Von Willebrand disease a stone unturned

Dr. Saroar Jahan Rajib

Resident Phase –B

Department of Hematology , BSMMU

• In 1926, a Finnish physician, Erik von Willebrand, published a description of a new bleeding disorder that he observed in a family living in a Islands in the Baltic Sea.

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• VWD is characterized by excessive mucocutaneous bleeding, such as heavy menstrual bleeding, epistaxis, easy bruising, prolonged bleeding from minor wounds and the oral cavity, and gastrointestinal bleeding, as well as bleeding after dental work, childbirth, and surgery, with musculoskeletal bleeding, including joint bleeding seen in more severe cases.

• It is the most common bleeding disorder known in humans

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• It is inherited equally between men and women

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• However, women are more likely to come to medical attention because of gynecologic and obstetric bleeding.

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• VWD prevalence estimates range from ;1 in 100 to 1 in 10 000.

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Pathogenesis

• VWF is synthesized exclusively in endothelial cells and megakaryocytes.
• The VWF monomer is assembled into higher-order multimers , a structure required for optimal adhesive function, and performs two major functions in hemostasis.

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• First, VWF serves as the initial critical bridge between circulating platelets and the injured blood vessel wall.

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• Second, VWF serves as the carrier in plasma for FVIII, ensuring its stability and localizing it to the initial platelet plug for participation in thrombin generation and fibrin clot formation.

• Schematic of von Willebrand factor (VWF) processing and secretion from endothelial cells. VWF dimers are formed in the endoplas
• mic
• reticulum, where VWF begins to be glycosylated. VWF dimers are transported to the Golgi, where the VWF undergoes further glycosylation and
• sulfation. Multimerization begins in the Golgi and continues within the secretory granules (Weibel-Palade bodies). A small amount of immature VWF
• is released constitutively (i.e., without regulation or storage) from endothelial cells as dimers or very small multimers. VWF is also released continuously
• from both the luminal and abluminal endothelial cell surfaces by constitutive-like (or basal) secretion. This VWF has been processed in the Golgi and
• may be transiently stored in an intermediate secretory granule or Weibel-Palade bodies. Mature VWF is packaged and stored as ultralarge multimers
• in Weibel-Palade bodies. This ultralarge VWF is released from the luminal surface of stimulated endothelial cells by regulated secretion. Once in circu
• lation,
• VWF multimers undergo proteolysis by ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif member 13) under
• moderate to high shear conditions. (Adapted with permission from Johnsen J, Lopez JA. VWF secretion: What's in a name? Blood 112(4):926–927, 2008.)

• VWF is required for the adhesion of platelets to the sub endothelium, particularly at moderate to high shear force.

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• VWF performs this bridging function by binding to two platelet receptors, GPIb and GPIIb/IIIa, as well as to specific ligands within the exposed sub endothelium at sites of vascular injury.

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• Binding of VWF to its platelet receptors generally does not occur in the circulation under normal conditions.

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• However, the interaction of VWF with exposed ligands in the vessel wall, combined with high shear stress conditions, facilitates VWF binding to platelet GPIb and subsequent platelet adhesion and activation.

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• Activation of platelets leads to the exposure of the GPIIb/IIIa complex, an integrin receptor that can bind to fibrinogen ,VWF, and other ligands

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• Which forms the platelet–platelet bridges required for thrombus propagation.

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• In other hand the noncovalent interaction between FVIII and VWF is required for the stability of FVIII in the circulation

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• FVIII bound to VWF is also protected from proteolytic degradation by activated protein C

Classification

Clinical Features

• The bleeding symptoms can be quite variable among patients within the same family and even in the same patient over time.
• Mucocutaneous bleeding is the most common symptom in patients with type 1 VWD.

-Epistaxis occurs in approximately 60% of type 1 VWD patients.

-Easy bruising and hematomas in 40%.

-Menorrhagia in 35%.

-Gingival bleeding in 35%.

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-Gastrointestinal bleeding occurs in approximately 10% of patients.

-Bleeding after dental extraction in 50%.

-Bleeding after trauma or wounds in 35%.

-Postpartum bleeding in 25%.

-Postoperative bleeding in 20%.

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• Hemarthroses in patients with moderate disease are extremely rare and are generally only encountered after major trauma.

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• Aside from an infrequent type 3 patient, death from bleeding rarely occurs in VWD.

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• Thrombocytopenia is a common feature of type 2B VWD and is not seen in any other form of VWD.

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• Patients often present in 2nd or 3rd decade with prolonged bleeding after dental extraction or surgery.

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• Patient should be screened using bleeding assessment tool except who’s 1^st degree relatives are affected.

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Laboratory Diagnosis

• Factor VIII activity (factor VIII:C):

The coagulant property of the factor VIII protein (this term is sometimes used interchangeably with factor VIII)

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• Factor VIII antigen (VIII:Ag)

The antigenic determinant(s) on factor VIII measured by immunoassays, which may employ polyclonal or monoclonal antibodies

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• VwF - FVIII binding study:

Ability of VwF to bind and carry FVIII in circulation, ELISA is preferable method for this test

• Von Willebrand factor antigen (VWF:Ag):

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The antigenic determinant(s) on VWF measured by immunoassays , which may employ polyclonal or monoclonal antibodies.

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• Ristocetin cofactor activity (VWF:RCo):

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The property of VWF that supports ristocetin-induced agglutination of washed or fixed normal platelets

• Von Willebrand factor collagen-binding activity (VWF:CB):

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The property of VWF that supports binding to collagen, measured by enzyme-linked immunosorbent assay (ELISA)

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• The RIPA assay is based on Light Transmission Aggregometry [LTA]

-Varying concentrations of Ristocetin is used - Low dose Ristocetin 0.5mg/mL and High dose Ristocetin 1.5, 5mg/mL . 

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-It employs Platelet Rich Plasma [PRP] from the patient. The agonist [Ristocetin] is added and the degree of agglutination is recorded

�-Results are expressed as the concentration of Ristocetin [mg/mL] able to induce 30% agglutination of platelets.

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•  Incases in which there is enhanced agglutination to low dose Ristocetin, it is important to distinguish between Type 2B VWD and PT-VWD. 

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• This can be undertaken by:�i. Screening for mutations in the VWF and GP1BA genes�ii. Mixing studies which involve:�  

MIX A) Patient plasma and healthy control platelets�    MIX B) Donor plasma and patient platelets��

• LTA is performed using low doses of Ristocetin and the pattern of results observed.

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• If the abnormality lies within the VWF protein (Type 2B VWD) then Mix A will demonstrate agglutination whereas Mix B will not

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• Whereas if the mutation is in the GpIB receptor then Mix A will show no agglutination but Mix B will.

Management�

DESMOPRESSIN

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• DDAVP has become a mainstay for the treatment of mild hemophilia and VWD because it is relatively inexpensive, widely available, and avoids the risks of plasma-derived products.

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• DDAVP is an analogue of antidiuretic hormone that acts through type 2 vasopressin receptors to induce secretion of FVIII and VWF, likely via cyclic adenosine monophosphate–mediated secretion from the Weibel-Palade bodies in endothelial cells.

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• Patients with type 1 VWD treated with DDAVP release unusually high-molecular-weight VWF multimers into the circulation for 1 to 3 hours after the infusion.

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• Therapy with DDAVP often increases the FVIII activity, VWF:Ag, and ristocetin cofactor activity to two to five times the basal level.

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• Approximately 80 percent of type 1 VWD patients have excellent responses to DDAVP.

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• DDAVP is administered at a dose of 0.3mcg/kg continuous intravenous infusion over 30 minutes with a maximum dose of 20 mcg.

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• DDAVP is also available for subcutaneous injection (at the same 0.3mcg/kg dose).

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• Intranasal form of DDAVP is available (at a fixed dose of 300mcg for adults and 150mcg for children), which appears to be similar in efficacy to intravenous administration.

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• In patients for whom DDAVP is potentially the treatment of choice, a test dose should be given at the planned therapeutic dose and route.

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• VWF antigen, VWF activity, and FVIII activity levels should be determined immediately before administration of desmopressin, ;30-60 min after administration of desmopressin, and ;4 h post administration, because in type 1C VWD, there is a rapid decrease in VWF levels.

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• An increase of at least 2 times the baseline VWF level and the ability to achieve both VWF and FVIII levels of >0.50 IU/mL were required to consider the patient responsive to desmopressin.

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• For patients with type 1 VWD who are undergoing surgical procedures, DDAVP can be administered 1 hour before surgery and approximately every 12 hours thereafter for up to two to four doses before loss of clinically significant response.

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• Approximately 20 to 25 percent of patients with VWD do not respond adequately to DDAVP.

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• Type 2 VWD patients are less likely to have a response than type 1 patients, and virtually no patients with type 3 VWD respond.

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• The response to DDAVP of patients with type 2A VWD is variable. Although most patients respond only transiently, some patients exhibit complete hemostatic correction after DDAVP infusion.

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• Common side effects of DDAVP administration are

-Mild cutaneous vasodilation resulting in a feeling of heat

-Facial flushing

-Tachycardia

-Tingling

-Headaches.

• The potential for dilutional hyponatremia, especially in elderly and very young patients and with repeat dosing, requires appropriate attention to fluid restriction, as it may result in seizures.

• Desmopressin is generally contraindicated in patients with

-Active cardiovascular disease (eg , coronary heart disease, cerebrovascular disease, and peripheral vascular disease).

-Patients with seizure disorders.

-Very young patients.

-Patients with type 1C VWD in the setting of surgery.

-Patients with type 2B VWD.

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VON WILLEBRAND FACTOR REPLACEMENT THERAPY

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• For type 3 VWD patients and other patients unresponsive to DDAVP, the use of selected virus-inactivated, VWF-containing FVIII concentrates is generally safe and effective.

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• Most standard FVIII concentrates and all recombinant FVIII products are not effective in VWD because they lack clinically significant quantities of VWF.

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• The objective is to elevate FVIII:C and VWF:RCo until bleeding stops and healing is complete.

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• In general, replacement goals of FVIII:C and VWF:RCo should be initial replacement to greater than 100 IU/dL and maintenance of greater than 50 IU/dL for 7 to 14 days for major trauma, surgery, or central nervous system hemorrhage.

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• Greater than 30 to 50 IU/dL for 3 to 5 days for minor surgery or bleeding.

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• Greater than 50 IU/dL for delivery and continued for at least 3 to 5 days in the postpartum period;

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• Greater than 30 to 50 IU/dL for 1 to 5 days for dental extractions and minor surgery;

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• Greater than 20 to 50 IU/dL for mucous membrane bleeding or menorrhagia.

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• Avoidance of supratherapeutic replacement doses (>200 IU/dL VWF:RCo, >250 IU/dL FVIII) is necessary to avoid increased risk of thrombosis.

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OTHER NONREPLACEMENT THERAPIES

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• Fibrinolytic inhibitors, such as ε-aminocaproic acid or tranexamic acid, have been used effectively in some VWD patients.

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• Antifibrinolytics are commonly used alone or in conjunction with DDAVP or a plasma-derived VWF replacement product.

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• Estrogens or oral contraceptives have been used empirically in treating menorrhagia. In addition to their effects on the ovaries and uterus, some estrogens can increase plasma VWF levels.

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• Recombinant activated factor VII (rFVIIa, or NoVo Seven) has also been successfully used in VWD patients with severe hemorrhage refractory to VWF replacement therapy and in bleeding patients with anti-VWF antibodies.

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• Topical drugs such as fibrin sealants or topical bovine thrombin may also be considered when standard VWD therapies fail to provide adequate local hemostasis.

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Special situations

• Desmopressin is contraindicated in type 3 VWD because of a lack of efficacy and in type 2B VWD because of increased platelet binding with subsequent thrombocytopenia.

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• In patients with VWD and cardiovascular disease who require treatment with antiplatelet agents or anticoagulant therapy, it is preferred giving the necessary antiplatelet or anticoagulant therapy over no treatment.

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• Either hormonal therapy (CHC or levonorgestrel-releasing intrauterine system) or tranexamic acid over desmopressin is preferable to treat women with VWD with heavy menstrual bleeding who do not wish to conceive.

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• Tranexamic acid over desmopressin is preferable to treat women with VWD and heavy menstrual bleeding who wish to conceive

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• In women with VWD for whom neuraxial anesthesia during labor is deemed suitable, the target VWF activity level is 0.50 to 1.50 IU/mL to allow neuraxial anesthesia.

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• VWF activity levels should be maintained at 0.50 IU/mL while the epidural is in place and for at least 6 hours after removal.

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