Chapter 59: von Willebrand Disease

von Willebrand disease (VWD)

• A congenital bleeding disorder resulting from a quantitative or qualitative deficiency of von Willebrand factor (VWF)

• VWF is a plasma glycoprotein with essential platelet-dependent function in primary hemostasis and a carrier for factor VIII (FVIII) in the circulation

• Acquired von Willebrand syndrome presents as a similar bleeding disorder

Epidemiology

Prevalence:

Inherited: 0.01–1%

• 0.01% of population using the number of patients seen at specialized hemostasis centers

• 1% of population using population-based screening (the most common inherited bleeding disorder)

Acquired: 0.04–0.13%

Male to female ratio: 1:1

Rodeghiero F et al. Blood 1987;69:454–459

Sadler JE et al. Thromb Haemost 2000;84:160–174

Werner EJ et al. J Pediatr 1993;123:893–898

Classification of Inherited VWD

Work-up

Treatment Principles

Background:

1. Until 2001, cryoprecipitate was the therapeutic mainstay for bleeding in VWD

2. After 2001, concerns for potential transmission of bloodborne pathogens, led to use of plasma-derived factor VIII (pdFVIII) products enriched in VWF

Indications:

1. Unlike patients with hemophilia in whom treatment may be administered regularly to prevent bleeding, patients with VWD generally have less frequent and less severe clinical bleeding and usually receive treatment only in anticipation of an invasive procedure or for trauma

2. An exception may be patients with type 3 VWD who might receive replacement therapy regularly particularly if they bleed repeatedly into the joints (secondary prophylaxis)

Rationale:

1. Replace the primary hemostasis defect (VWF deficiency)

2. FVIII synthesis is not defective in VWD, but its half-life is severely reduced because VWF is its natural carrier and stabilizer. Consequently, FVIII is also deficient but the intrinsic coagulation defect is secondary to that of VWF

3. Satisfactory hemostasis in VWD depends on achieving adequate plasma levels of both VWF (mediating primary hemostasis) and FVIII (responsible for fibrin formation in secondary hemostasis)

4. Hemostasis is satisfactory when the ristocetin cofactor activity (VWF:RCo)—a measure of VWF activity—is more than 0.6 IU/mL (60% of normal)

Determinants of therapeutic efficacy:

1. FVIII:C levels: Main determinants for the control of soft tissue and surgical bleeding

2. Functional VWF levels: Main determinants for the control of mucosal tract hemorrhages

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. N Engl J Med 2004;351:683–694

Treatment Options

von Willebrand Disease—Therapeutic Options: Desmopressin Acetate (DDAVP, 1-Deamino-8-D-Arginine Vasopressin)

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. N Engl J Med 2004;351:683–694

Rodeghiero F et al. Blood 1989;74:1997–2000

Intravenous Administration

Note: Intravenous administration is preferred for treatment of acute bleeding episodes

Test dose

1. Measure VWF:RCo and FVIII levels before administering desmopressin acetate

2. Desmopressin acetate 0.2–0.3 mcg/kg (not to exceed 20 mcg) intravenously in 50 mL 0.9% sodium chloride injection (0.9% NS) over 20–30 minutes

3. Measure VWF:RCo and FVIII levels at 1 and 4 hours after administration. Expect 2–4-fold increases in VWF and FVIII levels at 30–60 minutes, falling over 6–12 hours

Therapeutic dose

1. Desmopressin acetate 0.2–0.3 mcg/kg (not to exceed 20 mcg) intravenously in 50 mL 0.9% NS over 30 minutes; may be repeated every 12–24 hours for 3–4 doses

Intranasal Administration (eg, Stimate Nasal Spray, 1.5 mg/mL)

Test dose

1. Measure VWF:RCo and FVIII levels before administration

2. Administer according to patient weight:

    Patient weight ≤ 50 kg: Desmopressin acetate 1 spray (150 mcg) intranasally in 1 nostril

    Patient weight > 50 kg: Desmopressin acetate 2 sprays (300 mcg) intranasally, 1 spray in each nostril

3. Measure VWF:RCo and FVIII levels at 1 and 4 hours after administration. Expect 2- to 4-fold increases in VWF:RCo and FVIII levels at 1 hour after administration, falling over 6–12 hours

Therapeutic dose

1. Administer according to patient weight:

    Patient weight ≤50 kg: Desmopressin acetate 1 spray (150 mcg) intranasally in 1 nostril

     Patient weight >50 kg: Desmopressin acetate 2 sprays (300 mcg) intranasally, 1 spray in each nostril. Repeat every 12–24 hours for 2–4 doses

Toxicity

Efficacy

Notes

1. Advantage: Unlimited availability and avoidance of plasma concentrates

2. Response is generally consistent. Perform a test dose at the time of diagnosis to establish the individual pattern of response and to predict clinical efficacy

3. Tachyphylaxis may develop with repeated doses. Follow patients clinically, and/or measure VWF:RCo levels to assess response after >3–4 doses or after >3–4 days of use

4. Contraindicated in type 2B VWD, because the platelet count may drop to a level that might contribute to bleeding (<30,000–50,000/mm³)

5. Adults should limit fluid intake to 1 L during the 24-hour period after receiving desmopressin acetate

6. Avoid desmopressin acetate use in patients with known atherosclerosis or unstable coronary artery disease

7. Desmopressin acetate is not absolutely contraindicated in children, but usually it is not administered to children ≤2 years old

8. Desmopressin acetate has little oxytocic activity, and hence, may be used during pregnancy

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. Blood 2005;105:3382

Mannucci PM. N Engl J Med 2004;351:683–694

von Willebrand Disease—Therapeutic Options Virally Inactivated FVIII/VWF Concentrates: Antihemophilic Factor/von Willebrand Factor Complex (Human) (Humate-P, Alphanate, Fanhdi)

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. N Engl J Med 2004;351:683–694

Indications for FVIII/VWF concentrates:

1. Demonstration of inadequate response to a test dose of DDAVP (“severe” type 1, type 2, type 3)

2. Patients in whom DDAVP is contraindicated

3. Prediction of prolonged treatments with desmopressin (potential or actual tachyphylaxis)

Problem with FVIII/VWF concentrates:

1. High plasma levels of FVIII are a strong risk factor for venous thrombosis

   • Venous thrombosis in VWD: 4 cases after treatment with a VWF/FVIII concentrate used to ensure competent hemostasis during invasive and surgical procedures

   • Venous thromboembolism in VWD: 7 cases in 12,640 yearly treatments over 10 years

Makris M et al. Thromb Haemost 2002;88:387–388

Mannucci PM. Thromb Haemost 2002;88:378–379

Virally Inactivated Antihemophilic Factor/von Willebrand Factor Complex (Human) (FVIII/VWF) Concentrates

Humate-P, Alphanate, and Fanhdi are approved in the United States and in some European countries for use in VWD and are labeled with VWF:RCo units. Ristocetin cofactor units are used to calculate dose (refer to product-specific labeling)

Humate-P (CSL Behring)

1. Pasteurized

2. Average VWF:RCo-to-factor VIII ratio: 2.4:1

3. Efficacy and safety established in 2 prospective and several retrospective studies

Lethagen S et al. J Thromb Haemost 2007;5:1420–1430

Thompson AR et al. Haemophilia 2004;10:42–51

Alphanate (Grifols) and Fanhdi (Grifols)

1. Virally inactivated by solvent/detergent and heating

2. VWF:RCo-to-FVIII ratio: varies by product lot (Alphanate)

3. Efficacy and safety established by 2 prospective studies and a few retrospective studies

Bello IF et al. Haemophilia 2007;13(Suppl 5):25–32

Mannucci PM et al. Blood 2002;99:450–456

Other FVIII/VWF concentrates

1. Various products, virus-inactivated

2. Several small retrospective studies

Monitoring Replacement Therapy

1. Surgical procedures: Measure plasma levels of FVIII and/or VWF:RCo every 12 hours on the day of surgery, then every 24 hours or as dictated by clinical circumstances

2. It is not usually necessary to monitor replacement therapy in patients with spontaneous minor bleeding

3. Every physician encounter: Careful clinical follow-up because bleeding may not correlate well with factor levels; careful clinical monitoring is needed

Notes

1. Fresh-frozen plasma contains both FVIII and VWF, but the large amounts that are needed to attain hemostatic concentrations may cause volume overload. In addition, plasma is not generally inactivated for infectious agents and is not recommended

2. Eight to 12 bags of cryoprecipitate (each bag contains 80–100 units of FVIII, a 5–10-times greater concentration than fresh-frozen plasma) can normalize FVIII and VWF levels and stop or prevent bleeding. However, methods for inactivating infectious agents are not routinely applicable to this plasma fraction. Thus, cryoprecipitate is not recommended. Use only for very serious bleeding when virally inactivated concentrates are not available

Regimen: Antihemophilic Factor/von Willebrand Factor Complex (Human) Products Humate-P

1. General: A stable, purified, sterile, lyophilized concentrate of human antihemophilic Factor (FVIII) and human von Willebrand Factor (VWF) to be administered by the intravenous route in the treatment of patients with classical hemophilia (hemophilia A) and von Willebrand disease (VWD). Factor VIII is an essential cofactor in activation of Factor X, leading ultimately to formation of thrombin and fibrin. The VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein FVIII. The activity of VWF is measured as VWF:RCo

2. Indications: Adult and pediatric patients with severe von Willebrand disease and mild-to-moderate von Willebrand disease where use of desmopressin is known or suspected to be inadequate for:

   • Treatment of spontaneous and trauma-induced bleeding episodes

   • Prevention of excessive bleeding during and after surgery

3. Administration and dosage (see also tables below):

   • The dosage should be adjusted according to the extent and location of bleeding

   • As a rule, 40–80 IU VWF:RCo (corresponding to 17–33 IU factor VIII in Humate-P) per kg body weight are given every 8–12 hours

   • Repeat doses are administered for as long as needed based on repeated monitoring of appropriate clinical and laboratory measures

   • Expected levels of VWF:RCo are based on an expected in vivo recovery of 2 IU/dL rise per 1 IU/kg VWF:RCo administered

   • The administration of 1 IU of factor VIII per kg body weight can be expected to lead to a rise in circulating VWF:RCo of approximately 5 IU/dL

4. Properties:

   • Humate-P has been demonstrated in several studies to contain the high-molecular-weight multimers of VWF. This component is considered to be important for correcting the coagulation defect in patients with VWD. Bleeding time decreased when Humate-P was administered to patients with VWD (types 1, 2, and 3). This effect was correlated with the presence of a multimeric composition of VWF similar to that found in normal plasma

   • The virus-reduction steps in the manufacturing process include: (a) cryoprecipitation, (b) Al(OH)₃ adsorption, glycine precipitation, and sodium chloride precipitation, and (c) pasteurization in aqueous solution at 60°C (140°F) for 10 hours

Efficacy

Toxicity and Adverse Effects

1. The most serious adverse reaction observed is anaphylaxis. The most commonly reported are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock) reported in 6 of 97 (6%) subjects in a Canadian retrospective study

2. Thromboembolic events have also been observed

3. Other adverse events that were considered to have a possible or probable relationship to the product in 4/97 (4%) subjects included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus

4. For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding

5. In a prospective, open-label, safety and efficacy study of Humate-P in VWD patients with serious life- or limb-threatening bleeding or who were undergoing emergency surgery, 7 of 71 (10%) subjects experienced 9 adverse reactions, including mild vasodilation (1/9), allergic reactions (2/9), pruritus (1/9), and paresthesia (2/9)

6. Among 63 VWD patients who received Humate-P during and after surgery, the most common adverse events were postoperative hemorrhage (35 events in 19 patients with 5 patients experiencing bleeding at up to 3 different sites), postoperative nausea (15 patients), and postoperative pain (11 patients)

Regimen: Antihemophilic Factor/von Willebrand Factor Complex (Human) Products Alphanate/Fanhdi

Alphanate (Antihemophilic Factor/von Willebrand Factor [AHF/VWF] Complex [Human]) Sterile, lyophilized powder for injection, product labeling, dated June 2011. Manufactured and distributed by Grifols Biologicals Inc., Los Angeles, CA

• Grifols manufactures both Alphanate and Fanhdi. The latter is marketed outside the United States

1. General: Alphanate contains a labeled amount of FVIII expressed in IU FVIII/vial and Willebrand factor:Ristocetin cofactor activity in IU VWF:RCo/vial. The ratio of VWF:RCo to FVIII in Alphanate varies by lot, so dosage should be reevaluated whenever lot selection is changed. Dosage and duration of treatment depend on the severity of the VWF deficiency, the location and extent of bleeding, and a patient's clinical condition. Overdosage resulting in FVIII levels above 150% should be avoided

2. Indications: Adult and pediatric patients with severe von Willebrand disease as well as patients with mild-to-moderate von Willebrand disease where use of desmopressin is known or suspected to be inadequate for:

   • Treatment of spontaneous and trauma-induced bleeding episodes

   • Prevention of excessive bleeding during and after surgery

     Note: The products are not indicated for patients with severe VWD (Type 3) who are undergoing major surgery

3. Administration:

   • Replacement therapy is given intravenously over 15–20 minutes within 10–30 minutes before a planned procedure by a slow intravenous infusion at a rate not greater than 10 mL/min

4. Dosage (see tables below):

   • Adults: Preoperative dose of 60 IU VWF:RCo/kg of body weight; subsequent doses of 40–60 IU VWF:RCo/kg of body weight at 8–12-hour intervals postoperatively as clinically needed for 1–3 days

   • Pediatric: Preoperation dose of 75 IU VWF:RCo/kg body weight; subsequent doses of 50–75 IU VWF:RCo/kg body weight at 8–12-hour intervals postoperatively as clinically needed for 1–3 days

5. Properties:

   • Alphanate is prepared from pooled human plasma by cryoprecipitation of FVIII, fractional solubilization, and further purification employing heparin-coupled, cross-linked agarose, which has an affinity for the heparin-binding domain of VWF/FVIII:C complex

   • The product is (a) treated with a mixture of tri-n-butyl phosphate (TNBP) and polysorbate 80 to inactivate enveloped viruses and (b) subjected to heating at 80°C (176°F) for 72 hours to inactivate enveloped and nonenveloped viruses

Toxicity and Adverse Effects

1. Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with Alphanate should be discontinued, and emergency treatment should be sought

2. Development of activity-neutralizing antibodies has been detected in patients receiving FVIII containing products. Development of alloantibodies to VWF in type 3 VWD patients have been occasionally reported in the literature

3. Thromboembolic events may be associated with AHF/VWF Complex (Human) use in VWD patients, especially in the setting of known risk factors

4. Intravascular hemolysis may be associated with infusion of massive doses of AHF/VWF Complex (Human)

5. Rapid administration of a FVIII concentrate may result in vasomotor reactions

6. Plasma products carry a risk of transmitting infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk

7. The most frequent adverse effects reported with Alphanate in >5% of patients, include:

   • Respiratory distress

   • Pruritus, rash

   • Urticaria

   • Facial edema

   • Paresthesia

   • Pain

   • Fever

   • Chills

   • Joint pain

   • Fatigue

Efficacy

Regimen: VWF Concentrate Wilfactin (Human von Willebrand Factor) (Licensed in a Few European Countries)

Borel-Derlon A et al. J Thromb Haemost 2007;5:1115–1124

1. General: A pure VWF concentrate almost devoid of FVIII developed and used in France since 1989 to correct the primary von Willebrand factor (VWF) defect and avoid supraphysiologic plasma levels of factor VIII

2. Indications:

   • Prevention and treatment of hemorrhages or surgical bleeding in von Willebrand Disease (VWD) when desmopressin acetate treatment alone is ineffective or contraindicated

   • Elective major surgery, particularly when repeated infusions are foreseen and patients are at high risk for thrombosis (old age, cancer surgery, orthopedic surgery)

   • Long-term secondary prophylaxis in von Willebrand patients when indicated

     • Target joints

     • Recurrent GI bleeding

     • Recurrent epistaxis in children

3. Administration:

   • A concomitant priming dose of FVIII concentrate (30–40 IU/kg) is recommended in patients with severe bleeding episodes and to those with baseline plasma FVIII levels below 20 IU/dL (Only 38% of spontaneous bleeding episodes needed a priming dose of FVIII)

      Borel-Derlon A et al. J Thromb Haemost 2007;5:1115–1124

   • When a priming dose of FVIII is needed, recombinant or plasma-derived FVIII concentrates may be used. Infuse Wilfactin first, immediately followed by the FVIII product in the same venous access

   • Scheduled procedures: Administer Wilfactin only 12–24 hours before surgery in order to allow endogenous FVIII to attain plasma levels of at least 60 IU/dL at the time of surgery

   • Emergency procedures: Administer a priming does of FVIII together with Wilfactin before surgery in order to attain a FVIII peak of at least 60 IU/dL

4. Dosage:

    See table below

5. Properties:

   • Treated with 3 virus-inactivation/removal methods: solvent/detergent, 35-nm nanofiltration, dry heat treatment (80°C [176°F] for 72 hours)

   • VWF:RCo (IU/mg protein) ≥50

   • VWF:RCo-to-FVIII ratio = 1

Efficacy

Adverse Events

Patient characteristics:

• Fifty patients followed over a median of 21 months (range: 1–42 months)

  • Thirty-five patients were followed for ≥12 months; 25 patients were followed for ≥2 years

• At the end of the studies, 6.7 million IU of VWF concentrate had been administered during 2389 infusions over 2046 exposure days

• Fifteen patients also received 150,000 IU of recombinant or plasma-derived FVIII

Adverse events:

• Possible or probable (4%): Mild pruritus and chills

• Doubtful: Vein inflammation and malaise

• Clinically overt thrombosis: None

• anti-VWF:RCo antibodies detected: None

Regimen: von Willebrand Disease—Therapeutic Options Antifibrinolytic Agents Aminocaproic Acid (Eaca), Tranexamic Acid

Mannucci PM. N Engl J Med 1998;339:245–253

Mannucci PM. N Engl J Med 2004;351:683–694

1. General:

   • The manifestations of bleeding that are most frequently seen in von Willebrand's disease—such as epistaxis and menorrhagia—are sustained, in part, by the rich fibrinolytic activity of mucosal tracts. Local fibrinolytic activity in the buccal mucosa and gums also compromises hemostasis during dental extractions. These findings are the basis for the therapeutic use of antifibrinolytic amino acids in von Willebrand's disease

   • These synthetic agents inhibit the activation of plasminogen to plasmin, and, at high doses, inhibit plasmin

2. Indications:

   • Less-severe forms of mucosal bleeding, menorrhagia, epistaxis, dental procedures

   • Adjuncts to desmopressin acetate or replacement therapy with virally inactivated FVIII/VWF concentrate

3. Contraindications:

   • Contraindicated in patients bleeding from the upper urinary tract because of a risk that clots that do not lyse will be retained in the ureter and bladder and may cause ureteral obstruction

   • Long-term use as this may lead to thrombosis. Use only intermittently for bleeding episodes

   • Patients with evidence of an active intravascular coagulation process

4. Administration and dosage:

   • Aminocaproic acid (also, epsilon-aminocaproic acid, EACA, 6-aminohexanoic acid, Amicar)

      Aminocaproic acid 50–60 mg/kg orally every 4–6 hours, or

      Aminocaproic acid 50–60 mg/kg intravenously over 30–60 minutes diluted in 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) to a concentration within the range 10–100 mg/mL, every 4–6 hours, or

      Aminocaproic acid 200–360 mg/kg by continuous intravenous infusion over 24 hours diluted in 0.9% NS or D5W to a concentration within the range 10–100 mg/mL (maximum dose of 24,000 mg/day)

   • Tranexamic acid

      Tranexamic acid 20–25 mg/kg orally every 8–12 hours, or

      Tranexamic acid 20–25 mg/kg intravenously in 25–500 mL 0.9% NS or D5W every 8–12 hours at a rate NOT greater than 1 mg/min to prevent hypotension

      Notes: These agents should be used intermittently for bleeding episodes. Long-term use may lead to thrombosis. The duration of use for episodes of bleeding in VWD patients is usually 3–5 days

      Both aminocaproic acid and tranexamic acid accumulate in persons with impaired renal function; that is, dosages and administration schedules must be modified in renally impaired patients

      Notes on Monitoring Antifibrinolytic Therapy:

     Aminocaproic acid or tranexamic acid

      Renal function tests at baseline and periodically, thereafter, for the duration of use

     Clinically assess antifibrinolytic response

      Tranexamic acid

      Retinal changes or focal retinal degeneration developed in 4 different animal models following oral or intravenous tranexamic acid at doses from 3–40-times recommended usual human doses for durations of several days or longer. The incidence of lesions has varied from 25–100% of animals treated and was dose-related. At low doses, some lesions appeared to be reversible

      No retinal changes have been reported or noted in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden

5. Practical considerations:

   • May be sufficient in managing the less-severe forms of mucosal bleeding

   • More often, these are prescribed as adjuncts to replacement therapy with desmopressin and plasma concentrates during both minor and major surgery

   • Aminocaproic acid and tranexamic acid use is contraindicated in patients with coexisting bleeding originating in the upper urinary tract or urinary bladder

   • Antifibrinolytics should not be administered with factor IX complex or antiinhibitor coagulant concentrates, because the risk of thrombosis may be increased

6. Adverse effects:

   The side effects of tranexamic acid and aminocaproic acid are dose dependent

   • Nausea: Common

   • Vomiting: Occasional

   • Abdominal pain: Occasional

   • Headache: Occasional

   • Thrombotic complications: Rare. The incidence of thrombotic events secondary to the inhibition of the fibrinolytic system is unknown, but may be particularly increased in those patients who have some underlying predisposition to develop thrombosis

   • Less-common side effects:

     1. Hypotension

     2. Cardiac arrhythmias

     3. Rhabdomyolysis

     4. Retinal changes and focal retinal degeneration in animal models following oral or intravenous tranexamic acid

     5. Hypotension, bradycardia, and arrhythmia after rapid intravenous administration of aminocaproic acid

Note: Aminocaproic acid is a derivative and analog of the amino acid, lysine, which makes it an effective inhibitor for enzymes that bind lysines. Such enzymes include proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis. These synthetic agents inhibit the activation of plasminogen to plasmin and at high doses, inhibit plasmin

Regimen: von Willebrand Disease—Therapeutic Options Topical Agents

Mannucci PM. N Engl J Med 1998;339:245–253

Mannucci PM. Blood 2001;97:1915–1919

Topical therapies can be placed locally on accessible bleeding sites, such as oral or nasal bleeding; they may be used until bleeding is controlled

1. Absorbable gelatin sponge (eg, Gelfoam) soaked with topical thrombin

   • Water-insoluble, off-white, nonelastic, porous, pliable product prepared from purified pork skin gelatin, USP, granules and water for injection, USP

   • Able to absorb and hold within its interstices, many times its weight of blood and other fluids

   • Gelfoam sterile sponge may be cut without fraying

   • There is a theoretical risk for antigenicity given they are derived from nonhuman sources, but to date no adverse events have been linked to gelatin formulations

     Note: Thrombin bypasses all steps in the coagulation cascade and helps to convert fibrinogen to fibrin which forms a clot

   Topical thrombin (eg, Thrombostat, Thrombin-JMI)

   • Derived from bovine thrombin

   • Can be saturated into absorbable gelatin sponge

   Topical thrombin (Recothrom, other products)

   • Recombinant thrombin

   • Available in vials containing 5000 or 20,000 units of sterile recombinant topical thrombin powder for solution

   • Can be saturated into absorbable gelatin sponge

2. Topical fabric soaked with topical thrombin

3. Microfibrillar collagen hemostat (eg, Avitene, other products)

   • Active absorbable topical hemostatic agent

   • Bovine collagen is processed and purified into water-insoluble acid salts that initiate platelet activation

   • Easy removal with irrigation and suction

   • Various products available in pads, foam sponge, and powder formulations

     1. Avitene Flour (powder) microfibrillar collagen hemostat

     2. Avitene microfibrillar collagen hemostat

        Benefits:

        • Effective in controlling arterial bleeding

        • Conforms and adheres to irregular spaces

        • Available in 0.5-, 1-, and 5-g containers

     3. Avitene Sheets

        Benefits:

        • Cut to any shapes or sizes

        • Clings tenaciously to hemorrhages

        • Ideal for use on flat surfaces or to wrap vessels and anastomosis sites

        • Available in 3 sizes of nonwoven web sheets

     4. Avitene Ultrafoam Collagen Sponge

        Benefits:

        • Active absorbable topical hemostatic agent

        • Reduced thrombin usage may lower costs

        • Available in 4 sizes

Regimen: von Willebrand Disease—Therapeutic Options Platelet Concentrates

Castillo R et al. Blood 1991;77:1901–1905

Mannucci PM. N Engl J Med 2004;351:683–694

1. Used infrequently in VWD patients

2. Use when mucosal tract hemorrhages are not controlled despite adequate factor VIII and VWF:RCo levels

3. Platelet concentrates [4 × 10¹¹ to 5 × 10¹¹] are given together with factor VIII/VWF concentrates in an attempt control bleeding

4. Transfused normal platelets are thought to be hemostatically effective because they contain VWF that they transport and localize from flowing blood into sites of vascular injury

5. Platelets from human leukocyte antigen-compatible donors should be used if repeated or frequent use is likely

von Willebrand Disease: Special Therapeutic Settings Management of Patients with von Willebrand Disease During Pregnancy and Delivery

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. Blood 2005;105:3382

Mannucci PM. N Engl J Med 2004;351:683–694

General:

• No evidence that VWD, even severe type 3, impairs fertility in affected women or that miscarriages are more frequent in these patients than in women without VWD

• Patients with VWD have a higher rate of postpartum hemorrhage compared with 3–5% among the general population

  • 16–29% in the first 24 hours

  • 22–29% after 24 hours

• Type 1 or 2 VWD: Levels of VWF and FVIII rise 2–3-fold greater than baseline during the second and third trimesters of pregnancy, but fall rapidly after delivery

• Type 2 VWD: Although levels of VWF and factor VIII increase, complete normalization of hemostasis may not occur because part of the increased VWF is qualitatively abnormal but may not sustain VWF activity

• Type 2B VWD: Thrombocytopenia may develop or worsen

• Type 3 VWD: The risk of bleeding is greater because there is no physiologic increase in the FVIII:C and VWF levels

• FVIII levels are the best predictor of bleeding during and after delivery

  • The risk of bleeding at delivery is minimal when FVIII level >50 units/dL

  • The risk of bleeding at delivery is increased if FVIII level <20 units/dL

• Monitor patients for VWF and FVIII levels:

  • Once during the second and third trimesters of pregnancy

  • Within 10 days before the expected delivery date

  • For 2 weeks after delivery

• Monitor clinically for at least 2–4 weeks after delivery when the risk of bleeding is increased

• During and after delivery, measures aimed at rapid and complete contraction of the uterus are of utmost importance to prevent excessive bleeding

Therapy:

• Indications for treatment intervention:

  • FVIII level <20 units/dL: Administer desmopressin acetate or factor VIII/VWF concentrates at the time of delivery and for 3–4 days thereafter

  • Generally, 3–4 doses of factor VIII/VWF concentrates (40–60 IU VIII:C per kg, or 40–60 IU VWF:RCoF per kg) per day are needed to avoid postpartum bleeding

  • VWF and FVIII activity should be >50 units/dL for caesarean section or epidural anesthesia; replacement therapy should also be given if an episiotomy is required

  • Type 3 disease: Because VWF levels remain low, daily doses of factor VIII/VWF concentrates during and after delivery are needed to prevent bleeding

• Cesarean section: Reserve for usual obstetrical indications

• Desmopressin acetate may be used in pregnancy because it does not cause uterine contractions

von Willebrand Disease: Special Therapeutic Settings Acquired von Willebrand Disease

Federici AB. Expert Opin Investig Drugs 2000;9:347–354

Veyradier A et al. Thromb Haemost 2000;84:175–182

General:

• Acquired VWD is associated with a number of disease states including:

  • Lymphoproliferative diseases

  • Autoimmune diseases

  • Malignancies

  • Essential thrombocythemia

  • Hypothyroidism

  • Valvular heart disease particularly aortic stenosis, and may also occur with mitral valve prolapse

  • Drugs

• Putative mechanisms include:

  • Accelerated clearance of von Willebrand factor from plasma because of its absorption on the surface of abnormal cells

  • Formation of complexes with other plasma proteins

  • Heightened in vivo proteolysis

  • Inactivating autoantibodies

• When possible, successful treatment of the underlying disease associated with acquired VWD usually leads to resolution of a bleeding diathesis

• The choice among therapeutic options is often determined by an increase in plasma factor levels after the administration of test doses

• Most frequently used options for therapy include:

  • Desmopressin acetate

  • Factor VIII/VWF concentrates

  • Immune globulin intravenous (human) (IVIG)

Therapy:

For life-threatening bleeding:

• FVIII/VWF concentrates should be used initially to attempt to reach therapeutic levels of VWF (and factor VIII) quickly

• Although specific recommendations are not published, it is reasonable to administer FVIII/VWF concentrate 50–70 units/kg (VWF activity) and follow the response both clinically and with FVIII and VWF activity levels at 1–2 hours, 4–6 hours, and 8–12 hours to assess response

• If not contraindicated, desmopressin acetate may also be administered

Bleeding that is not life-threatening:

• A trial of desmopressin acetate is recommended in all patients with acquired VWD

• Measure VWF and factor VIII at baseline, and monitor levels at intervals over the 4–6 hours after desmopressin acetate administration to evaluate the response

Bleeding that is not life-threatening, but did not respond to a trial of desmopressin acetate:

• Administer either IVIG or virally inactivated FVIII/VWF concentrates

• The choice between FVIII/VWF concentrates and IVIG should be based on the underlying cause of the acquired VWD

Immune globulin intravenous (human) (IVIG):

• Patients with demonstrable antibodies to VWF with underlying lymphoproliferative disorders and IgG monoclonal gammopathies are more likely to respond to IVIG than those without antibodies

• Administer 1 g/kg body weight per day for 2 consecutive days

• Monitor FVIII and VWF activity before and at intervals for 7–15 days after infusion for IVIG

  Notes:

  • IVIG may have a longer duration of action than desmopressin acetate or FVIII/VWF concentrates

  • Response to IVIG may not be observed until 2–3 days after a dose is administered

Virally inactivated factor VIII/VWF:

• Administer intravenously virally inactivated FVIII/VWF concentrate 50–60 units/kg

• Monitor FVIII coagulant activity and VWF factor levels at baseline and at intervals over the next 12 hours to assess the half-life of the infused factor

  Note:

  • Patients with demonstrable circulating antibodies (6–15% of cases) may require larger doses of FVIII/VWF concentrate (50–100 units/kg)

Additional treatment options used in small numbers of patients with acquired VWD:

• Plasmapheresis or extracorporeal immunoadsorption for life-threatening bleeding unresponsive to other measures

• Glucocorticoids, such as prednisone, beginning at 1 mg/kg per day orally, or prednisolone 1 mg/kg per day intravenously, and gradually decrease (taper) the dose over several weeks

• Other immunosuppressive agents, such as cyclophosphamide or rituximab

von Willebrand Disease: Special Therapeutic Settings Alloantibodies to von Willebrand Factor

Mannucci PM. Blood 2001;97:1915–1919

Mannucci PM. N Engl J Med 2004;351:683–694

General:

• Ten to 15% of patients with type 3 VWD develop anti-VWF alloantibodies after transfusion of FVIII/VWF concentrates

• In some patients, FVIII/VWF concentrates may not be effective and may cause serious or fatal anaphylaxis

• Patients with type 3 VWD are generally not screened for alloantibodies unless there is suspicion of an antibody suggested by:

  • A lack of response to replacement therapy

  • Occurrence of anaphylaxis with replacement therapy

  • Another family member with VWD who developed an antibody

Therapy:

• There is limited experience in the treatment of patients with alloantibodies to VWF

• Treatment options include:

  • Recombinant activated FVII (F7): 90 mcg/kg by intravenous injection over 2–5 minutes every 2 hours for 2–3 doses. Assess response clinically

  • Recombinant FVIII by continuous intravenous infusion to maintain FVIII levels at approximately 0.5 units/dL. This approach may require huge doses to displace antibodies and restore hemostatic competency (eg, 5000–8000 units/hour in an adult). Monitor FVIII levels

von Willebrand Disease: Special Therapeutic Settings Preparation and Management of Patients with von Willebrand Disease for Dental Procedures

General:

Prophylactic treatment depends on the type of dental procedure to be performed

Therapy:

Routine examinations and cleaning:

• Can generally be performed without increasing FVIII/VWF levels

• Patients with a history of excessive bleeding with dental prophylaxis or nonserious procedure-related bleeding:

  • Desmopressin acetate may be given prior to a procedure, and/or

  • Aminocaproic acid may be administered usually for 1–3 days

Special circumstances in which factor concentrate and/or antifibrinolytic therapy should be given before and possibly after a dental appointment:

• Deep cleaning:

  • Patients who have heavy plaque and/or calculus accumulation in which bleeding is likely to be induced with scaling

• Block local anesthesia or mandibular block:

  • Dependent on the severity of a patient's VWD

• Dental extractions:

  • Before an extraction, virally inactivated FVIII/VWF concentrate is administered to raise the level to ~50 IU/dL for uncomplicated extractions or to 50–100 IU/dL for difficult or multiple extractions

    • Usually, further administration of FVIII/VWF concentrate is not required

  • Aminocaproic acid starting 4–8 hours before surgery and continuing with 2–3 g orally 4 times daily for 5–7 days after dental work is completed

    Tranexamic acid may also be used