Immune-mediated coagulopathy (IMC) is considered an under-recognized medical condition, and many orthopaedic surgeons are unaware of IMC1. To our knowledge, this case report illustrates the first published cases of this condition and its relevance to total knee arthroplasty and knee arthroscopy. All patients were informed that data concerning their cases would be submitted for publication, and they provided consent.
Case 1. An eighty-three-year-old man with no personal or family history of bleeding disorders had undergone staged bilateral total knee arthroplasty. Ten years later, the patient presented with pain in the left knee. Because of polyethylene-wear osteolysis, he underwent a revision arthroplasty. Postoperative medication included warfarin for deep vein thrombosis (DVT) prophylaxis. Four days after surgery, he was discharged to a rehabilitation center.
Ten days after the hospital discharge, the patient developed sanguineous drainage from the surgical incision. Upon readmission to the hospital, he had been on warfarin for fourteen days. Laboratory data showed an international normalized ratio (INR) of 2.8 and a prothrombin time of 30.9 seconds (normal, 11.5 to 15 seconds). The partial thromboplastin time was elevated at 67.7 seconds (normal, 22.4 to 36.9 seconds). At that time, all anticoagulation medications were discontinued. Vitamin K and fresh-frozen plasma were administered to correct the prothrombin time and the partial thromboplastin time, but they were ineffective. The hemoglobin level fell to 6.0 g/dL, and he was treated with multiple transfusions. On the fifteenth day of hospitalization after readmission, the patient underwent surgery for evacuation of a large hematoma and debridement of necrotic tissue; he was administered enoxaparin for DVT prophylaxis. Serum studies identified that he was positive for the lupus anticoagulant, and he had a low-titer factor VIII inhibitor. This led to the hematologist’s diagnosis of acquired IMC, and the patient was treated with factor VIII inhibitor bypass activity (FEIBA) and rituximab, which stabilized the hemarthrosis.
One month later, the patient presented to the emergency room with another knee hemarthrosis that he had developed after a fall. The patient was not on FEIBA or rituximab at the time of the fall. He refused additional surgical intervention. Aspiration cultures were positive for Staphylococcus epidermidis. The Infectious Disease Service treated him with intravenous vancomycin and cefepime for six weeks, with the intent of prescribing lifelong oral-suppression therapy. The patient returned to the extended care facility, and approximately one month later, he was readmitted to the hospital with an infected left total knee arthroplasty, with extensive necrosis that included the quadriceps tendon. He agreed to and underwent resection arthroplasty. This hospital stay was complicated by delirium, respiratory distress, and worsening renal function. At the request of the family and the patient, he was discharged with hospice care after a month-long hospitalization, and he ultimately died.
Case 2. A sixty-six-year-old man had undergone a routine elective total knee arthroplasty and was discharged four days postoperatively on warfarin therapy (7 mg daily) for DVT prophylaxis. Three weeks later, the patient presented to the emergency room with wound dehiscence and a substantial hematoma. Because the INR was 3.8, the warfarin was withheld. Culture specimens were positive for Pseudomonas aeruginosa, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus. He was treated by the Infectious Disease Service with intravenous daptomycin and cefepime.
The medical history did not reveal any previous bleeding disorders. Attempts to normalize the INR were unsuccessful, despite the use of several doses of vitamin K and ten units of fresh-frozen plasma. Thorough laboratory evaluation revealed a factor VII inhibitor, and the patient was treated with observation.
Five days later, the patient underwent operative debridement, explantation, and placement of an antibiotic-impregnated spacer; he was discharged two weeks following the procedure. Prior to surgery, the INR had been 2.1. Five days after this surgery, the patient returned to the emergency room with a dehiscence of the inferior aspect of the wound. The INR was mildly elevated at 1.5, even though he had been off warfarin for several weeks.
Over the next several months, the patient was admitted to the hospital on three different occasions. During this time, the Hematology Service continued to monitor the acquired factor VII inhibitor disorder. The patient continued to decline medically, and despite the current care, he had a persistently draining wound. The recommendation at that time was for an above-the-knee amputation. However, he refused such intervention and ultimately decided to seek care in another state.
Case 3. A thirty-eight-year-old man had undergone an uncomplicated outpatient knee arthroscopy for a meniscal tear. On postoperative day five, the patient presented to our office with sanguineous discharge from the portal sites. Surgical evacuation of a hematoma was performed without complication, and the culture results were positive for Staphylococcus aureus. An additional debridement was performed with a complete synovectomy. The patient was placed on intravenous oxacillin and was seen by the Hematology Service. Although the patient denied any previous history or family history of bleeding disorders, a low-titer factor VIII inhibitor disorder was found during the workup. One week after the synovectomy, he was readmitted to the hospital because of increased pain and swelling. Upon discharge, he was on intravenous vancomycin therapy at home for six weeks. He ultimately did well with no additional sequelae. He regained knee motion, and the hemarthrosis resolved without any specific hematologic treatment.
We report three cases of patients who presented with recurring hemarthrosis following elective knee surgery. While postoperative bleeding may result from a number of issues, it was determined that all three of these patients, who had no prior history of blood disorders, had developed IMC, which was manifested as exaggerated laboratory coagulation values that continued even after discontinuation of oral anticoagulation, treatment with multiple transfusions of fresh-frozen plasma, vitamin K administration, or factor assays.
IMC can result from inhibition of clotting factors after exposure to nonhuman coagulation proteins such as bovine thrombin2. In our patients, previous exposure to bovine thrombin was unknown, but it may have been likely since topical bovine-derived thrombin has been used as a hemostatic agent in a number of different surgical procedures.
Two of these cases involved the development of a low-titer factor VIII inhibitor. One was treated with FEIBA and rituximab, and the other resolved without the use of specific hematologic treatment.
Acquired IMC is an immune-mediated bleeding diathesis that results from the production of inhibitors, primarily consisting of polyclonal immunoglobulin G autoantibodies3, which typically interfere with the normal clotting properties of factor VIII4. The occurrence of acquired IMC is infrequent, with an incidence of only one to four cases per million per year5. This diagnosis should be contemplated in patients with sudden onset of bleeding who have no personal or family history of coagulopathy6. Most cases of acquired factor VIII inhibitors are idiopathic, but they may be associated with recent exposure to a surgical procedure, the postpartum state, malignancy, drugs, or other autoimmune disorders7. Laboratory findings usually include an elevated partial thromboplastin time, a normal bleeding time, a normal prothrombin time, a decreased factor VIII level, and the atypical presence of factor VIII inhibitors8. Onset usually occurs after the age of fifty9. Treatment objectives are to stop acute bleeding episodes and eliminate factor VIII autoantibodies10,11.
Products that consist of variable amounts of deliberately activated vitamin K-dependent factors have been used to bypass the need for factor VIII activity. One example is FEIBA, which has been used for over thirty years for the treatment of patients with factor VIII inhibitors; it provides good-to-excellent hemostatic efficacy in 89% of bleeding events12-14.
The function of T lymphocytes in the pathogenesis of autoimmune diseases is well established; however, more recent data suggest that B cells also play an important role in supporting the development and perpetuation of autoimmunity15,16. Rituximab is a monoclonal antibody that works against CD20, the pan-B cell antigen that induces a rapid in vivo reduction of normal B lymphocytes17. Because of its efficacy on B-lymphocyte reduction, rituximab has been considered a new and very promising therapeutic strategy in the treatment of acquired IMC18,19. Rituximab has proven to be safe and highly effective in eliminating low titers of factor VIII inhibitors (<100 BU/mL). For patients with an inhibitor titer of more than 100 BU/mL, a combination of prednisone with cyclophosphamide or other cytotoxic drugs should be initiated9.
The patient in Case 2 developed an immune-mediated factor VII inhibitor. Factor VII is a vitamin K-dependent zymogen, which when activated, binds to tissue factor (TF), a transmembrane protein strongly expressed by cells in the adventitia of blood vessels. The TF-VII(a) pathway is now known to be a leading hemostatic mechanism20. Possible mechanisms for disruption of this system include inhibitors of factor VII or activated factor VII function, inhibitors that accelerate factor VII clearance, or granulocyte-associated proteases that cleave factor VII21.
In conclusion, IMC is a rare disorder that disrupts coagulation factors. To our knowledge, there are no other cases in the orthopaedic literature regarding IMC and its relation to elective knee arthroplasty and arthroscopy.
Note: The authors would like to acknowledge Thomas O. Schwab, MD, and John McClure, MD, for their assistance in providing patients for this report.
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.