Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary thrombo-embolism (PTE), carries significant mortality and morbidity. As a result of the increasing awareness and improvement in diagnostic facilities, the hospital admissions have increased dramatically in China. Recent publications have reported the increasing incidences of PTE and DVT in hospitalized patients.1-3 A national project of multicenter studies on VTE has been carried out since 2002 by China Venous Thromboembolism Study Group. A broad spectrum of research including the epidemiology, diagnosis, management, and basic research of PTE and DVT was carried out in the past 10 years. We briefly summarized the current research on VTE in this group.
CLINICAL EPIDEMIOLOGICAL STUDIES OF VTE
It is necessary to identify the high risk patients for VTE for the purpose of reducing VTE incidence. Medical illness and surgery account for equal proportion of VTE. Traditional independent risk factors for VTE include advanced age, surgery, trauma, confinement (in patients with stroke, heart failure and intensive care), active cancer, hormone therapy and pregnancy.
The predictive values of different risk factors are different; this may influence the physicians’ decision for preventing the event. Clinical manifestations and risk factors in 388 patients with DVT were studied by Sun et al,3 and 80.4% of the patients with DVT were involved with risk factors. Advancing age (>40 years, 88.9%), heart disease (43.0%), hypertension (35.1%), long-term immobilization (21.1%) and infection (20.1%) were regarded as common risk factors.
A perspective study of 488 cases of acute stroke was also reported by Sun et al.4,5 The prevalence of DVT was 21.7%. In a multivariate analysis, the results suggested that old age, female, bedridden and high DVT assessment scores >2 were independent risk factors for DVT in acute stroke. A cross-sectional study was carried out to observe the prevalence, incidence and risk factors of DVT in patients from intensive care unit (ICU).6 The incidence of DVT was 11.90% within 48 hours, and 26 patients (15.12%) had new episodes of DVT in the 10-14 days follow-up.
Active cancer accounts for almost 20% of incident VTE events occurring in the community. Risk factors of VTE in cancer include aging, cancer progression and cancer-related operation, as well as other factors such as long time in bed, chemotherapy and central vein catheterization. It should be watchful of PTE in cancer patients undergoing operation, especially within the first two postoperative weeks.7 Clinical manifestation of VTE in cancer patient is often atypical. Sometimes VTE is the first signal of malignancy.
A post hoc analysis was used to identify the risk factors of DVT in PTE by Yang et al.8 The data showed that oedema of lower-limb, phlebitis and calf swelling >1 cm seemed to be risk factors for DVT.
CLINICAL MANIFESTATIONS AND DIAGNOSTIC INVESTIGATIONS OF VTE
Descriptive studies of clinical manifestations of PTE
Descriptive studies of clinical manifestations of PTE were mainly based on the database including 516 cases of PTE from 50 hospitals over 20 provinces in China.9,10 The clinical manifestations of acute PTE are dyspnoea, chest pain and cough; haemoptysis is not common. Tachypnea is the most frequent sign. Other signs such as cyanosis, P2 accentuation, syncope, systemic hypotension, shock, can be found more frequently in massive and sub-massive PTE, but not in non-massive PTE, which is classified according to PTE guideline in China.11,12 However, the clinical features of elderly patients are not typical because of the complications, which need more attention in clinical practice.
Diagnostic evaluations of different imaging techniques in VTE
The importance to standardization of medical imaging diagnosis in VTE should be attached.13 Lung ventilation/quotient (V/Q) image, CT and echocardiography are the most popular diagnostic technique for PTE; ultrasound of legs is the most common diagnostic modalities for DVT.
Since the introduction of CT pulmonary angiography (CTPA), the field of PTE has been growing by leaps and bounds and is now an established discipline. CTPA is now carried out as a routine examination in every major medical center throughout China with a very respectable complication rate. Clinical scoring system combined with multi-detector CTPA has been explored to determine whether acute PTE can be quantitatively predicated.14 A total of 570 consecutive inpatients with highly suspected PTE underwent prospective CTPA at the time of initial diagnosis. Three clinical predication scoring systems (Wells’, Geneva's and revised Geneva's) were used to estimate PTE in low, moderate and high probability groups. The threshold value for the prediction of PTE by the 3 scoring systems was measured. The 3 scoring systems can be used for both inpatients and emergency cases, while the Wells’ score system might be more accurate for predicting PTE.
Echocardiography is very important for the evaluation of diagnosis, clinical outcome and the prognosis of VTE. It provides useful markers to evaluate the right ventricular function, which is necessary for risk stratification of PTE. Right ventricular dysfunction (RVD) is the main difference between intermediate risk and low risk PTE. PTE combined with RVD is also a potential indication for thrombolytic therapy. Zhu et al15-17 analyzed the RVD in PTE. A multiple Logistic regression model implied that the increased right/left ventricular end-diastolic diameter ratio (RVED/LVED) and systolic pulmonary artery pressure (SPAP) might be independent predictors of adverse 14-day clinical outcomes. The cut-off values of RVED/LVED and SPAP were 0.67 and 60 mmHg, respectively. Hemodynamic instability, 14-day clinical outcome, and SPAP were independent harbingers for 3-month outcomes. The changes of right ventricular function on echocardiography showed a broad spectrum after different therapeutic strategies of acute PTE. Change of echo parameters after treatment might be important to identify the patients with persistent pulmonary hypertension which possibly developed chronic thromboembolic pulmonary hypertension (CTEPH) in the long-term follow-up.
CLINICAL TRIALS OF DIFFERENT MANAGEMENT STRATEGIES FOR VTE
The improvement of management of VTE reflects the change in the recognition of aetiologies and the awareness of PTE in modern China over the past decade. Recombinant tissue-type plasminogen activator (rt-PA) and urokinase (UK) and streptokinase have recommended for thrombolytic therapy for acute massive PTE. Optimal dosing of the rt-PA is important in treating PTE. Wang et al18 compared the efficacy and safety of rt-PA 50 mg/2 h regimen with 100 mg/2 h regimen in acute PTE patients in a prospective, randomized, multicenter trial. Progressive improvements in RVD, lung perfusion defects and pulmonary artery obstructions are found to be similarly significant in both treatment groups. Compared with the 100 mg/2 h regimen, 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating the PTE patients.
In the second trial, we demonstrated that UK-2 h regimen, a much lower dose (20 000 IU/kg) than those used in previous trials (3 million IU/2 h),19 produced similar improvements in pulmonary circulation and right heart dysfunction as the UK-12 h regimen. This study demonstrated that UK-2 h regimen displayed similar efficacy and safety as the UK-12 h regimen in treating acute PE with either hemodynamic instability or massive pulmonary artery obstruction. Given the convenience, lower cost, we suggest that body weight adjusted UK-2 h regimen can be used for PE treatment.
The efficacy, safety and cost of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) were compared in a separate study. We found that both heparin and low molecular heparin are effective, with the same clinical outcome and low adverse effect rate on acute massive PTE. A meta-analysis20 was performed to evaluate the efficacy and safety of LMWH and UFH as the initial treatment. The author concluded that initial subcutaneous therapy with the LMWH appeared to be as effective and safe as intravenous UFH in the initial treatment of PTE. LMWH is more convenient for clinical practise which makes it possible for home treatment.
DVT might show various response to different therapy compared with PTE. The effect of DVT in acute PTE after thrombolytic and anticoagulant therapy was analyzed.21 The normalization rate of DVT is low during 14-day treatment, and recurrence rate is high. The results after three months follow-up showed that new asymptomatic recurrent DVT was found in 10.4% patients.
Interventional therapies or Amplatz catheter thrombus ablation is optional for acute PTE with contraindication of thrombolytic and anticoagulatory therapy, or unsuccessful cases. Pulmonary thromboendarterectomy is a good choice for CTEPH after comprehensive evaluation. Ren et al22 evaluated the improving reliability and safety of pulmonary thromboendarterectomy and perioperative management for CTEPH. The outcome of the surgical procedure needs to be further investigated according to an evaluative system.
BASIC AND TRANSLATIONAL RESEARCH ON VTE
Genetic polymorphisms in the evaluation of VTE
Inherited abnormalities of the hemostatic system predispose to thrombosis, and are termed inherited thrombophilias. Molecular epidemiology research has been carried out. The prevalence of prothrombin 20210G/A mutation in the general population is estimated to be 2.3% for its heterozygous form. However, the prothrombin G20210A mutation is very rare in China.23 It implies that the variant of the prothrombin gene is probably not the main cause of VTE in the Chinese population.
Carriers of the A allele of the fibrinogen -455G/A polymorphism have increased plasma fibrinogen levels. Studies of fibrinogen polymorphism have been performed mainly among Caucasians. The association between beta-fibrinogen gene -455G/A, -148C/T polymorphisms and VTE in Chinese Han population had been investigated.24 The presence of A allele of fibrinogen beta -455 was found to be a greater risk factor in cases than in controls. Complete linkage disequilibrium was found between fibrinogen beta -148C/T and -455G/A mutation.
PAI-1 is the principal inhibitor of tPA and urokinase (uPA), the activators of plasminogen and hence fibrinolysis. The prevalence of polymorphisms in the PAI-1 promoter 4G/5G polymorphisms in Chinese Han population and the association with PTE had been determined.25 The author also concluded that the presence of 4G allele of PAI-1 gene was found to be a greater risk factor for PTE, and the 4G/5G and 4G/4G genotypes were associated with the pathogenesis of PTE.
Endothelial cells normally have an antithrombotic effect, largely due to membrane-bound thrombomodulin (TM) and endothelial protein C receptor (EPCR). A case-control study in patients with PTE and CTEPH has been performed to test our hypothesis that the subjects with the polymorphisms of the genes of TM (-33 G/A and 1418 C/T) might carry higher risks of venous thrombosis formation, leading to acute PTE and CTEPH.26
VKORC1 and CYP2C9 are important genetic factors affecting warfarin dose requirement. In the Chinese Han population, patients with PTE allele frequencies of CYP2C9*3 C.1075A>C (rs1057910), 13 c.269T>C and VKORC1 -1639G>A (rs9923231) were 4.3, 0.7 and 8.6%, respectively using amplification refractory mutation system (ARMS) assay.27
Plasma biomarkers in the development of venous thromboembolism
It is useful to have valuable biomarkers to enable early identification of high risk of VTE and allow the diagnosis and treatment assessment. The changes of blood coagulative and fibrinolytic system and the function of pulmonary vascular endothelium are possible indicators to evaluate the course of acute PTE and after anticoagulant or thrombolytic treatment.
The plasma level of D-dimer, TM, protein C (PC), protein S(PS), t-PA, PAI-1, and antithrombin (AT) activity were measured.28,29 Apparent imbalance in the blood coagulative and fibrinolytic system and pulmonary vascular endothelium damage occur in the patients with acute PTE. The plasma concentrations of TM, PC and PS and the association between those plasma markers and the risk of PTE were determined in a prospective study.30 A positive linear correlation was found between plasma TM concentration and age in female patients.
Peng et al31 evaluated the plasma levels of endothelin-1 (ET-1), t-PA, PAI-1, AT and D-dimer and the blood serum levels of nitrogen monoxide (NO) in the patients with PTE at different time points before and after therapies. ET-1 and D-dimer changed significantly after thrombolytic therapy, while ET-1, NO and AT showed dramatic change after anticoagulation therapy. Zhang et al32 investigated the changes of serum cardiac troponin I (TnI) in patients with acute PTE. The increase of serum TnI is correlated with pulmonary artery pressure, right ventricular function and the prognosis of the PTE. These changes may be useful in the risk stratification of PTE patients.
Exploring new method for specific biomarkers might provide high sensitivity and specificity in discriminating patients with VTE. The discovered biomarkers might show great potential for early diagnosis of thromboembolic diseases.
Animal models and translational research of VTE
Animal models provide a bridge between clinical and the laboratory bench. Different animal models of experimental VTE have been used to investigate mechanisms of thrombosis. Most are based on reproducing in animals known risk factors for thrombosis. None of these models fully reproduces the features of human VTE.
Animal model of PTE for thrombolytic therapy evaluation
A canine model of PTE for evaluating the effects of thrombolytic therapy was established.33 The preparations of radioactive blood clots in vitro were made from fresh whole blood (from 6 donors) mixed with 99mTc-SC. The canine model of PTE was induced by these clots. This canine model was also used to compare the thrombolytic effects of the two dosing regimens with UK.34 There was a thrombolytic peak in the UK-2 h group at the first four hours after infusion of agent. For the fresh thrombi, the UK-2 h regimen is superior to the UK-12 h due to its higher thrombolytic ratio and prompt thrombolytic property. Wang et al35 compared experimental canine PTE treatment effects among domestic recombinant single-chain urokinase-type plasminogen activator (scu-PA), rt-PA, and heparin. The effects of domestic recombinant scu-PA in experimental PTE resemble that of rt-PA in terms of the improvements of hemodynamic and angiography, better than heparin.
Animal models for pathology and pathophysiology investigation
Wu et al36 evaluated the effect of acute multiple microthromboembolism on circulation, ventilation, lung histology, and the coagulatory and fibrinolytic functions. The authors found that multiple microthromboembolism caused lung injury and thrombosis. Pulmonary artery pressure was increased at the early stage, but ventilation was not affected. The level of D-dimer changed at the early stage.
The level of mRNA and protein of the pulmonary surfactant-associated protein-A (SPA) might reflect the natural history of PTE. Liu et al37,38 explored the effect of LMWH on the changes of SPA of rats in acute PTE. The lung SPA decreases significantly in acute PTE and LMWH can increase the SPA, which may be one of mechanisms of LMWH in treatment of PTE. Ji et al39,40 established a rat model of VTE. The successful rate of VTE can be increased when thrombin is slowly injected from the distal end of femoral vein blocked by micro-clip in addition. The age and nature of thrombi before the embolization were related to the outcome of emboli, alterations of pulmonary arterial intima well as in femoral veins.
In animal models the ischemia-reperfusion injury is found to be relevant with apoptosis induced by neutrophils, and the exudation of inflammatory cells and protein are involved. Deng et al41 explored the effects of polymorphonuclear cells (PMN) on lung ischemia reperfusion (I/R) injury in a canine model of PTE. PMN with enhanced activities and decreased apoptosis rate, were involved in the cellular mechanisms of the lung I/R injury in this model of PTE.
Animal models of thromboembolic pulmonary hypertension
The effects of different durations of thromboembolism in an animal model mimicking CTEPH were evaluated.42 In the two-week group, the well organized thrombi were partially re-canalized and surrounded and invaded by hyperplastic tissues from pulmonary artery wall. Different manifestations on pulmonary arteriography and varied degree of organization of thrombi were evidences at different time after embolization.
In terms of the basic and translational research of CTEPH, the effect of ion channel and Ca2+ in human pulmonary artery smooth muscle cells (PASMCs) proliferation has been investigated in PAH and CTEPH models by Wang et al.43 Zhang et al44 investigated the pulmonary vascular remodelling. Significant changes were found such as the formation of new endomembrane, the main pathological change, and the molecular mechanisms include the abnormal ratio of MMP-9/TIMP-1, and the increased expression of monocyte chemo attractant protein-1 (MCP-1) and platelet derived growth factor-B.
The fibrinolytic function of endothelial cells plays an important role in the pathophysiology of pulmonary vascular diseases. Liu et al45 evaluated the effects of pro-urokinase, a new thrombolytic drug that is currently being tested for the treatment of PTE, on the expression of u-PA and u-PA receptor (u-PAR). They suggested that the combination of u-PA with u-PAR might be a critical pathway for the induction of u-PA expression.
VTE is a common problem in modern China. Great achievements have been made in VTE in the past 10 years. The risk factor, diagnosis, management and mechanisms of VTE have been better understood. Clinical trials of PTE, in particular, have shown remarkable advances, especially in managing VTE. Efficient prevention and therapy method have been developed to reduce morbidity and mortality of VTE. The research of the mechanisms, risk factors and therapeutic targets in the VTE has also provided us with a vital opportunity to reassess and recognize the disease.46
It should be mentioned that it might be difficult for us to make a full spectrum of VTE research in China. Other colleagues in different groups have also contributed significantly to the progress of VTE. We also emphasize that it is necessary to organize more and more multicenter, randomized, double-blind, placebo-controlled trials in the clinical studies. More clinical work and further studies should be done on VTE in the near future.
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