CC
A 16-year-old White female is referred to your office for evaluation of an asymptomatic radiopaque mass of the maxilla consistent with a complex odontoma.
HPI
The lesion was identified on routine radiographic examination for an unerupted primary premolar. There was no history of pain, fever, swelling, or drainage from the area.
PMHX/PDHX/medications/allergies/SH/FH
The patient’s parents denied any significant past medical history. However, on further questioning, a history of prolonged bleeding, including heavy menstruation and several episodes of epistaxis without the need for hospitalization, were identified (positive history of abnormal bleeding). This was first noted after the loss of her mandibular primary incisors. Careful questioning also revealed a history of “easy” bruising on her extremities. The parents recall previous episodes of prolonged bleeding with other family members. (Von Willebrand’s disease [vWD] is an autosomal dominant disorder.) The remaining history was negative.
Examination
General. The patient is a well-developed and well-nourished cooperative female in no apparent distress whose height and weight are above the 50th percentile.
Maxillofacial. There is no notable facial swelling. During intranasal examination with a nasal speculum, slight epistaxis was noted. Intraoral examination reveals bilateral buccal mucosa ecchymosis (skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels).
Chest, abdomen, and extremities. Multiple petechiae (pinpoint-size hemorrhages of small capillaries, often seen with quantitative and qualitative platelet dysfunction) are seen on the upper and lower extremities, abdomen, and chest.
Imaging
A panoramic radiograph reveals a well-defined radiopacity of the right anterior maxilla with multiple teethlike structures and an associated impacted first premolar (consistent with a compound odontoma). No routine imaging studies are necessary to evaluate vWD unless there is a suspicion of internal hemorrhage, especially in the setting of trauma.
Labs
The initial laboratory studies to evaluate for vWD should include routine coagulation studies (complete blood count [CBC] with platelets, prothrombin time [PT], partial thromboplastin time [PTT], international normalized ratio [INR], bleeding time). These are good general screening tests that can be ordered at the discretion of the physician. The CBC is generally normal, except in vWD type 2B, in which the platelet count may be decreased. Patients may also have microcytic anemia because of iron deficiency, especially females with menorrhagia. Bleeding time is a good screening test, although it is not sensitive or specific. Normal results do not rule out vWD. PT and INR are normal. However, the PTT, in addition to measuring factor VIII activity, may also measure concurrent deficiencies with other clotting factors. This may be prolonged in vWD type 2N, severe disease type 1 deficiency, and type 3.
However, even if screening test results are normal, if vWD is suspected, more specific hemostatic assays should still be performed.
There are other laboratory tests used to screen for and diagnose vWD:
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Plasma von Willebrand factor (vWF) levels (vWF:RCo, ristocetin cofactor activity assay, used to measure platelet aggregation). Plasma vWF levels may vary from day to day. They are influenced by stress, pregnancy, hormone replacement therapy, and blood type (individuals with type O have decreased levels); a single level within the reference range does not exclude the disease.
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Plasma vWF antigen. The total plasma concentration of vWF protein, depending on the assay, could be the total of vWF binding sites or the total vWF protein present in the plasma. It does not reflect molecular structure; therefore, this value could be normal in patients with abnormal multimers.
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Factor VIII activity. This is a measure of the cofactor function of the clotting factor (factor VIII) in plasma.
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The ristocetin (an antibiotic) cofactor activity assay is the gold standard for diagnosis of vWD; however, it is difficult to obtain an accurate level. The levels of vWF rise during pregnancy and periods of stress and with hormone replacement therapy; therefore, patient anxiety may acutely elevate the vWF level despite a relative deficiency. A positive screening test result or a high index of suspicion based on the clinical history may indicate further testing is necessary.
When abnormalities are detected in the above listed testing, a number of specialized coagulation studies may be performed to determine the subtype of vWD. A vWF multimer and ristocetin-induced platelet aggregation can also be used to confirm the diagnosis in addition to the subtype. There are also collagen binding assays that can indicate a loss of high molecular weight (HMW) multimer and binding of factor VIII by vWF, which is not used to identify type 2N but is still used. A newer test is the vWF:GP1BA that determines how well vWF binds to this platelet receptor. An additional test that now has years of usage is the platelet function test, which is dependent on vWF and platelet function. This is used as a screening test for vWD because of its high specificity and sensitivity and has proven to be highly reliable.
Assessment
Compound odontoma of the maxilla requiring removal, complicated by vWD.
Treatment
There are five modalities of treatment for patients with vWD:
- 1.
Desmopressin (1-desamino-8-D-arginine-vasopressin [DDAVP])
- 2.
vWF replacement therapy (using cryoprecipitate)
- 3.
Antifibrinolytic agents
- 4.
Topical agents (thrombin or fibrin sealants)
- 5.
Estrogen therapy in females with no contraindications
Desmopressin is a synthetic analog of antidiuretic hormone without vasopressor activity. It acts by increasing vWF and factor VIII levels by indirectly stimulating the release of vWF from endothelial cells. DDAVP may be administered intravenously, intramuscularly, or intranasally. If given intravenously or intramuscularly for acute bleeding, the dose is 0.3 μg/kg (maximum, 20 μg). Increases in vWF and factor VIII levels are seen within 30 to 60 minutes, with a duration of approximately 6 to 12 hours. Intranasal administration has gained popularity with patients who have less serious bleeding and for premedication before minor surgical procedures. The usual dose is 150 μg for children weighing less than 50 kg and 300 μg for larger children and adults. A test dose should be administered to observe the effects on vWF. DDAVP should not be administered to patients with type 2B vWD because it may worsen the disease (see the Discussion section). It also does not seem to be as efficacious in patients with severe bleeding disorders and type 3 disease, probably secondary to the lack of stored vWF.
Replacement therapy with vWF appears to be the gold standard for treatment. However, for cryoprecipitate (which contains factor VIII) to contain viable vWF, it cannot be pasteurized, only screened. If possible, this should be avoided because there is an increased risk of viral transmission. Most factor VIII concentrates do not contain sufficient high-molecular-weight vWF; however, the drugs Humate-P (human antihemophilic factor–vWF complex) and Alphanate (antihemolytic factor) do contain sufficient amounts. These drugs may be used with cryoprecipitate in patients with type 2B or type 3 vWD because these patients cannot be treated with DDAVP. In 2015, the US Food and Drug Administration approved recombinant vWF Vonvendi. For significant bleeding, the goal of replacement therapy is to maintain the activity of factor VIII and vWF between 50% and 100% for 3 to 10 days. Clotting factor concentrates may also be used containing both vWF and factor VIII (recombinant and plasma derived).
Fibrinolytic therapy with tranexamic acid (Amicar) can also be used. This prevents the lysis of blood clots and can be especially useful for bleeding from the mucous membranes. This class of drugs may be given orally or intravenously. With oral administration, the drug must be given three or four times over a 24-hour period (because of the medication’s short half-life) for 3 to 7 days. Topical agents such as Gelfoam (absorbable sponge made from gelatin) or Surgicel (oxidized regenerated cellulose) soaked in topical thrombin can also be used for local hemostasis, in addition to collagen products (plugs, Helistat) among others.
In several studies, estrogen was found to increase the levels of vWF in females taking oral contraceptives and hormone replacement therapy. However, no long-term studies have looked at the risk-to-benefit ratio for hormone replacement therapy in vWD, but it is definitely helpful during menorrhagia.
Treatment is determined by clinical findings and the extent of hemorrhage. There are no good laboratory tests that correspond with the severity of the disease. vWF is not a reliable marker of severity because this value can be artificially elevated in certain physiologic states, such as stress or pregnancy; therefore, a past history of bleeding is an important clue to the severity of the disease and to determination of optimal therapy.
Patients with the type 3 subtype require continuous surveillance, including possibly physical therapists, to follow up for joint effusions affecting joint mobility. They may also receive prophylactic infusions of vWF–factor VIII concentrate to prevent musculoskeletal bleeding and joint damage.
The current patient was referred to a hematologist for preoperative consultation and evaluation. Subsequently, the patient had normal ristocetin activity and platelet levels. The hematologist recommended premedication with 150 μg of DDAVP and four doses of Amicar postoperatively for 24 hours. The patient was subsequently sedated in the office, and the odontoma was removed. Surgicel was placed in the defect and sutured with resorbable sutures. Hemostasis was observed in the office before discharge. At 1-week follow-up, the patient denied any complications and was healing appropriately.
Complications
The most obvious complication of vWD is persistent hemorrhage. If hemorrhage is persistent after extractions, Surgicel, topical thrombin, collagen, direct pressure, and DDAVP may be used unless contraindicated. In the setting of acute bleeding, cryoprecipitate is the treatment of choice. Cryoprecipitate can be used to treat patients with all types of vWD. (Cryoprecipitate contains factors VIII and XIII, vWF, fibrinogen, and fibronectin. It can be stored at −18°C for up to 1 year.)
Each treatment regimen has various side effects. DDAVP may cause vasodilation, headache, hypotension, or hypertension (which is usually mild). More serious complications of DDAVP include tachyphylaxis (rapid development of immunity to a drug) and significant hyponatremia and seizures secondary to water retention. Therefore, DDAVP is usually limited to once-daily dosing, along with water restriction and careful monitoring of serum sodium levels. It is also contraindicated in patients with arterial vascular disease and if older than age 70 years or younger than 2 years.
Replacement with cryoprecipitate carries an increased risk of transmission of bloodborne pathogens secondary to the inability to adequately pasteurize the extract. Fortunately, as a result of the improved sensitivity of blood testing, the risk of transmission is low.
Prolonged use of antifibrinolytic therapy carries a risk of thrombosis. Hypercoagulable patients need to be carefully evaluated. Topical agents are generally safe but are costly and can only be used as a local measure. Certain preparations of topical thrombin may contain bovine factor V; broad exposure could precipitate the formation of antibodies to this factor that cross-react with human factor V, aggravating hemorrhage.
Discussion
Von Willebrand’s disease is the most common inherited bleeding disorder; however, recent guidelines have made the cutoff of diagnosis lower than what was previously (vWF of 30 IU/dL). This has decreased the number of patients diagnosed with vWD and created a subcategory as “having a risk for bleeding,” in which patients have a vWF level between 30 and 50 IU/dL. Most patients do not seek medical attention and are only diagnosed on the basis of unexplained heavy bleeding (e.g., during menstruation) or easy bruising. Bleeding history may become more apparent with age. This disorder is characterized by a mutation in vWF itself or in the amount of vWF produced. This factor is responsible for primary hemostasis by aiding platelet aggregation and adherence to the endothelial lining and by serving as a carrier protein for factor VIII. Factor VIII has a significantly shortened half-life when it is not bound to vWF; this is the reason factor VIII levels are evaluated through laboratory tests.
There are three subtypes of inherited vWD. Types 1 and 2 are typically autosomal dominant, but type 1 may also be inherited in a recessive manner as well as one of the subtypes of type 2 (2A). The number of cases caused by a de novo vWF variant is unknown. Type 1 is a quantitative deficiency in vWF itself. Symptoms range from mild to moderately severe ( Fig. 103.1 ). It is possible that the deficiency may be from abnormally fast clearance of the protein or inadequate production.
