In 1926, Finnish professor Eric von Willebrand described a bleeding disorder that affected 24 of 66 members of a family from the Åland Island of Foglo between Finland and Sweden.1-3 The disorder was characterized by mucocutaneous bleeding despite normal platelet counts and clot retraction. A young girl in this family bled to death during her fourth menstrual period. The etiology of this disorder eluded early investigators. Initially, von Willebrand believed that the hemorrhage was due to a defect in platelet function, or possibly an abnormality of the vasculature. This led to the disorder’s initial description as “vascular hemophilia.”1,4 Further investigations found a correlation of decreased plasma concentrations of factor VIII in the coagulation cascade. More importantly, improvement in coagulation was found with transfusion of fresh frozen plasma. Ultimately, it was discovered that patients with the disorder were deficient in a certain plasma protein that has become known as von Willebrand factor.1-4
von Willebrand disease is caused by a quantitative or qualitative deficiency in von Willebrand factor.1-7 With a prevalence of 1% to 3% in the general population, it is the most common inherited bleeding disorder.1-7 Scandinavian countries appear to have the highest prevalence of the disorder.4 Table 1 presents the most common subtypes of von Willebrand disease. Most subtypes of von Willebrand disease are transmitted autosomal dominantly, though the most severe type (type 3) is transmitted as an autosomal recessive trait.1-7 Figure 1 demonstrates the role of von Willebrand factor in platelet aggregation and hemostasis.
Clinical manifestations of the disease include mucocutaneous hemorrhage (usually in the form of nose bleeds), menorrhagia, and easy bruising and bleeding. In the more severe cases, gastrointestinal bleeding and spontaneous hemarthrosis can occur.1-7 Oftentimes, patients with von Willebrand disease are identified after demonstrating excessive bleeding during a dental or surgical procedure.1,2
Despite the prevalence of von Willebrand disease, there is a paucity of information in the English orthopedic literature regarding general management of the disorder in the orthopedic patient population. This article provides an orientation to the orthopedic problems that can be caused by von Willebrand disease and a basic framework for diagnosing and managing orthopedic patients with von Willebrand disease.
|Figure 1: Diagram of the roles of von Willebrand factor (von Willebrand factor) in platelet adhesion to the damaged wall of the blood vessel and subsequent platelet aggregation. Abbreviations: Gp=Glycoprotein. |
Diagnosis and Screening
Because of the relatively mild symptoms associated with type 1 von Willebrand disease, the initial presentation of the disease often is excessive bleeding during a surgical procedure.1,2 To identify these patients prior to the surgical procedure, a thorough screening by interview should be conducted. It is important to identify patients who report histories of easy bruising or excessive bleeding with dental work. Some work has been done on a rapid immunoassay that could identify type 1 von Willebrand disease by detecting decreased amounts of von Willebrand factor antigen. However, Biron et al5 noted that no patients identified in their series as having type 1 von Willebrand disease demonstrated excessive bleeding during surgery. Thus, it is unclear whether it is useful to screen for type 1 von Willebrand disease in the surgical patient.
Diagnosis of von Willebrand disease is based on laboratory findings of a qualitative or quantitative deficiency in von Willebrand factor (Table 2). Complete blood count is appropriate to look for anemia resulting from chronic blood loss, as well as for the presence of thrombocytopenia (as in type 2B von Willebrand disease). Activated partial thromboplastin time is necessary to detect decreases in the level of circulating factor VIII. Bleeding time helps to determine the severity of disease, but in mild type 1 von Willebrand disease, it will often be within normal limits.
To confirm a diagnosis of von Willebrand disease, several specific tests are performed. von Willebrand factor antigen is measured using an enzyme-linked immunosorbent assay. Activity of von Willebrand factor is also measured using the same method, looking specifically for the presence of glycoprotein Ib receptor on platelets, a receptor that is integral in the binding of von Willebrand factor to platelets after it is exposed to subendothelial collagen. Alternatively, a ristocetin cofactor assay can be used. This assay measures the ability of circulating von Willebrand factor to cause platelet aggregation.1,2
Diagnosis of von Willebrand disease can be challenging in mild disease because several external factors can transiently increase the amount of circulating von Willebrand factor. Among these are oral contraceptives, exercise, stress, pregnancy, and blood group.2 Patients with type O blood tend to have lower amounts of von Willebrand factor than patients with types A, B, or AB.2
Increased prevalence of certain medical conditions in patients with von Willebrand disease has also been reported. Among these are mitral valve prolapse, multiple myeloma, and lymphoproliferative disease.4 In addition, certain acquired forms of von Willebrand disease have been reported, including a report of hemostatic derangement similar to von Willebrand disease in a patient with systemic lupus erythematosus.4 Thus, if von Willebrand disease is diagnosed, it is worthwhile to look for signs of these other diseases, though a full workup to rule them out is not necessary.
Orthopedic Manifestations of von Willebrand Disease
Although little information in the orthopedic literature specifically addresses the treatment of patients with von Willebrand disease, the disease shares many similarities with other coagulopathies (eg, hemophilia) that have been studied more extensively. Several early papers on the subject of musculoskeletal problems in hemophilias mentioned von Willebrand disease as being rare, although it is now recognized as the most common hereditary bleeding disorder.1-7 Certain papers have also lumped token cases of von Willebrand disease into their cohorts of hemophilic patients.8-11 Orthopedic problems addressed in hemophiliacs commonly included spontaneous muscular bleeds, compartment syndrome, peripheral nerve lesions, joint contracture, and pseudotumors.9,12-14 Most prominent, however, is the literature regarding the management of hemarthrosis in hemophiliacs and the associated hemophilic arthropathy.9-26 A treatment algorithm for von Willebrand disease associated hemarthrosis and arthropathy is presented in Figure 2.
Figure 2: Treatment algorithm for von Willebrand Disease associated hemarthrosis and arthropathy.
Hemarthrosis can occur in the patient with von Willebrand disease,8,9,11 especially if it is type 3 disease. It is most commonly found in the elbow, knee, and ankle.9,12 It is thought that the relatively large amounts of synovium in these joints can be more easily pinched to create bleeding. Moreover, these diarthrodial joints are unable to withstand minor rotatory and angulatory strains.9,12 Hemarthrosis is of particular concern because it can lead to various orthopedic sequelae, including contracture and neuropathy.9,12,24-26 These patients present to the orthopedic surgeon with large effusions, limited range of motion, and disabling synovitis. Radiographs will demonstrate a large effusion.16 In patients with recurrent hemarthrosis, arthritic changes (osteophytes, subchondral cysts, irregular subchondral surfaces) often are seen from the degradation of cartilage caused by the inflammatory synovitis.20 More recently, magnetic resonance imaging has been demonstrated as the most accurate method of assessing hemophilic arthropathy. The characteristic findings of hemosiderin deposition in the synovium and synovial hyperplasia can assist in assessing the progression of disease (Figures 3, 4).27-29
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Figure 3: T2-weighted axial cut MRI of the knee demonstrating acute hemarthrosis. Figure 4: Lateral radiograph demonstrating chronic changes associated with hemophilic arthropathy. The shadow outlining the suprapatellar pouch is a result of hemosiderin deposition from multiple episodes of hemarthrosis.
Early diagnosis of von Willebrand disease is critical to minimize the sequelae of hemarthrosis. For minor hemarthroses, noninvasive techniques may be attempted. Compression bandages and administration of factor VIII concentrates is the first line of treatment. Intraarticular or systemic corticosteroids have been mentioned in the literature, though no good data has supported their use.16,22 Orthoses have been used with some success by Querol et al26 for the nonoperative treatment of hemophilic arthropathy. Houghton and Duthie9 recommended immobilization with a firm compression bandage or plaster-of-paris splint. However, in the larger joints at which hemarthroses are more common, resorption of the blood can take several weeks. This is thought to lead to the chronic joint changes associated with hemophilic arthropathy. In such cases, aspiration is sometimes appropriate to remove the blood and associated proteolytic enzymes responsible for subsequent destruction of cartilage. However, Hoskinson and Duthie12 warned that aspiration can often be difficult if more than 24 hours have elapsed since the onset of the bleed or if there is loculation. Thus, if aspiration is to be attempted, it should be performed within 24 hours of the onset of the hemarthrosis. Little evidence supports the use of repeated intraarticular aspiration as a method of treatment for spontaneous hemarthrosis.
Recurrent hemarthrosis in a patient with underlying coagulopathy leads to changes in the synovium and articular cartilage, although the pathogenesis is not entirely clear.15,19,22 While some initial hypotheses involved possible immunologic mechanisms as a cause for the arthropathy, a microscopic analysis by Andes et al15 found no evidence for this. McLardy Smith et al19 demonstrated increased glycosaminoglycan breakdown and decreased retention of chondroitin sulfate in hemophilic synovium, similar to what is seen in rheumatoid arthritis. The resultant change in cartilage matrix could lead to loss of cartilaginous stability, making it more susceptible to injury. It has also been noted that recurrent hemarthrosis leads to a proliferative synovitis that predisposes to further bleeding.
Surgical procedures often are used to treat these patients. The most largely described procedure is synovectomy, either open or arthroscopic. The indication for synovectomy is recurrent hemarthrosis that has not responded to medical management.16,20-22 Most authors agree that this procedure is best carried out in the younger patients without evidence of joint destruction, as these patients typically have the best results.16,20-22 Open synovectomy was initially described and found to be successful in preventing subsequent hemarthroses, but subsequent follow-up has revealed that this procedure frequently leads to decreased range of motion in the affected joint.16,20-22 Since then, other authors have described and advocated arthroscopic synovectomy as a less invasive method for achieving the same decrease in subsequent hemarthroses, with better range of motion postoperatively.21,22 The arthroscopic approach typically is carried out with both anterior and posterior portals to ensure complete resection of the synovium.21 It is important to treat these patients preoperatively with factor VIII concentrates to allow adequate hemostasis during the procedure. Excessive bleeding during the procedure could necessitate conversion to an open procedure.
Older patients with a history of recurrent hemarthrosis often present with symptoms of severe joint pain and radiological evidence of joint destruction. Synovectomy does not effectively reduce these symptoms. Typically, arthrodesis, realignment osteotomy, interposition arthroplasty, or total joint replacement is performed. Houghton and Dickson17 described 16 patients treated by arthrodesis for their symptoms of pain in the knees and ankles secondary to recurrent hemarthrosis. Their series was fraught with complications, including delayed union, wound infection, and hematoma, but they were able to decrease pain and further hemarthrosis.
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Smith et al18 had success with corrective osteotomies for patients in whom repetitive hemoarthropathies led to degenerative changes and varus deformity. In their series of 5 patients, after realignment osteotomy at the tibia, they found a halt in the progression of arthropathy and significant decrease in bleeding into other joints. Interposition arthroplasty was described by Smith et al8 in the elbow, as an alternative to arthrodesis or total joint replacement. In their series of 6 patients, they reported 4 of 6 patients were painfree with good range of motion and no evidence of instability after a mean follow-up of 30 months. Total joint replacement often is met with reservation in hemophiliacs given their usual young age. However, it has been found to be successful in some series.10,16 It has been noted that these patients typically have polyarticular involvement, and their daily function typically is less than normal. This results in less wear and, therefore, a more functional arthroplasty.10 In the elbow, a linked semiconstrained total elbow replacement is preferred to avoid loosening.10 It should be noted that these procedures have not been studied in large cohorts. Regardless of which procedure is used, careful planning and consultation with an anesthesiologist and hematologist is required to successfully manage the coagulopathy in the perioperative period.
Other Considerations for Treatment of Patients With von Willebrand Disease
Some general treatment guidelines should be followed in managing patients with von Willebrand disease. First, close consultation with a team of physicians, including an internist or pediatrician, hematologist, and anesthesiologist is recommended, especially when considering surgical intervention. It is worthwhile to be familiar with the adjunctive treatments used to manage von Willebrand disease perioperatively, including those listed in Table 3. Second, because of the extensive need for replacement therapy in patients with severe coagulopathies, some authors have recommended that, if possible, patients undergo one large procedure rather than multiple smaller procedures.12,14 Although the anesthetic risk is greater for a longer procedure, there is less risk with fewer surgeries, and a decrease in the amount of blood products used. Finally, certain common patient treatments and procedures must be used with caution in patients with von Willebrand disease. Simple procedures commonly used in medical care, such as intramuscular injections, rectal temperatures, and use of suppositories should be minimized to decrease the chance of accidental bleeding.7,9,12,13 Nonsteroidal antiinflammatory drugs and aspirin should also be avoided.13
von Willebrand Disease is the most common inherited bleeding disorder and can present challenges to orthopedic surgeons in managing perioperative bleeding and treating orthopedic problems that manifest as a result of the disease. Appropriate history taking is essential to identify these patients prior to surgery. The most effective management of von Willebrand disease will be achieved with close consultation between the surgeon, anesthesiologist, internist or pediatrician, hematologist, and patient. With appropriate planning, these patients can undergo major orthopedic procedures safely and effectively.
- Johnsen J, Ginsburg, D. von Willebrand disease. In: Beutler A, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 17th ed. New York: McGraw-Hill; 1995:1929-1945.
- Wilde JT, Cook RJ. von Willebrand disease and its management in oral and maxillofacial surgery. Br J Oral Maxillofac Surg. 1998; 36(2):112-118.
- Kurth AA, Ludwig G, Scharrer I. Prevalence, pathophysiology, diagnosis and treatment of von Willebrand syndrome in orthopaedic trauma patients. Orthopade. 1999; 28(4):366-374.
- Guyuron B, Zarandy S, Tirgan A. von Willebrand’s disease and plastic surgery. Ann Plast Surg. 1994; 32(4):351-355.
- Biron C, Machieu B, Rochette A, et al. Preoperative screening for von Willebrand disease type 1: low yield and limited ability to predict bleeding. J Lab Clin Med. 1999; 134(6): 605-609.
- Kouides PA. Females with von Willebrand disease: 72 years as the silent majority. Haemophilia. 1998; 4(4):665-676.
- Shah SB, Lalwani AK, Koerper MA. Perioperative management of von Willebrand’s disease in otolaryngologic surgery. Laryngoscope. 1998; 1998; 108:32-36.
- Smith MA, Savidge GF, Fountain EJ. Interposition arthoplasty in the management of advanced haemophilic arthopathy of the elbow. J Bone Joint Surg Br. 1983; 65(4):436-440.
- Houghton GR, Duthie RB. Orthopedic problems in hemophilia. Clin Orthop Relat Res. 1979; 138:197-216.
- Kamineni S, Adams RA, O’Driscoll SW, Morrey BF. Hemophilic arthopathy of the elbow treated by total elbow replacement. A case series. J Bone Joint Surg Am. 2004; 86(3):584-589.
- Hovy L. Joint preserving operations and endoprosthetic substitutions in hemophiliacs. Indications and long term results. Orthopade. 1999; 28(4):356-365.
- Hoskinson J, Duthie RB. Management of musculskeletal problems in hemophilias. Orthop Clin North Am. 1978; 9(2):455-480.
- Naranja RJ Jr, Chan PS, High K, Esterhai JL Jr, Heppenstall RB. Treatment of considerations in patients with compartment syndrome and an inherited bleeding disorder. Orthopedics. 1997; 20(8):706-709.
- Rodriguez-Merchan EC. Orthopaedic surgery in persons with haemophilia. Thromb Haemost. 2003; 89(1):34-42.
- Andes WA, Walker PD, Edmunds JO, Wulff KM. Hemophilic arthopathy: an immunologic study of the synovium. Scand J Haemotol Suppl. 1984; 40:221-224.
- McCollough NC III, Enis JE, Lovitt J, Lian EC, Niemann KN, Loughlin EC Jr. Synovectomy or total replacement of the knee in hemophilia. J Bone Joint Surg Am. 1979. 61(1):69-75.
- Houghton GR, Dickson RA. Lower limb arthodeses in haemophilia. J Bone Joint Surg Br. 1978; 60(3):387-389.
- Smith MA, Urquhart DR, Savidge GF. The surgical management of varus deformity in haemophilic arthropathy of the knee. J Bone Joint Surg Br. 1981; 63(2):261-265.
- McLardy Smith PD, Ashton IK, Duthie RB. A tissue culture model of cartilage breakdown in haemophilic arthopathy. Scand J Haematol Suppl. 1984; 40:215-220.
- Matsuda Y, Duthie RB. Surgical synovectomy for haemophilic arthropathy of the knee joint. Long-term follow-up. Scand J Haematol Suppl. 1984; 40:237-247.
- Wiedel JD. Arthoscopic synovectomy in hemophilic arthopathy of the knee. Scand J Haematol Suppl. 1984; 40:263-270.
- Kim HC, Klein K, Hirsch S, Seibold JR, Eisele J, Saidi P. Arthroscopic synovectomy in the treatment of hemophilic synovitis. Scand J Haematol Suppl. 1984; 40:271-279.
- Marmor L. Total knee replacement in hemophilia. Clin Orthop Relat Res. 1977; (125):192-195.
- Lancourt JE, Gilbert MS, Posner MA. Management of bleeding and associated complications of hemophilia in the hand and forearm. J Bone Joint Surg Am. 1977; 59(4):451-460.
- Katz SG, Nelson IW, Atkins RM, Duthie RB. Peripheral nerve lesions in hemophilia. J Bone Joint Surg Am. 1991; 73(7):1016-1019.
- Querol F, Aznar JA, Haya S, Cid A. Orthoses in haemophilia. Haemophilia. 2002; 8(3):407-412.
- Kilcoyne RF, Nuss R. Radiological assessment of haemophilic arthopathy with emphasis on MRI findings. Haemophilia. 2003; 9(Suppl):57-63.
- Kerr R. Imaging of musculoskeletal complications of hemophilia. Semin Musculoskeletal Radiol. 2003; 7(2):127-136.
- Dobon M, Lucia JF, Aquilar C, et al. Value of magnetic resonance imaging for the diagnosis and follow-up of haemophilic arthropathy. Haemophilia. 2003. 9(1): 76-85.
Drs Kroonen, Gillingham, and Provencher have disclosed no relevant financial relationships. Dr Morgan, CME Editor, has disclosed the following relevant financial relationships: Stryker, speakers bureau; Smith & Nephew, speakers bureau, research grant recipient; AO International, speakers bureau, research grant recipient; Synthes, institutional support. Dr D’Ambrosia, Editor-in-Chief, has disclosed no relevant financial relationships. The staff of Orthopedics have disclosed no relevant financial relationships.
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Correspondence should be addressed to: LCDR Leo T. Kroonen, MD, MC, USNR, Naval Medical Center San Diego, Department of Orthopaedic Surgery, 34800 Bob Wilson Dr, Suite 112 San Diego, CA 92134-1112.