| Background:Deep venous thrombosis (DVT) is a condition in which a blood clot forms in one or more of deep veins. According to Virchow’s triad theory, deep venous thrombosis occurs when bloodstream slows down, vascular wall injures or blood thickens. The typical symptoms of DVT include pain, heaviness, and cramps in the lower extremity.In recent years, although great progress has been made in diagnosis, treatment and prophylaxis of DVT, the incidence is on the rise. The presentation of deep vein thrombosis can vary greatly and clinical signs and symptoms are non-specific, which makes diagnosis challenging.As nearly 60% of undiagnosed deep venous thrombosis may be complicated with fatal pulmonary embolism, and some of patients eventually lead to Post-thrombotic Syndrome, which constitute a major healthcare problem.Timely and accurate diagnosis and treatment must be undertaken rapidly to avoid potentially fatal pulmonary embolism.The diagnosis of deep vein thrombosis is based on confirmatory imaging modalities.Doppler ultrasound is widely used due to its simplicity and non-invasive.However, the Doppler ultrasound has been found to have sensitivity and specificity for diagnosis symptomatic DVT of the proximal lower extremity, but for detection of thrombosis in proximal veins in asymptomatic or calf vein thrombosis patients, its reported summary specificities were generally low, ranging from 47% to 62%.In addition, ultrasound of the leg vein is not recommended as a first-line imaging investigation in patients presenting with symptoms and/or signs of PE and DVT in NICE guideline(2012).The diagnosis of DVT need Computed Tomography or venography and other imaging modalities. However.such imaging modalities are not always available and cannot widely used due to its invasiveness and expensiveness. It was reported the prevalence of deep vein thrombosis in suspected patient was only around 20～30%, suggesting that doctors have a low threshold for diagnostic testing. If all of suspected patient is requested to subject to these imaging modalities, the result has been an increased number of diagnosed DVTs but at less efficient use of resources and increased cost.With these considerations in mind, it is particularly important to make reasonable diagnosis strategy of DVT, reducing miss rate and narrow down the suspecteds. For the purpose mentioned above,NICE guideline recommended to developed clinical probability scores based on history and physical examination for predicting the probability of deep venous thrombosis before confirmation by objective testing.An increasing clinical probability score was associated with a higher probability of deep vein thrombosis. The clinical probability scores incorporate sign, symptoms, and risk factors to categorize patients as low, moderate or high probability for DVT and thus help determine the need for further workup. The most widely used clinical probability score is probably that developed by Wells and colleagues, and then various score have been developed to improve the clinical investigations for suspected deep venous thrombosis, including St.Andre score, Kahn score and Constans score. The clinical probability scores were developed by Western countries according to their ethnic features, disease spectrum and other different factors.Concerns have been raised that clinical probability scores may not be as safe and effective in Chinese patients.Studies confirmed that clinical probability scores can improve the efficiency of early dection and reduce the invasive examination and medical expense. However, whatever the clinical probability score may not be an accurate diagnosis method. It is recommended to clinical probability score combine other method in order to provide the most value in diagnosis.As the product of the fibrin degradation-dimer is an important biomarker to reflect the state of coagulation and fibrino lysis. Measurement of D-dimer may improve diagnostic strategies, but the test has many false-positive results.There is growing evidence that inflammation play an important role in thrombosis. The internal relation between thrombosis and inflammation has become one of the hot topics recently, considering as the pioneering extension of Virchow’s triad. On the one hand, inflammation can induce hypercoagulation:lab studies have demonstrated that the imbalance between pro-and anti-inflammatory activities promoted thrombus formation not only through its involvement in the coagulation cascade but also through deterioration of endothelial function. It has also been demonstrated that leukocyte adhesion and transmigration are the early events in the initiation of DVT. On the other hand, thrombosis burden can cause inflammation: Thrombosis may influence the expression of inflammatory cytokines and adhesion molecule, thus providing a trigger that may lead to local inflammatory response. It remains unclear if inflammation proceeds and promotes the development of hypercoagulable state, or rather a consequence of hypercoagulable state.Beside D-dimer testing, other laboratory biomarkers of inflammation (as indicated by C-reactive protein [CRP]) and biomarkers of prothrombotic state in DVT that represented platelet activation (P-selectin levels) and coagulation (fibrinogen) may be associated with deep vein thrombosis.And there are no current laboratory biomarkers or combination of laboratory biomarkers and clinical probability scores that can confirm the diagnosis, when ultrasound is unavailable.Acute proximal lower-extremity deep venous thrombosis is recognized as a cause of both PE and post-thrombotic syndrome. Therefore, an immediate treatment once diagnosed, prompt treatment is needed. Early thrombus removal is a logical approach.CDT involves a localized delivery of thrombolytic agents directly into the thrombus and may be effective in achieving local resolution and restoring venous patency while significantly reducing the risks of systemic bleeding complication. If predictors of successful thrombolysis can be identified during the early phase after starting the CDT, greater patient benefit might be expected by eliminating the necessary exposure to radiation from surveillance angiography and additional dose of contrast agents. In addition, the imaging modalities cannot judge whether the body is in the state of fibrinolysis or thrombolysis, increasing the limitations of monitoring development of DVT. Knowledge of predictive variables of CDT in acute DVT patients was crucial. The activities of coagulation and fibrinolysis are high after thrombosis, activation of the inflammatory response has been observed at the same time. Laboratory bio markers of coagulation (as indicated by D-dimer) and biomarkers of prothrombotic state in DVT that represented platelet activation (P-selectin levels) maybe associated with deep vein thrombosis and prospectively predict success or failure of catheter-directed thrombolysis for acute lower-extremity deep venous thrombosis. However, little research has been designed to investigate the changing pattern of serum concentration of D-dimer and P-selectin during catheter-directed thrombolysis in patients with acute proximal lower-extremity deep venous thrombosis and its related clinical significance.Using ROC curve, the diagnostic sensitivity、specificity、positive predictive value (PPV) and negative predictive value (NPV) for each of the studied clinical probability scores and laboratory biomarkers in current study were done. The aim of the study was evaluate the predicting value of clinical scores systems (Wells, St.Andre, Kahn and Constants scores) and laboratory biomarkers of hypercoagulability and inflammation (D-dimer, P-selectin,C-reactive protein and fibrinogen) for the diagnosis of deep venous thrombosis. We have to standardized medical practices and perfect the medical care system to improve the diagnostic accuracy and bring down the medical expense, avoiding medical resources waste. In addition, the purpose of the present study was also to identify whether D-dimer and P-selectin could be a potential predictor of successful thrombolysis undergoing catheter-directed thrombolysis.Part one. Predicting value of various clinical probability scoresandlaboratory biomarkersfor diagnosis of lower limb deep venous thrombosisObjective To evaluate the performance of clinical scores systems (Wells, St.Andre, Kahn and Constants scores) and laboratory biomarkers of hypercoagulability and inflammation (D-dimer, P-selectin,C-reactive protein, and fibrinogen) for the diagnosis of deep venous thrombosis.MethodsA total of 176 patients suspected with deep venous thrombosis was prospectively blinded evaluated with the four clinical-score systems and laboratory biomarkers. Sensitivity, specificity, PPV, NPV and ROC were calculated for four clinical scores and four laboratory biomarkers according to the results of Doppler ultrasound and/or Computerized Tomography, venography.Results Doppler ultrasound and/or Computerized Tomography, venography evidenced deep venous thrombosis in 51 out of 176 patients.(1)The sensitivity, specificity,PPV, NPV, Youden index was 100%,16.8%,32.9%,100%,36.8%, respectively, for Wells score; 11.7%,88.8%,30.0%,71.1%,0.5%, respectively,for St.Andre score;21.6%,89.6%,45.8%,73.7%,11.2%,respectively,for Kahn score;96.1%,75.4%,42.2%,96.7%,42.5%, respectively.for Constans score.ROC was 0.796 for Wells score, then followed by Wells score(0.697),Kahn score(0.600) and St.Andre score(0.516).(2)The concentration of D-dimer and P-selectin [(16.58±14.79)μg/mL、(134.30±46.68) ng/mL]in DVT group were significant higher than that in non-DVT group[(5.05±19.81)μg/mL、(80.86±29.61)ng/mL](P< 0.05).There were no significantly different of CRP and FIB in DVT and non-DVT group (P>0.05). (3)Making 0.5μg/mL of D-dimer as the criterion, of 176 suspected patients for DVT,110 cases with a positive D-dimer testing and 46 (41.8%) of them with a definite diagnosis as DVT,66 with a negative D-dimer testing and 5 (7.57%) of them with a definite diagnosis as DVT.Making 92.6ng/mL of P-selectin as the criterion, of 176 suspected patients for DVT,75 cases with a positive P-selectin testing and 44 (58.67%) of them with a definite diagnosis as DVT.101 with a negative P-selectin testing and 7 (6.93%) of them with a definite diagnosis as DVT.The sensitivity, specificity,PPV, NPV, Youden indexwas 90.1%,48.8%,41.8%,92.4%, 38.9%, respectively, for D-dimer testing; 86.2%,75.2%,58.7%,93.1%,61.4%, respectively, for P-selectin testing.ROC was 0.825 for D-dimer testing, which was similar as that of P-selectin testing (0.851). (4) The combination of Wells score and D-dimer:the sensitivity, specificity,PPV, NPV, Youden index was 100%,18%,34.5%, 100%,18.0%, respectively,for parallel combined testing to diagnosis with DVT;90.1%,67.6%,50.0%,94.0%,57.7%,respectively, for series combined testing to diagnosis with DVT.The combination of Wells score and P-selectin:the sensitivity, specificity,PPV, NPV, Youden index was 100%,27.7%,37.0%,27.7%, respectively,for parallel combined testing to diagnosis with DVT; 86.2%,84.3%, 65.7%,93.6%,70.5%, respectively,for series combined testing to diagnosis with DVT.The combination of Constans score and D-dimer:the sensitivity, specificity,PPV, NPV, Youden index was 99.6%,22.6%,33.0%,96.2%,22.2%, respectively,for parallel combined testing to diagnosis with DVT; 86.2%,84.3%,59.2%,94.0%, 59.2%, respectively, for series combined testing to diagnosis with DVT.The combination of Constans score and P-selectin:the sensitivity, specificity,PPV, NPV, Youden index was 99.4%,34.9%,37.0%,97.6%,34.3%, respectively,for parallel combined testing to diagnosis with DVT; 82.8%,86.7%,76.8%,93.3%,69.5%, respectively, for series combined testing to diagnosis with DVT. Using multivariable regression, ROC of above four combinations of clinical probability scores and laboratory biomarkers was 0.818,0.879,0.891 and 0.922, respectively.ConclusionOur results showed that Wells score and Constans score are superior to St.Andre and Kahn score, and P-selectin is similar to D-dimer for the diagnosis of DVT. The Constans score combined with P-selectin presented the best combination. With a suspicion of DVT,a high Constans score (≥2) and P-selectin above 92.6ng/mL could establish for the diagnosis of DVT.Part two. The clinical significance of D-dimer and P-selectin monitoring during catheter-directed thrombolysis for acute proximal lower-extremity deep venous thrombosisObjectiveTo investigate the changing pattern of serum concentration of D-dimer and P-selectin during catheter-directed thrombo lysis (CDT) in patients with acute proximal (ilio-femoral vein) lower-extremity deep venous thrombosis (DVT), and its related clinical significance.MethodsTwenty-three patients with acute proximal (ilio-femoral vein) lower-extremity DVT who received CDT from March 2015 to December 2015 were enrolled in this study. Those patients who were eligible for enrollment had documented symptoms of lower extremity swelling and/or pain,had proximal deep vein thrombosis(ilio-femoral vein).The diagnosis of DVT was confirmed by the Doppler ultrasound and/or venography findings. In all patients, anticoagulation was started with started with subcutaneous low molecular weight heparin.Warfarin was routinely started prior to hospital discharge and this was continued for at least 6 months. The dose was adjusted to maintain an international normalized ratio of 2.0-3.0. A 6-Fr multiple-side-hole infusion catheter was then gently inserted with the tip embedded in the proximal extent of the thrombus, and the catheter infusion holes were positioned within the substance of the thrombus. Urokinase was infused through catheter. Serum concentration of D-dimer and P-selectin were measured before, during CDT and after CDT in all subjects, respectively.Results DVT patients were divided into recanalization group (n=14 and un-recanalization group (n=7) based on the effect of CDT. Before CDT, There were no significantly different between the concentration of D-dimer and P-selectin in recanalization group and un-recanalization group[(20.49±13.61)μg/mL、 (141.54±41.69) ng/mL VS (18.84±9.22)μg/mL、(174.54±67.88) ng/mL, P>0.05]. In recanalization group, the concentration of D-dimer increased significantly(P<0.05), whereas the concentration of P-selectin did not change significantly at the 24h of CDT (P>0.05). In un-recanalization group, there was no significant change of the D-dimer (P> 0.05),whereas the concentration of P-selectin in increased significantly(P<0.05) at the 24h of CDT. Correlation analysis showed correlations of D-dimer and P-selectin with the effect at the 24h of CDT(rl=0.58, r2=-0.67, P<0.05).ConclusionsDetection of the concentration of D-dimer and P-selectin is valuable to evaluate and predict the effectiveness of CDT in acute DVT patients. |
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