The safety of highly vascular and invasive plastic

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1 Review Article Von Willebrand Disease: Screening, Diagnosis, and Management Ali Totonchi, MD; Yashar Eshraghi, MD; Daniel Beck, MS; Keith McCrae, MD; and Bahman Guyuron, MD The safety of highly vascular and invasive plastic surgery procedures is dependent on an intact and functionally normal coagulation system. Intraoperative and postoperative bleeding complications not only threaten the integrity of any cosmetic or functional result, but also, on rare occasions, they may prove life threatening to the patient as well. Most clotting factor deficiencies are detected with routine coagulation tests, including the prothrombin time (PT), partial thromboplastin time (PTT), and platelet count. However, this screening panel does not directly assess platelet function or adhesion and thus does not detect von Willebrand disease (vwd). Because of a highly variable expression pattern, vwd often remains subclinical in the absence of a strong hemostatic challenge and thus may not be suspected until excessive surgical bleeding occurs. Nevertheless, the frequency of this coagulation disorder would almost ensure that every plastic surgeon will encounter individuals affected by this disease, making a thorough understanding of vwd and its management absolutely necessary. The goal of this article is to familiarize the plastic surgeon with vwd, including the physiology of von Willebrand factor (vwf), the diagnostic criteria, classification, and molecular basis for Drs. Totonchi, Eshragi, Guyuron, and Mr. Beck are from the Department of Plastic and Reconstructive Surgery and Dr. McCrae is from the Division of Hematology and Oncology, Case Western Reserve University, Cleveland, Ohio. Dr. Guyuron is Professor and Dr. McCrae is Associate Professor. Von Willebrand disease (vwd), a hemorrhagic disorder mimicking a defect in platelet function, is the most commonly inherited coagulopathy, resulting in a deficiency that may prolong bleeding time and increase risk for major bleeding complications during surgery. Von Willebrand factor (vwf) serves a dual role in hemostasis: mediating the initial platelet adhesion to damaged endothelium at the site of vessel injury and stabilizing coagulation factor VIII, an important cofactor in the generation of a fibrin clot. Although quantitative or qualitative defects in vwf protein can manifest as a mild to severe bleeding disorder, many cases of vwd remain subclinical, barring major invasive stimuli, and undetected by either patient or clinician. Nevertheless, the frequency of this coagulation disorder would almost ensure that every plastic surgeon will encounter affected patients, making a thorough understanding of vwd and its management absolutely necessary. Surprisingly, there is little information concerning vwd in the plastic surgery literature. Our goal is to familiarize the plastic surgeon with vwd, including physiology, diagnostic criteria, classification, and molecular basis for multiple vwd variants, and diagnosis and management. (Aesthetic Surg J 2008;28: ) the multiple vwd variants, and the diagnosis and management of this disorder. PATHOPHYSIOLOGY Pro-vWF, a 2791 amino acid propeptide, is the primary translation product of the vwf gene synthesized by endothelial cells and megakaryocytes. Posttranslational processing cleaves the pro-vwf peptide into the vwf propeptide (vwf antigen), which is released into plasma, and the mature vwf peptide (a 230-kd monomer). 1,2 Monomers of mature vwf are assembled into variable-sized multimers via disulfide bridging of cysteine residues at both the amino and carboxy-terminal ends. Under physiological conditions, smaller complexes constitutively exit the cell and enter the circulation, where they bind and stabilize the coagulation factor VIII or undergo reduction and proteolytic cleavage. The size of circulating vwf multimers is also regulated through processing by the metalloprotease ADAMTS13 [KM1]. Large complexes, with up to 100-fold activity of monomeric fragments, are essential for normal platelet adhesion and aggregation after vascular injury in rapid-flow, high shear stress vessels such as arterial capillaries 2-7 Therefore multimers are retained in secretory granules of the synthesizing cell, the Weibel- Palade body in endothelial cells, and the a-granule in platelets and released to aid in vessel repair. 8,9 On vascular injury, vwf binds to the subendothelium. Initial recruitment of nonactivated platelets is pro- Aesthetic Surgery Journal Volume 28 Number 2 March/April

2 Table. Classification and characteristics of vwd Type Transmission Laboratory parameters FVIII:C BT vwf:ag RIPA 1 AD N/ /N N 2A AD/(AR) N/ /N /N 2B AD/AR N/ /N 2M AD N/ /N /N N/ 2N AR N N 3 AR Undetectable Undetectable AD, Autosomal dominant; AR, autosomal recessive; N, normal. moted through interaction between the glycoprotein (GP) Ib-a receptor (a component of the GPIb-IX-V glycoprotein complex) of platelets and its binding site in the A1 domain of vwf. After adhesion, platelets become activated, expose new receptors, and secrete the contents of their intracellular granules in a coordinated effort to recruit additional platelets to the site of injury. The growing platelet aggregate is tethered through crosslinking the newly exposed GP IIb/IIIa platelet receptors by divalent fibrinogen and platelet vwf. Final irreversible fixation of platelets is also mediated through the GP IIb/IIIa receptor in conjunction with a nonessential contribution from thrombin and fibrinogen to consolidate the thrombus. 10,11 Quantitative or qualitative defects in the vwf protein result in deficiencies in platelet adhesion and aggregation. Decreased platelet deposition at the site of vascular injury also impairs the formation of a platelet plug and eliminates the phospholipid-rich surface provided by platelets for subsequent reactions involving soluble coagulation factors and ultimately the conversion of fibrinogen to fibrin. VWF also stabilizes FVIII in the circulation by protecting it from inactivation and clearance Thus severe vwd with little or no vwf protein leads to a secondary deficiency of FVIII, which may manifest as pseudohemophilia. EPIDEMIOLOGY VWD is the most common inherited bleeding disorder. Prevalence is estimated at 1% to 2% and appears equally in both sexes and across all racial groups. However, heterogeneity and variable expression may cause the actual prevalence of vwd to be severely underestimated. It is likely that many cases of mild vwd remain undiagnosed barring major clinical insult. 15 Additionally, only a portion of those with a confirmed laboratory diagnosis ever experience clinically relevant hemorrhagic complications Several factors may influence the plasma levels of vwf protein and complicate the laboratory diagnosis of vwd. First, circulating levels of vwf protein correlate with blood type; vwf protein concentrations are significantly lower (75% of normal) in individuals with blood group O versus other blood groups, because of accelerated plasma clearance. Second, vwf levels rise by approximately 6 U/dL every decade after age Expectations for normal concentrations must be adjusted accordingly. Finally, vwf is an acute phase reactant and thus becomes elevated during times of stress or in association with conditions such as pregnancy and malignant disease. CLASSIFICATION AND GENETICS The vwf gene is located on chromosome 12p and contains 52 exons Congenital vwd has been subdivided on the basis of qualitative or quantitative deficiencies of vwf. 16 There are 3 primary types of vwd. Type 1 is associated with mildly decreased levels of vwf, type 2 involves qualitative vwf deficiency, and type 3 is characterized by a virtual absence of vwf 6 (Table 1). Quantitative or qualitative defects in vwf leading to the clinical sequelae of vwd can result from either a congenital or acquired defect, although the former is far more common. Acquired defects often arise in association with distinct comorbidities such as essential thrombocytosis. Type I vwd arises from an inherited, autosomal dominant trait resulting in a partial quantitative defect of functionally normal vwf protein. Type I is the most common form of vwd and accounts for approximately 75% of all congenital cases. Diagnosis of type I vwd may be complicated by the heterogeneity and numerous other factors, such as ABO blood type, that affect levels of vwf levels in apparently normal individuals. Normal vwf levels range from 75% in patients with type O blood, to 105% in patients with type A, 117% in type B, and 123% in type AB. 24,25 The severity of clinical symptoms in vwd varies widely depending on the level of functional vwf protein but symptoms generally do not become apparent until levels fall well below 50%. Type 2 vwd is characterized by a number of mutations in the vwf protein that cause qualitative functional and structural defects. These abnormalities result in either defective vwf (subtypes 2A, 2B, and 2M) or impaired vwf-factor VIII (FVIII) binding in subtype 2N. 26 Type 2A is the most common variant of type 2 vwd causing increased sensitivity to proteolysis Type 2B vwd is characterized by spontaneous binding of vwf to platelets, resulting in platelet agglutination, thrombocytopenia, and accelerated vwf clearance. Type 190 Volume 28 Number 2 March/April 2008 Aesthetic Surgery Journal

3 IIb vwd must be distinguished from platelet type vwd, which presents with similar manifestations as type 2 vwd, although the molecular defect involves the vwf receptor on platelets rather than vwf per se. Type 2M vwd is caused by mutations in the GP1b binding (A1) domain of vwf; this type of vwd is clinically similar to type 2A vwd but may be distinguished by the presence of high-molecular-weight multimers in type IIM Type 2N vwd is characterized by diminished binding of vwf to FVIII; thus the stability and half-life of FVIII in the circulation are diminished, and the level of circulating FVIII is markedly reduced despite a normal level of vwf:ag and multimeric structure. Type 3 vwd is rare and is characterized by a complete deficiency of vwf protein. Inheritance is typically autosomal recessive and involves large null mutations of the gene, but it may arise from a compound heterozygous state. The absence of vwf protein in type III results in a severe hemophilialike bleeding disorder compounded by loss of stability and rapid clearance of coagulation FVIII, leading to levels less than 5% of normal. 34 DIAGNOSIS The diagnosis of vwd requires attention to both clinical and laboratory components. Pertinent clinical information includes a positive family history and a history of excessive mucocutaneous bleeding. These symptoms may include epistaxis, menorrhagia, ecchymosis, gingival bleeding, and excessive surgical bleeding. 35 Although petechiae are more often associated with thrombocytopenia, some patients with vwd may have petechiae, especially after the use of aspirin or other nonsteroidal antiinflammatory drugs. 36 Patients who experience blood loss from menorrhagia and epistaxis in association with iron deficiency should be evaluated for an underlying bleeding disorder. 37 Laboratory testing confirms the diagnosis of vwd. Although the platelet count is usually normal in patients with vwd, a mild thrombocytopenia can be detected in type 2B or pseudo-vwd. The bleeding time is generally prolonged but may be normal in type 1 vwd and a normal platelet content of vwf, 38,39 and therefore not universally considered to be an important part of the diagnostic evaluation. The PT is usually normal, but PTT may be prolonged depending on the level of FVIII. Qualitative and quantitative measurements of vwf and FVIII are the most informative tests. 40,41 Immunologic assay generally reveals decreased levels of vwf antigen in type 1 vwd and decreased or normal levels in type 2; vwf antigen may not be detectable in type 3 vwd. The ristocetin cofactor assay (vwf:rco) is used to assess vwf activity. This assay depends on the ability of ristocetin to bind vwf and convert its conformation to an active form capable of binding and agglutinating platelets via platelet glycoprotein (Gp)Ib. Values for vwf:rco and vwf antigen (vwf:ag) are similar in type 1 vwd but may differ in type 2 vwd in which vwf antigen levels may be normal but its activity diminished, leading to lower vwf:rco activity (vwfrco:vwfag level > 0.7). The vwf multimer analysis complements the diagnostic evaluation; both high- and low-molecularweight multimers are present in type 1 vwd in decreased numbers, but in most subtypes of type 2 vwd the higher molecular weight multimers are selectively decreased (the exception to this is type 2M). Plasma levels of FVIII:C are markedly decreased (1% to 5%) in type 3 vwd. FVIII may be moderately reduced in type 1 or type 2 vwd. Except for type 2B vwd and platelet-type/pseudo vwd, in which the vwf-gp1b binding interaction is increased and thus the ristocetininduced platelet aggregation (RIPA) response is increased, RIPA is decreased in the other type 2 variants. 42,43 Plasma/platelet mixing tests may also be necessary to differentiate type 2B vwd and platelet pseudo-vwd. 44 Type 2N vwd may be distinguished from hemophilia by assessing the affinity of FVIII for vwf. Some type 2N vwd patients may present with normal vwf:ag and vwf:rco, as well as multimeric structure, but decreased FVIII plasma levels. 45,46 In addition to the bleeding time, the closure time, using the PFA-100, can be used as a screening test for vwd. Although this test has a significant false-positive rate and thus low specificity for vwd, the closure time may be more sensitive to the bleeding time for vwd diagnosis. 47,48 TREATMENT The most important factor in the management of vwd is the accurate detection of the type and severity of the disease. The goal of therapy is to normalize the decreased platelet adhesion characteristic of vwd, as well as the decreased FVIII plasma levels, when present. Two primary options are available for the treatment of vwd, desmopressin (DDAVP) and transfusional therapies with blood components. 49 Antifibrinolytic agents can be used alone or as an adjunct to standard treatments. 50 Desmopressin (1-deamino-8-D-arginine vasopressin), a synthetic vasopressin analog, is able to enhance the levels of FVIII and vwf primarily by enhancing release from endothelial stores. DDAVP is most effective in type 1 vwd, but in other types the response to treatment is variable. The administration of DDAVP in type 2B vwd may lead to transient thrombocytopenia due to release of the abnormal vwf molecule and thus is relatively contraindicated. 51 In type 1 or 2M vwd, test infusion with preinfusion and postinfusion vwf measurements predicts the usefulness of DDAVP treatment. Type 3 vwd usually does not respond to desmopressin whereas patients with type 2N vwd only experience transiently increased levels of FVIII because of the failure of the stabilizing effect of vwf. 52,53 Moreover, most individuals treated with DDAVP experience less benefit from repeated doses because of tachyphylaxis. 54,55 DDAVP is available in an intravenous form, and given at a dose of 0.3 µg/kg, 50 mixed with 50 ml of injectable saline solution, which is infused over 30 to 45 minutes while carefully monitoring the blood pres- Von Willebrand Disease: Screening, Diagnosis, and Management Volume 28 Number 2 March/April

4 sure. Concentrated forms are also available via intranasal administration. The adverse events related to infusion of DDAVP include tachycardia, headache, and facial flushing and are usually mild and transient. 40 Rare cases of hyponatremia have been reported. Thus DDAVP should either be used with caution on patients with history of coronary artery disease or should be avoided all together. FVIII- and vwf-containing plasma products can be used as an alternative treatment in patients in whom DDAVP is contraindicated or not effective. 56,57 These more predictable therapies are also used in patients facing a major hemostatic stress, such as extensive surgery. The most commonly used product is Humate P (CSL Behring, King of Prussia, PA), because of its content of high-molecular-weight vwf multimers. Levels of FVIII should be monitored after administration of these products as supratherapeutic levels may increase the risk of deep vein thrombosis Infusion of recombinant of FVIII may also be attempted in type 3 vwd that does not respond to FVIII/vWF containing blood products because of the presence of anti-vwf antibodies. 62 CLINICAL CASE A 57-year-old woman underwent rhytidectomy and fullface laser in 1996; her postoperative course was complicated with a hematoma recognized on postoperative day 1. Subsequently, the patient was taken to the operating room for hematoma evacuation. The patient s preoperative laboratory values were all within normal limits, and her anesthesia and post-anesthesia care unit records did not reveal uncontrolled hypertension throughout the perioperative period. These factors alerted the operative team to suspect a bleeding disorder. DDAVP was administered during the hematoma evacuation. The remainder of the recovery from surgery was uneventful. After surgery a von Willebrand panel was ordered, and a hematologist was consulted. A diagnosis of type-i vwd was made after a positive response to the test infusion of DDAVP and vwf level. The patient s next 2 surgeries for correction of eyelid ptosis in 2003 and for secondary rhytidectomy in 2007 were uneventful with preoperative infusion of DDAVP. DISCUSSION VWD was first described by Eric von Willebrand in Since then several subgroups of this disease have been described. The goal of this article is to demonstrate the importance of being familiar with this disease, and the potential problems that vwd may cause in plastic surgery patients. While the literature notes the prevalence of vwd in the population to approach 1%, the experience of the senior author (B.G.) suggests the disease is encountered to a greater degree in the surgical setting. Because routine coagulation screening test results such as the PT, PTT, and INR may be normal in these patients, and the presentation of vwd remains asymptomatic in the absence of preceding hemostatic stress, many cases remain undiagnosed before surgery. Excessive bleeding in the patient undergoing plastic surgery can dramatically affect surgical outcome. With the ability to perform greater numbers of procedures on an outpatient basis, the importance of a familiarity with vwd is essential to improve safety standards and ensure optimal outcomes for patients with this disorder. Therefore recognition of the potential presence of this underlying, possibly undiagnosed condition must be maintained by the plastic surgeon throughout the patient s perioperative evaluation, as well as during times of abnormal intraoperative or postoperative bleeding. There is surprisingly little information concerning vwd in the plastic surgery literature. The senior author conducted a retrospective study 64 in a group of 1000 patients who had undergone a plastic surgery procedure. Those with a history of excessive bleeding after surgery or an abnormal bleeding time, PT, or PTT with a subsequent extensive hematologic workup were selected. Nine of these patients were diagnosed with vwd (8 before and one after surgery). Another report regarding vwd and cosmetic surgery was published by Johnson et al 65 and defined the relationship between a tendency for bleeding in otoplasty in a dog model and diagnosis of vwd. A complete and thorough bleeding history demonstrating a tendency for excessive bleeding after trauma, previous surgeries or interventions, as well as any history of menorrhagia, will support an index of suspicion regarding vwd. Obtaining a vwd blood profile before surgery can lead to the diagnosis of this condition, help to define the vwd subtype, and circumvent possible sequelae. Even without a definitive diagnosis, a substantial degree of concern should warrant consultation with a hematologist. However, this type of consultation is rarely obtained before surgery in the outpatient setting. Thus infusion of DDAVP is recommended as the initial therapy to halt intraoperative bleeding of unknown cause. Likewise, patients who experience moderate to severe recurrent epistaxis as much as 6 to 7 days after a rhinoplasty often have a mild form of vwd and would generally benefit from therapeutic infusion of DDAVP. This approach has minimized the need for more invasive therapy in patients who experienced epistaxis after rhinoplasty in the senior author s practice over the last 27 years. Constitutional effects of the medication include transient headache, nausea, mild abdominal cramps, vulval pain, and occasional facial flushing. 66 The main contraindication of the drug is in patients with known hypersensitivity to desmopressin acetate. However, this drug should be used with caution in patients with coronary artery disease because it normalizes the coagulation system by up-regulating procoagulant factors. Additionally transient hypotension has been observed during infusion, whereas the urine output is reduced through the antidiuretic properties of DDAVP on renal tubules For these reasons, patients with electrolyte imbalances, patients who are predisposed for thrombus formation, and the elderly and pediatric populations require careful fluid balance monitoring after this drug is introduced. 192 Volume 28 Number 2 March/April 2008 Aesthetic Surgery Journal

5 As mentioned previously, vwd type 1, 2A, 2M, and 2N can benefit from DDAVP. In type 2B, which is associated with thrombocytopenia, DDAVP is contraindicated because of some reports indicating that it might worsen the thrombocytopenia. However, some investigators believe that DDAVP could benefit these patients, particularly for minor bleeding, 61 as long as the platelet count is normal. Type III, in which vwf is absent and no significant endothelial stores exist, will not respond to DDAVP. Considering that the group that responds to DDAVP constitutes more than 90% of the patients with vwd, it might not be unreasonable to administer DDAVP during or after surgery for patients with unexplained bleeding. CONCLUSION Given the prevalence of vwd, it is essential for plastic surgeons to become familiar with this disorder and its diagnosis and contemporary management. Familiarity with vwd will lead to increased patient safety and better surgical and cosmetic outcomes. 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Am J Veterinary Res 1985;46: Physician desk reference, 60th edition, pages: Accepted for publication December 5, Reprint requests: Bahman Guyuron, MD, Cedar Rd, Lyndhurst, OH Copyright 2008 by The American Society for Aesthetic Plastic Surgery, Inc X/$34.00 doi: j.asj Volume 28 Number 2 March/April 2008 Aesthetic Surgery Journal