Albumin and the fibrinogen-to-albumin ratio: Biomarkers for the acute phase response following total knee arthroplasty.

PURPOSE: Complications following total knee arthroplasty (TKA) lead to patient morbidity and cost. While acute phase reactants, such as c-reactive protein (CRP) and fibrinogen, have been used to predict complications following TKA, the extent and duration of changes in albumin levels following TKA are unknown. It is hypothesized that like CRP and fibrinogen, albumin, and the fibrinogen/albumin ratio (FAR) represent useful measures of the acute phase response (APR) following TKA. The purpose of this study was to describe the longitudinal course of albumin and FAR in healthy patients following TKA, relative to established biomarkers, and examine if the variance in albumin or FAR correlates with patient comorbidities. METHODS: This retrospective cohort study of patients undergoing TKA at a tertiary medical center. CRP, fibrinogen, and albumin values were collected pre- and post-operatively. An age-adjusted Charlson comorbidity index (CCI) was utilized as a measure of patient comorbidity status. RESULTS: The median preoperative albumin value was 4.3 g/dL, which dropped to 3.6 g/dL on postoperative day 1 following TKA. The albumin value returned to 93% of the baseline by postoperative week 2. The course of albumin inversely mirrored the course of CRP (r = -0.41). Median preoperative FAR was 0.087 g/L, which rose to 0.130 g/L by postoperative week 2 and returned to baseline by postoperative week 6. While preoperative FAR strongly correlated with postoperative week 2 values (r = 0.74), there was a weak positive correlation between age-adjusted CCI and pre-operative FAR (r = 0.24) in patients undergoing primary TKA. CONCLUSION: Albumin levels follow a predictable postoperative decline that inversely correlates with CRP in healthy patients following TKA. Given the low cost and abundance of laboratories offering albumin levels, direct albumin levels and/or albumin ratios such as FAR may be underutilized biomarkers for monitoring the APR following TKA.

Novel preclinical murine model of trauma-induced elbow stiffness.

BACKGROUND: Peri-articular injury may result in functional deficits and pain. In particular, post-traumatic elbow stiffness is a debilitating condition, precluding patients from performing activities of daily living. As such, clinicians and basic scientists alike, aim to develop novel therapeutic interventions to prevent and treat elbow stiffness; thereby reducing patient morbidity. Yet, there is a paucity of pre-clinical models of peri-articular stiffness, especially of the upper extremity, necessary to develop and test the efficacy of therapeutics. We set out to develop a pre-clinical murine model of elbow stiffness, resulting from soft tissue injury, with features characteristic of pathology observed in these patients. METHODS: A soft tissue peri-elbow injury was inflicted in mice using cardiotoxin. Pathologic tissue repair was induced by creating an investigator-imposed deficiency of plasminogen, a protease essential for musculoskeletal tissue repair. Functional testing was conducted through analysis of grip strength and gait. Radiography, microcomputed tomography, and histological analyses were employed to quantify development of heterotopic ossification. RESULTS: Animals with peri-elbow soft tissues injury in conjunction with an investigator-imposed plasminogen deficiency, developed a significant loss of elbow function measured by grip strength (2.387 ± 0.136 N vs 1.921 ± 0.157 N, ****, p < 0.0001) and gait analysis (35.05 ± 2.775 mm vs 29.87 ± 2.075 mm, ***, p < 0.0002). Additionally, plasminogen deficient animals developed capsule thickening, delayed skeletal muscle repair, fibrosis, chronic inflammation, and heterotopic ossification; all features characteristic of pathology observed in patients with trauma-induced elbow stiffness. CONCLUSION: A soft tissue injury to the peri-elbow soft tissue with a concomitant deficiency in plasminogen, instigates elbow stiffness and pathologic features similar to those observed in humans. This pre-clinical model is valuable for translational studies designed to investigate the contributions of pathologic features to elbow stiffness or as a high-throughput model for testing therapeutic strategies designed to prevent and treat trauma-induced elbow stiffness.

Characterizing the Acute Phase Response in Healthy Patients Following Total Joint Arthroplasty: Predictable and Consistent.

BACKGROUND: During surgery, trauma to musculoskeletal tissue induces a systemic reaction known as the acute phase response (APR). When excessive or prolonged, the APR has been implicated as an underlying cause of surgical complications. The purpose of this study was to determine the typical APR following total joint arthroplasty in a healthy population defined by the Charlson Comorbidity Index (CCI). METHODS: This retrospective study identified 180 healthy patients (CCI < 2) who underwent total joint arthroplasty by a single surgeon for primary osteoarthritis from 2013 to 2015. Serial measurements of C-reactive protein (CRP) and fibrinogen were obtained preoperative, perioperative, and at 2 and 6 weeks postoperative. RESULTS: Postoperative CRP peaked during the inpatient period and returned to baseline by 2 weeks. Fibrinogen peaked after CRP and returned to baseline by 6 weeks. Elevated preoperative CRP correlated with a more robust postoperative APR for both total hip arthroplasty and total knee arthroplasty, suggesting that a patient's preoperative inflammatory state correlates with the magnitude of the postoperative APR. CONCLUSION: Measurement of preoperative acute phase reactants may provide an objective means to predict a patient's risk of postoperative dysregulation of the APR and complications.

Plasmin Prevents Dystrophic Calcification After Muscle Injury.

Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.

Elevated d-Dimer Is Not Predictive of Symptomatic Deep Venous Thrombosis After Total Joint Arthroplasty.

BACKGROUND: Serum d-dimer is a common screening test for symptomatic deep venous thrombosis (DVT) after total joint arthroplasty. This study characterized the longitudinal resolution of d-dimer measurements after total hip and knee arthroplasty (THA/TKA) over a 6-week period. The authors hypothesized that serum d-dimer would not return to baseline or be below the institutional threshold for a positive test at 6 weeks after uncomplicated total joint arthroplasty, suggesting that quantitative d-dimer has limited clinical utility for postoperative DVT screening. METHODS: An institutional review board-approved retrospective cohort study was conducted with consecutive patients between January 2013 and June 2015. A total of 177 adult patients aged 40-88 years who underwent a primary hip or knee arthroplasty with a Charlson Comorbidity Index <3 were included in the study. Serum d-dimer was measured at preoperative, perioperative, and postoperative 2- and 6-week time points. RESULTS: d-dimer measurements peaked 2 weeks postoperatively for both TKA and THA. At the 6-week time point, the peak serum d-dimer measurement resolved by 54.3% and 76.6% for TKA and THA, respectively. At 6 weeks after operation, 92% of THA patient and 100% of TKA patients had serum d-dimer measurements higher than the institutional threshold (0.40 µg/mL) for a "positive" quantitative test. No symptomatic DVTs were reported for the THA and TKA cohorts during the study period. CONCLUSION: The results suggest that serum d-dimer is an ineffective screening test for the diagnosis of symptomatic DVT in the acute postoperative period. The authors propose that extravascular fibrinolysis, a process essential for wound healing, has a crucial role in the prolonged elevation of serum d-dimer in the postoperative period.