assessment of clinical pretest probability (PTP) [3-5]. For the latter, validated scoring systems are available [6]. Depending on its negative likelihood ratio, the particular D-dimer assay should be restricted to patients with low PTP or can also be safely applied for exclusion in patients with moderate PTP. D- dimer is not considered useful in patients with high PTP [7]. In the Ray et al study, 3 patients with false-negative results were characterized as high PTP.

The second aspect is the consideration of a number of variables associated with a lower bClot burden.Q In Ray’s study, one or more of these factors were observed in most of

the patients with false negatives, including the location of the clot, the duration of symptoms (age of the clot) and prior anticoagulation. Although D-dimer has a lower sensitivity for smaller clots in distal deep vein thrombosis [8] or subsegmental pulmonary embolism [9], missing distal clots is considered a low concern because of uncertainty on clinical significance and lack of data on the benefit of treatment [10,11]. The duration of symptoms is relevant when interpreting test results, because D-dimer decreases with the time elapsed from the onset of symptoms [12,13]. Finally, D-dimer results reported from blood obtained after starting heparin should be interpreted with caution, because D-dimer decreases by about 25% within 24 hours after injection [14]. In addition, vitamin K antagonists are known to decrease D-dimer levels [15].

In summary, in contrast to the report by Ray et al, a highly sensitive assay such as VIDAS D-dimer exclusion in conjunction with proper observation of patient-related variables will lead to safe exclusion of VTE in a large proportion of suspected outpatients.

Wim P.M. Houdijk PhD Scientific Advisor Cardiovascular Disease Global Marketing & Strategic Development bioMe’rieux bv, Boseind 15, 5281 RM Boxtel

The Netherlands E-mail address: [email protected]



  1. Ray P, Bellick B, Birolleau S, et al. Referent D-dimer enzyme-linked immunosorbent assay testing is of limited value in the exclusion of Thromboembolic disease: result of a practical study in an ED. Am J Emerg Med 2006;24:313 – 8.
  2. Stein PD, Hull RD, Patel KC, et al. D-dimer for exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med 2004; 140:589 – 602.
  3. Ten Cate-Hoek AJ, Prins MH. management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J Thromb Haemost 2005;3:2465 – 70.
  4. Kelly J, Hunt B. A clinical probability assessment and D-dimer measurement should be the initial step in the investigation of suspected venous thromboembolism. Chest 2003;124:1116 – 9.

0735-6757/$ – see front matter D 2007

256 Correspondence

  1. Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004;329:821 – 8.
  2. Kelly J, Hunt BJ. The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism. J Thromb Haemost 2003;1:1888 – 96.
  3. Righini M, Aujesky D, Roy PM, et al. clinical usefulness of D-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism. Arch Intern Med 2004;164:2483 – 7.
  4. Jennersjo CM, Fagerberg IH, Karlander S, et al. Normal D-dimer con- centration is a common finding in symptomatic outpatients with distal deep vein thrombosis. Blood Coagul Fibrinolysis 2005;16:517 – 23.
  5. De Monye’ W, Sanson BJ, MacGillavry R, et al. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med 2002; 165:345 – 8.
  6. Righini M, Paris S, Le Gal G, et al. Clinical relevance of distal deep vein thrombosis. Review of literature data. Thromb Haemost 2006;95: 56 – 64.
  7. Le Gal G, Righini M, Parent F, et al. Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost 2006;4: 724 – 31.
  8. D’Angelo A, D’Alessandro G, Tomassini L, et al. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis. Thromb Haemost 1996;75:412 – 6.
  9. Heit JA, Minor TA, Andrews JC, et al. Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med 1999; 123:235 – 40.
  10. Couturaud F, Kearon C, Bates SM, et al. Decrease in sensitivity of D-dimer for acute venous thromboembolism after starting anticoagulant therapy. Blood Coagul Fibrinolysis 2002; 13:241 – 6.
  11. Ke’vorkian JP, Halimi C, Segrestaa JM, et al. Monitoring of patients with deep-vein thrombosis during and after anticoagulation with D-dimer. Lancet 1998;351:571 – 2.

The effect of the gravitation of the moon on acute myocardial infarction

To the Editor,

A number of studies have reported a daily and yearly variation in the occurrence of acute myocardial infarction (AMI) [1,2]. It has been shown that the Circadian variation of AMI is the result of an increase in the incidence of Plaque rupture during the morning hours [3]. These studies have shown a relation between the solar motion and the occurrence of AMI. Less information is available regarding the effect of the moon on coronary artery disease. Previous reports have shown lunar phases do not relate to the occurrence of AMI [4,5]. The period it takes the moon to orbit around the earth and the period of the phase of the moon are different. These periods are referred to as the sidereal month and synodic month, respectively. One sidereal month is 27.32 days, and after that time, the moon has returned to the same point in the heavens. The synodic month is 29.53 days, the time after which the moon returns to exactly the same position relative to the sun. The moon moves in an easterly direction relative to the earth, by 3608/

29.53 = 12.28 each day, and relative to the earth, by 3608/

27.32 = 13.28. The difference between the sidereal and synodic daily motion of the moon is equal to the daily motion of the sun. This becomes immediately clear if we consider that the daily motion is nothing other than the angular velocity in astronomical units. A previous report has shown that a blind man has a circadian rhythm based on the motion of the moon [6]. As well as the sun, the moon may control our biological clock. The study of the timing and activity at occurrence of AMI may provide clues to preventive measures. There have, however, been few studies concerning the gravitation of the moon. The aim of this study was to investigate the relation between the occurrence of AMI and the gravitation of the moon.

Our study population was composed of 1369 (1009 men, aged 64.4 F 11.5 years) consecutive patients with the first AMI within 12 hours of the onset of symptoms from Baba Memorial Hospital; Tane General Hospital; Ikuwakai Memorial Hospital; Osaka City University, Osaka; and Tsukazaki Memorial Hospital, Hyogo, Japan. The diagnosis of AMI was determined by the standard criteria [3]. In the coronary care unit, the staff of each hospital carefully reviewed the patients’ detailed clinical history by interview and identified the time of onset. In this study, we defined cases when AMI was developed during bed rest or while sitting as bonset at rest.Q

The distance from the center of the moon to the center of the earth was calculated with the NASA’s Software: NASA Jet Propulsion Laboratory Solar System Simulator, Universal gravitation of the moon was derived by G * m/d2 ( G is universal gravitation constant, 6.67259 x 10–11m3 s–2 kg–1; m is the magnitude of the moon; d is the distance between the center of the moon and the center of the earth). The relationship between m/d2 and the cases of AMI were determined.

Fig. 1 This bar graph shows the relation between the phase of the moon and the occurrence of acute myocardial infarction.