Von Willebrand disease

Common inherited bleeding disorder caused by the deficiency or dysfunction of von Willebrand factor resulting from mutations in the gene encoding this multimeric glycoprotein.

Partial quantitative deficiency of plasma von Willebrand factor (VWF) is responsible for the majority of cases of von Willebrand disease (VWD), the most common inherited human bleeding disorder.

0.6% of the general population coincidentally has bleeding symptoms and reduced VWF levels and highlight the significant risk for false-positive diagnosis of partial quantitative VWD.

Pathophysiology underlying low VWF levels suggest reduced VWF synthesis and/or secretion from endothelial cells rather than enhanced VWF clearance.

Synthesized by endothelial cells and megakaryocytes.

After synthesis endothelial cells store von Willebrand factor as an ultra large multimer in Weible-Palade bodies.

For the bleeding state work-up assessing prothrombin time, activated partial thromboplastin time, fibrinogen level, and VWF levels (VWF:Ag, WF ristocetin cofactor assay.

Has autosomal inheritance pattern, so men and women are equally likely to be affected.

VWF is a 2050 amino acid protein monomer that dimerizes to form a 250 kD basic subunit.

vWF is an adhesive multimeric plasma GLYCOPROTEIN that performs 2 major functions in hemostasis: it mediates platelet adhesion to injured subendothelium via glycoprotein 1Balpha, and it binds and stabilizes factor VIII in circulation, protecting it from proteolytic degradation by enzymes.

This subunit is then multimerized to sizes of 20-40 mers in plasma, with some polymers greater than 100 mers.

High molecular weight polymers are important for maintaining hemostasis during high shear stress.

Prevalence in the general population estimated from 0.1-1%.

Results in significant bleeding in about 1 in 1000 subjects.

Most common inherited disorder of platelet vessel wall interaction and involves both quantitative and qualitative defects of von Willebrand factor, a mediator of platelet function and carrier of FVIII protein.

Most common congenital autosomal bleeding disorder.

Has no geographical or ethnic predilection.

Increased prevalence of the recessive forms, such as type 2N and type 3 Von Willebrand disease, in areas with high rates of cosanguibity

Females outnumber males 2:1, despite both sexes inheriting the mutant VWF alleles with equal frequency: due to excessive mucocutaneous bleeding in reproductive age women: childbirth and menorrhagia.

Characterized by abnormal platelet function, expressed as a prolonged bleeding time.

A prolonged bleeding time is it consistent finding and maybe accompanied by decreased factor VIII procoagulant activity.

Quantitative or qualitative defects of vW factor may be congenital or acquired.

The congenital disorder is autosomally dominant in most cases.

The inherited abnormalities are associated with the defect in the von Willebrand’s affected gene on chromosome 12.

The 175-kb VWF gene located on the short arm of chromosome 12 and comprises 52 exons.

In some patients the coexistence of impaired response of plasminogen activator and telangiectasia suggests the presence of the regular defect or more extensive endothelial abnormalities.

In patients with a marked bleeding phenotype, assaying clotting factor assays (factor II [FII], factor V, factor VII, factor VIII, factor IX, factor X, factor XI, and factor XIII), platelet aggregometry, and platelet nucleotide testing.

In low VWF patients with a marked bleeding phenotype, a complete full clotting factor screen and platelet-aggregation studies to exclude the possibility that additional coagulation defects may be present.

Low VWF patients are advised to minimize nonsteroidal anti-inflammatory drug exposure.

Low VWF patients are informed to contact for a hemostatic treatment plan should any dental work, operations/procedures be required or should they become pregnant.

More than 20 different clinical and laboratory types have been described, but 3 broad types are described.

Type 1 is the most common by far, accounting for approximately 75% of cases.

In type 1 disease the level of von Willebrand factor is low, but the protein functions normally.

Most families with type 1 VWD, inherit the condition in an autosomal-dominant manner.

The genetic and molecular bases underlying the pathogenesis of low VWF levels remain poorly understood

The diagnosis of low VWF levels should be a clinicopathological one, reliant on both the presence of low VWF levels and a personal history of bleeding.

Type 2 accounts for approximately 20% of cases, the VWF level may be normal but protein functions abnormally.

In type 3, the rarest type, almost no VWF is present.

International consensus guidelines recommend that patients with reduced plasma VWF antigen (VWF:Ag) levels and bleeding phenotypes be considered in 2 distinct subsets.

First, patients with marked reductions in plasma VWF levels (<30 IU/dL) usually have significant bleeding phenotypes and should be classified with “type 1 VWD.”

In contrast, patients with intermediate reduced plasma VWF levels (in the range of 30-50 IU/dL) should be considered in a separate category labeled “low VWF levels.”

These patients with low VWF commonly display variable bleeding phenotypes and often do not have VWF gene sequence variations.

The pathophysiology underlying low VWF levels remains largely undefined, diagnosis and management of these patients continue to pose significant difficulties.

Treatment options for patients with low VWF and significant bleeding phenotypes include: antifibrinolytic agents, such as tranexamic acid or aminocaproic acid, DDAVP, and VWF-containing concentrates.

Platelet vWF is released from the alpha granules by various agonists, and isubsequently rebinds to the GP IIB/III a complex.

The largest multimers promote platelet adhesion by binding to the platelet glycoprotein Ibalpha- IX-V surface receptors.

ADAMTS13 cleaves ultra large multimers , preventing inappropriate platelet adhesion and thrombosis.

Ultra large von Willebrand secretion from endothelial cells is stimulated by inflammatory cytokines TNF-alpha, IL-8,, IL-6, Shiga toxin, estrogen and other agonists.

vW factor made of subunits consisting of domains D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2, forming disulfide linked multimers of 20 million daltons or more.

Posttranslational modification of the primary gene product results in vWF multimeters ranging in size from 500 kD to 10 million kD or larger

Multimer size is vital to prothrombin function of vWF and regulation of multimers size by ADAM family metalloproteinase, ADAMTS13

Unusually large-vWF multimers may be the pref2241ed substrate for ADAMTS13.

ADAMTS-13 (A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves vWF at the Tyr 1605-Met 1606 bond within A2 domain, preferentially under blood flow conditions of high intravascular shear stress, resultng in cleavage of the vWF multimers, especially the larger or high molecular weight multimers.

Inability to cleave unusually large-vWF multimers to smaller sizes may result in their accumulation and lead to enhanced platelet adhesion, aggregation and thrombotic thrombocytopenic purpura.

Occurs in approximately 1% of the population without ethnic predilection.

More than 20 distinct clinical and laboratory subtypes have been described.

Types 1 and 3 have deficiencies or absence of von Willebrand factor protein and type 2 disease associated with a functionally abnormal protein or specific lack of large multimers of von Willebrand factors.

Type I most common type typically has a slightly prolonged PTT, modest Factor VIII deficiency, decreased von Willebrand factor antigen and activity, and abnormal ristocetin platelet aggregation.

Type 1 associated with decrease of all molecular weight multimers of von Willebrand factor.

Type I associated with mild to moderate reduction in functionally normal VWF.

Type I disease the milder form of the disease and comprises 85-90% of all such patients.

In type I disease factor VIII levels usually slightly higher than the von Willebrand factor level, and may be in the normal level.

In type I disease about 65% of index cases have VWF mutations.

In type I disease about 70% of VWF variants are missense substitution of influencing VWF trafficking, storage, secretion, and clearance.

In many cases there is overlap between normal patients in clinical and laboratory outcomes, and diagnostic criteria must focus on presence of bleeding symptoms, reduced von Willebrand levels, autosomal inheritance of the phenotype.

Type II involves the expression of functionally abnormal VWF and occurs in 20-35% of patients.

Types 2A and 2B is and autosomal dominant disorder characterized by the production of abnormal von Willebrand factor.

Von Willebrand factor bridges between subendothelium and specific receptors on platelet surface.

Ristocetin platelet aggregation responses are impaired in types 1, 2A and severe type 3 variants.

Type 2A not associated with thrombocytopenia.

Type 2A loss of highest and intermediate-molecular multimers of von Willebrand factor, and decreased ristocetin platelet aggregation.

Type 2a disease associated with missense variants in D1/D2/D’D3 assemblies, A2 and CTCK domains.

Type 2a disease associated with interference with HMW multimer formation, storage, and secretion.

Type 2a disease associated with ADAMTS13 proteolysis.

In normal individuals soluble vWF multimers fail to gain access to binding site on GP1bα, as accessibility is controlled by a disulfide linked double loop region below leucine rich repeats of GP1bα.

Type 2B disease mutations give rise to selective number of amino acid substitutions in A1 domain increasing VWF multimers which can spontaneously bind to platelets through a direct interaction with GP1bα.

Type 2B is associated with thrombocytopenia because the abnormal von Willebrand factor causes platelet aggregation.

Type 2B disease has hyperaggregation to low dose ristocetin and normal response to standard ristocetin concentrations.

Type 2B associated with absent high-molecular weight multimers of von Willebrand factor.

Type 2N has a mutation in von Willebrand factor gene on chromosome 12 with phenotypically mild to moderate disease, with low factor VIII, normal von Willebrand factor activities.

Type 2N autosomal inheritance with women affected and Factor VIII gene is normal.

In type 2 von Willebrand disease factor VIII levels often 2-3 times higher than von Willebrand factor levels.

Type 3 von Willebrand factor is markedly decreased and no multimers are identified.

In type 3 disease factor VIII activity typically less than 10 IU dL.

In type 3 there is a virtual absence of VWF, and affects about 1 in 1 million people.

Arginine desmopressin increases von Willebrand factor activity in type 1 and approximately 50% of type 2A patients.

Since response to desmopressin varies patients should receive a trial dose with measured responses before it is used for a procedure.

Patients will have a similar response with each administration of desmopressin.

Arginine desmopressin contraindicated for type 2B disease.

In patients who do no respond or who cannot benefit from arginine desmopressin are managed by factor VIII concentrates.

Oral estrogens can induce von Willebrand factor synthesis.

Type 2B disease may not respond to arginine desmopressin and may make thrombocytopenia worse leading to thrombotic complications.

Type 3 disease associated with life threatening bleeds.

von Willebrand disease-type 2 sometimes associated with life threatening bleeding.

Type 1 rarely associated with life threatening bleeding.

Aspirin or NSAIDs may increase bleeding tendencies.

Can differentiate between VWD and hemophilia A since the former has low levels of VWF antigen and the latter has normal or high levels.

Ristocetin antibiotic mimics the interactions between VWF and platelet glycoprotein 1beta alpha; reflecting the alterations caused by VWF deficiency or dysfunction in the platelet-plug formation.

Epsilon aminocaproic acid and tranexamic acid are useful agents for treatment with oral procedures or oral bleeding.

In general elderly patients with increased risk of thrombosis should not be treated with desmopressin, since thrombotic complications may occur.

High circulating levels of catecholamines and or corticosteroid markedly increase factor VIII and von Willebrand’s factor, and can normalize elevated PTTs seen with severe von Willebrand’s disease.

Nausea and vomiting can increase vasopressin levels up to 100fold and double factor VIII and von Willebrand factor levels within minutes.

Acquired VWD (aVWD) is a rare disorder that mimics VWD, with less than 300 reported cases.

Acquired VWD related to reduced synthesis or increased clearance of VW factor.

 

Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. 

Acquired von Willebrand disease is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. 

A continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provides adequate hemostasis in aVWD resulting from MGUS.

The  efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy.