Hematology

von Willebrand Disease (VWD)

von Willebrand Disease (VWD)

What every physician needs to know

Von Willebrand factor (VWF) is a huge multimeric protein comprised of identical 280,000 Dalton monomeric subunits. VWF is critical in the initiation of hemostasis. VWF multimers are produced and secreted by endothelial cells (and platelets) and, because they bind to platelet glycoprotein (GP) I receptors, induce platelet adherence to long VWF multimeric “strings” anchored to injured or stimulated endothelial cells. In addition, VWF multimers in the subendothelium are exposed when endothelial cells are injured and desquamated; and plasma VWF multimers bind to platelet GP IIb-IIIa receptors on adjacent platelets, causing them to cohere (or aggregate).

Another important function of VWF multimers is to bind (non-covalently) coagulation factor VIII (FVIII) and protect it from proteolysis. VWF-bound FVIII is thereby capable of circulating for many hours longer than would be possible in the absence of transport by VWF multimers.

VWF is, therefore, indispensable for both platelet adhesion-aggregation and blood clotting.

Deficiency or defective VWF results in VWD, a common and usually mild congenital bleeding disorder. There are several types of congenital VWD. Types 1 and 3 are quantitative deficiencies in VWF production or release, whereas the several different subtypes of type 2 are qualitative (i.e., functional) VWF defects.

Type 1 accounts for approximately 75% of VWD and has an estimated prevalence as high as 1% in some populations. Type 2 WVD disease is less common, with subtypes 2A and 2B together accounting for approximately 25%. Type 3 is exceedingly rare (0.5-5/million). Ironically, many of the patients described by Dr. Eric von Willebrand in his initial studies done in the Aland Islands (between Sweden and Finland) in the 1920s had type 3 VWD.

Are you sure your patient has VWD? What should you expect to find?

VWD is usually an inherited bleeding disorder. Only rarely is it acquired. A family history of bleeding, especially affecting both males and females, suggests VWD. It is a mild bleeding disorder in many patients. Diagnostic evaluation is often initiated to determine the cause of easy bruising, excessive bleeding with dental extractions or surgery, recurrent epistaxis, or excessive menstrual bleeding.

Mucocutaneous bleeding is the most common symptom of most patients with VWD. Severe (type 3) and type 2N VWD are similar to severe hemophilia A in males in that joint and muscle bleeding also occur.

Beware of other conditions that can mimic VWD:

Hemophilia A and either quantitative or qualitative platelet disorders can resemble VWD clinically. Hemophilia A is an X-linked deficiency of FVIII that primarily affects males. VWD is an autosomal disorder (discussed further in “Pathophysiology”). Platelet-type (or “pseudo”-) VWD is a gain-of-function defect in platelet GP Ib with similar clinical and laboratory finding as type 2B VWD (see “Laboratory studies”).

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

A standard panel for the assessment of VWD includes tests on a patient plasma sample for VWF antigen, ristocetin cofactor and factor VIII coagulant activity. A technically more complex follow-up test that evaluates the distribution of VWF multimers is also useful in some patients.

VWD panel

(1) VWF antigen (VWF:Ag)is an enzyme-linked immunosorbent assay (ELISA) that uses anti-VWF antibody to quantify the plasma VWF:Ag level.

The mean value for plasma VWF:Ag varies with blood type. Patients with type O blood have a mean level of 74%; type A 103%; type B 110%; and type AB 126%.

(2) The ristocetin cofactor (RCoF) assaymeasures VWF functional activity in plasma. Ristocetin promotes the binding of large VWF multimers from plasma onto formalin-fixed normal platelets that retain exposed GP Ib (but not other) receptors after fixation. If normal (or the patient’s own) platelets are used instead of formalin-fixed platelets, the test is referred to as “Ristocetin-Induced Platelet Aggregation” (RIPA).

There is considerable variability in the RCoF assay. A single sample retested multiple times can vary within a range of at least 10-15%). In a few clinical laboratories, a collagen-binding test that measures the binding of large plasma VWF multimers from patient plasma to collagen is used instead of (or in addition to) the RCof assay.

(3) Factor VIII (FVIII) activity is decreased to varying degrees when VWF is quantitatively or qualitatively deficient/defective.

In VWD the decrease in FVIII is often not below a level (approximately 30% of normal) that prolongs the partial thromboplastin time (PTT).

The bleeding time test and PFA-100 (platelet function analyser-100) are screening tests that give variable results and are not uniformly reliable indicators of effective vs. ineffective hemostasis.

Testing for specific VWD types

VWD is classified into types 1, 2, and 3. Type 2 has several subtypes. These include type 2A, 2B, 2M and 2N. The majority of individuals with VWD have type 1. The results of tests on patient plasma using the standard VWD screening panel (VWF:Ag, RCoF and FVIII) provide initial information about the presence/type of VWD. Further evaluation to determine VWD type may require VWF multimeric analysis by gel electrophoresis.

Type 1 VWD --- VWF is not released (or produced) normally. Results of the three tests on patient plasma using the standard VWD screening panel are usually proportionately decreased to levels below normal. VWF multimeric analysis is not required for the diagnosis. Modest and proportional decrease in VWF:Ag and RCoF activity, along with a normal or slightly low FVIII level, identifies a patient with probable type 1 VWD. The diagnosis of many cases of VWD type 1, the most common type, is often uncertain unless the values for VWF:Ag and RCoF are consistently below approximately 30% of normal.

Type 2A VWD--- Large VWF multimers are either proteolyzed excessively or inadequately produced/released. The large VWF multimers are absent from patient plasma. Plasma RCoF activity is decreased significantly more than VWF:Ag.

Type 2B VWD --- The large VWF multimers in patient plasma have an abnormally increased affinity for GP Ib receptors on the surface of platelets, and cause mild-modest platelet aggregation and thrombocytopenia. RCoF activity is decreased more than VWF:Ag. VWF multimeric analysis demonstrates the selective decrease in large VWF multimers from patient plasma. The RIPA test demonstrates that a very low dose of ristocetin will induce the binding of the abnormal, hyper-adhesive VWF multimers from patient plasma to their own (or normal donor) platelets, inducing aggregation.

Platelet-type (“pseudo"-) VWD --- The clinical phenotype and VWD screening panel give results similar to type 2B VWD, including loss of the largest VWF multimers from the plasma and mild thrombocytopenia. The defect is a gain-of-function mutation in platelet GP Ib that causes excessive binding of large VWF multimers to the abnormal patient platelets. Diagnosis is by RIPA using patient (instead of normal) platelets to demonstrate that normal VWF (in normal plasma) induces the aggregation of patient platelets in the presence of a very low concentration of ristocetin.

Type 2M VWD --- VWF function is decreased, despite the presence of a normal VWF multimeric pattern. The most impressive finding is a RCoF activity that is decreased to levels that are much lower than VWF:Ag and FVIII levels.

Type 2N VWD --- This mimics hemophilia A, with low levels of FVIII and normal VWF:Ag, RCoF and multimeric pattern. VWF binds poorly to factor VIII, and this decreased binding exposes FVIII to accelerated proteolysis. The half-life of FVIII in the plasma is shortened, resulting in a low FVIII level.

Type 3 (severe) VWD --- Values for VWF:Ag and RCoF are extremely low. VWF multimers are either barely detectable or absent from patient plasma

Additional challenges to the diagnosis of von Willebrand disease

VWF may be elevated several-fold during an acute phase reaction. A patient with a significant deficiency of VWF may have values that increase considerably during infection or injury.

VWF also increases during pregnancy or during estrogen/oral contraceptive use. A normal result from a single diagnostic evaluation for VWD does not rule out the diagnosis unequivocally. If testing is being obtained during an acute phase reaction, then concurrent measurement of a plasma marker of inflammation (e.g., C-reactive protein) may be useful for test interpretation.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of VWD?

Radiographic studies are useful to help localize a bleeding site (e.g. retroperitoneal or intra-cranial).

If you decide the patient has VWD, what therapies should you initiate immediately?

The goals of treatment are rapid cessation and subsequent prevention of bleeding. This can usually be achieved with DDAVP and/or concentrates of “intermediate purity” containing both VWF and FVIII.

DDAVP (1-desamino-8-D-arginine vasopressin; desmopressin) induces the secretion into the circulation of VWF multimers stored in the Weibel-Palade bodies of endothelial cells. This raises the plasma level of both VWF multimers and FVIII. (The increased VWF multimers bind and transport more FVIII from FVIII synthetic sites in the liver and elsewhere.)

DDAVP is usually given as a 0.3 microgram/kg solution in 50 ml of saline over 20 minutes. The infusion can be repeated after 12 hours, and then every 24 hours up to 3-4 total doses. A therapeutic trial of DDAVP to determine patient responsiveness should be done before any use for surgical hemostasis. DDAVP is most effective in Type 1 VWD.

DDAVP must be used cautiously because repeated doses can cause dilutional hyponatremia and seizures. DDAVP should not be given to people with type 2B VWD because the increased binding of the abnormal VWF (with high affinity for platelet GP Ib) that would be released into the circulation by DDAVP can exacerbate thrombocytopenia.

More definitive therapies?

Humate-P is a concentrate that contains all VWF multimers and FVIII, and is given either by rapid IV infusion or (sometimes) continuous infusion. The product is labeled for both RCoF and FVIII dosing. (Other VWF-containing products are described and compared by Favoloro 2016 in the references.) For a bleeding episode, Humate-P is usually administered in approximately 40-80 international units (IU)/kg, followed by about half that dose (approximately 20-40 IU/kg) every 12 hours. Higher doses (approximately 50-60 IU/kg) may be necessary in emergency bleeding situations. Control of bleeding may require maintenance of plasma RCoF levels in the 30-100% range for a few days (minor injury or surgery) or up to 1-2 weeks (major injury/surgery).

FVIII levels will increase both as a result of the FVIII infused in the concentrate and the increased FVIII transport capacity provided by the infused VWF multimers.

Bleeding in VWD types other than type 1 is likely to require VWF-containing concentrate. This is also the case with type 1 VWD that is inadequately responsive to DDAVP.

Future therapy

A combination of recombinant VWF multimers + recombinant FIII has been used successfully in a prospective clinical trial of in type 3 and (severe) type 1 VWD patients. (See Mannucci, et al., Blood 2013 in references.). Recombinant VWF + recombinant FVIII (initially), and then subsequently recombinant VWF alone, also has been used to control bleeding in patients with severe VWD, type 2, and (severe) type 1 VWD. (See Gill, et al., Blood 2015 in references.) This latter recombinant VWF product is approved by the F.D.A. and licensed to Shire as “Vonvendi.”

What other therapies are helpful for reducing complications?

The anti-fibrinolytics, aminocaproic acid (Amicar; 50 mg/kg [up to a maximum of 5 grams] given 4 times daily) or tranexamic acid (25 mg/kg given 3 times daily) are especially useful in the management of oral/dental bleeding.

Estrogen or oral contraceptive pills can sometimes be effective in the management of bleeding (including menorrhagia) in women with VWD.

What should you tell the patient and the family about prognosis?

The prognosis for most patients with VWD is favorable, provided their bleeding is treated and prevented appropriately. Many individuals with VWD are followed routinely at a hemophilia treatment center.

Individuals with VWD should be discouraged from participating in high-impact sports/activities (football, boxing, rugby, wrestling, rodeo-type events, jumping from altitudes, etc.). Because of the special danger of head injury, helmets and protective gear are frequently recommended for some other sports (skateboarding, skiing, baseball). Patients on VWF prophylaxis should treat themselves whenever they can foresee potentially threatening activity.

What if scenarios

Most cases of VWD are inherited. Rarely, however, VWD is acquired in association with: (1) multiple myeloma, lymphoproliferative or myeloproliferative disorders (acquired VWD caused by anti-VWF autoantibodies to, or cell absorption of, large VWF multimers); (2) hypothyroidism (caused by decreased VWF synthesis); or (3) serious cardiac conditions associated with loss of large plasma VWF multimers. The latter include aortic stenosis or patients in whom there has been recent implantation of a left ventricular assist device (LVAD).

There is debate currently about whether or not the loss of large plasma VWF multimers in aortic stenosis or with LVAD implantation is directly related to stroke or gastrointestinal bleeding. Shear-induced platelet aggregation is known to be mediated by the attachment of large plasma VWF multimers to platelets. Extremely high shear forces are generated in aortic stenosis or in implanted LVADs.

The treatment for acquired VWD is usually correction of the underlying condition. If bleeding is serious, DDAVP +/- VWF-containing concentrate can be tried. If anti-VWF autoantibodies are present, then IV IgG (1 gram/kg for 1 or 2 days) or an immunosuppressive agent may be useful.

Pathophysiology

The gene encoding the VWF monomer is on chromosome #12. Expression of the mRNA for the VWF monomer is translated into a 280,00 Dalton protein that contains a series of different domains. These include contiguous non-identical regions (A domains) that: (a) bind to platelet GP Ib (the A1 domain); (b) contain the peptide cleavage site for ADAMTS-13, the VWF-cleaving protease (the A2 domain); and (c) bind to collagen (the A3 domain).

Within endothelial cells (and megakaryocytes), the synthesized, identical VWF monomers form dimers. The dimers then multimerize (polymerize) into VWF multimers ranging in molecular mass from large to colossal. These are stored in endothelial cell Weibel-Palade bodies where they await secretion, by cell injury or perturbation, in the form of ultra-long VWF multimeric strings anchored to the endothelial cell surfaces.

The ultra-long anchored VWF multimeric strings initiate hemostasis by binding (via A1 domains in their subunit VWF monomers) to platelet GP Ib receptors, thereby causing localized platelet adhesion (followed by aggregation). The endothelial cell anchored ultra- long VWF multimeric strings are cleaved within a few minutes into small, soluble VWF multimers that diffuse away from the endothelium to gather, bind non-covalently, transport, protect and deliver FVIII molecules for participation in the blood clotting process.

Examples of genetic alterations and their pathophysiological effects in VWD include the following:

  • Mutations located at various points in one of the two VWF genes cause delayed or diminished VWF release (VWD type 1). This can often be overcome by the intra-cellular signaling that follows the binding of DDAVP to a vasopressin receptor on endothelial cells.

  • Mutations at different locations in one of the two VWF genes encoding the A1 domain of VWF monomeric subunits can result in either gain-of-function (VWD type 2B) or loss-of-function (VWD type 2M) of VWF multimers.

  • Mutations at locations in one of the two VWF genes encoding the A2 domain can result in excessive cleavage of VWF multimers by ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin motifs, # 13), the VWF-cleaving protease (VWD type 2A).

  • Mutations that affect the FVIII-binding region at the N-terminus of VWF monomers encoded by each of the two VWF genes cause VWD type 2N, a homozygous or doubly heterozygous disorder.

  • Mutations at other locations in both VWF genes cause type 3 (severe) VWD. This is also a homozygous or doubly heterozygous disorder.

  • In contrast to VWD type 2N or VWD type 3, the other congenital types of VWD require only a single abnormal VWF gene to cause a bleeding disorder. These types of VWD are autosomal dominant.

What’s the evidence?

James, AH, Manco-Johnson, MJ, Yawn, BP, Dietrich, JE, Nichols, WL. "Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines". Obstet Gynecol. vol. 114. 2009. pp. 674-8.

(Summary of management in Ob-Gyn journal.)

Ruggeri, ZM, Ware, J. "von Willebrand factor". FASEB J. vol. 7. 1993. pp. 308-16.

(Classic paper by experts of great renown.)

Rodeghiero, F, Castaman, G, Tosetto, A. "How I treat von Willebrand disease". Blood. vol. 114. 2009. pp. 1158-65.

(Summary of excellent practical guidelines.)

James, PD, Goodeve, AC. "Von Willebrand disease". Genet Med. vol. 13. 2011. pp. 365-76.

(Helpful mixture of clinical and genetic information.)

Tiede, A, Rand, JH, Budde, U. "How I treat acquired von Willebrand syndrome". Blood. vol. 117. 2011. pp. 6777-85.

(Summary of excellent practical guidelines.)

Lenting, PJ, Casari, C, Christophe, OD, Denis, CV. "Von Willebrand factor: the old, the new and the unknown". J Thromb Haemost. vol. 10. 2012. pp. 2428-37.

(Recent overview.)

Rick, ME, Konkle, BA. "von Willebrand disease. In Consultative Hemostasis and Thrombosis". 2013. pp. 90-102.

(Excellent recent summary for clinicians.)

Castaman, G, Goodeve, A, Eikenboom, J. "Principles of care for the diagnosis and treatment of von Willebrand disease". Haematologica. vol. 98. 2013. pp. 667-74.

(Excellent recent summary for clinicians.)

Mannucci, PM, Kyrie, PA, Schulman, S. "Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand’s disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials". Blood Transfusion. vol. 17. 2013. pp. 1-8.

(Recent therapeutic guidelines with a master clinician as first author.)

Mannucci, PM, Kempton, C, Millar, C. "Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial". Blood. vol. 122. 2013. pp. 648-57.

Gill, JC, Castaman, G, Windyga, J. "Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease". Blood. vol. 126. 2015. pp. 2038-46.

(These two articles describe the use of recombinant VWF.)

Favoloro, EJ. "Towards personalized therapy for von Willebrand disease: a future role for recombinant products". Blood Transfusion. vol. 14. 2016. pp. 262-76.

(Detailed comparison of various therapeutic products for VWD.)
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