What is the best treatment for Type 3 von Willebrand disease (vWD)?
Recently, a very high purity VWF concentrate, which is not yet available in North America, proved clinically effective in a small cohort of type 3 VWD cases. Its very low FVIII content requires its infusion 6 to 8 hours before surgery to allow the infused VWF to stabilize the endogenously synthesized FVIII.
How is venous thrombosis treated in von Willebrand disease?
Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost. 2002;88(3):387–8 [PubMed] [Google Scholar] 46. Mannucci PM.
What is the aim of treatment for von Willebrand factor 8 deficiency?
The aim of treatment is to correct the dual defect of hemostasis caused by the abnormal/reduced von Willebrand factor and the concomitant deficiency of factor VIII.
What is type 2 von Willebrand disease?
Type 2 VWD is the next most common type. About 15% of people with VWD have Type 2. They usually have more severe bleeding problems than people with Type 1. In Type 2 VWD, there is enough von Willebrand factor but it does not work right.
What is von Willebrand disease?
Von Willebrand disease is a common autosomal inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor, a multi-adhesive protein that binds platelets to exposed subendothelium and carries factor VIII in circulation. As a result of von Willebrand factor deficiency or abnormality, levels of factor VIII, the protein deficient in hemophilia A, may be variably reduced. Clinical manifestations are mainly represented by mucous membrane and of soft tissue bleeding. Their severity is variable depending on the degree of von Willebrand factor and factor VIII reduction. While a clear-cut diagnosis is easy in severe von Willebrand factor reductions, the advantage of pursuing a definite diagnosis in mild or dubious cases should be weighed against the risk of over-medicalization. The aim of treatment is to correct the dual defect of hemostasis caused by the abnormal/reduced von Willebrand factor and the concomitant deficiency of factor VIII. Desmopressin is the treatment of choice for type 1 von Willebrand disease patients with factor VIII and von Willebrand factor levels of 10 U/dL or over who have proved responsive to a test-infusion with the compound. Von Willebrand factor/factor VIII concentrates are needed when desmopressin is ineffective (mainly type 2 and 3 von Willebrand disease).
What are the different types of VWD?
VWD is classified into three different types (Table 4).6Types 1 and 3 VWD reflect the partial or (virtually) complete quantitative deficiency of VWF, while type 2 VWD reflects qualitative defects of VWF. Type 1 is the most common form of VWD and is predominantly transmitted as an autosomal dominant trait often with incomplete penetrance (not all cases that inherit a VWF mutation demonstrate bleeding symptoms). Type 1 VWD is characterized by an equivalent mild to moderately severe reduction of VWF antigen (VWF:Ag) and ristocetin co-factor activity (VWF:RCo) in plasma. VWF multimers are essentially normal and certainly with a normal profile of high molecular weight forms, while plasma levels of FVIII are reduced, usually in proportion to VWF but often FVIII is higher than VWF. The severity of mucocutaneous bleeding symptoms usually correlates with the degree of their VWF and FVIII deficiencies. Type 2A is inherited mainly with an autosomal dominant pattern and the hallmark is represented by the lack of large and intermediate size VWF multimers. The laboratory hallmark of the most typical and frequent forms of type 2B is the heightened ristocetin induced platelet aggregation (RIPA) with mild to moderate thrombocytopenia and the absence of large multimers in plasma. In type 2M VWD the VWF multimer distribution is normal, but platelet-dependent VWF activities (VWF:RCo and/or von Willebrand factor collagen binding (VWF:CB)) are reduced. Type 2N is characterized by recessive inheritance, with mildly reduced or normal levels of VWF:Ag and VWF:RCo and a normal multimer pattern in most cases. Low plasma levels of FVIII (typically 5–40 U/dL) result from the decreased plasma half-life of FVIII, which cannot bind to VWF as a consequence of a qualitative abnormality of VWF. Type 3 VWD is inherited as an autosomal recessive trait and is characterized by undetectable levels of VWF (usually < 3 U/dL) and very low levels of FVIII (typically 1–5 U/dL), which may cause a more severe bleeding tendency characterized not only by mucocutaneous hemorrhages but also by hemarthroses and hematomas as in moderately severe hemophilia.
What is the first step in VWF testing?
The first step is to carry out a test with desmopressin. Candidates are those patients with basal FVIII and/or VWF:RCo below 30 U/dL. Patients with higher levels are very likely to respond and do not routinely require biological testing, although a test infusion may be useful in unraveling additional VWF abnormalities (e.g. shortened VWF half-life).
What is VWD based on?
The diagnosis of VWD is then based on the presence of reduced VWF:RCo (or VWF:CB) (<40 U/dL), with a further characterization of VWD type based on assessment of VWF:Ag, FVIII and multimer pattern. In general, VWF levels below 30 U/dL have been shown to be strongly associated with a significant clinical severity as assessed by a bleeding score17and the presence of mutations in the VWFgene.18However, levels under 40 U/dL and the presence of other relatives with equivalent levels are similarly a crucial clue for the diagnosis of mild VWD.14In these cases, bleeding history is milder and treatment usually rests on avoidance of anti-platelet drugs and antifibrinolytics as required.
How to diagnose VWD?
The diagnosis and appropriate classification of VWD usually requires an array of tests (Table 2) together with the evidence of a bleeding history, usually also present in other family members. The diagnosis should be undertaken in a specialized center for bleeding disorders that is capable of performing such assays accurately and providing the patients with a balanced view of their bleeding risk. When a diagnostic process is initiated, the physician should always take into consideration the practical advantage and the patient perspective of a specific diagnosis of VWD in any given patient, avoiding the risk of over-medicalization of patients with dubious or mild bleeding history.8A slightly reduced VWF level can be found even in normal subjects and bleeding symptoms are also frequently reported by ‘normal’ subjects.11–13For this reason, the patient should be interviewed about his/her bleeding history using a structured, written questionnaire to improve the quality of data collection and to reduce both intra- and inter-observer variability. Since in many cases the deficiency is mild and the risk of bleeding small, it is recommended that diagnosis be pursued especially in the presence of a significant bleeding history, obtained by using specifically designed questionnaires.13,14Collected data must be unambiguously interpreted to verify if the bleeding history is compatible with a bleeding disorder, and for this purpose a bleeding score (BS), accounting for both the number and the severity of the bleeding symptoms, may be useful. The BS is generated by summing the severity of all bleeding symptoms reported by a subject, and graded according to an a prioriscale.13,15Previous experience from the International Multicenter Study suggests that a bleeding score of 3 or over in males and of 5 or over in females could be considered as a useful cut off to identify adults with a bleeding diathesis in whom it is worth measuring VWF-related activities.13A novel questionnaire has been recently endorsed by the International Society on Thrombosis and Haemostasis (ISTH) to assess bleeding symptoms for the diagnosis of bleeding disorders.16
What is VWF/FVIII?
VWF/FVIII concentrates licensed for the treatment of von Willebrand disease in Europe.
What is the best treatment for a bleed in the mucosal tract?
Antifibrinolytic agents(i.e. tranexamic acid and epsilon aminocaproic acid), given orally, intravenously or topically, are useful alone or as adjuncts to replacement therapy (DDAVP or VWF/FVIII concentrates) for the prevention or treatment of bleeding in mucosal tracts, characterized by a high fibrinolytic activity.55Thus, they may be sufficient for the management of less severe forms of mucosal bleeding, epistaxis, menorrhagia or dental procedures and generally in mild VWF deficiencies. Furthermore, these agents are useful in association with replacement therapy during minor or major surgery involving mucosal surfaces. Tranexamic acid should be administered at a dose of 10–15 mg/kg 3–4 times a day, or more frequently if used as mouthwash for oral surgery or bleeding, and aminocaproic acid at a dose of 50–60 mg/kg every 4–6 h. These drugs are contraindicated in the management of urinary tract bleeding because of the risk of ureteral clots and hydronephrosis.
What is the molecular basis of von Willebrand disease?
Recent multicenter studies have clarified the molecular basis underlying the different von Willebrand disease (VWD) types, all of which are caused by the deficiency and/or abnormality of von Willebrand factor (VWF). These studies have suggested a unifying pathophysiologic concept. The diagnosis of VWD, remains difficult because its clinical and laboratory phenotype is very heterogeneous and may overlap with normal subjects. Stringent criteria are therefore required for a clinically useful diagnosis. In this paper, we delineate a practical approach to the diagnosis and treatment of VWD. Our approach is based on the critical importance of a standardized bleeding history that has been condensed into a final bleeding score and a few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII. This approach would help identify those subjects who will probably benefit from a diagnosis of VWD. The next step involves performing a trial infusion with desmopressin in all patients who fail to exhibit an enhanced responsiveness to ristocetin. On the basis of these results and through a series of illustrative examples, the clinician will be able to select the best approach for the optimal management of VWD, according to the patient's characteristics and clinical circumstances.
How old is a woman with von Willebrand disease?
A 25-year-old woman with unclassified von Willebrand disease asks for advice because she is 12 weeks into her first pregnancy. Her basal FVIII:C and VWF measurements are significantly reduced (FVIII:C 30 IU/dL, VWF:Ag 33 IU/dL, VWF:RCo 28 IU/dL).
How is desmopressin administered?
Desmopressin is usually administered at a dose of 0.3 μg/kg body weight by a subcutaneous or intravenous route or at a fixed dose of 150 to 300 μg by a metered-dose intranasal spray. To test patient responsiveness, a therapeutic dose of desmopressin is administered, and VWF:Ag, VWF:RCo, and FVIII:C are measured at baseline and after 60, 120, and 240 minutes. We define patients as “desmopressin responders” when they exhibit a peak level for both VWF:RCo and FVIII:C of more than 50 IU/dL, which is a concentration that may be considered sufficient for effective hemostasis during minor invasive procedures. 39 Assessment at 4 hours from infusion is advised to identify patients with increased clearance who are possible candidates for alternative treatments. 39, 41-43 However, patients with VWD Vicenza, which is associated with the R1205H mutation, and who show the shortest half-life of FVIII and VWF after desmopressin, can be effectively treated with desmopressin for most instances, including parturition. 43, 44 Patients with type 3 VWD are usually unresponsive to desmopressin, although some patients do experience an increase of FVIII:C to effective hemostatic levels, even without a change in the bleeding time (BT). 45 The compound is also acceptable to Jehovah's Witnesses. Because the responses in a given patient and within his/her family are consistent on different occasions, a test dose of desmopressin administered at the time of diagnosis will allow for future treatment plans to be drawn up.
What is the goal of VWD treatment?
The goal of the treatment of VWD is the correction of the low FVIII:C and of the low VWF. Clinical experience indicates that FVIII level is the best predictor of soft tissue or surgical bleeding, whereas VWF:RCo normalization is required for an appropriate treatment of mucosal bleeding. Desmopressin and transfusion therapy with blood products represent the 2 treatments of choice in VWD 41 ( Figure 1 ). Other forms of treatment can be considered as adjunctive or as an alternative to these 2 modalities.
How to predict VWD 20?
The main quantitative (type 1 and 3) or qualitative (type 2) forms of VWD 20 can be predicted by appreciating the impacts that the different mutations in one or both VWF alleles may exert on the complex processes of VWF synthesis, assembly, and secretion.
What is VWF in biology?
VWF is a nonenzymatic, multifunctional, and multimeric protein that acts as a bridging molecule between platelets and the vessel wall 18, 19 and as a carrier for plasma FVIII.
What is type 3 VWD?
Type 3 VWD, which is characterized by the presence of only trace amounts of VWF in plasma and platelets, is caused by compound heterozygous or homozygous frameshift or nonsense mutations or deletions that result in a null allele. 21 Accordingly, type 3 VWD is a recessive disease with a very low expected prevalence (1-2 cases/million). Carriers of a single null allele, such as the parents of type 3 patients, have VWF levels approximately 50 IU/dL, which is usually not sufficient to cause a significant bleeding tendency. 22
What is a phenotype of Von Willebrand disease?
Von Willebrand disease III (vWD Type 3), an inherited bleeding disorder, results from a lack or reduced level of a normal blood clotting protein and is characterized by spontaneous hemorrhaging and prolonged bleeding after physical trauma. vWD Type 3 is the most severe form. Phenotype: Von Willebrand disease (vWD) is an inherited bleeding disorder ...
What is vwf type 3?
vWD Type 3 is the most severe form of bleeding disorders and it is caused by a complete lack of vWF in the blood. Three mutations are associated with this type of disorder: vWF (Int16G>A, denoted vWFk) occurs in Dutch Kooiker, vWF (c.255Cdel, denoted as vWFt) occurs in Scottish Terriers and vWF (c.735Tdel, denoted vWFs) occurs in Shetland Sheepdog.
What type of disease does a dog with vwf have?
Dogs with vWF/vWF genotype may be affected and develop Von Willebrand disease Type 3, a blood clotting disorder. They will transmit this variant to all of their offspring.
What is a VWD test?
Genetic tests for vWD Type 1, vWD Type 2, and vWD Type 3 are offered by the VGL. Results from these tests can help breeders determine the genetic status of breeding stock and risk for bleeding disorder. For the recessive vWD Type 3, test results inform breeders to avoid matings between carriers, which could produce 25% of affected offspring. Veterinarians can use test results to confirm clinical findings and inform appropriate courses of treatment or management.
Can dogs with N/VWF have Von Willebrand disease?
Dogs with N/vWF genotype are not expected to have Von Willebrand disease Type 3, but are carriers. They may transmit this variant to 50% of their offpspring. Matings between two carriers are predicted to produce 25% Von Willebrand disease Type 3-affected puppies.
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Epidemiology
The type 3 disease is the rarest form of VWD, accounting for less than 5% of all cases. Annual incidence varies between countries ranging from 1/1,000,000 to 1/2,000,000 in Europe and the USA and with estimates of around 1/500,000 in countries where consanguinity is more frequent.
Clinical description
Onset usually occurs during the neonatal period or in infancy, but later onset has been reported. The bleeding anomalies are mainly characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, postpartum hemorrhage, gastrointestinal bleeding etc.) and prolonged bleeding after surgical interventions.
Etiology
The disease is caused by homozygous or compound heterozygous mutations (mainly missense or large mutations) in the VWF gene (12p13.3) that lead to synthesis of a truncated protein or allele silencing.
Diagnostic methods
Diagnosis is straightforward and is based on the absence of detectable VWF measured by all available methods (including functional and immunologic assays and agarose gel electrophoresis), accompanied by a secondary FVIII deficiency with a decrease to between 1 and 10% of normal levels.
Differential diagnosis
Measurements of VWF levels generally allow VWD type 3 to be distinguished from moderate hemophilia A. Type 3 VWD is also generally easy to distinguish from other hereditary forms of VWD.
Antenatal diagnosis
In at risk pregnancies, when the pathogenic variants have been previously identified in a family member, the identification of underlying VWF mutations may be used for prenatal diagnosis.
When will the new VWD guidelines be released?
NEW VWD Guidelines: What You Need To Know. New VWD Guidelines for the diagnosis and management of von Willebrand disease were released in January 2021. These updated guidelines are the result of a collaborative effort between the American Society of Hematology (ASH), the International Society on Thrombosis and Hemostatsis (ISTH), ...
How is VWD Diagnosed?
A combination of blood tests are used to diagnose VWD, including a VWF antigen test, which measures the amount of VWF in the blood, tests that measure clotting time and ability to form a clot, and tests measuring platelet function. Some of these tests may have to be repeated, because the levels of VWF can change due to stress, exercise, the use of birth control pills, pregnancy, and hyperthyroidism. People with VWD usually have less than 50% of normal VWF in their blood. After a diagnosis of VWD is discovered, an additional is given to determine the type. The best place for patients with bleeding disorders to be diagnosed and treated is at one of the federally funded hemophilia treatment centers (HTCs) that are spread throughout the country. HTCs provide comprehensive care from skilled hematologists and other professional staff, including nurses, physical therapists, social workers and sometimes dentists, dieticians and other healthcare providers. In addition, HTCs often have specialized labs that can run more accurate VWD testing.
How long does a VWD last?
The main symptoms of VWD are: Frequent (more than 5 a year) nosebleeds that last longer than 10 minutes. Bleeding from cuts or injuries that lasts longer than 10 minutes. Bruising easily, with bruises that are raised and larger than a quarter. Being told you are “low in iron” or have been treated for anemia.
What percentage of people have type 3 VWD?
Type 3 VWD is found in 5%-10% of patients. People with type 3 VWD have a very low levels or no VWF in their blood.. Some people with this type of VWD may also be low in factor VIII (factor eight). Symptoms are typically severe, and include spontaneous bleeding episodes, often into their joints and muscles.
How common is VWD?
VWD is the most common bleeding disorder, affecting up to 1% of the US population – or approximately 1 in every 100 people. It occurs equally in men and women. However, women may be more symptomatic due to heavy menstrual bleeding (periods). VWD occurs equally across all races and ethnicities.
How to take antifibrinolytics?
Antifibrinolytics are taken by mouth, as a tablet or liquid. MASAC recommends that a dose of clotting factor be taken first to form a clot, then aminocaproic acid, to preserve the clot and keep it from being prematurely broken down. Explore a complete list of FDA-approved therapies to treat VWD.
Why is DDAVP important?
Because of this, it’s important to restrict fluids so you don’t develop a condition known as hyponatremia, reduced sodium in the bloodstream.
What is a type 2 VWD?
Type 2 VWD has four subtypes A, B, M, and N: In Type 2A, the VWF multimers are not the right size. This stops the platelets from making a good platelet plug. In Type 2B, the VWF multimers are not the right size and the VWF becomes too active. It attaches to the platelets in the blood when it is not supposed to.
How many types of VWD are there?
There are three main types of VWD, numbered 1, 2, and 3. Type 2 has several subtypes. Each of these is described below. It is important for a person with VWD to know which type he or she has.
What type of VWD has the most symptoms?
Type 3 also has the most severe symptoms. People with Type 3 VWD have little or no VWF in their blood. Without VWF to act as a carrier, the amount of factor VIII in the blood also drops to low levels. People with Type 3 VWD have trouble making both a platelet plug and a fibrin clot.
What is the most common type of VWD?
Type 1 VWD is the most common type. About 85% of the people with VWD have this type. In Type 1 VWD , there is not enough von Willebrand factor (VWF) in the bloodstream. The VWF works correctly but the body needs more of it to adequately control bleeding. Since VWF protects factor VIII from being destroyed, a low level of VWF may also mean a lower level of factor VIII. A small number of people with Type 1 VWD can have severe bleeding at times.
Why is the VWF low in Type 2N?
In Type 2N, the VWF is not able to do its job as the carrier and protector of factor VIII . The level of factor VIII in the body is low because it doesn’t have the VWF to keep it from being broken down. With low levels of factor VIII, the body has trouble making a fibrin clot.
Does VWF stick to platelets?
The body quickly gets rid of the platelets with the attached VWF. This causes a shortage of both platelets and VWF in the blood. In Type 2M, the VWF is not able to stick to the platelets and a good platelet plug does not form.
Is VWD a hemophilia?
A person with Type 2N VWD can appear to have mild hemophilia with some of the same symptoms. It is not hemophilia, though, because the problem is with the VWF and not the factor VIII. Another name for Type 2N is Type 2 Normandy because it was first described in patients from the Normandy region in France.
