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Case Presentation Fulminant Heterotopic Ossication After Combat- related Amputation: A Report of 2 Cases Edward A. Dolomisiewicz, MD, Matthew E. Miller, MD, Benjamin K. Potter, MD Heterotopic ossication (HO) is the process of abnormal formation of lamellar bone in nonosseous tissues. In this case presentation, we describe patients with aggressive HO, which becomes symptomatic shortly after injury for which we have suggested the term fulminant heterotopic ossication.These atypical presentations of fulminant HO high- light the necessity for continued research directed at improved understanding of HO and may suggest a role for early partial surgical excision as a denitive management strategy. PM R 2014;6:279-283 INTRODUCTION Heterotopic ossication (HO) is the abnormal formation of lamellar bone in nonosseous tissues. The natural history and clinical implications of HO have been described in the setting of various injury types that involve the musculoskeletal and nervous systems. There is a high prevalence of HO, 63%-64.6%, after high-energy trauma in individuals with combat wounds [1,2]. In addition, 19% of those who develop combat-related HO require additional surgery, and up to 24% of these patients develop postoperative wound complications [3]. Although these statistics represent the impact of HO on military personnel, the clinical burden extends beyond the military health care system. It affects the Veterans Affairs hospitals and likely the civilian health care systems as these injured service members are discharged from service. The clinical manifestations that challenge both providers and patients include pain, skin breakdown, interference with prosthetic tting, and loss of joint motion. Typically, HO develops after precipitating events, such as burns, spinal cord injury, traumatic brain injury (TBI), or combat-related injuries, for example, amputations and open fractures [1,4]. Most investigators believe that the formation of HO is dependent upon 3 factors: a microenvironment conducive to bone formation, an inducing event or agent(s), and the presence of osteogenic precursors [1,5]. The most recent research has focused on more clearly identifying these microenvironmental factors [6,7]. In this case presentation, we describe 2 clinical cases of HO that occurred after combat-related injuries. We believe that these cases are of interest in that, in addition to developing severe, aggressive HO, both patients developed symptoms attributable to HO very early during the course of rehabilitation. CASE PRESENTATIONS Case 1 A 25-year-old, active duty white man sustained a traumatic left transtibial amputation, left closed femur fracture, unstable pelvic fracture, right open knee dislocation with severe right lower extremity soft-tissue injury, and mild TBI after a blast from an improvised explosive device. TBI classication was established in accordance with Department of Defense criteria based on loss of consciousness and anterograde amnesia, with the patient denying retrograde amnesia and alteration of consciousness. His overall Injury Severity Score (ISS) was calculated as 20, although recent evidence would suggest that the ISS may underestimate injury severity in combat casualties with major extremity amputations [8]. E.A.D. Department of Physical Medicine and Rehabilitation, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889. Address correspon- dence to: E.A.D.; e-mail: Edward.A.Dolomi- [email protected] Disclosure: nothing to disclose M.E.M. Department of Physical Medicine and Rehabilitation, Walter Reed National Military Medical Center, Bethesda, MD Disclosure: nothing to disclose B.K.P. Department of Orthopaedics, Walter Reed National Military Medical Center, Bethesda, MD Disclosures outside this publication: board membership, Society of Military Orthopaedic Surgeons and American Academy of Ortho- paedic Surgeons Board of Subspecialty Soci- eties; research member (no payment); grants/ grants pending, Congressionally Directed Medical Research Program/Peer-Reviewed Orthopaedic Research Program and US Navy Bureau of Medicine (money to institution) The views expressed in this article are those of the authors and do not reect the ofcial policy of the Department of Army, Department of Defense, or United States Government. All authors are employees of the United States Government. This work was prepared as part of their ofcial duties and, as such, there is no copyright to be transferred. Submitted for publication February 10, 2013; accepted October 12, 2013. PM&R 1934-1482/13/$36.00 Printed in U.S.A. ª 2014 by the American Academy of Physical Medicine and Rehabilitation Vol. 6, 279-283, March 2014 http://dx.doi.org/10.1016/j.pmrj.2013.10.004 279

Fulminant Heterotopic Ossification After Combat-related Amputation: A Report of 2 Cases

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Case Presentation

Fulminant Heterotopic Ossification After Combat-related Amputation: A Report of 2 CasesEdward A. Dolomisiewicz, MD, Matthew E. Miller, MD, Benjamin K. Potter, MD

Heterotopic ossification (HO) is the process of abnormal formation of lamellar bone innonosseous tissues. In this case presentation, we describe patients with aggressive HO,which becomes symptomatic shortly after injury for which we have suggested the term“fulminant heterotopic ossification.” These atypical presentations of fulminant HO high-light the necessity for continued research directed at improved understanding of HO andmay suggest a role for early partial surgical excision as a definitive management strategy.

PM R 2014;6:279-283

E.A.D. Department of Physical Medicine andRehabilitation, Walter Reed National MilitaryMedical Center, 8901 Wisconsin Avenue,Bethesda, MD 20889. Address correspon-dence to: E.A.D.; e-mail: [email protected]: nothing to disclose

M.E.M. Department of Physical Medicine andRehabilitation, Walter Reed National MilitaryMedical Center, Bethesda, MDDisclosure: nothing to disclose

B.K.P. Department of Orthopaedics, WalterReed National Military Medical Center,Bethesda, MDDisclosures outside this publication: boardmembership, Society of Military OrthopaedicSurgeons and American Academy of Ortho-paedic Surgeons Board of Subspecialty Soci-eties; research member (no payment); grants/grants pending, Congressionally DirectedMedical Research Program/Peer-ReviewedOrthopaedic Research Program and US NavyBureau of Medicine (money to institution)

The views expressed in this article are those ofthe authors and do not reflect the official policyof the Department of Army, Department ofDefense, or United States Government. Allauthors are employees of the United StatesGovernment. This work was prepared as partof their official duties and, as such, there is nocopyright to be transferred.

Submitted for publication February 10, 2013;accepted October 12, 2013.

INTRODUCTION

Heterotopic ossification (HO) is the abnormal formation of lamellar bone in nonosseoustissues. The natural history and clinical implications of HO have been described in thesetting of various injury types that involve the musculoskeletal and nervous systems.There is a high prevalence of HO, 63%-64.6%, after high-energy trauma in individualswith combat wounds [1,2]. In addition, 19% of those who develop combat-related HOrequire additional surgery, and up to 24% of these patients develop postoperative woundcomplications [3]. Although these statistics represent the impact of HO on militarypersonnel, the clinical burden extends beyond the military health care system. It affectsthe Veterans Affairs hospitals and likely the civilian health care systems as these injuredservice members are discharged from service. The clinical manifestations that challengeboth providers and patients include pain, skin breakdown, interference with prostheticfitting, and loss of joint motion.

Typically, HO develops after precipitating events, such as burns, spinal cord injury,traumatic brain injury (TBI), or combat-related injuries, for example, amputations andopen fractures [1,4]. Most investigators believe that the formation of HO is dependentupon 3 factors: a microenvironment conducive to bone formation, an inducing event oragent(s), and the presence of osteogenic precursors [1,5]. The most recent research hasfocused on more clearly identifying these microenvironmental factors [6,7]. In this casepresentation, we describe 2 clinical cases of HO that occurred after combat-related injuries.We believe that these cases are of interest in that, in addition to developing severe,aggressive HO, both patients developed symptoms attributable to HO very early duringthe course of rehabilitation.

CASE PRESENTATIONS

Case 1

A 25-year-old, active duty white man sustained a traumatic left transtibial amputation,left closed femur fracture, unstable pelvic fracture, right open knee dislocation with severeright lower extremity soft-tissue injury, and mild TBI after a blast from an improvisedexplosive device. TBI classification was established in accordance with Department ofDefense criteria based on loss of consciousness and anterograde amnesia, with the patientdenying retrograde amnesia and alteration of consciousness. His overall Injury SeverityScore (ISS) was calculated as 20, although recent evidence would suggest that the ISS mayunderestimate injury severity in combat casualties with major extremity amputations [8].

PM&R1934-1482/13/$36.00

Printed in U.S.A.

ª 2014 by the American Academy of Physical Medicine and RehabilitationVol. 6, 279-283, March 2014

http://dx.doi.org/10.1016/j.pmrj.2013.10.004279

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280 Dolomisiewicz et al FULMINANT HETEROTOPIC OSSIFICATION AFTER AMPUTATION

Blood products administered included 36 units of packedred blood cells, 3 units of whole blood, 2 units of freshfrozen plasma, 3 units of cryoprecipitate, and 1 six-pack ofplatelets early in his postinjury course. Serial wound de-bridements were performed, and negative pressure woundtherapy was used over open wounds. During the secondweek, the patient developed an angioinvasive fungal infec-tion of the right lower extremity necessitating a transfemoralamputation, which occurred 14 days after the blast injuries.His left lower extremity amputation was closed 18 days afterthe injury.

Approximately 45 days after injury, he developed bilat-eral lower extremity polymicrobial infections with woundcultures that demonstrated Escherichia coli, Klebsiella pneu-moniae, Enterococcus faecalis, and Pseudomonas aeruginosa,which were successfully treated with operative debridementand broad-spectrum intravenous antibiotics. About thistime, he began noticing discomfort in his left anterior thigh.Within several days, the pain at this site became so intensethat the slightest local pressure was intolerable. Bilaterallower extremity radiographic imaging demonstrated pro-gressive HO that involved the distal posteromedial rightthigh and the anterior left mid thigh. The HO was consid-ered severe by the Walter Reed Classification of HO, giventhat it occupied >50% of the soft tissues on a singleradiographic projection (Figure 1) [9]. The severe painpersisted despite pain management strategies, includingmultiple pain medications; thus surgical resection of HO wasperformed on postinjury day 55.

Two-and-a-half months after HO excision from theanterior middle thigh, the patient reported continued painrelief at that site; however, he began experiencing decreased

Figure 1. Radiograph of severe fulminant heterotopic ossifi-cation, which involves lower residual limbs from patient 1before surgical excision.

motion in his left knee and progressive pain in the right hipand femur, with loss of motion in the right hip. Thesymptoms in both limbs were attributed to HO developingin these other locations. Computed tomography imaging ofthe right extremity showed extensive HO, starting from theischial tuberosity and continuing inferiorly, eventuallyencasing the sciatic nerve and progressing circumferentiallyaround the amputation site. The maximum transversedimension was 6.2 cm, with 4 cm of posterior extension atthe proximal femur. In the left extremity, HO was visualizedalong the inferior pubic ramus in the region of the adductormuscles, with a maximum anterior measurement of 5.1 cm,and also surrounding the proximal distal femur, with amaximal anterior projection of 3 cm at the level of the leftmid femur. Surgical excision was delayed due to chronicwound healing concerns and the desire to wait for HOmaturation. The patient’s rehabilitation was further hinderedby chronic surgical wound healing issues, which resulted indelayed clearance for weight bearing. As a result, he was notfitted with prostheses until 8 months and 2 weeks after hisinitial injuries.

The pain associated with HO was not effectively managedwith prosthetic modification and pain medication; therefore,10 months after the original injury, surgical excision of HOfrom the right lower extremity and a left residual limbrevision with HO excision were performed. Additional sur-gery included HO excision from the left hemipelvis and theright femur, left knee lysis of adhesions, left quadriplasty,right thigh rotational flap, and debridement of right ampu-tation flap. Subsequent prosthetic fitting was pain free.

Case 2

A 22-year-old, active duty white man sustained a splenicrupture, traumatic left knee disarticulation amputation, rightlower extremity crush injury with fibula fracture and sub-sequent compartment syndrome, and mild TBI after animprovised explosive device blast. The mild TBI status wasbased on loss of consciousness, post-traumatic amnesia, andalteration of consciousness. His overall ISS was 29, andinitial blood products administered included the following:20 units of whole blood, 6 units of packed red blood cells,and 14 units of fresh frozen plasma.

Early in his postinjury course, he developed a series ofinfections, including a left lower extremity fungal infectionbefore wound closure, bacterial wound infection withEnterococcus faecalis, cytomegalovirus viremia, and venti-lator-associated pneumonia. All the infections were appro-priately treated; the patient’s physiologic status markedlyimproved, and his left amputation wound was closed 19days after the blast injury. About this time, he developedsevere pain in his left transfemoral amputation while he wasstill noneweight bearing. Pain became more problematicduring his preprosthetic physical therapy sessions, with greatlimitations because of posterior left extremity pain. On

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examination, HO was palpable, and there was concern forskin ulceration. In addition, HO in the right lower extremityresulted in failure of the previous skin graft. Radiographicand computed tomographic images were obtained, whichconfirmed extensive HO immediately deep to the skin sur-face at both medial and lateral aspects of the left thigh, whichextended over a 27 � 21-cm area considered severe whenusing the Walter Reed Classification (Figure 2). A follow-upradiograph of the right femur showed interval developmentof HO around the fracture site. When pain medicationsfailed to provide relief, and because of failure of the rightskin graft, surgical resection of bilateral HO was performed(approximately 5 weeks after the amputation was closed).The patient’s pain was successfully resolved.

Fourteen weeks after injury, the patient was cleared forweight bearing and was fitted with prostheses, but then hadpain with socket fitting caused by the residual HO. Pros-thesis modification resulted in pain relief, and his rehabili-tation progressed. Almost 2 months after the excision, heagain had HO-related pain in the distal and lateral aspect ofhis amputation. Bilateral femur radiographs showed a mildinterval increase of HO in the left amputation and no in-crease in the right lower extremity. Prosthetic modificationwas again successful.

Six months after the excision, the patient reported havingonly mild discomfort at the site of his left lower extremityHO excision. He described this symptom as minimal whencompared with other HO problem areas that elicited pain toinclude the distal lateral site on the left residual limb and 1

Figure 2. Radiograph of severe fulminant heterotopic ossifi-cation of the left femur of patient 2 before surgical excision ofsymptomatic heterotopic ossification.

now that involved his right hip because these sites were notpreviously excised. A repeat radiograph of the left lowerextremity (radiograph of right was not obtained) revealedextensive HO but without interval change. Although he stillexperienced pain in the amputation, he eventually was ableto manage the symptoms with prosthetic modification,physical therapy, oxycodone, and lidocaine patches, and, at1 year after injury, he was virtually pain free.

DISCUSSION

Given the aggressive, rapid growth, and early symptomaticnature of these patients’ HO, we have suggested the term“fulminant heterotopic ossification,” which we describe asrapidly accumulating symptomatic HO that occurs shortlyafter injury. Amputees with HO typically become symp-tomatic when pressure is applied to the affected areas of theresidual limb, as occurs when standing in a prosthesis. Thefirst step in alleviating this discomfort is prosthesis modi-fication, in which the architecture of the prosthesis ismodified to decrease point pressure. If these conservativeattempts fail, then surgical excision may be necessary and isoften the definitive treatment. The fulminant cases presentedherein are unusual in that these patients developed severesymptoms before prosthetic fitting and weight bearing, withlimited direct pressure on their symptomatic areas. There-fore, prosthesis modification is not applicable very early intheir course. Although the concept of successful early exci-sion is not new [10], it is not usually recommended; up to81% of patients with HO have been successfully managedwithout surgical excision, and risks inherent to surgery,such as wound complications or recurrence of HO, may beavoided [3]. In patients with fulminant HO, the standardmanagement of waiting months for HO maturation beforesurgical resection may be unreasonable due to pain, andthese 2 patients required resection for symptomatic reliefas early as 3 weeks after initial symptom presentation and55 days after injury.

Relatively little is known about why HO develops, and,moreover, why some individuals develop HO whereas othersdo not in the context of similar injury patterns. The afore-mentioned role of osteogenic precursors necessary for HOformation [5] has been more recently supported in patientswith blast injuries. Davis et al [11] showed that patients withblast injuries had a higher number of muscle-derived con-nective tissue precursor cells per gram of tissue than controlswithout blast injuries. Also, the patients with blast injurieswho developed HO had a higher number of osteogenicprecursor cells in addition to an increased number ofmuscle-derived connective tissue precursor cells [11]. Theseresearchers, who attempted to measure gene expression andcytokines, did caution that their study designs are tempo-rally limited and had relatively small sample sizes to study.The upregulation of cytokines and gene expression ispossibly a response to systemic and localized inflammation

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282 Dolomisiewicz et al FULMINANT HETEROTOPIC OSSIFICATION AFTER AMPUTATION

inherent to high-energy trauma and is associated with com-mon comorbidities to trauma, such as systemic and locali-zed infection. Although infection was not found to have astatistically significant association with HO developmentafter combat-related, high-grade open fractures in 1 study[12], bacterial colonization was statistically significant andwas found in 92% of wounds that developed HO inanother study [7], which suggests a possible association.Interestingly, the patients in this report on fulminantHO,whowere known to be immunocompetent before injury, hadsevere systemic infections classically associated with immune-compromised conditions (eg, cytomegalovirus and invasivefungal infections).

Localized insult to tissue, in addition to systemicinvolvement as mentioned above, likely contributes sub-stantively to fulminant HO formation. Potter et al [1] foundthat amputations closed within the initial zone of injurywere more likely to develop HO than amputations proximalto the zone of injury. In addition, negative pressure wounddressings have been implicated as a potential contributingfactor to HO formation [2,7], because it is thought thatthey can cause microtrauma [7] to the tissue that providesa hospitable microenvironment for HO to develop. Onestudy [7], which measured serum and wound effluent afterpulse lavage debridement of blast injuries and subsequentmanagement with negative pressure wound vacuum, sup-ports this theory. Increased levels of osteogenic cytokinesand chemokines were obtained from the blast-injured tissuesthat were exposed to wound vacuum before further wounddebridement. Several cytokines were found to have beenincreased, and it was found that interleukin 6 correlatedpositively with HO severity. Other factors, such as timingof surgery, effects of instrumentation, and manipulation oftissue, did not appear to influence the occurrence of HO,and open-reduction internal fixation versus external fixa-tion has demonstrated no difference in the rate of HOformation [2].

In contrast, TBI is a systemic insult that has been widelyassociated with HO formation [2,4,13-15]. Hendricks et al[14] reported that brain injury severity and autonomicdysregulation could predict HO formation and may con-tribute to a microenvironment that encourages HO. Intui-tively, having a TBI in the setting of polytrauma and severeinflammation could increase the likelihood of HO and pre-sumably increase its severity. However, contrary to civilianTBI reports, recent analyses have shown that TBI alone isnot an independent risk factor [2], and the severity of TBImay not be linked to HO formation [7] in patients withhigh-energy, combat-related extremity trauma. These find-ings coincide with earlier clinical assessments, which suggestthat neurologic insult as the only inducing agent mayenact HO via different mechanisms [4] when compared withthose in patients with polytrauma. The patients in thiscase series were all categorized as having a mild TBI ac-cording to Department of Defense criteria [16]. Accordingly,

TBI should be included as a possible inducing agent in thesecases.

Of all risk factors studied above, perhaps the greatest riskfactor involves systemic injury severity. Severity scores havebeen used in an attempt to objectively quantify injury pat-terns on the basis of severity and magnitude. Not surpris-ingly, researchers have found that an ISS > 16 in thepresence of multiple extremity injury has been associatedwith HO formation [2,7]. This also is consistent with thecases above and is supportive of overwhelming systemicinflammation as a major inducer of local HO formation.Interestingly, 1 characteristic common to both of our pa-tients with polytrauma fulminant HO is the fact that theyrequired massive transfusions as part of their early resusci-tation. The potential for blood products to contain or toinduce various cytokines [17] may contribute to systemicinflammation as well as immunosuppression, thus contrib-uting to subsequent HO formation. Interestingly 1 cytokinein particular, interleukin 6, is associated with blood pro-ducts and has also been suggested as a marker for HOseverity [7]. Accordingly, an area of future research couldmore closely analyze blood products for markers related toosteogenic induction, especially when implicated cytokinesand chemokines have been further delineated.

Given this complex pathophysiology, prevention strate-gies can be challenging for all types of patients with HO butoften more so for patients with polytrauma. Current pro-phylactic options include nonsteroidal anti-inflammatorydrugs, radiation therapy, and bisphosphonates [1]. Nonste-roidal anti-inflammatory drug use and radiation therapytreatments are contraindicated for patients with polytraumabecause of poor bone and wound healing issues as well aspotential medical complications. Specifically, other well-known adverse effects, such as gastrointestinal, renal, orbleeding complications associated with the use of nonste-roidal anti-inflammatory drugs may not be tolerated in thispopulation. As Forsberg and Potter [9] report, bisphospho-nate use is ineffective because HO recurrence occurs aftercessation. Accordingly, there are no current effective pro-phylactic strategies for preventing combat-related HO.

CONCLUSION

We reported 2 cases of fulminant HO that impeded rehabili-tation efforts because of severe pain and ulceration, whichnecessitated excision earlier than in other reported cases.These cases highlight important associations of fulminant HOwith TBI, infections, blood transfusions, injury severity, andoverall systemic and localized inflammation. They alsodemonstrate the necessity for continued research directed atimproved pathophysiologic understanding of HO and, ulti-mately, developing novel prophylactic measures. In themeantime, such patients with fulminant HOmay benefit fromvery early partial surgical excision as a definitive pain reliefoption, which was effective for our patients in both instances.

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REFERENCES1. Potter BK, Burns TC, Lacap AP, Granville RR, Gajewski D. Heterotopic

ossification in the residual limbs of traumatic and combat-related am-putees. J Am Acad Orthop Surg 2006;14:S191-S197.

2. Forsberg JA, Pepek JM, Wagner S, et al. Heterotopic ossification inhigh-energy wartime extremity injuries: Prevalence and risk factors.J Bone Joint Surg Am 2009;91:1084-1091.

3. Potter BK, Burns TC, Lacap AP, Granville RR, Gajewski DA. Hetero-topic ossification following traumatic and combat-related amputations.prevalence, risk factors, and preliminary results of excision. J Bone JointSurg 2007;89:476-486.

4. Garland DE. A clinical perspective on common forms of acquiredheterotopic ossification. Clin Orthop Relat Res 1991;263:13-29.

5. Chalmers J, Gray DH, Rush J. Observations on the induction of bone insoft tissues. J Bone Joint Surg Br 1975;57:36-45.

6. Jackson WM, Aragon AB, Onodera J, et al. Cytokine expressionin muscle following traumatic injury. J Orthop Res 2011;29:1613-1620.

7. Evans KN, Forsberg JA, Potter BK, et al. Inflammatory cytokine andchemokine expression is associated with heterotopic ossification inhigh-energy penetrating war injuries. J Orthop Trauma 2012;26:e204-e213.

8. Shin E, Evans KN, Fleming ME. Injury severity score underpredictsinjury severity and resource utilization in combat-related amputations.J Orthop Trauma 2013;27:419-423.

9. Forsberg JA, Potter BK. Heterotopic ossification in wartime wounds.J Surg Orthop Adv 2010;19:54-61.

10. Chalidis B, Stengel D, Giannoudis PV. Early excision and late excisionof heterotopic ossification after traumatic brain injury are equivalent: Asystematic review of the literature. J Neurotrauma 2007;24:1675-1686.

11. Davis TA, O’Brien FP, Anam K, Grijalva S, Potter BK, Elster EA. Het-erotopic ossification in complex orthopaedic combat wounds: Quan-tification and characterization of osteogenic precursor cell activity intraumatized muscle. J Bone Joint Surg Am 2011;93:1122-1131.

12. Ahmed SI, Burns TC, Landt C, Hayda R. Heterotopic ossification inhigh grade open fractures sustained in combat: Risk factors and prev-alence. J Orthop Trauma 2013;27:162-169.

13. Pape HC, Lehmann U, van Griensven M, Gansslen A, von Glinski S,Krettek C. Heterotopic ossifications in patients after severe blunttrauma with and without head trauma: Incidence and patterns of dis-tribution. J Orthop Trauma 2001;15:229-237.

14. Hendricks HT, Geurts AC, van Ginneken BC, Heeren AJ, Vos PE. Braininjury severity and autonomic dysregulation accurately predict het-erotopic ossification in patients with traumatic brain injury. ClinRehabil 2007;21:545-553.

15. Cipriano CA, Pill SG, Keenan MA. Heterotopic ossification followingtraumatic brain injury and spinal cord injury. J Am Acad Orthop Surg2009;17:689-697.

16. Defense and Veterans Brain Injury Center. Defense Centers of ExcellenceFor Psychological Health and Traumatic Brain Injury; Case Managementof Concussion/Mild TBI Guidance Document. Available at http://www.dvbic.org/sites/default/files/u9/TBI_CM-SOP-2013revisions-V0%206_6-5-2013.pdf. Accesed November 20, 2013.

17. Bordin JO, Heddle NM, Blajchman MA. Biologic effects of leukocytespresent in transfused cellular blood products. Blood1994;84:1703-1721.