para>Many cases of vWD are diagnosed in childhood, often during initial years of menstruation. vWD may be difficult to diagnose before 6 months of age. ‚
Pregnancy Considerations
Although levels of vWF increase during pregnancy, women with vWD are more likely to experience an increased incidence of obstetric complications that manifest with bleeding.
‚
ETIOLOGY AND PATHOPHYSIOLOGY
- vWF is a large, multimeric protein that is released from endothelial cells and is also carried within platelets inα-granules.
- vWF binds to collagen at sites of vascular injury and creates a surface for platelet adhesion through GP1b receptor. This results in platelet plug formation.
- vWF is also a carrier for FVIII and stabilizes this factor from degradation. A deficiency in vWF may result in lower levels of FVIII.
- When vWF is deficient or dysfunctional, primary hemostasis is compromised, resulting in increased mucocutaneous and postprocedural bleeding.
- Three major categories of vWD exist
- Type 1, the most common and mildest form, represents 60 " “80% of cases.
- Mild to moderate quantitative deficiency of vWF and concordant deficiency of FVIII
- Generally, a mild bleeding disorder
- Type 2 caused by qualitative defect in vWF accounts for 10 " “30% of cases and is divided into the following multiple subtypes.
- Type 2A is noted for loss of hemostatically active large multimers with low ristocetin cofactor/vWF activity.
- Type 2B, noted for increased binding affinity for platelets, is associated with thrombocytopenia, low ristocetin cofactor/vWF activity, abnormal ristocetin-induced platelet aggregation (RIPA), and loss of large multimers.
- Type 2M is noted for defective platelet or collagen binding without loss of large multimers.
- Type 2N demonstrates defective binding to FVIII, which results in increased clearance of Factor VIII and hemophilia A " “like picture
- Type 3 represents 1 " “5% of cases.
- Most severe form characterized by markedly decreased-to-undetectable levels of vWF and FVIII
- Manifests as hemophilia A with hemarthroses (1,2,3 and 4)
- Acquired form of vWD (AvWD) may be due to cardiovascular, hematologic, or autoimmune conditions, as well as tumors and medications.
- The pathophysiology of AvWD is related to the underlying cause and may result from shear induced cleaving of vWF in cardiovascular conditions, increased adsorption of vWF by certain tumor cells or activated platelets, or presence of anti-vWF autoantibodies detected in hematologic disorders.
Genetics
- The 175-kb gene for vWF is located on short arm of chromosome 12.
- Type 1 follows an autosomal dominant inheritance pattern, with variable expressivity.
- Type 2 varies but primarily follows an autosomal dominant inheritance pattern.
- Type 3 follows an autosomal recessive inheritance pattern (4).
COMMONLY ASSOCIATED CONDITIONS
AvWD may be found in patients with hematologic disorders such as MGUS and myeloproliferative neoplasms. Commonly associated cardiovascular conditions include aortic stenosis and LVAD placement. ‚
DIAGNOSIS
HISTORY
- Most patients with vWD have a positive family history of bleeding disorder; however, patients with mild forms of vWD and their families may be unaware of their disease. Those with acquired vWD usually have no family history of this disorder.
- The most important component of diagnosis is the hemostatic history often aided by specifically designed bleeding questionnaires.
- Common symptoms are those of mucocutaneous (recurrent epistaxis, menorrhagia, ecchymosis) or postprocedural bleeding. Hemarthroses are a rare presentation, mostly associated with types 2N and 3.
PHYSICAL EXAM
- Physical exam may be entirely normal, although there may be some ecchymoses.
- Findings suggestive of other causes of increased bleeding should be sought (liver disease, skin laxity, or telangiectasias).
DIFFERENTIAL DIAGNOSIS
- Primary hemostatic disorders: congenital thrombocytopenia or qualitative platelet defects, coagulation factor deficiencies
- Secondary hemostatic disorders: liver disease, uremia, connective tissue disorders, coagulation factor inhibitors
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- The specific tests for vWD include vWF antigen (vWF:Ag), vWF activity/ristocetin cofactor activity (vWF:RCo) (if available: collagen-binding activity [vWF:CB]) and FVIII activity; these tests should be ordered when suspicion for vWD is high. Additional specific tests include RIPA, vWF multimer analysis, vWF propeptide (vWFpp), and genetic testing.
- Other tests include CBC, PT/INR, aPTT, platelet function analyzer assay (PFA-100).
- Platelet count is often normal, except in type 2B or in AvWD when there is an underlying myeloproliferative disorder.
- Platelet function assays via PFA-100 (i.e., collagen/epinephrine and collagen/ADP closure time) are usually prolonged but may be normal in mild disease.
- PT/INR is normal, unless there is concurrent liver disease or warfarin/Coumadin use.
- Activated PTT may be prolonged if a decrease in FVIII accompanies vWD.
- Specific tests for vWD
- vWF antigen testing is done via immunologic methods
- vWF antigen testing has a positive predictive value (PPV) of 33% for detecting significant FVIII deficiency and a PPV of 80% for detecting ristocetin cofactor activity abnormalities.
- vWF antigen may be normal in type 2 vWD.
- Ristocetin cofactor activity is a functional assessment of vWF. Ristocetin promotes binding of platelets to vWF, and this activity is disproportionately reduced compared to vWF antigen in most forms of type 2 vWD.
- Ratio of vWF:RCo to vWF:Ag <0.5 to 0.7 may be used to differentiate type 1 from type 2 vWD.
- Alternatively, latex particle " “enhanced immunoassay may be used to quantify vWF activity. A specific monoclonal anti-vWF antibody directed against platelet GP1b " “binding site of vWF adsorbed onto the latex reagent reacts with plasma vWF proportional to the vWF activity.
- Collagen-binding activity, another functional assessment of vWF, is reduced in most forms of vWD.
- FVIII activity may be normal or mildly decreased in most types of vWD (in 2N and type 3, levels are markedly decreased).
- vWFpp is useful in accelerated clearance variants of vWD.
- vWF multimer analysis is performed by electrophoresis on agarose gel. This test differentiates patients with type 2 vWD.
- RIPA is useful in diagnosing type 2B vWD.
- FVIII-vWF binding assay activity is low in patients with type 2N vWD.
- Genotype testing may also be used especially for types 2 and 3 (1,2,3 and 4).
Follow-Up Tests & Special Considerations
- Unless patients have severe forms of vWD or are undergoing treatment, follow-up laboratory studies are not usually obtained.
- Patients with blood group O have 20 " “30% baseline lower levels of vWF antigen and ristocetin cofactor activity.
- vWF is an acute-phase reactant, so elevations may be seen in inflammatory conditions, liver disease, pregnancy (which may correct mild deficits), or with estrogen use.
TREATMENT
GENERAL MEASURES
- Most patients with type 1 vWD do not require activity restrictions.
- Patients with type 3 vWD should avoid contact sports.
- An emergency ID bracelet may be useful.
MEDICATION
First Line
- Desmopressin (DDAVP)
- Enhances release of vWF from endothelial cells
- Primarily effective for type 1 vWD; not to be used in type 2B
- Typically raises vWF by 2- to 3-fold from baseline levels (5)[B]
- Not effective in severe deficiencies, in types of vWD with defective vWF, or for prophylaxis prior to major procedures
- Dosed 0.3 Ž ¼g/kg (max 20 mg) IV/SC; intranasal (high concentration) spray: <50 kg: 150 Ž ¼g/day; >50 kg: 300 Ž ¼g/day (Stimate)
- Common side effects: flushing, tachycardia, water retention, hyponatremia
- Obtain repeat testing of ristocetin cofactor activity and FVIII 1 and 4 hours after infusion to evaluate peak response and clearance of DDAVP.
- Tachyphylaxis may develop with prolonged dosing; limit use to administering DDAVP once every 24 to 48 hours for 3 to 5 days.
- vWF and FVIII concentrates
- Plasma-derived vWF and FVIII concentrates of various purity such as Humate-P, Alphanate, Wilate, or Fandhi (not available in United States) are commercial concentrates of vWF and FVIII that are given in doses of 25 to 60 IU/kg/day based on clinical situation (6,7)[B]
- Administration of 1 IU/kg vWF:RCo concentrate raises the plasma RCo activity by approximately 2%.
- Dose of vWF concentrate may be adjusted for FVIII levels and ristocetin cofactor activity.
- FVIII levels should be monitored to avoid supranormal levels and possible venous thromboembolism (VTE).
- Contraindicated if patient develops alloantibodies to vWF
- New recombinant form of vWF concentrate is effective in clinical trials but not yet available for clinical use (8)[B].
- In patients with severe bleeding phenotype, prophylactic treatment is used.
- Cryoprecipitate
- Cryoprecipitate contains FVIII, fibrinogen, vWF, factor XIII, and fibronectin.
- Not considered as safe as the virus-inactivated plasma concentrates listed above and should not be used unless those are unavailable
- Antifibrinolytics
- Useful for mucosal bleeding
- Contraindicated in patients with hematuria due to risk of retention of large blood clots in the renal collecting system
- Given as adjunct to DDAVP
- Aminocaproic acid may be given at 50 to 70 mg/kg (max: 5 g; lower doses may be effective) q4 " “6h IV or PO.
- Tranexamic acid may be given at 10 to 15 mg/kg IV or 25 mg/kg (1,300 mg) PO q8 " “12h.
- Recombinant FVIIa/Novoseven
- Used for patients who develop alloantibodies to vWF
- Given as IV bolus of 90 Ž ¼g/kg q2h or 20 Ž ¼g/kg every hour until hemostasis is achieved
Second Line
- Oral contraceptives raise vWF/FVIII levels and have a role in the treatment of chronic menorrhagia.
- Platelets may be given as an adjunct to factor concentrates if hemostasis has not been achieved.
- IVIG has been useful in some patients with AvWD associated with monoclonal gammopathy (9).
- Recombinant FVIIa has been used effectively in patients with type 3 vWD.
ISSUES FOR REFERRAL
The diagnosis and management of vWD is not always straightforward; consider consultation with hematologist. ‚
SURGERY/OTHER PROCEDURES
Valve replacement or correction may be curative for patients with AvWD associated with underlying cardiovascular conditions. ‚
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- For patients with major bleeding or those undergoing major surgical procedures, levels of ristocetin cofactor/vWF activity and FVIII need to be restored to 80 to 100 IU/dL for first 2 days and then maintained >50 IU/dL for 5 to 7 days.
- For patients undergoing minor surgical procedures, maintain FVIII levels >50 IU/dL for 5 to 7 days.
- For patients delivering or in need of epidural anesthesia, obtain FVIII levels >50 IU/dL.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patients should be seen by a hematologist prior to invasive procedures for determination of perioperative management or advice regarding delivery. ‚
Patient Monitoring
Patients with mild disease do not require monitoring. ‚
DIET
No dietary restrictions are recommended. However, aspirin and other NSAIDs should be avoided due to their antiplatelet effects, which can exacerbate the bleeding phenotype. ‚
PATIENT EDUCATION
National Hemophilia Foundation: www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=182&contentid=47&rptname=bleeding ‚
PROGNOSIS
Most patients with vWD have a normal life expectancy. ‚
COMPLICATIONS
- Significant perioperative bleeding may occur.
- Patients with type 3 vWD and type 2N can have bleeding complications similar to patients with hemophilia A such as hemarthrosis and intracranial hemorrhage.
- Patients with aortic stenosis and AvWD are known to have higher rates of GI bleeding.
- Multiple transfusions may result in alloantibodies against vWF.
- Venous thromboembolism may result from supranormal levels of FVIII.
REFERENCES
11 Ng ‚ C, Motto ‚ DG, Di Paola ‚ J. Diagnostic approach to von Willebrand disease. Blood. 2015;125(13):2029 " “2037.22 Lillicrap ‚ D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood. 2013;122(23):3735 " “3740.33 Nichols ‚ WL, Hultin ‚ MB, James ‚ AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171 " “232.44 Laffan ‚ MA, Lester ‚ W, O 'Donnell ‚ JS, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167(4):453 " “465.55 Hanebutt ‚ FL, Rolf ‚ N, Loesel ‚ A, et al. Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders. Haemophilia. 2008;14(3):524 " “530.66 Mannucci ‚ PM, Chediak ‚ J, Hanna ‚ W, et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood. 2002;99(2):450 " “456.77 Thompson ‚ AR, Gill ‚ JC, Ewenstein ‚ BM, et al. Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). Haemophilia. 2004;10(1):42 " “51.88 Mannucci ‚ PM, Kempton ‚ C, Millar ‚ C, et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood. 2013;122(5):648 " “657.99 Tiede ‚ A, Rand ‚ JH, Budde ‚ U, et al. How I treat the acquired von Willebrand syndrome. Blood. 2011;117(25):6777 " “6785.
ADDITIONAL READING
- Kessler ‚ CM. Diagnosis and treatment of von Willebrand disease: new perspectives and nuances. Haemophilia. 2007;13(Suppl 5):3 " “14.
- Kumar ‚ S, Pruthi ‚ RK, Nichols ‚ WL. Acquired von Willebrand disease. Mayo Clin Proc. 2002;77(2):181 " “187.
- Lippi ‚ G, Franchini ‚ M, Salvagno ‚ GL, et al. Correlation between von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma. J Thromb Thrombolysis. 2008;26(2):150 " “153.
- Mannucci ‚ PM. Treatment of von Willebrand 's disease. N Engl J Med. 2004;351(7):683 " “694.
- Robertson ‚ J, Lillicrap ‚ D, James ‚ PD. Von Willebrand disease. Pediatr Clin North Am. 2008;55(2):377 " “392.
- Sciscione ‚ AC, Mucowski ‚ SJ. Pregnancy and von Willebrand disease: a review. Del Med J. 2007;79(10):401 " “405.
SEE ALSO
Algorithms: Bleeding Gums; Ecchymosis ‚
CODES
ICD10
- D68.0 Von Willebrands disease
ICD9
- 286.4 Von Willebrands disease
SNOMED
- 128105004 von Willebrand disorder (disorder)
- 128106003 von Willebrand disease type 1 (disorder)
- 128107007 von Willebrand disease type 2 (disorder)
- 128108002 von Willebrand disease type 3 (disorder)
CLINICAL PEARLS
- vWD varies from a minor to severe bleeding disorder; affects 1 " “2% of the U.S. population.
- It is important to determine the exact type of vWD (1, 2, or 3) to guide treatment.
- AvWD should be considered in patients with acquired bleeding disorder if they have underlying predisposing conditions.