Is routine thromboprophylaxis justified among Indian patients sustaining major orthopedic trauma? A systematic review

Venous thromboembolism (VTE) is one of the most common preventable cause of morbidity and mortality after trauma. Though most of the western countries have their guidelines for thromboprophylaxis in these patients, India still does not have these. The increasing detection of VTE among Indian population, lack of awareness, underestimation of the risk, and fear of bleeding complications after chemical prophylaxis have made deep vein thrombosis (DVT) a serious problem, hence a standard guideline for thromboprophylaxis after trauma is essential. The present review article discusses the incidence of DVT and role of thromboprophylaxis in Indian patients who have sustained major orthopedic trauma. A thorough search of ‘PubMed’ and ‘Google Scholar’ revealed 10 studies regarding venous thromboembolism in Indian patients after major orthopedic trauma surgery (hip or proximal femur fracture and spine injury). Most of these studies have evaluated venous thromboembolism in patients of arthroplasty and trauma. The incidence, risk factors, diagnosis and management of VTE in the subgroup of trauma patients (1049 patients) were separately evaluated after segregating them from the arthroplasty patients. Except two studies, which were based on spinal injury, all other studies recommended screening/ thromboprophylaxis in posttraumatic conditions in the Indian population. Color Doppler was used as common diagnostic or screening tool in most of the studies (eight studies, 722 patients). The incidence of VTE among thromboprophylaxis-receiving group was found to be 8% (10/125), whereas it was much higher (14.49%, 40/276) in patients not receiving any form of prophylaxis. Indian patients have definite risk of venous thromboembolism after major orthopedic trauma (except spinal injury), and thromboprophylaxis either by chemical or mechanical methods seems to be justified in them.

M ajor orthopedic trauma (which includes spine, hip and pelvi-acetabular fractures; multiple long-bone fractures of the lower extremity) is a compelling risk factor for development of venous thromboembolism (VTE) and its potential sequelae pulmonary embolism (PE) 1 . Thromboprophylaxis by means of chemical and mechanical methods have significantly reduced morbidity and mortality in such patients. 1 Despite uncertainty about few aspects of VTE, the extensive research on this subject has helped many western surgeons to reach at some concrete conclusion; and as a result, 99% of them use thromboprophylaxis after trauma and elective orthopedic surgeries. 2 Thromboprophylaxis after trauma is still not widely practiced in India, 3 the cause of which can be attributed to lack of awareness, underestimation of the problem, fear about thromboprophylaxis complications and most importantly the popular belief among surgeons that Indians have low incidence of deep venous thrombosis (DVT). Contrary to previous belief, most of the recent studies show increasing incidence of VTE among the Indian and Asian population, and it is almost equivalent to that reported in Caucasians. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Nandi et al. while reviewing the Chinese literature found an increasing incidence of VTE among the Chinese population, and they placed the orthopedic surgery of the lower limbs in the high-risk group. 18 Similarly among the Japanese population, the rate of incidence of VTE after arthroplasty surgeries was found to be increasing over the last four decades, though not Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients equivalent to that in North America and Europe. 19 In a multinational and multi-ethnic study on Asian population, Piovella et al. concluded that the incidence of venographic thrombosis in the absence of thromboprophylaxis after arthroplasty and hip fracture surgery is equivalent to that in the western countries. 8 Many authors believe that the factors responsible for this changing trend are increase in life expectancy and change in dietary habits (increased fat intake) and lifestyle of the Asian/ Indian population over the last two decades. [4][5][6]9 Nandi et al. reported that other than genetic factors, certain acquired traits like dietary habits and lifestyle are important factors responsible for VTE. Most of the studies which have reported very low incidence of DVT in India have been conducted in patients undergoing elective orthopedic surgery and used color duplex for diagnosis. [20][21][22] In the absence of any study in this population under the high-risk condition of trauma, it is unwise to assume that Indians are genetically protected against VTE after trauma. The reluctance among Indian surgeons to provide thromboprophylaxis to trauma patients may have serious medicolegal implications. In the present scenario, a standard guideline for providing thromboprophylaxis to trauma patients in the Indian subcontinent is urgently needed, which should be practical and acceptable for all. In the present article, the severity of the VTE problem is weighed against the potential complications of thromboprophylaxis, like hemorrhage, wound hematoma, infection, thrombocytopenia and most importantly the cost-benefit ratio. The present review is conducted to answer the frequent question raised by most of the orthopedic surgeons: "Is thromboprophylaxis justified among Indian population after major orthopedic trauma?"

MAtEriAls And MEthods
A thorough search of 'PubMed' with keywords 'venous thromboembolism,' 'Indians,' 'trauma' could not find any article. On searching 'Google Scholar' with the same key words, 10 references were available that were based on venous thromboembolism in Indian patients after orthopedic trauma surgeries. 11,14,15,17,21,[23][24][25][26][27] Most of these studies have evaluated venous thromboembolism in both patients of arthroplasty and patients of trauma. There is no prospective multicentric studies on VTE after major orthopedic trauma. All the above articles were thoroughly reviewed, and only trauma subgroup of patients (n=1049 excluding the arthroplasty patients) was evaluated regarding the incidence, risk factors, diagnosis and treatment.

rEsults
The study designs, fracture types and incidence rates of VTE among thromboprophylaxis-receiving and non-thromboprophylaxis-receiving groups in the Indian studies have been depicted in Table 1

discussion
Limitations due to the scarcity of Indian studies on VTE after major orthopedic trauma have restricted us in formulating a guideline for thromboprophylaxis. Hence the literature available on trauma conditions among the western population was also studied, compared with Indian data and extrapolated to the best of our understanding of the subject. Conclusions were reached by discussion among authors over every point, and finally a protocol for thromboprophylaxis in major trauma patients was designed, with special consideration to Indian population.

Incidence of VTE in major orthopedic trauma in Indian population
The incidence of VTE and its complications is more in patients undergoing major orthopedic surgery than in those undergoing other surgical procedures 4 . Lee et al. (2008) have reported 20.1% incidence of VTE in patients undergoing orthopedic surgery as compared to 30% in those undergoing general surgery. 5 This was a retrospective review of hospital records, and they agreed that there was a lack of awareness regarding VTE among orthopedicians and reluctance on their part to investigate patients with lower limb symptoms of VTE at their setup. There is lack of prospective multicentric trials on VTE in orthopedic-trauma patients in the Indian population. Among the 10 selected studies that were reviewed, the incidence of VTE was reported to be about 14% after hip Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients or proximal femur fractures and their interventions, without receiving any prophylaxis; whereas it was only 8% when prophylaxis was administered. The data is almost similar to that of Leizorvoicz et al., 4 who conducted an exhaustive review of literatures and reported 18% incidence of DVT in Asian patients not receiving any thromboprophylaxis after hip fracture surgery. However, these Indian studies are not multicentric and randomized. There is no study on VTE in pelvi-acetabular traumatized patients, and a proper study on spine-injured patients is also not found. None of the studies have evaluated for pulmonary embolism, which may occur in isolation also. The actual severity of the problem is difficult to assess with the present literature, and multicentric studies with inclusion of all major orthopedic trauma (pelvi-acetabular fractures; hip, proximal femur, major long-bone fractures; and spine injuries) would be required for true assessment of VTE.
The severity of VTE among non-resident Indian patients also In the largest multicentric, centrally audited venographic trial among Asian patients, Piovella et al. found incidence of DVT to be 41% in patients undergoing total hip replacement (THR), total knee replacement (TKR) and hip fracture surgery without prophylaxis. 8 Incidence of proximal DVT was 10.2%, and 4.4% cases having isolated muscular vein DVT were not included in calculation of DVT incidence rate (total incidence, 45.4%). They pointed out that rate Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients of proximal DVT after TKR was 17.1%, which is on higher side of the range reported from western countries. Some of the 19 centers included in the trial were from India; and on country-wise analysis of data, Indians have not been found to have low risk of VTE. 8 There is wide variation in incidence of DVT reported from India (0%-71%), mainly due to difference in diagnostic modalities and different indices of suspicion. 5,6 After reviewing the Indian literature [ Table 1], we found that Indian patients have also definite risk of DVT after major orthopedic trauma other than spinal injuries.

Pathogenesis
The pathogenesis of VTE after trauma has not been studied extensively in Indian/Asian literature. Western literature reveals that pathogenesis of VTE in trauma starts immediately after injury, much before the patients present at the hospital. In them, all the three factors mentioned by Virchow (endothelial damage, vascular stasis, hypercoagulability) are present. 28 Most trauma cases need some kind of surgery, which adds further insult, and the manipulation during surgery can result in dislodgement of preformed thrombus. 29 A prolonged immobility after trauma or surgery further accelerates the event of thrombus formation. It has been shown that trauma patients have decreased serum level of antithrombin III due to release of tissue factor in circulation, thus favoring coagulation, sometimes in the contralateral limb. 30,31

Risk factors
Americal College of Chest Physicians (ACCP) recognizes presence of certain factors as high risk for VTE, like malignancy, obesity, estrogen use, past history of VTE, cardiac or respiratory failure, etc. 29 However, attempts to identify factors that consistently predict risk for VTE in trauma have met with little success, mainly because presence of major trauma itself is a major risk factor. Napolitano et al. identified age >60 years, Injury Severity Score >30, length of hospital stay, spinal injury and Trauma and Injury Severity Score >85 as important predictors of VTE. 32 Geerts et al. also identified older age and spinal injury as high risk indicators but found Injury Severity Score to be unreliable. 1 They also found surgery, blood transfusion and fracture of femur or tibia as important predictors of VTE. They reported DVT rate of 46% in patients younger than 30 years and concluded that all patients sustaining major trauma should be considered at high risk for VTE irrespective of presence or absence of risk factors, 1 a statement which is supported by other studies as well. 30 Even ACCP, which in its earlier recommendation advised chemoprophylaxis in trauma patients having one additional risk factor, now recommends routine chemoprophylaxis in major trauma. 29

Diagnostic modality
Incidence of reported VTE varies to a major extent depending on the diagnostic modality used. 5 There is no single best method for diagnosis. 30 The common noninvasive diagnostic modalities include compression ultrasonography (USG), real-time B mode compression and color Doppler USG. While duplex ultrasound is most acceptable to surgeons as noninvasive, portable mode, many consider it insensitive, especially in the setting of trauma. 1,22,30 Venography is considered gold standard by many investigators; however, it is invasive, cannot be performed if the patient is allergic to contrast has renal failure and it can cause problems due to extravasations of contrast. 30 Geerts et al. found that nearly 30% of venograms in trauma patients yielded inadequate study, 1 while Montgomery et al. found these to give false-negative results in 58% of cases of pelvic thrombi when compared to magnetic resonance venography (MRV). 35 MRV is very costly; needs transportation of patient to MRI room, which is not always possible; and needs an expert MR radiologist. 30 Further, many of the small clots detected by MRV may not be clinically significant. 36 Figure 1]. [41][42][43][44] In most of the previous studies color Doppler was used for evaluation of DVT. 11,15,23,25,27 The relative low incidence of DVT in some Indian studies is because of the use of duplex ultrasound as the diagnostic tool. 44

Thrombus location
Moser and Lemoine, using a combination of venography, impedance plethysmography, radio fibrinogen scanning, and ventilation perfusion lung scanning, reported no evidence of PE in 21 patients with calf--deep vein thrombosis, whereas more than 50% of patients with proximal thrombosis had lung scan evidence of PE. 45 Many workers agree that proximal DVT has a higher risk of embolisation causing PE and leading to death. 1  chemoprophylaxis in Asians/Indians is that most of the thrombi in this population are distal, which are less likely to progress to symptomatic VTE, and most of these resolve without any consequence. 9 12 Saraf found three (42.8%) cases of proximal DVT out of seven cases of VTE in spinal injury patients, and all of these died because of PE. 25 Rajgopalan found five (62.5%) cases of proximal and three cases of distal DVT, in which a majority of patients in the study group had femoral fracture interventions. 27 Bagaria et al. reported 3/9 cases of proximal DVT, 5/9 of distal DVT and 1/9 of PE confirmed on necropsy. 26   in another report found 100% and 96.66% of distal DVT in patients receiving and not receiving prophylaxis therapy, respectively. He suggested that though most of the DVTs in the Indian subcontinent appear to be distal in location, these DVTs have high potential for migration and subsequent embolisation. 14 Unlike patients undergoing elective surgery, in trauma patients, thrombogenesis begins in preoperative period and most of the thrombi are proximal. 1,30,32,46 Although the distal thrombi have a lower risk of embolisation and chronic venous insufficiency, they cannot be considered having no risk. Without prophylaxis they are more likely to propagate proximally, which substantially increases the risk of pulmonary thromboembolism. 50 In fact, Wang et al. have concluded that isolated calf-muscle DVT shows results comparable to major leg-vein DVT in terms of clinical symptoms, late DVT and proximal propagation; they warned that isolated calf-muscle DVT is a significant clinical entity and should be treated accordingly. 9 The influence of genetic makeup on risk of VTE cannot be ruled out. 51 However, is this genetic protection sufficient in the setting of major trauma, wherein every patient is at high risk irrespective of presence or absence of other risk factors?
Most authors found a relatively higher incidence of proximal DVT in the Indian population except Agarwala et. al. and none of the studies suggested distal DVT to be a benign entity but advised to treat it aggressively if noticed. 14,27

Prevention of VTE
Before formulating a guideline for thromboprophylaxis therapy in VTE in the Indian population, the recommendations of American College of Chest Physicians (ACCP) and American Academy of Orthopedic Surgeons (AAOS) should be discussed in brief. The ACCP guidelines on prevention of VTE are prepared by a multidisciplinary, international group of clinician-methodologists, including orthopedic surgeons. ACCP recommendations are based primarily on the results of randomized trials in which VTE (symptomatic and asymptomatic) and bleeding are the primary outcomes [ Table 2]. 33 In addition to extensive formal peer review, the primary principle of the ACCP guidelines is to have a transparent link between the evidence and the graded recommendations. The major differences between the two guidelines are that the ACCP lays greater emphasis on DVT prevention and aggressive anticoagulation, whereas AAOS emphasizes fatal-PE prevention over DVT prevention and it has stratified the thromboembolic disease risk and bleeding risk. 33 Because of the paucity of Indian studies in non-arthroplasty conditions, our view on the treatment or prevention of DVT is based on the western literature and the above two guidelines. However, multicentric randomized control trials with and without prophylaxis are needed for better clarification about DVT prophylaxis.

Screening vs. prophylaxis
Some authors suggest routine surveillance in all major trauma cases as chemoprophylaxis does not ensure complete protection, 20 while most favor routine thromboprophylaxis as noninvasive surveillance leaves a significant number of patients at risk of PE. 1,52,53 Probably the most balanced approach is to use routine thromboprophylaxis in trauma patients, with selective screening of high-risk patients. 30,32,33

Mode of prophylaxis
At present, there is little doubt left regarding the best method of prophylaxis under trauma conditions. Mechanical methods (graduated compression stocking, intermittent pneumatic compression, mechanical foot pumps and foot impulse technology) play a definite role in prevention of DVT, 30,36 but when used alone have proved to give insufficient protection in trauma patients. 52,54-56 They cannot be used in patients having below-knee injuries, fixators and traction devices, and there is the problem of compliance as well. 54 However, they are valuable in cases where chemoprophylaxis is contraindicated due to increased risk of bleeding (because of intracranial, abdominal or chest injuries or other reasons); and during early stages posttrauma, when hemodynamic stability has not been achieved and the patient is waiting for surgery. 30 They may also be used as an adjunct to chemoprophylaxis in trauma patients at high risk of VTE. 30,32,33 In the Indian scenario, the stockinet (above-knee stockings) should be applied to the lower limbs in all polytrauma patients unless it is contraindicated (thigh circumference >81 cm/ incontinence) or impractical Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients because of leg injury. 41,42 The effectiveness of these mechanical devices in the Indian population has not been evaluated extensively. Bhan et al. proved the beneficial effect of a mechanical device, viz., low-intensity electrical stimulation by lymphavision, in polytrauma patients and after elective surgeries. 24 The routine use of vena caval filters as advocated by some workers 52,55 is probably an over-aggressive approach, and they should only be used Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients in cases of proven proximal thrombi. 30 Their routine use cannot be justified, as they are very costly, need high level of expertise and do not protect against recurrent DVT and post-phlebitis syndrome. 30,33

Low-dose unfractionated heparin vs. low-molecular weight heparin
Low-dose unfractionated heparin (LDUH) given subcutaneously for prevention of VTE is ineffective in trauma patients, 46,56 although it has got some role in VTE prevention under other conditions. 33,56 This is probably because the thrombogenic stimuli in trauma overwhelm the beneficial effect of unfractionated heparin. 30 The greater bioavailability, more predictable dose-response characteristics, longer half-life, greater efficacy and a lower incidence of heparin-induced thrombocytopenia with low-molecular weight heparin (LMWH) as compared with those with unfractionated heparin makes it a suitable agent to be used in trauma patients. 30,33 Its superiority over mechanical prophylaxis and unfractionated heparin has been proved in several studies. 37,46,56 The protection offered by it is however not absolute, 56 and it is justified to supplement it with mechanical compression devices and serial screening in trauma patients with high risk of VTE. The risk of bleeding with LMWH is small (2%-5%) and acceptable considering the dramatic decrease in proximal thrombi which are at high risk of embolisation. 30 However, one must ensure hemodynamic stabilization before initiating chemoprophylaxis, which usually takes 24 to 36 hours from the time of occurrence of injury. 30 14 . However, they did not notice any bleeding complication following thromboprophylaxis.

Oral anticoagulant
Oral anticoagulants (Vitamin-K Antagonist like warfarin) are not a practical means for thromboprophylaxis in acute trauma because of delayed onset and prolonged action after withdrawal. Montgomery et al. advised to start oral anticoagulant after two weeks of injury; 30 however, we are of the opinion that oral anticoagulants can be safely started in postoperative period if hemodynamic stabilization has been ensured and patient does not require any more surgery. It usually takes four days to act, which is a safe period against postoperative bleeding. As no further surgical intervention is needed, the drug can be continued with INR (International Normalized Ratio) monitoring (INR in between 2 to 3) and dose adjustment. Another advantage of oral anticoagulants is their low cost. The thromboprophylaxis should be continued till the patient can be mobilized. 30,33 Anti-platelet agents like aspirin are not suggested by ACCP/VTE group as a prophylactic measure in hip fractures and multiple trauma conditions. 33,41,42 However, American Academy of Orthopaedic Surgeons (AAOS) recommends aspirin in combination with mechanical prophylaxis in high-risk patients of bleeding. We support the AAOS guidelines in such high-risk conditions. This study has its own limitations: (1) the review is entirely based on Indian studies, which lack multicentric and randomized control trails; and (2) statistically significant data about VTE after trauma in the Indian population are not available.

Treatment of acute VTE
Multicentric randomized control clinical studies are required at different aspects of VTE. There is a definite need to increase awareness about VTE among Indian clinicians and surgeons .3,5 Every hospital should have a formal written thromboprophylaxis protocol of its own, as repeatedly advised by ACCP. 33 Sen, et al.: Posttraumatic thromboprophylaxis in Indian major orthopedic trauma patients conclusion In major-trauma patients, we suggest routine chemoprophylaxis using subcutaneous LMWH after hemodynamic stabilization has been ensured as evidenced by stable hemoglobin level, stable vitals and stable urine output. The patients having isolated upper-limb fractures or isolated lower-limb injury should not be put on chemoprophylaxis. 33 Patients having head injury, incomplete spinal-cord injury or any other contraindication for chemoprophylaxis should be put on mechanical prophylaxis in the form of graduated stockings (aspirin can be added). Both the methods should be used in major-trauma patients having additional risk factors for VTE. Oral anticoagulants (like warfarin) should be started in postoperative period, and chemoprophylaxis should be continued till patient is mobilized adequately.
We do not suggest routine screening; however, patients having clinical suspicion of VTE despite get ting chemoprophylaxis should be investigated using color duppler USG. Patients found positive for VTE should be treated with intravenous heparin and warfarin, and their oxygen saturation should be monitored on a pulse oxymeter. Patients with fall in oxygen saturation or with any other signs of PE should be investigated by ventilation perfusion scan or pulmonary angiography, as available. The treatment should be shifted to oral anticoagulants (like warfarin) when INR of 2-3 is achieved for at least 24 hours. 61 Patients having DVT and no pulmonary embolism can be treated with intravenous heparin or subcutaneous LMWH, depending upon other indications for hospitalization. Intravenous heparin followed by oral anticoagulants for hospitalized patients is advocated because of their time-tested efficacy and cost-effectiveness and because monitoring of INR and Activated Partial Thromboplastin Time can be easily performed in a patient who has to remain hospitalized for reasons other than DVT (excluding PE). We do not advice hospitalization of patients for DVT per se, and they can be discharged on subcutaneous LMWH or weight-based subcutaneous unfractionated heparin. 61 Treatment of a proved thrombotic episode should be continued for three months, with either LMWH or oral anticoagulants.