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Hemophilia A is a rare genetic disorder involving a deficiency of clotting factor VIII. Coagulation factor replacement therapy has prolonged the life expectancy of patients with hemophilia, but recurrent hemarthrosis of major joints is often a common occurrence. Therefore, orthopaedic adult reconstructive surgeons increasingly encounter hemophilic arthropathy in young adults and consider treating with total joint arthroplasty. In this report, the authors describe a patient with hemophilia A and severe knee osteoarthritis, who was subsequently treated with primary total knee arthroplasty. This rare case is an opportunity to explore a variety of unique clinical scenarios specific to patients with hemophilia, including the maintenance of optimal factor VIII levels through clotting factor infusions and prevention of a venous thromboembolic event.
Hemophilia A and B are rare, inherited bleeding disorders that occur owing to mutations in the factor VIII or factor IX gene, respectively. Each of these clotting factors plays a role in the intrinsic pathway of blood coagulation [
]. These disorders are known to be X-linked recessive and are thus much more commonly seen in males. The prevalence of hemophilia A is approximately 1 in 5000 male live births and that of hemophilia B is about 1 in 30,000 male live births [
Lifelong factor replacement therapy is essential to increase life expectancy and minimize complications, including musculoskeletal bleeding. However, such orthopaedic complications may still occur due to suboptimal dosing of factor therapy, poor medication adherence, or the development of inhibitors (antibodies that target factor VIII or factor IX) [
]. As a result, patients with hemophilia may develop orthopaedic manifestations such as hemarthrosis. Repeated bleeding into the joints, most commonly the ankle, elbow, and knee, leads to cartilage damage and degenerative articular changes, potentially leading to severe osteoarthritis [
Given the consequences of hemophilia on articular tissues, elective procedures such as arthroscopic synovectomy, osteotomy, arthrodesis, arthroplasty, and revision arthroplasty may be considered in select patients [
]. As the life expectancy for patients with hemophilia continues to improve with medical advancements, orthopaedic surgeons may be increasingly tasked with performing elective total joint arthroplasty in these patients.
Surgery in patients with hemophilia is challenging given the high risk of bleeding and infection [
]. The purpose of this article is three fold: (1) to outline the clinical course of a patient with hemophilia A who underwent elective total knee arthroplasty (TKA), (2) to review the reported outcomes of total joint arthroplasty for hemophilic arthropathy, and (3) to describe the clinical and surgical considerations for managing these patients.
A 24-year-old man with moderate hemophilia A (factor VIII deficiency) and history of recurrent hemarthroses presented to the arthroplasty clinic for evaluation of right knee pain. His baseline factor VIII level was 3%, and he had no history of a factor VIII inhibitor. His chief complaints included left ankle pain and right knee pain spanning a few years. He denied pain in his left knee or either hip. To ambulate, he used 2 crutches and an Arizona ankle brace (ArizonaAFO, Inc., Mesa, AZ) due to pain. At this time, he was receiving antihemophilic factor recombinant (Kogenate, Bayer Pharmaceuticals, Leverkusen, Germany) 4000 units (±10%) infusions 3 times weekly at the recommendation of his pediatric hematologist. On physical examination, he walked with an antalgic gait and could not rise from a seated position without using his hands to push off for assistance. He lacked 20 degrees of flexion and did not exhibit any apparent valgus or varus deformity. A radiograph of the right knee demonstrated well-preserved joint space with some arthritic changes. A magnetic resonance imaging examination without contrast showed tricompartmental arthritis with erosive changes and extensive hemosiderin deposition lining the joint (Fig. 1). Given his World Health Organization (WHO) classification of morbid obesity (BMI: 42.43), the patient was advised to undertake conservative measures such as physical therapy, weight loss, and exercise to optimize his health before considering total joint arthroplasty.
Approximately 2 years later, he returned to the clinic and expressed that his right knee discomfort had become refractory to conservative measures and thus requested consultation to proceed with surgical intervention. At this time, his BMI had decreased to 39.14, and he was now taking antihemophilic factor recombinant (Eloctate, Bioverativ Therapeutics Inc., Waltham, MA) 4500 units 2 times weekly. Approximately 5 months before this presentation, the patient's regimen was changed from Kogenate to Eloctate—an extended half-life antihemophilic recombinant factor VIII product. The transition to Eloctate decreased the frequency of his infusions from 3 times weekly to 2 times weekly.
On physical examination, he had increased difficulty transitioning from chair to standing. Range of motion progressed from full extension to approximately 120 degrees of gross flexion. A mild knee effusion was present. Updated radiographs of the right knee demonstrated joint space narrowing and cystic changes beneath the joint line, suggesting progressively worsening tricompartmental osteoarthritic degenerative changes (Fig. 2).
Given the fact that his symptoms had worsened, radiographs suggested further arthritic damage, and he had failed conservative management, the option of surgical intervention was reviewed with the patient. The risks, benefits, and alternatives to TKA were discussed with the patient. Short-term risks included hemarthrosis in the knee joint, wound drainage, and infection. Long-term risks included uncertainty concerning the longevity of the implants in younger patients and the possibility of subsequent revision surgeries. Although previous reports have assessed longevity of TKA implants overall, the lifespan of implants in younger patients is not well studied. The 20-year TKA implant survival rate is estimated to be 89.7%, with the lifetime revision rate for males 50-54 years of age (the youngest age group studied in this investigation) is estimated to be 29.6% [
], the standardized preoperative, intraoperative, and postoperative protocols would need to be adjusted. For this reason, a team-based approach was used to optimize the clinical management of the patient. In the weeks before the surgery, the pediatric hematology team at our institution recommended that the patient remain on Eloctate 4500 units twice weekly until surgery to protect against bleeding. Ten days before surgery, the patient completed a pharmacokinetic (PK) study using antihemophilic factor recombinant (Kogenate) 5000 units (±10%). This allowed the hematology team to create an individualized plan for the dosing and frequency of factor VIII infusions to assure adequate hemostasis during and after the procedure. Kogenate was used (rather than Eloctate) as the former product is on formulary at our institution and the patient had a 20-year history of good response to this agent. Finally, the patient was advised to stop all over-the-counter nonsteroidal anti-inflammatory drugs and vitamins 7 days before surgery per standard protocol.
Immediately before surgery, the patient received a preoperative dose of antihemophilic factor recombinant (Kogenate) 5000 units (±10%). The hematology team recommended that pharmacologic venous thromboembolic event (VTE) prophylaxis was not to be given as the risk for bleeding was greater than the risk for either a deep venous thrombosis (DVT) or fatal pulmonary embolism. However, intermittent pneumatic compression devices (IPCDs) were recommended to be used perioperatively and postoperatively. Intraoperatively, an additional dose of Kogenate was available in case of unexpected or excessive bleeding.
Postoperatively, the hematology team recommended measuring the factor VIII activity level, and a regimen of Kogenate 5000 units every 8 hours for the first 24 hours after surgery. On the first day after surgery (postoperative day 1), the patient's Kogenate 5000 units infusion frequency was anticipated to be changed to once every 12 hours and titrated based on his recorded factor VIII trough levels. The dose of the Kogenate infusion was anticipated to be titrated to maintain a factor VIII level of greater than 80% 3 days postoperatively and greater than 50% for the remainder of the in-patient hospitalization. Discharge was anticipated when the patient exhibited a stable hemoglobin level, postoperative hemostasis was assured, and adequate factor VIII levels were consistently obtained. At discharge, the infusion protocol was developed by our Hemophilia Treatment Center team. In addition, nonsteroidal anti-inflammatory drugs were not given for pain control due to their anti-platelet effect.
On the day of surgery, the patient received 2 grams of intravenous (IV) cefazolin, 160 mg of IV gentamicin, and 1 gram of IV tranexamic acid before incision. Preoperative examination under anesthesia of the right knee demonstrated range of motion of 0 to 110 degrees, with 5 degrees of passively correctable varus. In addition, it was noted that there was no tibial or femoral deformity present that would preclude the use of intramedullary guides. A tourniquet was placed appropriately before the surgery. A medial parapatellar arthrotomy was performed to expose the knee joint. On entering the knee, we observed significant cartilage wear in addition to tricompartmental osteoarthritis. There was also abundant synovial hypertrophy with hemosiderin staining. Fronds of synovium were systematically debrided and sent to pathology (Figure 3, Figure 4), which were consistent with changes seen with recurrent hemarthroses.
When the prosthetic implants were placed, final range of motion was 0 to 130 degrees with smooth patellar tracking and well-balanced collateral ligament stability at 0, 30, 45 and 90 degrees. Meticulous hemostasis was obtained after final tourniquet release. Once the capsule was closed in a watertight manner, 1 gram of intra-articular tranexamic acid (TXA) was injected into the joint for topical hemostasis. After the surgery, he was placed in a compressive dressing with a knee immobilizer, and IPCDs were appropriately applied. Postoperative radiographs demonstrated successful prosthesis placement (Fig. 5).
Postoperatively, the patient was given a dose of 2 grams of IV cefazolin. His postoperative factor VIII levels were noted to be 134%. The patient's Kogenate infusion frequency followed the anticipated postoperative protocol of every 8 hours for the first 24 hours after surgery. On the first postoperative day, he was transferred to our local sister hospital which houses both the special coagulation laboratory and the Hemophilia Treatment Center staff, thereby facilitating closer clinical and laboratory monitoring. The patient continued to receive Kogenate 5000 units ±10% as per the original protocol until postoperative day 3, when his factor VIII level was noted to be 171%. At the guidance of the Hemophilia Treatment Center team, his infusion protocol was then adjusted to Kogenate 3500 units ±10% twice a day. On the fourth postoperative day, his knee immobilizer was removed, and gentle active seated knee range of motion was initiated. On the fifth postoperative day, he was discharged. It was decided that this infusion protocol be adjusted to Kogenate 5000 units ±10% once a day for the week after discharge. One week after discharge, his protocol was changed to Kogenate 5000 U ±10% every other day and before physical therapy sessions. One month after discharge, the same regimen was maintained, with the adjustment of the dosage to Kogenate 3000 units ±10%.
During his hospitalization, early ambulation was encouraged by the in-patient physical therapy team, and IPCDs were used for DVT prophylaxis. He received Tylenol as needed for pain management, and all nonsteroidal anti-inflammatory drugs were avoided. Furthermore, on discharge, the patient was advised to avoid all elective dental procedures for 6 months.
Pathologic review of the specimens collected intraoperatively (Figure 3, Figure 4) revealed synovial cell hyperplasia and deposition of hemosiderin pigment.
At 2 weeks postoperatively, his antimicrobial occlusive dressing was removed, and skin staples were removed. At the 6-week postoperative follow-up appointment, the patient stated that his right knee pain had resolved and that he was able to ambulate independently. He also denied any bleeding or discharge from the incision site since the day of surgery. Follow-up anteroposterior and lateral radiographs were ordered (Fig. 6) and noted that the implants remained in acceptable position. He exhibited nonpainful range of motion from 0 to 108 degrees of flexion.
In this article, we present a patient with hemophilia A who underwent right TKA. This case raises several special considerations regarding preoperative, perioperative, and postoperative management.
TKA in patients with hemophilia has been shown to be effective and to significantly improve quality of life [
]. The prevalence of infection after primary TKA in patients with hemophilia ranges from 0 to 17% in the literature, which is higher than the reported prevalence of 1-2% seen in TKA patients who do not have hemophilia [
] suggested that patients with hemophilic arthropathy may be at higher risk of an intraoperative popliteal artery injury. Another investigation found an overall complication rate (major and minor, including infection) of 31.5% in patients with hemophilic arthropathy undergoing TKA [
The hematologic protocols from our institution highlight the importance of adjusting daily infusions based on daily factor VIII trough levels. Some centers have optimized factor levels by using a pharmacokinetic-guided, maximum a posteriori Bayesian analysis to adjust the clotting factor infusion dosage on a day-to-day basis [
]. In addition, optimizing factor VIII levels in patients with hemophilia undergoing TKA is of utmost importance in reducing the rates of bleeding as well as infection. In fact, postoperative clotting factor levels of 100% have been associated with a decreased infection and failure rate [
]. The optimal target clotting factor level after TKA, however, has been subject to discussion in the hemophilia population. Various studies have reported different postoperative clotting factor target levels after TKA. In a meta-analysis of studies assessing hemophilia patients undergoing TKA [
]. In these reports, a taper was subsequently applied for a hospitalization longer than 1 week.
Our case also shows the importance of using intra-articular TXA to decrease intraoperative and postoperative bleeding risk in the hemophilia population. A prior investigation of 34 patients with hemophilia undergoing TKA showed that a combination of IV and intra-articular TXA significantly reduced perioperative blood loss, transfusion rates, and postoperative knee swelling [
]. This referenced study also showed that that total amount of factor VIII administered postoperatively was reduced in cases using TXA.
Although the use of DVT prophylaxis is of standard protocol in most patients undergoing total joint arthroplasty, the hemophilia population represents a unique cohort in which the risk of bleeding with pharmacologic DVT prophylaxis must be weighed with the risk of venous thromboembolism. The incidence of major bleeding in patients with hemophilia undergoing total hip arthroplasty or total knee arthroplasty in the setting of low-weight molecular heparin use is estimated to be 50% [
]. Weighing the risk of surgical site bleeding against risk of DVT/pulmonary embolism is challenging. As DVTs typically occur more frequently in older patients, nonpharmacologic VTE prophylaxis may be preferred over chemoprophylaxis in the generally younger population of patients with hemophilia undergoing TKA [
]. However, in older patients or patients with additional comorbidities, VTE chemoprophylaxis may be considered on a case-by-case basis.
Current controversies and future considerations
The optimal clotting factor type, dosing protocols, and target factor levels in the perioperative and postoperative period for patients with hemophilia undergoing TKA have been a subject of debate and several controversies exist. Currently, there is no definitive clotting factor infusion protocol for patients with hemophilia undergoing TKA. Therefore, investigations should be performed to determine optimal dosing regimens and narrow factor level target ranges to prevent the catastrophic complication of hemarthrosis. Furthermore, an improved understanding of the risk of pharmacologic VTE prophylaxis in patients with hemophilia undergoing TKA may be warranted for different age groups. The question of whether nonpharmacologic prophylactic measures are acceptable for higher-risk patients (such as older patients or patients with other conditions such as obesity or malignancy) should be investigated further across a larger sample size. For our patient, the use of IPCDs and early ambulation was used as the risk for major bleeding and infection was felt to outweigh the risk for VTE.
Medical innovations in the clinical management of patients with hemophilia A or B have allowed for greater survival and improved quality of life, but recurrent hemarthrosis of major joints remains a common problem, leading to hemophilic arthropathy of the knee, ankle, and elbow. As a result, there is likely to be a higher incidence of total joint arthroplasty in this patient population at a young age. Given the associated increased risks of revision, loosening, and infection, patients with this disorder warrant additional precautions and planning in the perioperative and postoperative periods. One should medically optimize the patient and take great care to avoid the complications of major bleeding or infection by optimizing factor VIII levels in the perioperative period. During surgery, meticulous hemostasis must be obtained at each step of the surgical exposure, using electrocautery, canal plug(s), and TXA. Knee compression and an initial period of immobilization for 5-7 days should be considered to reduce the risk of postoperative hemarthrosis, and the surgeon should likely avoid VTE chemoprophylaxis in low-risk patients. Establishing close collaboration and co-management strategies with an expert hematology team are critical to ensure the safety of the procedure, and long-term maintenance of factor VIII level is also needed to help prevent future hemarthrosis in the knee joint after arthroplasty.
In patients with hemophilia, there is a high risk for recurrent hemarthroses of major joints, which may eventually lead to hemophilic arthropathy and the need for joint replacement.
Clotting factor infusion protocols should be developed in collaboration with the institution's hematology staff to minimize risk of bleeding. In the perioperative period, dosing amount and frequency should be titrated based on daily factor VIII levels.
If possible, chemoprophylaxis for venous thromboembolic events can be avoided given the high risk of major bleeding and hemarthrosis at the surgical site. Instead, nonpharmacologic prophylaxis including IPCDs and early ambulation can be used.
Which joints are most commonly affected by osteoarthritis in patients with hemophilia?
Knees and hips
Ankles and knees
Hips, elbows, and shoulders
Knees, ankles, and elbows
Answer E: Based on literature and clinical findings, the knees, ankles, and elbows are the most commonly affected joints in hemophilic arthropathy.
For most patients with hemophilia, what is the preferred means of postoperative venous thromboembolic event prophylaxis in patients with hemophilia?
Low-weight molecular heparin
IPCDs and nonpharmacologic means of prophylaxis
Answer C: Given the high risk of intraoperative and postoperative bleeding (and the ensuing risk for infection), nonpharmacologic means of DVT prophylaxis is preferred. The key to this question is the use of “most.” Some patients may be deemed high risk for developing a DVT, and thus, the choice for using chemoprophylaxis must be performed on a case-by-case basis.
On sending the synovium from a patient with hemophilia undergoing TKA to pathology, what would be the pigment isolated?
Answer B: On pathology analysis, patients with hemophilia will have hemosiderin lining the synovium in the setting of hemarthrosis.
Past, present and future of hemophilia: a narrative review.
One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.artd.2019.12.008.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.