Hemarthrosis

Etiology

Hemarthrosis can occur in a variety of diseases and disorders, but it is most commonly classified into 3 categories: traumatic, nontraumatic, and postoperative. Traumatic injury is the most common cause of hemarthrosis. Nontraumatic hemarthrosis can be caused by a variety of bleeding disorders that are either hereditary or acquired. Hereditary bleeding disorders include hemophilia and other inherited coagulation factor deficiencies, such as factor XI deficiency.[1][2] Examples of acquired bleeding disorders include advanced liver or renal disease, vitamin K deficiency, disseminated intravascular coagulation, or anticoagulation medication use. Other, rarer causes of nontraumatic hemarthrosis include:

• Neurologic: Reflex sympathetic dystrophy, diabetic neuropathic arthropathy 
• Infectious: Septic bacterial arthritis
• Vascular: Vitamin C deficiency, ruptured peripheral artery aneurysms, osteoarthritis (degenerative tears of peripheral arteries associated with a posterior horn of the lateral meniscus)
• Neoplasms: Benign synovial hemangiomas, pigmented villonodular synovitis, or any malignant tumor arising near a joint cavity or metastatic [3][4]

Postoperative recurrent hemarthrosis is frequently associated with total knee arthroplasty and has also been described as an uncommon complication following arthroscopy.[5]

Epidemiology

The exact prevalence of hemarthrosis among individuals with hemophilia is unknown; however, reports suggest that up to 50% experience hemarthrosis at some point in their lifetime. Joint trauma increases the chance of developing hemarthrosis in this population.[6] Based on a cohort study of 1145 consecutive patients who developed a traumatic hemarthrosis of the knee, approximately half had an anterior cruciate ligament (ACL) injury, and the annual incidence of ACL injury was 77 per 100,000 inhabitants, with a significant difference between men (91 per 100,000) and women (63 per 100,000). In those 16 years of age or younger, lateral patellar dislocation was the most frequent structural injury associated with traumatic hemarthrosis of the knee both in boys (39%) and girls (43%); in this age group, the annual incidence of lateral patellar dislocation was 88 per 100,000 and higher in boys (113 per 100,000) than girls (62 per 100,000).[7]

Pathophysiology

The cascade of inflammatory events that contribute to chronic osteoarthritic injury is complex.[8][9][10] An impaction or traumatic event can trigger a cyclical inflammatory response progressing to arthrosis.[8][9] This process involves damage to the extracellular matrix of the cartilage and irreversible chondrocyte necrosis. Matrix disruption leads to joint derangement, including collagen fibrillation, release of glycosaminoglycans (GAGs; sugar chains in connective tissue), and other pro-degenerative substances. Altogether, this cartilaginous detritus, this debris, interacts with chondrocytes, osteoblasts, macrophages, fibroblasts, and immune cells (eg, primarily T-cells).

Subsequently, there is a release of an inflammatory cytokine flurry of interleukin (IL)1, IL4, IL6, IL8, IL17, tumor necrosis factor (TNF)-α, cathepsins (involved with bone resorption), and complement factors. Also released are proangiogenic factors (eg, vascular endothelial growth factor) by CD69+ cells (macrophages/monocytes), thereby promoting synovial vascularization.[11] These compounds further assault the synovial cells and chondrocytes in the area, leading to further cartilage degradation. Synovitis is characterized by hyperplasia, vascularization, villi formation, and fibrin deposition, which, along with the presence of macrophages, releases transforming growth factor-β and other proteins, thereby setting the area up for rebleeding. The result is the formation of osteophytes.

Additionally, erythrocyte degradation from hemarthrosis contributes to joint pathology. With the dissolution of the joint blood, heme is released via macrophages and monocytes. The heme permeates the synovium, overwhelming its capacity to remove it and thus leaving the synovium laden with hemosiderin. This predisposes the cartilage to breakdown and causes synovial hyperplasia with neoangiogenic vessels that are frail and predisposed to bleeding at the site. There is increased joint effusion with capsular distension, thus, pain. Concurrent with the red cell/heme damage, monocytes and macrophages also create toxic matrix metalloproteases and hydroxy radicals. These substances are caustic to chondrocytes, causing their apoptosis. There is also a significant cytokine release. There is a cumulative and irreversible cartilaginous and articular damage due, in part, to a progressive and often irreversible impairment of proteoglycan synthesis. Contractures may occur, and arthrofibrosis is likely to occur. 

Traumatic hemarthrosis typically occurs in the setting of intra-articular injury with ligamentous, osseous, and/or cartilage damage leading to a bloody synovial fluid collection.[12] Postoperative hemarthrosis from total knee arthroplasty has been attributed to the development of intra-capsular vascular tissue, which subsequently causes bleeding into the joint after joint replacement surgery. Lipohemarthrosis develops from marrow fat leakage into the synovial fluid, usually resulting from intracapsular fractures or extensive intra-articular soft tissue injury (see Images). Lateral Knee Showing Lipohemarthrosis, Radiograph; Lateral Knee Fracture With Lipohemarthrosis, Radiograph; and Knee Showing Nondisplaced Patellar Fracture With Lipohemarthrosis, Computed Tomography).[13] 

Histopathology

The histopathology of hemophilic arthropathy can be divided into early and late disease characteristics. In early disease, there is synovial hypertrophy and fibrosis, which displays changes similar to rheumatoid arthritis. Progression of the disease shows disruption of cartilage and subchondral cyst formation from interosseous bleeding. The intra-articular bleeding has direct toxic effects, leading to the destruction of cartilage and bone. Iron in the form of ferric citrate stimulates human fibroblast cells to proliferate. Studies involving mice imply hemarthrosis leads to blood vessel hyperplasia, which may explain the predisposition for hemophiliacs to experience recurrent intra-articular bleeding.[14][15]

Toxicokinetics

Rodenticides are superwarfarins that, upon ingestion, can cause spontaneous bleeding in multiple sites, including acute hemarthrosis. Patients can be asymptomatic up to 72 hours after ingestion. Gastrointestinal symptoms can be present early in the course of poisoning, and spontaneous bleeding can present as early as 8 hours after exposure. Treatment involves the intensive administration of Vitamin K1.[16]

History and Physical

In most patients, particularly those without underlying neurologic sensory deficits or bleeding disorders, the cause of hemarthrosis is usually apparent from the history, as it often follows a clearly recognized traumatic event. Following an injury with intra-articular damage, the swelling from bloody synovial fluid accumulation is typically rapid within a few hours. Pain is a significant component; however, it may take time to develop, or may be minimal or absent in patients with preexisting impaired sensation. The range of motion of the affected joint is typically significantly reduced.

Certain locations and types of injury following a traumatic incident are more likely to develop a hemarthrosis. Intra-articular elbow fractures, including those of the radial head, are consistently associated with hemarthrosis. The knee is a frequent site of hemarthrosis, with the most common mechanism being forced twisting of the loaded joint. The majority of these posttraumatic hemarthroses are from ligamentous and meniscal damage. Anterior cruciate ligament (ACL) tears are the most common, representing 70% of posttraumatic hemarthrosis of the knee, followed by 10% to 15% patellar subluxation/dislocation injuries, 10% from meniscal tears, 2% to 5% from osteochondral fracture fragments, and 5% represented by other injuries, including posterior cruciate ligament or capsule tears. Depending on the site and kind of injury, tenderness to palpation of the joint lines or patella may be present, and clinical tests for joint laxity may be positive.[17]

Lipohemarthrosis indicates a fracture with intra-articular extension or significant intra-articular soft tissue injury, such as ligament or meniscus. If a lipohemarthrosis of the knee is identified, suspect in order of likelihood:

• Tibial plateau fracture: Lateral plateau fractures are often associated with ACL and the medial collateral ligament injuries.
• Tibial spine avulsion: The anterior attachment point of ACL, which is more common in young patients who have tougher ligaments than bones.
• Femoral condyle fracture: This is associated with popliteal artery and fibular nerve injury, although uncommon.

If hemarthrosis occurs spontaneously or after minimal trauma, bleeding disorders such as hemophilia should be suspected. Hemarthrosis is the most common musculoskeletal manifestation of hemophilia. Severe hemophilia (less than 1% of normal factor activity) causes hemarthrosis in 75% to 90% of patients, with the first attack typically occurring between the ages of 2 and 3. Any joint can be affected; however, the knee is the most common site. Patient history regarding family history, extensive or prolonged bleeding during or after surgery, use of anticoagulant medications, and diet habits should be elicited to help determine whether the presence of a bleeding diathesis exists.[18]

Clinical presentation of hemophilia with hemarthrosis can vary by age. In adults and older children, a prodromal stiffness or tingling typically precedes pain and swelling. In infants, signs of hemarthrosis may include irritability and decreased use of the affected limb. Bleeding into the hip joint is concerning due to the greater risk of increased intra-articular pressure and osteonecrosis of the femoral head. In hemophilic hemarthrosis, one joint is typically affected at a time; however, bilateral joint involvement is possible.[18][19]

Evaluation

A suspected hemarthrosis can be evaluated by plain radiographs, computed tomography scan, or MRI. The preferred initial imaging modality is film radiology of the involved joint and surrounding bones. Further evaluation with a computed tomography scan is warranted if a fracture is not seen but strongly suspected. MRI may be able to diagnose ligamentous or other soft tissue injuries as the cause of hemarthrosis. Ultrasound in the right clinical setting can help identify and characterize intra-articular fluid collections.[20]

Arthrocentesis and joint aspirate fluid analysis may be required for a definitive diagnosis. The synovial fluid from a hemarthrosis may appear red, pink, or brown, depending on the cause of bleeding. Joint aspiration and subsequent analysis can differentiate simple effusion, hemarthrosis, lipohemarthrosis, and septic arthritis. Arthrocentesis can also significantly relieve pain. The presence of lipid globules in the aspirate represents a lipohemarthrosis.

If the initial synovial fluid aspirate is nonbloody but bright red blood soon appears after withdrawing fluid, this indicates a traumatic hemarthrosis. A true hemarthrosis typically does not clot due to fibrinolysis, compared to a bloody aspirate from traumatic aspiration that does coagulate. Centrifugation of the synovial fluid aspirate and examination of the supernatant may also help discern the difference between true hemarthrosis and traumatic aspiration. A true hemarthrosis will display a serous appearance of the synovial fluid supernatant with xanthochromia.[21]

Lipohemarthrosis can be detected using arthrocentesis, plain radiographs, computed tomography scans, MRI, and, in a minority of patients, ultrasound. A linear interface between 2 different densities with an effusion suggests lipohemarthrosis. This feature results from the entry of marrow fat into the joint cavity and is highly suggestive of an intra-articular fracture. One series demonstrated that 65% of patients with intra-articular fractures did not have fat-fluid levels on plain radiographs; however, all patients with lipohemarthrosis visible on plain radiographs were found to have intra-articular fractures. On plain radiographs, a single fluid-fluid level, representing layering of blood and fat, can suggest lipohemarthrosis, although it may occur even without visible fat globules. A double fluid-fluid level, showing layering of fat, blood, and serum, is specific for lipohemarthrosis and can be observed on ultrasound, computed tomography, or MRI.

The sonographic finding of lipohemarthrosis may be used as a sensitive surrogate marker for intra-articular fracture. When used alone for the evaluation of acute knee trauma, plain radiographs can miss up to 21% of fractures. Suppose a lipohemarthrosis is identified on either plain film or ultrasound. In that case, there should be a high suspicion for an occult fracture, which should prompt further evaluation with a computed tomography scan.[22][23]

Treatment / Management

Treatment of hemarthrosis involves general measures applicable to any acute episode and interventions targeting the underlying cause. Initial management of acute hemarthrosis includes immobilization, ice, and compression. Analgesics may be used for pain control, particularly to facilitate diagnostic imaging. Arthrocentesis serves a dual role, providing diagnostic information and therapeutic relief by reducing joint pressure from the effusion.[24]

Clinically significant hemarthrosis is rare in patients receiving therapeutic anticoagulation, and these patients typically tolerate arthrocentesis. In the uncommon cases of persistent or recurrent hemarthrosis, treatment options may include clotting factor repletion with fresh frozen plasma or reversal of anticoagulation using the appropriate pharmacologic agent. For recurrent postoperative hemarthrosis, revision angioplasty may be necessary, while ruptured aneurysms may require vascular surgical intervention or arterial embolization. Recurrent hemarthrosis often originates from periarticular hypertrophy of a vascular synovium.[25][26][27] Angioplasty with embolization is considered when conservative measures—joint aspiration, immobilization, and cessation of anticoagulants—fail. Synovectomy may also be an option.(B2)

Recurrence after embolization can exceed 25%, often due to vessel collateralization or recanalization; however, even if embolization is unsuccessful, it can help map or define the surgical field for subsequent intervention.[28] Compared with surgery, angioplasty with embolization is generally less invasive. For benign tumors, arthroscopic or open synovectomy remains the treatment of choice to prevent recurrent hemarthrosis.(B3)

Special treatment considerations are required for hemophiliacs presenting with acute hemarthrosis. Coagulation factor replacement should be administered promptly at the first sign of joint bleeding—including the prodromal phase of stiffness or tingling before pain and swelling—ideally within 2 hours of bleed identification. For bleeding into the hip, target joints, or trauma-associated hemarthrosis, higher factor activity levels of 80% to 100% are recommended. The recommended dose is 50 units/kg of factor VIII for hemophilia A and 100 to 120 units/kg of factor IX for hemophilia B. For hemarthrosis in peripheral joints, such as knees, elbows, or ankles, factor activity should be raised to at least 40% to 50% (25 units/kg of factor VIII for hemophilia A and 50–60 units/kg of factor IX for hemophilia B).

Emicizumab, a monoclonal antibody, is a newer therapeutic alternative for hemophilia A.[29][30][31][32] This bridges factor IXa and factor X, mimicking factor VIII activity, and is effective as prophylaxis and in patients with factor VIII inhibitors. Medications with antiplatelet activity, such as nonsteroidal anti-inflammatory drugs, should be avoided. Arthrocentesis is generally unnecessary when diagnosing joint bleeding in patients with known hemophilia. If required to rule out septic arthritis or relieve pressure from accumulated blood, it should only be performed after factor replacement has raised specific factor levels.[33] In hemophiliacs with target joints experiencing repeated hemorrhage, a short course of glucocorticoids may help reduce pain and swelling from synovial inflammation, provided there are no signs of infection. Surgical intervention may be indicated for chronic synovitis or arthropathy, including synovectomy for recurrent bleeding or joint replacement for severe joint damage.[34][35](A1)

Differential Diagnosis

The differential diagnosis of an acute joint effusion includes other notable disease processes. Conditions which can be mistaken for an acute hemarthrosis include:

• Septic arthritis
• Lyme disease
• Tuberculosis
• Gout (monosodium urate crystals)
• Pseudogout (calcium pyrophosphate crystals)
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Leukemia
• Seronegative spondyloarthropathies (psoriatic arthritis, reactive arthritis, inflammatory bowel disease arthritis)
• Osteoarthritis

This may be especially true if the association with trauma is remote, unclear, or unknown. Arthrocentesis with synovial fluid analysis, diagnostic imaging, and further laboratory workup specific to these other disease processes may be required to differentiate between the causes of an acute joint effusion.

Prognosis

With appropriate treatment, including arthrocentesis when indicated, the acute swelling and pain of hemarthrosis can improve substantially within days, although complete resolution may take several weeks. In cases caused by intra-articular fractures or significant soft tissue injury, orthopedic surgery may be necessary. After the hemarthrosis resolves, a structured rehabilitation program aimed at restoring range of motion, weight-bearing capacity, and joint strength is recommended. For patients with hemophilia, a physical therapist experienced in hemophilia management is ideal.[19]

Complications

Severe or recurrent hemarthrosis can destroy intra-articular cartilage and lead to degenerative arthritis. The toxic effects of blood within the joint lead to synovial hypertrophy and fibrosis. In hemophiliacs, joints that undergo chronic inflammatory changes from repeated hemarthrosis are referred to as ‘target joints.’ Recurrent or prolonged bleeding can cause chronic, disabling arthropathy due to internal joint derangement and impaired movement. Chronic arthropathy occurs in approximately 20% of hemophiliacs, but recurrent hemarthrosis can be prevented with prophylactic administration of coagulation factors.[13][19]