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Gingival enlargement in von Willebrand disease: A case report Abstract von Willebrand disease (vWD) is an inherited bleeding disorder affecting both the sexes with a prevalence of approximately 1% in general population. The cause for bleeding in this disorder can be attributed to the primary deficiency or defect in von Willebrand factor (vWF) that results in the platelet adhesion abnormalities. It is characterized by bleeding episodes that may be severe and life threatening, menorrhagia in females, epistaxis, and gingival bleeding and enlargement. A case of 29-year-old female having all the characteristic features of vWD is presented. The family history revealed consanguineous marriage of the parents. The patient was initially on oral contraceptives, but later she underwent diagnostic hysteroscopy with endometrial ablation with roller ball to treat menorrhagia. INTRODUCTION Von Willebrand disease (vWD) is a congenital bleeding disorder resulting from a quantitative or qualitative deficiency of von Willebrand factor (vWF), a plasma glycoprotein with essential platelet-dependent functions in primary hemostasis and a carrier for factor VIII in the circulation.[1] The worldwide prevalence of this disease ranges from 0.6 to 1.3%.[23] The gene for vWF is located on chromosome 12, and therefore, the disorder is inherited in an autosomal fashion. In most families, it appears to be inherited dominantly.[4] vWF is synthesized in two cell types. In the vascular endothelium, vWF is synthesized and subsequently stored in secretory granules (Weibel–Palade bodies) from which it can be released by stress or drugs such as desmopressin [1-desamino-8-d-arginine vasopressin (DDAVP)], a synthetic analogue of vasopressin. vWF is also synthesized in bone marrow megakaryocytes where it is stored in platelet alpha-granules from which it is released following platelet activation.[5] vWF circulates as a series of high-molecular-weight (HMW) multimers, the larger multimers being essential for normal platelet-dependent vWF function under the high shear stress conditions present in the microvasculature. vWD is considered to be the commonest of the inherited bleeding disorders, usually presenting as a mild to moderate disorder typically with easy bruising or bleeding from mucosal surfaces.[1] Based on the separation of vWF multimers or subunits of varying molecular weights by electrophoresis, the disorder can be subgrouped into four types. Type 1 accounts for approximately 85% of occurrences, with all the multimeric forms present in reduced concentrations; type 2 is characterized by an absence of HMW multimers and occurs in 10–15% of vWD patients; type 3 (autosomal recessive inheritance) is rarely seen in homozygous individuals, characterized by less than 1% Factor VIII (FVIII), prolonged bleeding time (>15 min), and reduced level (<1%) of vWF; and type 4 is also known as pseudo or platelet-type von Willebrand disorder.[6] In most instances, the deficiency is relatively mild, although patients with severe deficiency may experience spontaneous gingival bleeding, epistaxis, and ecchymosis.[7] Presenting symptoms may include epistaxis, bleeding after dental extraction, bleeding from minor cuts or abrasions, postoperative bleeding, gingival bleeding, easy bruising, postpartum hemorrhage, joint bleeding, and gastrointestinal bleeding.[89] Among women with the diagnosis of vWD, 48% reported easy bruising, 44% epistaxis, 51% gingival bleeding, and 84% presented with menorrhagia.[1011] In one cross-sectional study, compared to controls, women with vWD were also more likely to report other gynecologic conditions, including ovarian cysts (52%), endometriosis (30%), leiomyomas (32%), endometrial hyperplasia (10%), polyps (8%), and hysterectomy (26%), in addition to menorrhagia.[10] The cause of gingival bleeding and enlargement in such women can also be attributed to the intake of oral contraceptives as the first line treatment for menorrhagia. Patients with this disease usually present with a normal platelet count, normal clotting time, normal serum fibrinogen, and normal prothrombin time, but the bleeding time is increased to an extremely variable degree.[12]. Figure 1 Image showing gingival enlargement in a patient of von Willebrand's disease Figure 2 Image showing enlarged palatal gingivae but normal palatal mucosa Figure 3 Image showing grade-I clubbing of finger nails Figure 4 Orthopantamogram Figure 5 Two month post operative view CASE REPORT Case history A 29-year-old female patient, resident of Nishat, Srinagar, reported to the Department of Periodontics and Oral Implantology, Government Dental College, Srinagar with the complaints of recurrent bleeding and swelling of gums. Medical history revealed that she was a known case of vWD. She had a history of cholecystectomy and right ovarian cystectomy 9 years back. The patient was previously on oral contraceptives as medication for menorrhagia. She underwent diagnostic hysteroscopy with endometrial ablation with roller ball to cure menorrhagia 5 years back, and since then, she has had no menstrual bleeding. The patient was hypertensive for the last 5 years and was on medication for that. The patient also complained of frequent urinary tract infections. Family history revealed consanguineous marriage between her parents. Pedigree analysis of the family revealed that the patient's father, mother, maternal and paternal uncles, and one of her three brothers were also suffering from vWD. Past dental history revealed extraction of six teeth in the past and there was history of blood transfusions before each extraction which were continued even after the extractions till the bleeding stopped, i.e. six times in a month. General and extraoral examination The patient had overall normal physical and mental development. Extraoral examination revealed the presence of pallor, anemia, and grade I clubbing of finger nails. Intraoral examination The soft tissue examination of the gingiva revealed spontaneous bleeding on slightest provocation. Red, soft, edematous gingiva was present with loss of stippling. There was generalized gingival enlargement. Rest of the oral mucosa including palate and tongue were normal on inspection and palpation. There was caries in relation to 24, 26, and 28. Grade III calculus and extrinsic stains were present because of absence of tooth brushing due to the fear of uncontrolled gingival bleeding during the same. Radiographic examination Orthopantomogram examination of the patient revealed no significant findings except the carious involvement of few teeth. Laboratory investigations The macroscopic urine examination was normal and microscopic examination revealed the presence of occasional pus cells and epithelial cells. No red blood cells, no casts, and no crystals were present. Table 1 shows the list of various laboratory investigations carried out to reach at the diagnosis of the disease. Table 1 List of laboratory investigations carried out Diagnosis In view of the above findings, the patient was diagnosed to be suffering from either type 2A or 2B vWD. The cause of gingival bleeding could thus be attributed to vWD primarily, but gingival enlargement appears to be due to hormonal treatment (intake of oral contraceptives) for menorrhagia and local factors primarily. Dental management On her first dental visit, Plaque index (by Silness and Loe) and Gingival index (by Loe and Silness) were recorded. The scores were found to be on the higher side and were noted as the baseline periodontal parameters. On the same day, supragingival plaque removal was done with extreme caution taking care not to touch the gingiva. Betadine irrigation was done meticulously (supragingivally). The patient was prescribed chlorhexidine mouthwash twice a day. On her second visit, thorough consultation was taken from a physician. Various hematological and other laboratory investigations were carried out. Supragingival scaling was done and the patient was given oral hygiene instructions. On her subsequent visits, again oral prophylaxis was carried out and oral hygiene instructions were reinforced. Conservative treatment of various carious lesions was carried out. As per physician's consultation, further gingivectomy was planned to treat gingival enlargement. The surgery was performed in the Department of Periodontics, Government Dental College, Srinagar. Since the patient was suffering from type 2 vWD, she was treated prior to the surgery with factor VIII replacement. Tranexamic acid was given before and for 7 days after surgery. The surgery was carried out under local anesthesia and the procedure was performed quadrant-wise. Gelfoam was used as local therapy to control bleeding during the procedure. Postoperative instructions were given and the patient was recalled after 24 h to examine for signs of bleeding. The patient was prescribed acetaminophen for pain control and antibiotics for infection control. The patient was kept on chemical plaque control and was instructed not to do toothbrushing in the surgical area for at least 4 weeks. Additional doses of factor VIII replacement were given postoperatively as needed. Regular follow-up appointments were fixed and the patient was kept under strict observation for signs of bleeding, infection, or delayed healing in future. Patient's general health and oral hygiene were apparently normal on subsequent follow-ups. At 1 month postoperatively, the plaque and gingival indices were recorded again and the results showed great improvements compared to the baseline scores. DISCUSSION Erik Adolf von Willebrand first recognized the disorder in 1926 in a study conducted on the inhabitants of the Aland Islands. Epidemiologic studies indicate that it is the most common bleeding disorder, affecting approximately 1% of the population. However, only a fraction of people come to medical and dental attention because of bleeding symptoms.[13] Table 2 shows the revised classification of vWD.[14] vWD is an autosomally inherited congenital bleeding disorder involving a qualitative or quantitative deficiency of vWF. vWF is a protein that is critical for proper platelet adhesion and protects against coagulant factor degradation. This results in recurrent bleeding episodes. In fact, many cases of vWD go undiagnosed, and bleeding during dental treatment may be the first sign of underlying disease.[15] In this disease, there is factor VIII deficiency, prolonged bleeding, and activated partial thromboplastin time (aPTT), but prothrombin time and platelet count are normal.[15] Table 3 shows laboratory values for vWD, according to the National Heart, Lung and Blood Institute (NHLBI), 2012 update.[16] Table 2 Revised classification of vWD Table 3 Laboratory values for vWD, according to National Heart, Lung and Blood Institute (NHLBI), 2012 update The results of the specific tests performed in this case to diagnose vWD are not suggestive of type 1 vWD, since the multimeric analysis and ristocetin-induced platelet aggregation (RIPA) are normal in type 1. Also, it is not type 3 vWD because all multimers and RIPA are absent in type 3. The pattern here is suggestive of type 2A or 2B vWD, given the low vWF: Ag and vWF: Rco and the VWF: Rco to VWF: Ag ratio being < 0.7. A consanguineous marriage is usually defined as a marriage between people who are second cousins or closer.[17] As a result of these marriages, the rare autosomal recessive disorders run in close families and tribes. Thus, due to autosomal recessive inheritance, the rare congenital coagulation bleeding disorders, congenital platelet functional disorders, and vWD become common. Family history in this case revealed consanguineous marriage between the patient's parents. Pedigree analysis of the family revealed that the patient's father, mother, maternal and paternal uncles, and one of her three brothers were also suffering from vWD. The most commonly reported symptom among women with the diagnosis of vWD or suspected bleeding disorder is menorrhagia, but additional symptoms or signs also may be present.[810] Treatments include ways to increase endogenous plasma concentration of vWF, replace vWF, or promote hemostasis without affecting vWF. With mild vWD and menorrhagia combination, hormonal contraceptives are the first-line treatment. In a study involving women with the diagnosis of vWD, 88% reported improvement in menorrhagia with oral contraceptives alone.[818] An exaggerated response to local irritants occurs in gingival tissues on intake of oral contraceptives in the form of inflammation that ranges from mild edema and erythema to severe inflammation with hemorrhagic and hyperplastic gingival tissues.[19] Kalkwarf reported that the response may be caused by an altered microvasculature, increased gingival permeability, and increased synthesis of prostaglandin.[20] Newer hemostatic agents include antifibrinolytics such as epsilon-aminocaproic acid and tranexamic acid.[21] Endometrial ablation is a general term for any technique that removes or destroys the endometrium (lining of the uterine cavity). Endometrial ablation is a treatment for menorrhagia (heavy menstrual bleeding). It is an alternative to hysterectomy for the treatment of menorrhagia in a younger woman who has no desire for future fertility but wishes to preserve her uterus and in a older woman with obesity or medical contraindications for hysterectomy.[22] There are many different techniques for performing endometrial ablation. The entire endometrium is ablated by electrocautery using a resectoscope, roller ball, or a combination of two.[22] In a “roller ball” endometrial ablation, a ball-shaped electrode is used to deliver energy to the endometrium, not unlike a microwave. This destroys the endometrium. Success rates of nearly 90% are obtained with about 60% of the patients reporting amenorrhea.[22] Treatment depends on the clinical condition of the patient and the type of vWD that is diagnosed. Available treatment options include cryoprecipitate, factor VIII concentrates that retain HMW vWF multimers (Humate-P, Koate-HS), and desmopressin (DDAVP). Patients with type 1 vWD are the best candidates for desmopressin therapy. It is not effective for type 3 vWD and most variants of type 2 vWD. These patients are treated with factor VIII replacement that retains the HMW vWF multimers. In short, more severe forms of vWD require preoperative factor VIII concentrates or cryoprecipitate infusion. Patients with milder forms respond favorably to administration of DDAVP (desmopressin) before periodontal surgery or tooth extraction.[2324] Current dental management of vWD Preoperative Consult the hematologist and confirm the diagnosis. Establish the variant and treatment modality. Most patients can be treated in the dental office. Those with type 3 vWD may be hospitalized. Treat any acute oral infection. Maintain good oral hygiene. Construct palatal splints for multiple extractions in patients with type 3 or type 2N variants, so that mechanical displacement of the clot in wound healing by secondary intention is prevented.[25] Operative Treat with DDAVP, Epsilon-aminocaproic acid or tranexamic acid, or factor VIII replacement (Humate-P or Koate-HS) prior to the procedure. Use good surgical technique. Control bleeding using local measures like gelfoam, fibrin glue, etc., Place splint (palatal).[25] Postoperative Examine for signs of bleeding within 24–48 h. Additional doses of DDAVP, EACA, and factor VIII are given as needed. Examine for the signs of allergy to factor VIII. Bleeding can be managed through local means; if these fail, additional systemic therapy may be needed. If infection occurs, treat by local and systemic means. Avoid aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Acetaminophen with or without codeine may be used.[25] CONCLUSION Oral care providers must be aware of the impact of bleeding disorders on the management of dental patients. Furthermore, prophylactic, restorative, and surgical dental care of patients with vWD is best accomplished by practitioners who are knowledgeable about the pathology, complications, and treatment options associated with this condition. The early interception of this disease is very much important in preventing the exaggerated symptoms and further complications.