Chapter 24: Venous Thromboembolic Disease in Patients with Skeletal Trauma

Robert Probe, David Ciceri

Chapter Outline

Introduction

Unbeknownst to Rudolph Virchow, when he described the classic triad of factors that lead to thrombotic disease in the nineteenth century, he was also providing an accurate depiction of the contemporary orthopedic trauma patient. To varying degrees, these individuals all have endothelial injury, stasis, and hypercoagulability as a part of their physiologic response to injury. Validating this triad as contributory to this potentially lethal disease, recent decades have produced reports suggesting that over half of polytraumatized patients without prophylaxis will develop thrombi within their legs.21 This epiphany has led traumatologist to recognize that strategies to mitigate risks are an essential component of the comprehensive care of trauma patients. Unfortunately, despite universal recognition of risk, pulmonary embolism (PE) remains the third most common cause of death in patients surviving the first 24 hours following trauma.2 It is becoming increasingly clear that PE and deep vein thrombosis (DVT), collectively referred to as venous thromboembolic disease (VTE) is a complex interplay of fluid dynamics, bioactive factors, and mechanics. This chapter will focus on the pathophysiology of the clotting pathways in the trauma patient, examine the subsets of trauma patients and their inherent risk of VTE, explore the pharmacologic and mechanical measures that can reduce the incidence, and conclude with a discussion of diagnostic and therapeutic strategies. 

Pathophysiology

Clot formation is a process involving the interaction of the endothelium, subendothelial matrix, platelets, and circulating proenzymes (zymogens). Traditionally, the coagulation cascade has been conceptualized as consisting of two intersecting arms, the extrinsic and intrinsic pathways. This construct, although recognized as a fairly drastic simplification, served adequately in many routine clinical settings when the major therapeutic options for anticoagulation were unfractionated heparin (UFH) and warfarin. In this schema, the extrinsic pathway was activated by the interaction of tissue factor and factor VII. Factor VIIa then activated factor X and the common coagulation pathway. The intrinsic pathway was felt to be initiated by exposure to a foreign surface (test tube) or damaged vessel surface causing activation of factor XII followed by factors XI, IX, and ultimately X and the common pathway (Fig. 24-1). 
Figure 24-1
Intrinsic and extrinsic pathways leading to cross-linked thrombin clot.
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It is now recognized that clot formation is a dynamic process in constant interplay with processes maintaining blood fluidity, retarding clot formation, and causing clot dissolution. These processes act in concert to rapidly achieve hemostasis even at the level of the myriad minor injuries which occur in the microvascular level every day. At the same time, these vital processes must limit clot formation to the actual site of vascular injury and restore patency of the micro- and macrovasculature. These systems are also closely interrelated to a host of other systems which mediate local and systemic inflammation. 
Vessel injury triggers muscular contraction of the vessel wall and exposure of platelets to the subendothelial matrix. This is termed primary hemostasis. Platelets adhere to the exposed subendothelial tissue by a variety of mechanisms depending upon local shear stress conditions. This is followed by changes in platelet morphology, secretion of a host of products that enhance clot formation, aggregation, and surface expression of a negatively charged phosphatidylserine which serves as a catalytic surface for coagulation factors.39 
The first stage of the coagulation cascade, initiation, is triggered by exposure of tissue factor to factor VII and small amounts of circulating activated factor VIIa. This leads to the formation of the extrinsic tenase complex which produces small amounts of FIXa, FXa, and thrombin. The amplification phase occurs at the platelet surface and the resulting intrinsic tenase complex (FIXa:VIIIa) and prothrombinase complex (FXa:FVA) leads to significant thrombin generation. The propagation phase is dependent upon an adequate number of platelets to support continued high levels of thrombin production that leads to the conversion of fibrinogen to fibrin and a stable fibrin clot.3 The clinical consequences of venous thrombus formation are diverse. The majority of thrombi serve the purpose of hemostasis and ultimately undergo fibrinolysis with restoration of physiologic flow; however, there are circumstances in which this process becomes pathologic. These include obstructive DVT, thromboembolism (VTE), and obstruction of the pulmonary vascular flow (PE). This review is intended to examine the prophylaxis, diagnosis, and treatment of these disease states in the setting of orthopedic trauma. 

Trauma-Related Thromboembolic Risk Factors

Appropriate prophylaxis against thromboembolic disease in the setting of trauma requires striking a balance between the risk of morbidity from a thrombosis and the risk of prophylaxis causing harm through bleeding.14 Trauma has been identified as one of the strongest risk factors leading to thromboembolism. In a venographic study of 349 patients, Geerts et al.21 identified a 58% rate of DVT and 18% incidence of proximal vein thrombosis in their population of patients with an Injury Severity Score (ISS) of >9 in the absence of any prophylactic measures. Natural history analysis of more contemporary studies is challenged by the fact that significant variation exists in the timing and method of prophylaxis, the screening tools utilized, and the definition of disease.28 Despite these challenges, an understanding of relative risk between subsets of trauma patients is an important component of any risk benefit analysis. 

Injury Severity Score

There are a multitude of reasons why the polytrauma patient is predisposed to thromboembolic disease. These patients are typically immobile, often ventilator-dependent, and subject to a hypercoagulable state.51 In the era prior to prophylaxis, patients requiring transfusion, those with head injury, spinal cord injury, lower-extremity fracture, and those with pelvic fracture were found to be at increased relative risk of deep thrombosis.21 While the dramatic increase in prophylactic measures has led to a substantial reduction in the incidence of VTE, the association of increasing injury severity with disease persists. In a review of the German National Trauma Data Bank, Paffrath et al.49 noted an overall 1.8% incidence of “clinically significant” thromboembolic disease despite the vast majority of patients receiving prophylaxis. Within this group, multivariate analysis suggested ISS as a significant independent variable (Fig. 24-2). In a review of the American National Trauma Data Bank over the period 1994 through 2001, Knudson et al.35 identified an overall rate of VTE of 0.36% in 450,375 patients. Independent risk factors in this review included an age ≥40 years, the presence of lower-extremity fracture (Abbreviated Injury Score [AIS] ≥ 3), the presence of a major head injury (AIS ≥3), days requiring mechanical ventilation greater than 3, the presence of a venous injury, and the need for at least one major operative procedure (Table 24-1). 
Figure 24-2
Rising incidence of VTE with increasing injury severity score.
 
(Reproduced with permission from: Paffrath T, Wafaisade A, et al. Trauma Registry of DGU. Venous thromboembolism after severe trauma: Incidence, risk factors and outcome. Injury. 2010;41(1):97–101.)
(Reproduced with permission from: Paffrath T, Wafaisade A, et al. Trauma Registry of DGU. Venous thromboembolism after severe trauma: Incidence, risk factors and outcome. Injury. 2010;41(1):97–101.)
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Figure 24-2
Rising incidence of VTE with increasing injury severity score.
(Reproduced with permission from: Paffrath T, Wafaisade A, et al. Trauma Registry of DGU. Venous thromboembolism after severe trauma: Incidence, risk factors and outcome. Injury. 2010;41(1):97–101.)
(Reproduced with permission from: Paffrath T, Wafaisade A, et al. Trauma Registry of DGU. Venous thromboembolism after severe trauma: Incidence, risk factors and outcome. Injury. 2010;41(1):97–101.)
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Table 24-1
Risk Factors Associated with VTE (Univariate Analysis)
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Table 24-1
Risk Factors Associated with VTE (Univariate Analysis)
Risk Factor (Number with Risk) Odds Ratio (95% CI)
Age ≥40 yrs. (n = 178,851) 2.29 (2.07–2.55)
Pelvic fracture (n = 2,707) 2.93 (2.01–4.27)
Lower-extremity fracture (n = 63,508) 3.16 (2.85–3.51)
Spinal cord injury with paralysis (n = 2,852) 3.39 (2.41–4.77)
Head injury (AIS ≥ 3) (n = 52,197) 2.59 (2.31–2.90)
Ventilator days >3 (n = 13,037) 10.62 (9.32–12.11)
Venous injury (n = 1,450) 7.93 (5.83–10.78)
Shock on admission (BP < 90 mm Hg) (n = 18,510) 1.95 (1.62–2.34)
Major surgical procedure (n = 73,974) 4.32 (3.91–4.77)
 

p <0.001 for all factors.

 

Risk factors associated with univariate analysis of venous thromboembolic disease from the National Trauma Data Bank.

 

Reproduced with permission from: Knudson MM, Ikossi DG, Khaw L, et al. Thromboembolism after trauma: An analysis of 1602 episodes from the American College of Surgeons National Trauma Data Bank. Ann Surg. 2004;240(3):490–496.

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Spinal Cord Injury

Several studies have noted large increase in relative risk of VTE with spinal cord injury.53 The stasis that results from the absence of vascular tone combined with the attendant loss of muscle contractions are likely contributory factors to this heightened risk. In an analysis of the spinal cord injury patients within the National Trauma Data Bank, identified rates of VTE were 3.4% for high cervical (C1 to C4), 6.3% for high thoracic (T1 to T6), and 3.2% with lumbar injury. Additional independent risk factors from the Data Bank included increasing age, increasing ISS, male gender, traumatic brain injury, and chest trauma.46 

Head Injury

Many of the same predisposing features of the spinal cord injured patient also apply to the head injured patient. In a review of 577 patients with head injury AIS > 3, a DVT incidence of 34% was identified when only mechanical prophylactic measures were utilized with weekly duplex ultrasound screening. In this series, the incremental risk of clinical VTE with other injuries was also noted. In patients with isolated head injury, the DVT rate was 26% compared to 35% in those patients with associated injury. In addition to head injury, advancing age, ISS > 15, and the presence of a lower-extremity injury were strong predictors for developing DVT in this study.17 

Fracture Risks

Fractures of the lower extremity and pelvis have also been noted to increase the risk of VTE. The natural history of operatively treated fractures can be inferred from the work of Abelseth et al.1 In an era prior to routine prophylaxis, a prospective study of 102 patients with lower-extremity fracture was conducted. Patients were examined with venography, an average of 9 days following injury, and followed clinically for 6 weeks. The overall incidence of clinically occult DVT was 28% and rose as the level of skeletal injury became more proximal. Other independent risk factors noted in this series included older age, longer operating times, and longer times before fracture fixation.1 
Another fracture specific concern arises in those patients provisionally stabilized with damage control external fixation. The forced joint immobilization inherent to this technique and the limitations for the application of sequential pneumatic devices raises concern over the VTE risk. In a retrospective review, Sems et al.59 evaluated 143 patients with bridging frames for an average of 18 days who received low-molecular-weight heparin (LMWH) as prophylaxis against VTE. In this group, there were only three cases of VTE and each was in a patient with multiple concomitant injuries. This review would suggest that under protection of appropriate prophylaxis, temporary bridging external fixation does not produce additive risk of DVT. 
Geriatric hip fractures present another patient population at risk for VTE. The recognized effects of advancing age, immobility, and proximal femoral fracture are collectively causes for concern. Without prophylaxis, rates of 50% for DVT and 4% for PE are reported in systematic review.27 This risk also increases with delay to surgery. In a review of 101 consecutive patients with >24-hour delay to surgery, Smith et al.60 demonstrated a correlation between the length of delay and DVT identified by duplex ultrasound screening. Despite LMWH prophylaxis, the overall group demonstrated a DVT rate of 10% with those with a DVT averaging a 5.7-day delay and those without averaging a 3.2 day delay. 
While the majority of available literature on VTE focuses on the incidence of DVT, the most feared complication is PE because of its potential for mortal consequences. Knudson et al. analyzed the National Trauma Data Bank and determined that in this large data set, the overall incidence of PE was 0.49% with an 11% mortality.35 Head injury, more than three ventilator days, chest injury, pelvic fracture, lower-extremity injury, spine injury, and shock were all independent variables associated with this complication. 

Nontraumatic Risk Factors

In light of the fact that risk factors for VTE appear to be additive, individual patient risk factors unassociated with trauma must also be considered when determining composite risk. The use of estrogen-based oral contraceptives is common in the female trauma population and carries distinct additional risk. From pooled data, the estimated odds ratio for VTE from these drugs is 3.8. This additional risk is compounded in the obese and in those patients over the age of 40.42 
In addition, genetically determined protein abnormalities predispose to VTE. The most common of these are protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden, and prothrombin mutations. In a review of patients presenting with VTE, one of these deficiencies was present in 35% compared to an incidence in the general population of 10%.45 Relative risk for these genetic tendencies range from 2.2 to 8.5 times higher than the unaffected population.44 
While testing for these deficiencies is complex and costly, a simple family history can be of significant value. A history of VTE in one or more first-degree relatives under age 50 should raise the question of a genetic predisposition. This was most conclusively shown in a population-based study of the incidence of VTE according to the presence or absence of VTE in a sibling. Standard incidence ratios for VTE were 2.27, 51.9, and 53.7 for patients with one, two, or three or more affected siblings, respectively.6 
With the multitude of important individual risk factors and their variable weighting, it becomes a complex equation to incorporate all of these factors and their relative risk into a composite risk profile. Several scoring systems have been developed to assist the practitioner in calculating a cumulative risk. One such scoring system is the Caprini Index (Table 24-2).10 This index coalesces multiple clinical parameters into a single sum that then stratifies patients into low, moderate, high, or highest risk. While no specific guidelines exist in the setting of fracture management, it would seem prudent to give consideration to some form of prophylaxis in patients with scores of 3 or greater (moderate risk) and the need for lower-extremity immobilization. In the setting of more significant trauma, it should be noted that major fracture of the lower extremity places patients in the highest-risk category by definition. The usefulness of this screen; therefore, applies only to those fractures that are low risk in isolation, but become high risk because of the cumulative effect of injury factors and idiosyncratic predisposition. 
 
Table 24-2
Caprini Index
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Table 24-2
Caprini Index
Each Risk Factor Represents 1 Point Each Risk Factor Represents 2 Points
  •  
    Age 41–60 yrs
  •  
    Minor surgery planned
  •  
    History of prior major surgery
  •  
    Varicose veins
  •  
    History of inflammatory bowel disease
  •  
    Swollen legs (current)
  •  
    Obesity (BMI > 30)
  •  
    Acute myocardial infarction (<1 mo)
  •  
    Congestive heart failure (<1 mo)
  •  
    Sepsis (<1 mo)
  •  
    Serious lung disease including pneumonia (<1 mo)
  •  
    Abnormal pulmonary function (COPD)
  •  
    Medical patient currently at bed rest
  •  
    Leg plaster cast or brace
  •  
    Other risk factors________________
  •  
    Age 60–74 yrs
  •  
    Minor surgery (>60 min)
  •  
    Arthroscopic surgery (>60 min)
  •  
    Laparoscopic surgery (>60 min)
  •  
    Previous malignancy
  •  
    Central venous access
  •  
    Morbid obesity (BMI > 40)

Each Risk Factor Represents 3 Points Each Risk Factor Represents 5 Points
  •  
    Age over 75 yrs
  •  
    Major surgery lasting 2–3 hrs
  •  
    BMI > 50 (venous stasis syndrome)
  •  
    History of SVT
     
    , DVT/PE
  •  
    Family History of DVT/PE
  •  
    Present cancer of chemotherapy
  •  
    Positive factor V Leiden
  •  
    Positive prothrombin 20210A
  •  
    Elevated serum homocysteine
  •  
    Positive lupus anticoagulant
  •  
    Elevated anticardiolipin antibodies
  •  
    Heparin-induced thrombocytopenia (HIT)
  •  
    Other thrombophilia

  •  
    Elective major lower-extremity arthroplasty
  •  
    Hip, pelvis, or leg fracture (<1 mo)
  •  
    Stroke (<1 mo)
  •  
    Multiple trauma (<1 mo)
  •  
    Acute spinal cord injury (paralysis)(<1 mo)
  •  
    Major surgery lasting over 3 hrs
For Women Only (Each Represents 1 Point)
  •  
    Oral contraceptives or hormone replacement therapy
  •  
    Pregnancy or postpartum (<1 mo)
  •  
    History of unexplained stillborn infant, recurrent spontaneous abortion (≥3), premature birth with toxemia or growth-restricted infant
Type_____________________ Total Risk Factor Score
 

The Caprini index can be used to sum the factors thought to be of additive risk in predisposition to venous thromboembolic disease. Patients with scores greater than 3 should have consideration given to prophylaxis.

 

BMI, Body mass index.

 

Reproduced with permission from: Caprini JA. Individual risk assessment is the best strategy for thromboembolic prophylaxis. Dis Mon. 2010;56(10):552–559.

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Chemical Prophylactic Options

Aspirin

Several characteristics of acetylsalicylic acid make it an attractive agent for the prevention of DVT. It is inexpensive, easily administered, and produces a low rate of bleeding. The antiplatelet effect that results from the inhibition of thromboxane A2 disrupts an important component of clot initiation and formation. 
In a group of 13,356 patients undergoing surgery for hip fracture or joint replacement, a relative risk reduction of 36% was noted by using low-dose aspirin.54 Aspirin has also been shown to be effective in prospective trials in the reduction of risk for secondary DVT.5 While these findings of benefit are attractive, it does not appear as though the treatment effect is as large as that offered by LMWH. To date, large prospective trials in the setting of trauma are lacking. Currently, aspirin’s use for VTE prophylaxis should be restricted to patients in low-to-moderate risk categories as an alternative to no prophylaxis or to situations where extended prophylaxis is desired. 

Heparin

The realization of the effectiveness of low-dose UFH led to its rapid adoption as one of the earliest forms of chemical prophylaxis against DVT. The anticoagulant effect of heparin is complex, but primarily involves the activation of antithrombin III through an increase in flexibility and activity of its reactive site.7 Heparin also possesses a strong electrostatic attraction to thrombin and other cascade proteases (IX, Xa) creating a direct binding which limits their biologic effect.25 One notable concern over the use of UFH is the potential for heparin-induced thrombocytopenia (HIT). While conflicting reports exist, UFH appears to have a much narrower therapeutic index when compared to LMWH. In a systematic review of prophylaxis in spinal cord injury patients, UFH had a 2.6 odds ratio for DVT and a 7.5 odds ratio for bleeding complications when compared to LMWH.53 Given these factors, the best indication of UFH is in the short-term perioperative period of moderate-risk patients with advantages being restricted to its reduced cost. 

Low-molecular-weight Heparin

In 1976, it was discovered that the direct factor Xa binding mechanism of heparin could be selected for by decreasing the size of the heparin molecule.29 This preferential inactivation of factor Xa was found to be more effective than UFH in one of the earliest prospective trials of DVT prophylaxis. Geerts et al.22 studied 360 trauma patients randomized to treatment with either UFH or LMWH. Their results showed a reduction in the rate of proximal DVT from 15% to 6% with the use of LMWH.22 LMWH, including dalteparin, enoxaparin, and tinzaparin are cleared through renal mechanism and have a greater bioavailability and longer plasma half-life than heparin. Early recommendations for enoxaparin dosing called for twice daily administration. Several studies have suggested equivalent efficacy with once daily dosing.56 Because of the short half-life, this provides windows without anticoagulation that allow for surgical procedures while simultaneously reducing administration cost. More recently, some have suggested variable dosing based on either weight or factor Xa inactivation.43 To date, increased effectiveness with dose adjustment has not been shown and most continue with the standard dosages of enoxaparin of 30 mg bid or 40 mg daily. Because of its renal excretion, reduced dosing should be considered with calculated creatinine clearance below 30 mL/min. LMWH has emerged as the drug of choice in the majority of trauma patients for VTE prophylaxis. The probable improved effectiveness over UFH and the shorter half-life in comparison to fondaparinux, rivaroxaban, and dabigatran make it an ideal drug in the setting of trauma. 

Fondaparinux

Fondaparinux is a synthetic pentasaccharide which closely mimics the active pentasaccharide of heparin. This molecule targets factor Xa exclusively with the aim of facilitating a more predictable regulation of coagulation and an improved therapeutic index.66 In a prospective hip fracture trial of 1,711 patients, fondaparinux was found to have a greater incidence reduction than enoxaparin 8.3% versus 19.1% for VTE. Importantly, the improved risk reduction was not accompanied by an increased rate of bleeding.19 While impressive in this phase III hip fracture trial, this decrease in VTE rate was not reproduced in a retrospective single center review for a larger population undergoing major orthopedic surgery. Donath et al.16 noted similar rates of VTE and mortality in their comparison of LMWH to fondaparinux with an increased rate of distal DVT in the fondaparinux group. In trauma, Lu et al.41 found fondaparinux prophylaxed group to have a DVT rate of 1.2% in high-risk patients. While this study had no controls, it does provide some indication that it may prove effective in trauma prophylaxis. 
Rivaroxaban and apixaban are two other direct factor Xa inhibitors that have the advantage of predictable gut absorption allowing for oral administration. In a large prospective series of total hip and total knee patients, rivaroxaban has shown significant risk reduction for DVT without increase in bleeding complications. Dabigatran is another newly developed oral agent that is effective by virtue of its direct inhibition of thrombin. The drug has performed impressively in a comparative trial of stroke prevention in patients with atrial fibrillation. Despite their promise, to date, no large studies examining the performance of these drugs in the trauma setting have been performed. The lengthened half-life and irreversibility of these agents is cause for concern in the early days following trauma; however, because of their ease of administration, a role may evolve for their use in extended prophylaxis postdischarge.15 

Timing of Administration

As the heightened risk of VTE can begin immediately after trauma, prophylactic measures are most effective when administered as soon as the immediate risk of bleeding has passed. This requires that the patient be warmed, volume resuscitated, and any consumptive coagulopathy reversed. Even after these milestones are achieved, some clinical situations continue to be controversial with regard to the advisability of chemical prophylaxis. These would include hemorrhagic intracranial injury and spinal cord injury. In the latter situation, recent systemic review suggests that chemical prophylaxis can be instituted within 72 hours of injury without additional risk of neurologic complication.11 Similarly, in hemorrhagic head injury, large retrospective reviews are also demonstrating that closely monitored administration of chemical prophylaxis within 72 hours does not lead to an increased incidence of recurrent bleeding.36 Taking advantage of the relatively short 4.5-hour half-life of enoxaparin, a pragmatic protocol is to discontinue dosing the evening prior to any invasive procedure. Following the procedure, dosing is resumed when clinical judgment suggests that primary hemostasis has occurred. This is typically 8 to 12 hours following most surgeries. Longer delays may be warranted when the consequences of bleeding carry high morbidity such as with intracranial or spinal procedures. 

Mechanical Devices

While the body of evidence regarding safe chemical prophylaxis is increasing, there will always be situations in which bleeding concern exist with this strategy. These situations have led to interest in the effects of mechanical prophylaxis in the prevention of VTE. External mechanical devices can be broadly categorized as graduated compressive stockings and pneumatic pumps. The principle of the compressive stockings is to reduce the predisposition to venous stasis by reducing the resting volume of extremity veins. This theory has been validated through ultrasonic volume estimates with and without stockings and the clinical benefit documented in a systematic review.58 Although the biologic and clinical evidence suggests that graduate compression stockings are an effective, relatively cheap, and more comfortable thromboprophylactic measure, they appear less effective overall than intermittent pneumatic compression (IPC).40 

Intermittent Pneumatic Devices

IPC devices are postulated to be useful in VTE prevention by initiating return flow of blood pooled within the venous system. In circumstances where chemical prophylaxis is contraindicated, IPC has demonstrated a significant reduction in relative risk of VTE.12 A few randomized trials comparing mechanical methods to chemical alternatives have been performed. In a study of 442 trauma patients, Ginzburg et al.23 demonstrated a DVT rate of 2.7% in the IPC group compared to 0.5% in the group prophylaxed with LMWH group. PE rates and bleeding rates were comparable.23 In a population of 120 randomized patients with head and spinal trauma, Kurtoglu et al.38 found no difference in the rate of DVT, PE, or mortality between treatment randomized groups treated with either LMWH or isolated IPC. Prospectively studying a population of 290 total hip patients, Warwick et al.67 found no difference in rates of VTE between those randomized to foot pumps or those randomized to LMWH. They did note a significant increase in limb swelling and wound drainage in the LWMH group. While these comparatively small studies suggest effectiveness, combined systemic review concludes that their efficacy is not that of chemical prophylaxis.26 The contemporary role of mechanical devices has evolved into four categories: (1) Patients at low risk, (2) patients with a bleeding diathesis, (3) transient use in trauma patients with concern for bleeding, and (4) as an adjunct in patients deemed at high risk. Relative to the third category, prospective study has shown safety in delay of 7 days prior to LMWH administration in high-risk trauma patients bridged with the use of foot pumps.61 Relative to the fourth category, mechanical devices have been shown to be an effective addition to chemical prophylaxis. In a systematic review of 7,431 patients, Kakkos et al.31 identified a risk reduction for DVT from 3% to 1% when chemical prophylaxis was added to mechanical. Similarly, combined therapy reduced PE rates from 4% to 1%. Given this demonstrated efficacy and the absence of risk, the addition of mechanical prophylaxis, should be given consideration in all high-risk patients. 

Inferior Vena Cava Filters

The use of inferior vena cava (IVC) filters in trauma patients, as in most other types of patients, is highly controversial. Accepted indications for IVC filter placement are patients at very high risk of VTE with an absolute contraindication to chemical thromboprophylaxis; bleeding on anticoagulation for a PE or DVT; and re-embolization despite therapeutic anticoagulation. IVC filters can be permanent or retrievable and may be placed using fluoroscopy or even at the bedside using intravascular ultrasound. 
It is exceptionally difficult to prove an outcome benefit for an expensive intervention which is associated with infrequent short-term complications and uncertain long-term risks when the incidence of clinically significant PE even in the highest-risk patients is relatively low with other mechanical and chemical prophylactic measures. This benefit is so uncertain that the 2012 American College of Chest Physicians (ACCP) guidelines do not recommend the use of IVC filters as prophylactic measure for trauma patients.26 Some recent literature may support questioning that recommendation. Angel et al.4 published a review on the use of retrievable IVC filters for prophylaxis and treatment in 6,834 patients in 37 studies which met the authors’ selection criteria. The individual studies were of intermediate quality, but the authors concluded that retrievable IVC filters seemed to be effective in preventing PE (1.7% all indications). Long-term complications were infrequent, but could be severe: Filter migration (<1% except G2 filter), filter fracture, IVC thrombosis or stenosis (2.8%), and IVC perforation. One repeatedly reported problem which was highlighted in this review was the poor rate of device retrieval which occurred in only 34% of these 6,000 patients. Strategies to improve this retrieval rate have included removal prior to discharge and the creation of filter registries with retrieval protocols. These have proven moderately successful with improved retrieval rates of 59%.57 
Kidane et al.34 published a systematic review of the prophylactic use of IVC filters in trauma patients in 2012. The studies are all matched with historical control or case series limiting the conclusions which can be reached. The incidence of subsequent PE ranged from 0% to 9.1% and PE-associated mortality was 0% to 0.8%. The incidence of device-related complication was also very low although limited by the duration of patient follow-up in most studies. The most common complication was device migration/tilt. Device tilt was a radiologic determination and could be associated with a reduction in efficacy, but that clinical outcome was not observed in these studies. Given the existing uncertainty in the existing data, these authors do infrequently place an IVC filter in an occasional very high-risk patient when VTE chemoprophylaxis cannot be administered or must be significantly delayed beyond 3 or 4 days after injury (Fig. 24-3A–D). When they are placed, we coordinate our efforts with the trauma administrative support team to help ensure that they are removed prior to hospital discharge whenever possible. 
Figure 24-3
 
(A) Computed tomography of the head demonstrating right frontal epidural hematoma, (B) closed tibial shaft fracture, (C) retrievable filter placed because of concern over the safety of chemical prophylaxis and risk of VTE, and (D) intramedullary nail treatment of tibial shaft fracture following filter placement.
(A) Computed tomography of the head demonstrating right frontal epidural hematoma, (B) closed tibial shaft fracture, (C) retrievable filter placed because of concern over the safety of chemical prophylaxis and risk of VTE, and (D) intramedullary nail treatment of tibial shaft fracture following filter placement.
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Figure 24-3
(A) Computed tomography of the head demonstrating right frontal epidural hematoma, (B) closed tibial shaft fracture, (C) retrievable filter placed because of concern over the safety of chemical prophylaxis and risk of VTE, and (D) intramedullary nail treatment of tibial shaft fracture following filter placement.
(A) Computed tomography of the head demonstrating right frontal epidural hematoma, (B) closed tibial shaft fracture, (C) retrievable filter placed because of concern over the safety of chemical prophylaxis and risk of VTE, and (D) intramedullary nail treatment of tibial shaft fracture following filter placement.
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Screening

Routine screening of patients with high risk of VTE has not proven to be an effective strategy. Borer et al.9 compared the incidence of PE during a period in which no screenings were performed and a period when both ultrasound and magnetic resonance venography were performed in patients with pelvic or acetabular fractures. In this series of 973 patients, the rates of PE actually increased from 1.4% to 2%. The value of pelvic screening was also challenged by Stover63 who identified a high rate of false-positive testing with both computed tomographic venography and magnetic resonance venography. 
Despite its common use in practice, the use of routine screening with compression ultrasonography has not been recommended because of the low yield. One exception to this may be the high-risk patient who was not effectively prophylaxed following injury. The known high incidence of VTE in this setting makes consideration of ultrasound screening reasonable. 

Diagnosis

Despite recommendations to avoid routine screening, there are clinical signs which suggest the need to rule out VTE in the perioperative period. These would include inordinate limb swelling, tachycardia, hypoxia, hemoptysis, and unexplained fever. The clinical examination findings associated with DVT have long been acknowledged to have a poor predictive value. In a systematic review that examined the effectiveness of differential calf diameter, limb swelling, erythema, Homan’s sign, and tenderness, Goodacre et al.24 found that none of these findings possessed the sensitivity or specificity to accurately predict disease. The single finding with the best predictive value was the presence of a differential of 2 cm or greater in calf diameter. This carried a likelihood ratio when positive of 1.8 and when negative of 0.57.24 Time from injury also does little to affect the probability of VTE as there is relatively even distribution of events in the 4 weeks following injury. 
Improving diagnostic probability with history and physical examination has been improved with the use of composite scoring. One of the more commonly used composite scores was described by Wells et al. (Table 24-3).68 This scoring system has been through modifications with both the original and modified scores being of helpful predictive value in the outpatient setting. This score rapidly allows patients to be placed into categories of low, intermediate, or high risk of DVT with corresponding rates of DVT of 7%, 18%, and 37%.18 
 
Table 24-3
Wells Score (PE)
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Table 24-3
Wells Score (PE)
Clinical signs and symptoms compatible with DVT 3
PE judged to be the most likely diagnosis 3
Surgery or bedridden for more than 3 d during past 4 wks 1.5
Previous DVT or PE 1.5
Heart rate >100 mins 1.5
Hemoptysis 1
Active cancer (treatment ongoing or within previous 6 mos or palliative treatment) 1
 

≤4, LOW (or “PE Unlikely”) pretest probability; 4.5–6, MODERATE pretest probability; >6, HIGH pretest probability.

 

Adapted with permission from: Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: Increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83(3):416–420.

X
Knowing an individual’s risk has bearing on testing sequence. In patients with a low risk of disease, a sensitive test for D-dimer is a reasonable screen. D-dimer is the final fragment of the plasmin-mediated degradation of cross-linked fibrin. Plasma D-dimer has proven to be a highly sensitive test for the presence of VTE with plasma levels being elevated eightfold. It also has advantage in that pelvic thrombi, often invisible to the ultrasonographer, can be detected in addition to being sensitive to PE, which may occur in the absence of DVT. The drawback with D-dimer as a diagnostic tool is its limited specificity. Conditions such as age, hospitalization, systemic inflammation, and surgery can all raise D-dimer level. With these characteristics, this tool then becomes effective in outpatient situations of low probability as a test of exclusion and insufficiently specific to initiate aggressive anticoagulant therapy.55 In circumstances of intermediate or high risk, the more effective strategy is to directly investigate the entire lower limb with compression ultrasonography when DVT is suspected. This imaging technique has proven both 83% sensitive and 98% specific for both distal and proximal thrombotic disease.33 
Just as disease Wells scores can predict DVT probability, a separate score exist for estimating probability of a PE. Risk stratification using this tool results in incidences of 75%, 17%, and 3% found respectively in the high, intermediate, and low-risk groups. 
Just as in DVT, low-risk patients may have disease excluded with a sensitive D-dimer test; however, high-risk patients are best evaluated with pulmonary imaging (Table 24-4). Classically, this has involved either a pulmonary angiogram or ventilation perfusion scanning. More recently, these invasive and low-resolution tests have been supplanted with multidetector computed tomography pulmonary angiography with a reported sensitivity of 83% and specificity of 96%.62 One consequence of this improved imaging resolution is that previously missed asymptomatic subsegmental emboli are now being diagnosed.65 
 
Table 24-4
Wells Score (DVT)
View Large
Table 24-4
Wells Score (DVT)
Active cancer (treatment ongoing or within previous 6 mos, or palliative treatment) 1
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or regional anesthesia 1
Localized tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling >3 cm compared to asymptomatic leg (measuring 10 cm below tibial tuberosity) 1
Pitting edema confined to the symptomatic leg 1
Nonvaricose collateral superficial veins 1
Previously documented DVT 1
Alternative diagnosis at least as likely as DVT –2
 

≤0, LOW pretest probability; 1 or 2, MODERATE pretest probability; ≥3, HIGH pretest probability.

X

Treatment

When prophylaxis fails and VTE is diagnosed, the reasons for treatment are fourfold: Prevention of clot extension, prevention of acute PE, prevention of recurrent thrombosis, and limiting late complications of DVT. When considering DVT, clots identified proximal to the calf are treated more aggressively as 90% of the DVT-related cases of acute PE stem from proximal DVT.20 Because of the need for prompt anticoagulation, treatment is initiated with therapeutic doses of one of the fast-acting agents to include LMWH, fondaparinux, UFH intravenous heparin, or adjusted-dose subcutaneous heparin. Assuming patients are ambulatory and at low bleeding risk, outpatient management can be considered. Simultaneous with the initiation of one of these agents, vitamin K agonist (warfarin) is initiated for extended treatment. Heparin agents are continued for a minimum of 5 days with at least 2 days of overlap with warfarin at therapeutic levels.26 As an alternative to dual agent therapy, oral rivaroxaban 15 mg twice daily has recently been shown to be effective for both the initial and extended treatment of DVT.13 The treatment simplification and safety offered by this single oral medication is likely to make this an increasingly popular treatment strategy. Once the acute pain and swelling of the DVT improves, patients are encouraged to resume activity and rehabilitation appropriate to their orthopedic injury. When DVT is precipitated by a transient risk factor such as trauma, the recommended duration of anticoagulant treatment is 3 months. 
Beyond the traditional anticoagulation treatment strategy just outlined, increasing attention is being paid to reduction of post-thrombotic symptoms with acute thrombolysis. While current evidence of effectiveness is not strong, consideration of thrombolysis should be given in cases of large iliofemoral clot and in the unusual cases of phlegmasia cerulea dolens.47 
In contrast to proximal DVT, there is much less consensus on the appropriate treatment of clot restricted to the veins of the calf. Many authors recommend an aggressive approach with treatment similar to proximal DVT, while others recommend close observation. Small retrospective series report similar outcomes with ultrasound monitoring or therapeutic anticoagulation,64 while others have demonstrated the effectiveness of short-course anticoagulant therapy.50 At a minimum, these patients should be followed with clinical or ultrasound monitoring. 
Aggressive treatment of clinically relevant PE is imperative as it reduces the mortality rate from 30% to 6%.32 First-line therapy is directed at respiratory and circulatory support. Hypoxia is addressed with oxygen therapy and in extreme cases, mechanical ventilation for impending respiratory failure. Hypoperfusion is addressed with cautious fluid resuscitation and early introduction of vasopressors to guard against right heart overload.37 Empiric anticoagulation should be utilized if there is no excessive risk for bleeding and a high clinical suspicion for PE exist. Once PE is confirmed, anticoagulation should be continued as the 25% risk of recurrent thromboembolism exceeds the 3% risk of significant hemorrhage. LMWH is preferred for hemodynamically stable patients with PE as evidence suggests lower mortality, less major bleeding, and fewer recurrences of thromboembolic events when compared to UFH.32 In cases where contraindication to rapid anticoagulation exist, consideration of IVC filter should be given. In cases where hemodynamic stability is not rapidly restored with resuscitation, consideration of thrombolytic therapy or embolectomy is warranted. Just as in DVT, urgent anticoagulation is transitioned to oral warfarin and continued for 3 months in patients with transient risk factors.32 
While this aggressive therapeutic intervention is warranted in documented pulmonary emboli that result in hypoxia, hypotension or tachycardia, the increasing ability of modern imaging to detect small clots, raises the question of appropriate treatment for physiologically irrelevant segmental and subsegmental pulmonary thrombi. In a retrospective review of 312 orthopedic trauma patients with documented PE treated with anticoagulants, 12% incurred surgical site bleeding complications.8 As the natural history of these small pulmonary thrombi are unknown, judgment and shared decision making become necessary to balance the risks and benefits of traditional anticoagulation. 

Authors’ Treatment Recommendations for Prophylaxis

 
 

It is universally recognized that trauma in general and skeletal trauma in particular are strong risk factors for VTE. Regardless of ultimate prophylactic intervention, it is incumbent upon the treating physician to carefully consider the patient’s risk of VTE morbidity and react to this risk with a commensurate prophylactic strategy.

 

Unfortunately, the multitude of patient and injury variables compounded by an incomplete body of scientific evidence makes dogmatic recommendations for VTE prophylaxis impossible. The quest for a set of routine universally accepted interventions is also challenged by the disparate views of clinicians. The ACCP has a long history of diligent review of existing evidence with regard to the prophylaxis of VTE. Their ninth edition of these guidelines was published in 2012 based on available evidence26 and is felt to be a significant improvement over previous versions as increasing acceptance of mechanical measures and bleeding complications are now incorporated into their recommendations. Also incorporated into the latest guidelines are the practical issues of patient acceptance with latitude provided based on patient desires.

 

The value of these guidelines is that they provide the clinician ready access to evidence- based conclusions that lie within an enormous body of scientific work. The disadvantage of strictly adhering to evidence-based guidelines is that there are likely prophylactic algorithms that safely, conveniently, and inexpensively provide adequate protection that have not been rigorously studied. The following section of author’s preferred guidelines will largely follow the recommendations of the ACCP and this is not the case, mention will be made.

Isolated Fractures

Regardless of fracture site, promoting mobilization to the extent permitted by the injury raises cardiac output, augments venous flow through muscle compression, and should be encouraged as a first-line prevention of VTE. In isolated fractures of the upper extremity and those of the ankle and foot, strong evidence does not suggest that routine prophylaxis is effective in lessening the risk of VTE and is therefore not recommended. In a review of 4,696 patients undergoing shoulder fracture repair within the English National Health Service Data Set, Jameson et al.30 found no difference in VTE rates before or after institution of a national protocol to provide LMWH prophylaxis. Similarly, in a retrospective review of 1,540 operatively treated ankle fractures, Pelet et al.52 found that the overall incidence of VTE of 2.99% was not affected by chemical prophylaxis. It should be recognized that in this group where prophylaxis is not routinely recommended, the risk presented by injury is additive to baseline patient risk. This makes assessment of an individual’s predisposing factors advisable before making recommendations for no prophylaxis. In patients with 3 or greater on a Caprini score and presenting with these “low-risk” fractures, shared decisions with the patient regarding the need for prophylaxis should be strived for. While evidence is nonexistent in this population, an argument could be made for aspirin, LMWH, or oral factor X inhibitors for those patients concerned over the risk of VTE. The ACCP recommends no prophylaxis in injuries to the foot and ankle. 
Isolated fractures of the pelvis, femur, and tibia are all known to place patients in the highest-risk categories of VTE. In this population, LMWH carries the greatest strength of evidence. In the preoperative period, the short half-life allows for surgical windows if single daily dosing is administered in the evening. In a survey of the membership of the Orthopaedic Trauma Association (OTA), LMWH was the preferred principle agent of prophylaxis for approximately 75% of respondents. Of those utilizing LMWH, half utilized the single daily dose and half split dosing.48 Because of the relatively low cost and additive effectiveness, a convenient form of mechanical prophylaxis could be justified in the early days following injury. In the OTA survey, mechanic methods of prophylaxis were added 40% of the time and most commonly involved graduated compressive stockings with or without pneumatic compression. While good data do not exist for length of treatment, it would seem beneficial to continue such dosing until patients are easily mobilized from bed. Once patients are mobile and discharged from the hospital, a common practice without supporting evidence is the recommendation for 81 mg of aspirin for 1 month. This practice is not recommended by the ACCP. 
The geriatric hip fracture population likely represents a subgroup at heightened risk because of the cumulative effects of age, proximal fracture, and resultant immobility. In this setting, extending treatment with LMWH until 28 days is recommended because of their frequent delay in return of function. 
In the setting of polytrauma with ISS > 10, there appears to be sufficient concern for VTE to routinely prophylax with LMWH. The controversies that persist in this population include the specific contraindications to chemical prophylaxis and the threshold for adding mechanical to chemical prophylaxis. With regard to the former question, there is a moderate amount of evidence that patients with traumatic brain injury can safely receive prophylaxis with LMWH, if they are clinically stable and computed tomography shows no evidence of progression. There are no similar outcome data regarding early initiation of chemical prophylaxis in patients who have suffered spinal cord injury. In those situations where the immediate risk is deemed unacceptably high, mechanical prophylaxis should be emphasized. The contraindication to chemical prophylaxis should be reevaluated and prophylaxis introduced when bleeding risk diminishes. Given the evidence of effectiveness with mechanical devices, these should always be utilized when chemical means are not employed and employed in combination with patients at high risk such as those with SCI, head injury, pelvic trauma, and prolonged ventilation. 
In conclusion, it is imperative that those caring for skeletal trauma are cognizant of the heightened risk for VTE in their patients. It is equally important to have knowledge of the multitude of chemical and mechanical methods by which this risk may be mitigated. Recent decades have seen a rapidly morphing series of guidelines to help direct our preventative efforts. Given the significance of the disease, its potential for mortality and the plethora of newly released chemical prophylactic agents, it is likely that alternative strategies will continue to evolve. 

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