 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Von Willebrand's disease (vWD) is the most common inherited abnormality of hemostasis and is usually inherited in an autosomal dominant fashion. The dysfunction is due to a qualitative or quantitative abnormality of von Willebrand factor (vWF), leading to a disruption of primary hemostasis. Normally, vWF mediates the adhesion and aggregation of platelets to subendothelium in blood vessels with high shear force, such as arteries. In addition, vWF protects factor VIIIc against degradation by forming a complex with it. Patients present most commonly with mucosal bleeding, easy bruising, menorrhagia, and excessive bleeding following surgery. Hemarthroses and deep hematomas may occur in severe cases. A panel of tests is required to screen adequately for the disorder, because screening tests such as the bleeding time and APTT may be normal. The APTT is abnormal only in those cases of vWD with low levels of factor VIIIc. The panel includes factor VIIIc assay, von Willebrand factor antigen, ristocetin cofactor (RcoF), and ristocetin induced platelet aggregation (RIPA).
VWD is divided into 3 main types depending on whether the dysfunction is due to a quantitative (types 1 & 3) or qualitative (type 2) deficiency in vWF.
Treatment Options Treatment of vWD can be accomplished by stimulating the release of endogenously stored vWF or infusing exogenous vWF. Treatment of vWD
DDAVP (1-deamino-8-d-arginine vasopressin) promotes accelerated release of endogenous vWF from storage sites. DDAVP is the treatment of choice for Type 1 vWD. It can be used prophylactically prior to surgery and to treat bleeding. Type 1 vWD patients with baseline plasma levels of vWF antigen in the 10 to 20 IU/dL range or higher are those who are more likely to reach post-DDAVP levels sufficient to attain hemostasis. DDAVP is usually ineffective for Type II variants and Type III. It can cause thrombocytopenia in Type 2B patients. A therapeutic trial of DDAVP before an elective procedure is advisable. Baseline factor VIII level and quantitative vWF antigen should be obtained before the trial. A DDAVP dose of 0.3 ug/Kg of body weight diluted in 50 - 100 mL of saline is infused IV over 30 minutes. Factor VIII and vWF are measured at 1, 4 and 8 hours after infusion. Responsive patients have will have a three-fold increase in Factor VIII:C and a two-fold increase in vWF within 30 minutes. Increased levels should persist for 8 to 10 hours. Baseline and post-infusion platelet counts should be measured in unclassified patients to screen for thrombocytopenia. If the trial is successful, the same intravenous dose can be used for prophylaxis or treatment of bleeding. Doses should be repeated on a daily basis for most bleeding episodes. Tachyphylaxis may occur with more frequent dosing or after 3-4 consecutive days. It can be overcome by waiting 24-48 hours before giving the next dose. Side effects include flushing, headache, hyponatremia, and hypotension. Hypotension is most often associated with rapid infusion. It is especially important to monitor Infants and surgical patients for hyponatremia. DDAVP can also be administered by subcutaneous and intranasal routes. The subcutaneous dose is 0.3-0.4ug/kg and the intranasal dose is 300ug/kg. The response obtained with intranasal administration is variable and may be impaired by inflamed nasal mucosa. Antifibrinolytic amino acids, such as epsilon aminocaproic acid (Amicar) are often prescribed as an adjunct to desmopressin therapy when treating epistaxis, oral cavity bleeding, bleeding associated with dental procedures, and menorrhagia. Amicar interferes with the lysis of newly formed clots by saturating the binding sites on plasminogen and preventing its attachment to fibrin. Amicar can be given orally or intravenously at a dose of 50 - 60 mg/kg every 4 to 6 hours. Factor Replacement Therapy for vWD Factor replacement is recommended for patients with Types 2 and 3 vWD and for Type 1 patients who do not respond adequately to DDAVP. Factor VIII concentrate containing multimeric vWF is preferred over cryoprecipitate because of the decreased risk of viral transmission. The FDA has licensed Humate P® for use in vWD. Humate P is an intermediate purity Factor VIII product that contains high molecular weight vWF multimers, which are critical for platelet adhesion. Alphanate® and Koate DVI® are not licensed for vWD but contain sufficient quantities of high molecular weight vWF to be effective. Factor VIII Concentrates Derived from Human Plasma that contain vWF
Humate P is labeled in RCof units and in Factor VIII units. The recommended dosage of Humate P is 20-40 IU FVIII:C per kg or 40-80 IU vWF:RCoF per kg depending on the vWD type and bleeding severity. One vWF:RCoF unit per kg should raise the plasma vWF:RCoF level by 1.5 IU/dL. The plasma half life of vWF:RCoF is much shorter than Factor VIII, 8 hours versus 24 hours. Examples of minor bleeding include epistaxis, oral mucosal bleeding and menorrhagia. Examples of major bleeding include GI, CNS and trauma. Humate P Dosage Guidelines for vWD Based on RCoF
If Humate P is not available, the dosage of Alphanate SD or Koate DVI should be based on Factor VIII levels. Factor VIII:C Dosage Guidelines for vWD
Plasma Factor VIII levels should be monitored daily and the dose adjusted accordingly. The patient's plasma Factor VIII level should increase 2U/dL for each 1 IU/kg infused. A patient's own FVIII level will begin to rise within 4 to 8 hours after infusion of vWF. Cryoprecipitate should not be used except in life and limb-threatening emergencies when vWF-containing Factor VIII concentrate is not immediately available. A reasonable dose of cryoprecipitate is 1 bag for every 5 Kg of body weight. This dose should be repeated every 8 to 12 hours. The amount of von Willebrand factor contained within a given unit of cryoprecipitate is highly variable and dependent upon the donor's plasma level. Additional therapeutic intervention is indicated in certain clinical situations. Type 3 patients who continue to bleed and have a prolonged bleeding time should receive platelets. MFC ® (Avitene) strips are available for packing of the anterior nares to help accelerate coagulation in prolonged epistaxis. Pregnancy causes a progressive increase in vWF. Determination of which obstetrical patients will require therapy for delivery should be based on the factor VIII level and not the vWF level. Patients with factor VIII levels >50% usually do not experience increased bleeding with vaginal delivery or C-section. Bleeding can be significant when the Factor VIII level is < 20%. A patient with Factor VIII levels < 50% should receive DDAVP or Factor VIII concentrate prior to delivery. If prolonged bleeding occurs during delivery, then Factor VIII concentrate should be given regardless of the Factor VIII level. Three to 4 daily doses of Factor VIII concentrate are usually necessary to avoid postpartum bleeding. Pregnant patients with type 2B vWD may develop thrombocytopenia due to increasing vWF levels. Factor concentrate can be given just prior to delivery to reverse thrombocytopenia. Inhibitors to von Willebrand factor Repetitive administration of vWF to patients with Type 3 vWD causes alloimmunization in about 15% of patients. Additional doses can cause an anamnestic response. Low level inhibitors can be overwhelmed by administration of high doses. Pseudo-von Willebrand's disease Pseudo vWD results from a platelet membrane defect and is not part of the classification of vWD. Platelet membrane glycoprotein Ib has an increased affinity for vWF that causes binding of vWF to platelets and consequent platelet agglutination and thrombocytopenia. DDAVP and Humate P are contraindicated because they can cause a precipitous drop in the platelet count. Patients should be treated with a single donor platelet unit or 6 to 8 random donor platelet concentrates for minor hemorrhages. More severe bleeding may require additional platelet transfusions. Acquired von Willebrand's Disease (von Willebrand's syndrome) Diseases or medications that interfere with the function of vWF cause acquired vWD. Diseases include autoimmune disorders, monoclonal gammopathies, lymphoproliferative disorders, adenocarcinoma, squamous cell carcinoma, hepatoma, hypothyroidism, and intestinal telangiectasia. The most commonly associated drug is valproic acid. Acquired vWD is comparable to Type 1 or 2A vWD. Patients may be either asymptomatic or experience mild to severe hemorrhage. Treatment should be directed at the underlying disease whenever possible. Therapeutic options include DDAVP, Amcicar and Humate P. DDAVP has a shortened effect in acquired disease and is contraindicated for patients taking valproic acid because it may precipitate seizures. Antifibrinolytic therapy can be used for oral and nasal mucosal bleeding. Factor concentrates have a shortened half-life and may not be successful. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||
