von Willebrand Disease

The most common hereditary bleeding disorder is von Willebrand disease (VWD), it is present in 1 2% of the general population.

Because VWF is an acute-phase protein, stress will increase its level.

VWD is inherited autosomally, but most centers report more affected women than men. VWD is classified on the basis of whether the protein is : Type 1: Quantitatively reduced, but not absent Type 2 : Qualitatively abnormal Type3: Absent

vWF has two functions: Plays an integral role in mediating adherence of platelets at sites of endothelial damage, promoting formation of the platelet plug Binds and transports FVIII, protecting it from degradation by plasma proteases.
PATHOPHYSIOLOGY:

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VWF is a large multimeric glycoprotein that is synthesized in megakaryocytes and endothelial cells, VWF is stored in platelet -granules and endothelial cell Weibel-Palade bodies. The highest molecular weight multimers of VWF are responsible for the normal interaction of VWF with the subendothelial matrix and platelets. During normal hemostasis, VWF adheres to the subendothelial matrix after vascular damage. When VWF binds to the subendothelial matrix, the conformation of VWF is changed so that it causes platelets to adhere to VWF through their glycoprotein IB (GPIb) receptor. These platelets are then activated, causing the recruitment of additional platelets and exposing phosphatidylserine, which is an important regulatory step for factor V- and factor VIIIdependent steps in the clotting cascade. VWF also serves as the carrier protein for plasma factor VIII. A severe deficiency of VWF causes a secondary deficiency in factor VIII, even though the gene for factor VIII is normal. This is the cause of autosomal deficiency of factor VIII, now known to be a molecular abnormality of VWF and known as type 2N VWD

CLINICAL MANIFESTATIONS:

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Patients with VWD usually have symptoms of mucocutaneous hemorrhage, including excessive bruising, epistaxis, menorrhagia, and postoperative hemorrhage, particularly after mucosal surgery, such as tonsillectomy or wisdom tooth extraction. If a menstruating female has iron deficiency, a detailed history of bruising and other bleeding symptoms should be elicited and further hemostatic evaluation undertaken. Because VWF is an acute-phase protein, stress will increase its level. Thus, patients may not bleed with procedures that incur major stress, such as appendectomy and childbirth, but may bleed excessively at the time of cosmetic or mucosal surgery. Bruising symptoms may diminish during pregnancy because VWF levels may double or triple during pregnancy. Rarely, patients with VWD may have gastrointestinal telangiectasia. This combination results in major bleeding and accounts for numerous hospital admissions for patients with severe disease. In patients with type 3, or homozygous, VWD, bleeding symptoms are much more profound. These patients are usually diagnosed early in life and may have severe epistaxis or menorrhagia that results in major blood loss and possibly shock. Patients with severe type 3 VWD may have joint hemorrhages or spontaneous central nervous system hemorrhages.

LABORATORY FINDINGS:

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long bleeding time long partial thromboplastin time, these findings are frequently normal in patients with type 1 VWD. Normal results on screening tests do not preclude the diagnosis of VWD. Because there is no single assay that has demonstrated the ability to rule out VWD, if the history is suggestive of a mucocutaneous bleeding disorder, VWD testing should be undertaken, including: o Quantitative assay for VWF antigen, o testing for VWF activity (ristocetin cofactor activity), o testing for plasma factor VIII activity, o determination of VWF structure (VWF multimers), o platelet count. Platelet count is usually normal in most patients Type 2B disease or platelet-type disease (pseudo-VWD) lifelong thrombocytopenia. Levels of VWF vary with blood type (type O < A < B < AB), which can confound the clinical diagnosis of hereditary VWD.

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Molecular genetics may clarify the diagnosis of type 1 VWD, but other genetic modifiers may exist outside the gene for VWF and significantly influence the diagnosis. The milder the patient's phenotype, the greater the difficulty in diagnosis

GENETICS:

Chromosome 12 contains the gene for VWF

VON WILLEBRAND DISEASE VARIANTS: Type 1 VWD:

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is the most common form and accounts for 85% of cases. Bleeding symptoms include epistaxis, bruising, and menorrhagia. If bleeding is excessive, desmopressin (DDAVP) administration at a dose of 0.3 g/kg IV will increase the level of VWF and factor VIII by 3- to 5-fold. Intranasal DDAVP (Stimate) is particularly helpful for the outpatient treatment of bleeding episodes. The dose is 150 g (1 puff) for children weighing <50 kg and 300 g (2 puffs) for those weighing >50 kg.

Type 2A VWD :

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caused by the abnormal proteolysis of VWF, with only the smallest VWF multimers being present. This results in a reduction in VWF antigen with a much greater reduction in VWF activity. Although DDAVP is safe in these patients, it is not always effective, because normal multimers are not maintained in plasma. Significant bleeding should be treated with VWF replacement therapy.

Type 2B VWD :

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caused by one of several mutations resulting in hyperactive VWF. The abnormal VWF binds spontaneously to platelets, with resulting rapid clearance of VWF and platelets. The higher molecular weight multimers of VWF are preferentially cleared from the circulation, and moderate to severe thrombocytopenia is common. The laboratory diagnosis is based on the finding that the hyperactive 2B VWF binds to platelets and agglutinates them at low concentrations of ristocetin, a concentration that would not agglutinate normal platelets. If DDAVP is given to these patients, the abnormal hyperactive 2B VWF will be released and more profound thrombocytopenia might occur. Patients with 2B VWD usually respond to the infusion of VWF

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Type 2M VWD:

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caused by mutations that result in reduction of the platelet-binding function of VWF. Thus, levels of VWF activity are significantly lower than the levels of VWF antigen. Type 2M vWD results from of an abnormal binding site on vWF for platelet GP Ib, resulting in reduced ristocetin cofactor (R:Co) activity (functional defect). Binding of this protein to factor VIII is normal; thus, factor VIII levels are similar to those of VWF antigen. DDAVP will increase VWF and factor VIII levels but the released type 2M VWF may not have sufficient activity to cause cessation of bleeding. Thus, VWF replacement therapy may need to be used

Type 2N VWD:

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caused by the reduction of factor VIII binding by VWF. This disorder has also been termed autosomal hemophilia. With this variant, platelet interaction with VWF is normal, VWF binds weakly (or not at all) to factor VIII, resulting in rapid clearance of factor VIII that is weakly complexed to VWF. The factor VIII level is reduced much more than VWF levels. Commonly, patients who have symptomatic bleeding are compound heterozygotes who have inherited a gene for type 1 VWD from 1 parent and a gene for type 2N VWD from the other.

Type 3 VWD : The homozygous or compound heterozygous inheritance of VWF deficiency. Patients exhibit undetectable plasma levels of VWF and low, but measurable, levels of factor VIII. These patients will have major hemorrhage, but only rarely have joint hemorrhages. This severe, very rare form occurs in approximately 1:250,000 individuals. Major features :Intracranial hemorrhage, major epistaxis, and menorrhagia in women Bleeding episodes require treatment with VWF-containing concentrates. VWF is both a plasma and a platelet protein. treatment with VWF-containing concentrate corrects only the plasma VWF level, patients with severe bleeding may need to be transfused with platelet concentrates to correct the deficiency of platelet VWF. DDAVP is not effective in type 3 VWD

Platelet-type (pseudo-) VWD : This platelet disorder has a phenotype similar to type 2B vWD. This results in thrombocytopenia and a loss of high molecular weight VWF multimers, which are indistinguishable from those seen in type 2B VWD Platelet-type pseudo-vWD is due to a gain-of-function mutation defect in the GPIBA gene which causes the production of an abnormal GP1b-1X in the platelet GP1b receptor on platelets. Excessive binding of vWF to platelet GP Ib recepter causes platelet activation and vWF removal from the circulation plasma concentrations of vWF are reduced and platelet aggregation is increased. Bleeding in this disorder should be treated with platelet transfusions.

Acquired von Willebrand Disease:

Seen in : Wilms tumor, polycythemia vera, other neoplasms, autoimmune diseases (e.g., systemic lupus erythematosus [SLE]), myeloproliferative disease, lymphoproliferative disorders various drugs, as well as in individuals with angiodysplastic lesions. Proposed mechanisms include specific auto-antibodies, adsorption onto malignant cell clones and depletion in conditions of high vascular shear force. Treatment :
DDAVP infusion is the initial treatment of choice for achieving hemostasis, plasma-derived FVIII/vWF concentrates are the second choice. IVIG, plasmapheresis and/or immunosuppressive drugs may be useful for eliminating antibody.

DIFFERENTIAL DIAGNOSIS:

The differential diagnosis of mucocutaneous bleeding includes abnormalities of platelet number, platelet function, or the vessel wall In caring for children, it is important to remember that the most common cause of such findings is trauma, especially nonaccidental trauma child abuse
COMPLICATIONS:

In adolescent females, blood loss due to menorrhagia can lead to severe anemia, either acutely, with signs and symptoms of hypovolemia, or chronically, caused by iron deficiency. Individuals with type 3 VWD can have joint or muscle bleeding similar to individuals with hemophilia

Treatment :
Abbreviations: DDAVP, desmopressin; EACA, amicar; Factor VIII: vWF concentrated

Current replacement therapy uses plasma-derived VWF containing concentrates that also contain factor VIII. VWF distributes only to the intravascular space, because it is so large. During plasma fractionation, VWF multimers are altered to a variable extent. Therefore, 1 U/kg will increase the plasma level by 1.5%. The plasma half-life of both factor VIII and VWF is 12 hr, but the alteration of VWF during fractionation results in half-lives of 810 hr when concentrates are infused. Purified or recombinant VWF concentrates (containing no factor VIII) may become available in the near future. These will be useful in prophylaxis or in presurgical management. When used for acute bleeding these VWF concentrates, which contain little or no factor VIII, may need to be supplemented by an infusion of recombinant factor VIII for the 1st infusion. If only VWF is replaced, endogenous correction of the factor VIII level takes 1224 hr. Dental extractions and sometimes nosebleeds can be managed with both DDAVP and an antifibrinolytic agent, such as -aminocaproic acid (Amicar).