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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 5  |  Issue : 5  |  Page : 411-418
Qualitative D-Dimer in deep vein thrombosis: A single center prospective study from Kashmir India


1 Department of Medicine, SKIMS, Srinagar, Kashmir, India
2 Department of Pathology, GMC Jammu, Srinagar, Kashmir, India
3 Department of Radiology, SKIMS, Srinagar, Kashmir, India

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Date of Web Publication27-Dec-2012
 

   Abstract 

Objective: The aim of our study was to study the significance of qualitative D-dimer in the diagnosis of deep vein thrombosis. Study Design: Prospective analysis. Setting: Tertiary care hospital. Materials and Methods: One hundred and twenty nine patients of suspected deep vein thrombosis were included in the study and further categorized as likely or unlikely to have deep vein thrombosis on Wells scoring system. The patients in both the likely and unlikely categories were then randomly assigned to undergo D-dimer testing (D-dimer group) or to undergo ultrasound imaging alone (control group). The patients with pre text clinical probability score as unlikely and with negative D-dimer test were considered not to have DVT. The primary event was recurrent venous thromboembolism in both the groups during three months of follow-up. Results: A total of one hundred and twenty nine patients with suspected DVT were included in the study. Sixty five patients were randomly assigned to D-dimer group and sixty four to the doppler group. The diagnosis of DVT was established in 41 (31.78%) patients. Among patients in whom DVT was ruled out by the initial diagnostic evaluation one case of deep vein thrombosis was confirmed in the D-dimer group (1/55, 1.8%; 95% confidence interval, 1.6 to 5.2%) and two cases in the Doppler group (2/51, 3.92%; 95% confidence interval, 1.5 to 9.34%) during three months of follow-up. The use of D-dimer resulted in lesser number of USG (0.66 tests per person) in the D-dimer group as compared to (1.23 tests per person) in the Doppler group. Forty patients (31%) in the D-dimer group did not require ultrasound imaging. Conclusion: The diagnostic performance of qualitative D-dimer assay combined with a clinical pre text probability score can also rule out DVT safely in low probability scores without significantly compromising safety.

Keywords: Deep vein thrombosis, D-dimer, Doppler ultrasonography

How to cite this article:
Singh DP, Dhobi GN, Naik M, Sofi F, Bali BK, Shaheen F, Shah Y. Qualitative D-Dimer in deep vein thrombosis: A single center prospective study from Kashmir India. Ann Trop Med Public Health 2012;5:411-8

How to cite this URL:
Singh DP, Dhobi GN, Naik M, Sofi F, Bali BK, Shaheen F, Shah Y. Qualitative D-Dimer in deep vein thrombosis: A single center prospective study from Kashmir India. Ann Trop Med Public Health [serial online] 2012 [cited 2018 Aug 16];5:411-8. Available from: http://www.atmph.org/text.asp?2012/5/5/411/105121

   Introduction Top


Venous thromboembolism is an important medical problem. The incidence of venous thrombotic diseases is increasing in population and at least one risk factor is present in 75% of patients who develop it. Venous thrombosis commonly develops in the deep vein of the leg or the arm or in the superficial veins of the extremities. Untreated deep venous thrombosis can result in pulmonary embolism, a potentially fatal outcome.

Of patients presenting with symptoms of deep venous thrombosis, only 30% actually have the disorder. [1] In the emergency department medical decisions must be made rapidly to identify, safely and accurately, the 70% of patients with symptoms who do not have deep venous thrombosis and likewise to identify those who do have the disorder is critical. As clinical signs and symptoms are nonspecific, DVT must be confirmed by objective methods. The predictive sensitivity of assessment increases to 75% when risk factors and possible alternative diagnoses are incorporated into a pretest clinical assessment. Today most of the hospitals use the noninvasive compression ultrasonography which has high sensitivity and specificity for proximal DVT whereas the sensitivity for calf vein thrombosis is slightly lower. [2],[3],[4],[5] Twenty percent of patients who present with symptomatic deep venous thrombosis of the leg have isolated calf-vein thrombosis, and 30% of those patients will have subsequent extension of the clot into the proximal system. Hence, serial ultrasound studies to detect extension of a clot into the proximal system are necessary. Sequential ultrasound analysis is expensive, however, and definitive diagnosis and treatment may be delayed. Wells et al. showed that with the use of pretext clinical-probability scoring system in which patients are divided into low, intermediate, and high risk groups on the basis of clinical criteria, deep venous thrombosis could be safely ruled out on the basis of a single negative ultrasound result in patients who had a low clinical-probability score. [6]

D-dimer assays have been explored as tools for the diagnosis of deep venous thrombosis. D-dimer fragments are produced during the degradation of thrombin generated fibrin clots by plasmin. D-dimer and fragment E are the final products of complete fibrinolysis. Hence, the presence of D-dimer is a telltale clue that blood clotting has been initiated. [7]

The generation of monoclonal antibodies to the D-dimer fragment is the basis for the three main methods of D-dimer detection : T0 he enzyme linked immunosorbent assay (ELISA), the latex agglutination assay, and whole blood agglutination. ELISA is highly sensitive and provides quantitative results, but it is not specific for deep venous thrombosis, [8] since it detects low levels of fibrin in a variety of conditions, such as infection, inflammation, vasculitis, pregnancy, trauma, and hemorrhage and after surgery, in association with incisions; moreover, ELISA is technically time consuming.

Latex-agglutination assays are inexpensive and rapid but have a sensitivity of 80%, making them unsuitable for the diagnosis of deep venous thrombosis. Quantitative, automated latex assays, such as IL-Test D-dimer, in which the degree of D-dimer induced latex agglutination is measured by the decrease in light transmittance at 405 nm, are both sensitive and rapid, but they require special equipment. Whole blood agglutination assays, such as SimpliRED, are qualitative red cell agglutination assays in which the monoclonal antibody specific for D-dimer is linked to a monoclonal antibody that binds to red cells. The results of whole blood D-dimer assays have been criticized as being operator dependent. An assay must approach 100% sensitivity to be the sole criteria for deciding whether a patient has deep venous thrombosis. However, D-dimer assays with a high negative predictive value for deep venous thrombosis may be useful for ruling out this disorder in patients with symptoms. [9],[10]

A strategy combining clinical assessment with D-dimer testing in the initial evaluation of outpatients with suspected deep venous thrombosis is a potentially powerful means to rule out this disorder rapidly and safely. [11],[12] D-dimer assays have not been standardized, however, and the results of the study by Wells et al. cannot necessarily be extrapolated to results obtained by other laboratories or with other D-dimer assay methods. Nevertheless, clinicians should strongly consider the D-dimer management strategy, in the evaluation of outpatients with possible deep venous thrombosis. Before implementing the strategy the hospital laboratories should validate their D-dimer assay method.

In conclusion D-dimer assay with a high negative predictive value for deep venous thrombosis, in conjunction with a pretest clinical scoring system, allows unnecessary ultrasound studies to be safely omitted in the evaluation of outpatients.


   Materials and Methods Top


This study was conducted in the department of internal medicine, Sher-i-Kashmir Institute of Medical Sciences Srinagar, prospectively over a period of two years from September 2005 to August 2007.

Inclusion criteria

All patients with suspected deep venous thrombosis were included in this study.

Exclusion criteria

Patients were excluded if they were suspected to have pulmonary embolism, if they had a life expectancy of less than three months, if they had used therapeutic doses of anticoagulants or treatment doses of low-molecular-weight heparin for more than 48 hours, if they were pregnant, if they were under 18 years of age, if they resided where they were inaccessible to follow-up, if their symptoms had resolved for more than 72 hours before presentation, if they were allergic to the contrast agent, or if they refused or were unable to give consent.

Using a clinical model, physician will evaluate the 100 patients and categorized them as likely or unlikely to have deep venous thrombosis on Well's scoring system [Table 1]. Patients with a score of less than two were considered unlikely, and those with a score of two or more were considered likely, to have deep vein thrombosis. The patients in both the likely and unlikely categories were then randomly assigned to undergo ultrasound imaging alone (control group) or to undergo D-dimer testing (D-dimer group).
Table 1: Clinical model for predicting the pretest probability of deep venous thrombosis

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In the D-dimer group patients underwent ultrasound imaging if they were judged clinically as likely to have deep vein thrombosis or if they were judged clinically unlikely but the D-dimer test was positive. Patients who were judged clinically unlikely and there D-dimer test was negative underwent no ultrasound imaging. A second test was performed only in the patients judged clinically likely to have deep-vein thrombosis who had an initial negative ultrasound test and a positive D-dimer test. D-dimer testing was performed with latex agglutination assay (qualitative).

In the control group all patients underwent ultrasound imaging of the proximal veins. For patients who had been judged clinically unlikely to have deep-vein thrombosis, the diagnosis of deep-vein thrombosis was excluded if the ultrasound was negative. For those who had been judged likely to have deep-vein thrombosis, a second ultrasound was performed one week later if the first test was negative.

Ultrasonography was performed with a high-resolution 5- or 7.5-Mhz linear array transducer. The deep veins were evaluated for compressibility at 1-cm intervals from the common femoral vein to the point where the popliteal vein joins the calf veins. In patients with no history of deep-vein thrombosis, deep-vein thrombosis was diagnosed if the vein was non compressible. In patients with a history of deep-vein thrombosis, deep-vein thrombosis was diagnosed if there was a new non compressible site or if the diameter of the clot had increased by at least 4 mm from a previous measurement. If the change in clot diameter was 1 mm or less, recurrence was ruled out. If the clot diameter had increased by 1.1 to 3.9 mm, the ultrasound examination was repeated one week later.

After obtaining the consent of patients categorizing was done using well's clinical scoring system as clinically likely or unlikely and the patients were randomly assigned to D-dimer group or control group. The ultrasonographers and the laboratory technicians performing the D-dimer tests were unaware of the patients' assignments.

Surveillance and follow-up

Patients receiving a diagnosis of deep-vein thrombosis were treated with conventional anticoagulant therapy. Other patients were asked to report to or call the hospital if they had symptoms compatible with venous thromboembolism, and there condition was reviewed one week and three months after presentation.

Statistical analysis

Statistical analysis was performed by using the statistical package for Social Sciences (SPSS Version 15.0). A P value of <0.05 was taken as statistically significant.


   Results Top


A total of 141 patients were screened, of whom 129 were eligible. Informed consent was obtained from them. Of these, 65 were assigned to D-dimer group and 64 were assigned to control group by randomization. The base-line characteristics of the two groups were similar [Table 2].
Table 2: Demographic and clinical characteristics of the patients

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The mean age of the patients overall was 45.7 (±17.65) yrs. Mean age in D-dimer group was 45.1 yrs and in control group was 46.4 yrs. Mostly patients were age group of 31-60 (50.4%), followed by < 30 years (28.2%), then > 60 years (19.8%). Mean duration of symptoms was 23 (±28.5) days in D-dimer group and 17.8 (±24.8) days in the control group. Male to female ratio was 1.16 in D-dimer group and 1.13 in the control group. Over all it was 1.17:1 [Table 2], [Figure 4].
Figure 1: Diagnostic algorithm and patient's outcome in the D-dimer group judged clinically likely to have deep venous thrombosis

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Figure 2: Diagnostic algorithm and patient's outcome in the control group judged clinically unlikely to have DVT

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Figure 3: Pie chart showing comorbid conditions in patients with DVT

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Figure 4: Graph showing number of male and females in different age groups

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In occupation, sedentary: Non-sedentary ratio was 1.64:1 in D-dimer group and 1.06:1 in control group, over all it was 1.32:1 [Table 2].

Most of the patients were married, with married: Unmarried ratio was 7.12:1 in D-dimer group and 9.66:1 in the control group. Clinically, swelling of the limb was the commonest symptom [Table 2], followed by swelling and pain of the limb.

In co morbid conditions, hypertension was commonest (26%) [Table 3], followed by malignancies (19.6%), diabetes (12.5%), tuberculosis (7.1%), miscellaneous (33.9%) comprising stroke, operated patients, fracture limb. One patient had oral contraceptive intake [Table 3], [Figure 3].
Table 3: Comorbid conditions


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No. of cancer patients in D-dimer group was 8 (12.3%) and in control group 3 (4.68%). Malignancies includes Ca esophagus (3), periampullary carcinoma (1), Ca ovary (1), Renal cell carcinoma (1), secondaries in brain (1), Ca stomach (1), Ca prostate (1), Non Hodgkin lymphoma (1) and Ca colon (1). No. of patients developing deep venous thrombosis due to surgery or immobilization was 12 (18.4%) in D-dimer group and 10 (15.6%) in control group. One patient had factor-V Leiden positive [Table 3].

On abdominal ultrasonography, 6 (4.6%) patients had splenomegaly, 5 (3.87%) had hepatomegaly, 1 (0.7%) had peripheral lymphadenopathy, 1 (0.7%) had central lymphadenopathy (paraaortic), 2 (1.5%) had prostate enlargement, 5 (3.87%) had renal cyst, 5 (3.87%) had cholelithiasis, dilated CBD and abdominal hematoma [Table 4].
Table 4: USG findings in DVT patients


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Most of the patients presented with unilateral limb involvement and in 11 (8.4%) patient's complaints were of bilateral involvement.

Laboratory parameters revealed that mean hemoglobin was 11.08 (±2.34), Mean total leucocytic count was 8.03 (±3.38), mean platelet count was 181 (±130), Mean erythrocytic sedimentation rate was 37 (±19), mean MCV 81.5 (±17.02), mean MCH was 42.6 (±27.1), mean MCHC was 31.2 (±3.44), mean serum urea was 50 (±39), mean serum creatinine was 1.13 (±0.8), mean blood glucose was 117 (±50.3), mean serum total protein was 6.7 (±1.08), mean serum albumin was 3.37 (±0.6), mean serum bilirubin was 0.9 (±0.7), mean serum SGOT was 63.2 (±40.5), mean serum SGPT was 48.4 (±42.9), mean serum alkaline phosphatase was 282.6 (±130.5), mean serum calcium was 8.7 (±1.19), mean serum phosphorus was 4.23 (±1.83), mean uric acid was 6.15 (±2.33), mean serum LDH was 600.2 (±291.3), mean creatine kinase was 333 (±1105), mean serum sodium was 134 (±5.2), mean serum potassium was 3.48 (±1.0), Mean prothrombin time was 16.7 (±6.02), mean activated partial thromboplastin time was 34.6 (±11.5), mean INR was 1.40 (±0.69), mean prothrombin index was 82.5% (±19.6) [Table 5].
Table 5: Different laboratory parameters in DVT patients

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Of the 129 patients who completed the follow-up, 16 (24.6%) in the D-dimer group and 25 (39%) in the control group had deep vein thrombosis, for an overall prevalence of 31.78%. Fifty six (43.41%) were categorized likely to have deep vein thrombosis; 26 of these patients (46.42%) had proximal vein thrombosis. Seventy three were categorized as unlikely to have deep vein thrombosis; 15 of these (20.54%) had proximal deep vein thrombosis. These rates include events that occurred during the three month follow-up [Figure 1] and [Figure 2].

Of the 64 control patients who completed follow-up, 36 were categorized as unlikely and 28 as likely to have deep vein thrombosis. Ten patients in the former had deep vein thrombosis (27.7%), of which 2 occurred during follow-up (5.5%). These both events occurred on days 31 and 35 after initial presentation.

Of the 28 control patients categorized as likely to have deep vein thrombosis, 15 (53.5%) had deep vein thrombosis: 13 had deep vein thrombosis at presentation, 2 had at the one-week repeated ultrasound examination. Overall, in the control group 4 of the 43 patients (9.3%) in whom deep-vein thrombosis was initially considered to have been ruled out had confirmed deep-vein thrombosis on three month follow-up.

Of the 65 patients assigned to the D-dimer group who completed follow-up, 37 were categorized as unlikely and 28 as likely to have deep-vein thrombosis. Five patients in the former group had deep-vein thrombosis (13.51%), one of which occurred during follow-up (3.7%). Twenty seven patients (41.5% of the entire D-dimer group) had a negative D-dimer test and therefore did not undergo ultrasound testing. Five of these patients returned during follow-up: 1 with suspected pulmonary embolism and 4 with suspected deep-vein thrombosis. One of these patients had deep-vein thrombosis on 1 week of follow-up. Ten patients had a positive D-dimer test and underwent ultrasound imaging, which confirmed proximal deep-vein thrombosis in 4 patients and was negative in 6, none of whom subsequently had deep-vein thrombosis. The negative predictive value of the D-dimer test was 96.2%, and the positive predictive value was 40%.

Of the 28 patients in the D-dimer group who were categorized as likely to have deep-vein thrombosis, 11 had deep vein thrombosis, 10 at presentation and 1 at the one week repeated ultrasound examination. Five patients returned during follow-up: all with suspected deep-vein thrombosis, none of which proved later. The positive predictive value of the D-dimer test was 72.33% and negative predictive value was 61.53%.

Among all patients who underwent D-dimer testing, one (1.53%), in whom deep-vein thrombosis was initially ruled out had deep-vein thrombosis during follow-up.

Rates of various thrombo embolic events on follow-up in D-dimer group and control group was statistically not significant (1.53% vs 3.12%) (P >0.05). The mean number of ultrasound per patients was 1.23 in the control group and 0.66 in the D-dimer group.

In D-dimer group no. of cases with proximal vein thrombosis of lower limb was 6 (46.1%), distal vein thrombosis 2 (15.3%) and both 5 (38.4%). In control group, proximal vein thrombosis was seen in 16 (72.7%) distal vein thrombosis in 2 (9%) and both 4 (18.1%). Over all proximal vein thrombosis was seen in 22 (62.8%), distal in 4 (11.4%) and both in 9 (25.7%).

Overall, the sensitivity and specificity of D-dimer in diagnosis of deep venous thrombosis was 97.4% and 85.9%, respectively. The positive and negative predictive value of D-dimer was 77.6% and 98.5%, respectively. The positive and negative likelihood ratio of d dimer was 6.90 and 0.03.

The sensitivity and specificity of Doppler USG in deep venous thrombosis was 86.5% and 100%, respectively. The positive and negative predictive value was 100% and 91.9%, respectively.

The sensitivity and specificity of D-dimer in diagnosis of deep venous thrombosis in cancer patients was 54.5% and 58.5%. The positive and negative predictive value of D-dimer in cancer patients was 10.9% and 93.2%.


   Discussion Top


Venous Thromboembolism (VTE) is associated with substantial morbidity and mortality. The clinical signs and symptoms are non-specific, widely varying from asymptomatic to sudden death of all patients presenting with symptoms suggestive of DVT, only 30% actually have the disorder. In Accidental Emergency room, it is critical to identify the patients with DVT promptly and the diagnostic methodology used should be accurate and safe, since 70% of patients with the symptoms will not have DVT. However, the predictive sensitivity of assessment increases to 70% if the risk factors and alternative diagnosis are incorporated into a pretest clinical assessment. [6] We also used one such pretest clinical model in our patients to increase outcome of the test.

The diagnostic algorithm of VTE is an evolving field ranging from gold standard of venography to non-invasive tests like real time B-mode venous compression USG. However, the sensitivity of most of these tests is 73% at best to detect Calf vein Thrombosis, thus a need to repeat the test on follow-up which involves risk of VTE and cost of the repeated test. To solve this problem, role of D-dimer has been evaluated as screening test for diagnosing DVT, since D-dimer is a telltale clue of the initiation of blood clotting in the body. [7] We also put forth the hypothesis that the use of D-dimer in our patient population with suspected DVT, will limit the use of repeat USG without compromising safety and accuracy.

In our study, most of patients were in the age group of 31-60 years with disease occurrence rarely in late adolescence [13],[14] which is consistent with previous studies. The mean duration of symptoms in our study population has been 12-21 days (D-dimer and control group, respectively) which is higher than that documented in previous studies. [15] This could be because our patients took time to reach the only tertiary care hospital due to lack of the diagnostic facility in the periphery in this part of world. The risk factors like malignancies were found in 19.6% of patients, which is similar to previous studies (20%). [16],[17],[18] Among malignancies GI tract cancers followed by Ca-Ovary, renal cell carcinoma, CA prostate and NHL were encountered which is consistent with the previous studies. We found 15.6% of patients were immobilized due to surgery and caused DVT. This is also similarly documented in literature. [1],[17],[18]

In our study, proximal vein thrombosis seen in 22 (62.8%), distal in 4 (11.4%) and both in 9 (25.7%); previous study revealed the same findings. [19]

We have documented that in patients presenting with suspected deep vein thrombosis, a diagnostic protocol using D-dimer testing and clinical judgment to select patients for ultrasound imaging is as safe and feasible as a protocol combining clinical judgment with USG imaging for all. The addition of D-dimer to a diagnostic algorithm has the potential to make the diagnosis of deep vein thrombosis more convenient and economical even in the outpatients. In patients who are considered clinically unlikely (by Well's model) [2] to have DVT and who have a negative D-dimer test, the diagnosis of DVT can safely be excluded without the need for further diagnostic testing. Use of the D-dimer testing also reduces the need for repeated USG testing in patients who are likely to have deep vein thrombosis and establishes a definitive diagnosis on the very day of presentation in a larger proportion of patients. In patients with suspected DVT the diagnostic protocol that have been proved safe and economical, have used repeated USG testing and pretest clinical probability estimation with USG. Several previous studies have revealed that the high negative predictive value of D-dimer testing in our patients with suspected deep vein thrombosis may be used as a part of diagnostic algorithm. [20],[21],[22],[23] The value of combining clinical estimation of probability with imaging tests has been confirmed in many studies. [24],[25],[26] However, only a few studies have compared these strategies in randomized fashion.

Our study demonstrates that the use of D-dimer testing to rule out DVT benefits from clinical probability. This shown by finding that the negative D-dimer results in patients who were unlikely to have DVT eliminated the need for USG testing in over 41.5% of the patients in D-dimer group. In the group judged likely to have DVT, we were able to limit the need for a repeat USG test to the patients with D-dimer test positive. Moreover, this strategy has the additional advantage of increasing proportion of patients who will have a positive result on the repeat test.

Venous Thromboembolism developed on follow-up in only 1 patient in each group in whom DVT was ruled out. There was no significant difference in thrombo embolic phenomenon on follow-up between two groups. Hence, the safety by utilizing the D-dimer test was not compromised. This safety has also been revealed in large trials reported in literature. [2],[27],[11],[20]

Also the overall number of USG examinations was reduced to 0.67 tests per patient in D-dimer group compared to 1.23 in control group. This has a great economic impact without compromising safety. This is in agreement with observation in literature.

Our study has a limitation; we used D-dimer latex agglutination assays (qualitative) assessment for confirmation of deep-vein thrombosis which has a sensitivity of only 80%. However, even by qualitative assessment we can easily rule out deep-vein thrombosis in those patients who are categorized as unlikely to have deep-vein thrombosis on Well's Scoring System.

The sensitivity and negative predictive value for D-dimer were 97.4% and 98.5%, respectively, similar with previous studies. [12],[26],[28],[29]

In our study, the sensitivity and specificity of D-dimer in diagnosis of DVT in cancer patients was 54.5% and 58.5%. The positive and negative predictive value of D-dimer in cancer patients was 10.9% and 93.2%; in previous studies negative predictive value of D-dimer test was 100% and 97% among cancer patients with low pretest probability (PTP) score. [10],[30]

Hence, incorporating D-dimer testing into a diagnostic strategy with clinical estimation of pretest probability and USG imaging simplifies the diagnosis of DVT without compromising the safety.

 
   References Top

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26.Anderson DR, Wells PS, Stiell I, MacLeod B, Simms M, Gray L, et al. Management of patients with suspected deep vein thrombosis in the emergency department: Combining use of a clinical diagnosis model with D-dimer testing. J Emerg Med 2000;19:225-30.  Back to cited text no. 26
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27.Bockenstedt P. D-dimer in venous thromboembolism. N Engl J Med 2003;349:1203-4.  Back to cited text no. 27
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28.Kelly J, Hunt BJ. 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.  Back to cited text no. 28
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29.ten Wolde M, Kraaijenhagen RA, Prins MH, Büller HR. The clinical usefulness of D-dimer testing in cancer patients with suspected deep venous thrombosis. Arch Intern Med 2002;162:1880-4.  Back to cited text no. 29
    
30.Di Nisio M, Rutjes AW, Büller HR. Combined use of clinical pretest probability and D-dimer test in cancer patients with clinically suspected deep venous thrombosis. J Thromb Haemost 2006;4:52-7.  Back to cited text no. 30
    

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Correspondence Address:
Davinder Pal Singh
Department of Medicine, Sher-I-Kashmir Institute of Medical Sciences Soura, Srinagar - 190 011, Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.105121

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