Von Willebrand factor

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Von Willebrand factor
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Von Willebrand factor is a plasma derivate that is FDA approved for the treatment of hemophilia A and surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease in whom desmopressin (DDAVP) is either ineffective or contraindicated.. Common adverse reactions include edema of face, pruritus, rash, urticaria. nausea, dizziness, headache, paresthesia, pharyngitis, pain, shivering and factor VIII disorder.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hemophilia A: Control and prevention of bleeding episodes
  • Dose (units) = body weight (kg) x desired FVIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
    • Frequency of intravenous injection of the reconstituted product is determined by the type of bleeding episode and the recommendation of the treating physician.
Von Willebrand Disease: Surgical and/or Invasive Procedure in Adult and Pediatric patients
  • Dosage: Pre-operative dose of 60 IU VWF:RCo/kg body weight; subsequent doses of 40-60 IU VWF:RCo/kg body weight at 8-12 hour intervals post-operative as clinically needed.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Von Willebrand factor in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Von Willebrand factor in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Von Willebrand Disease: Surgical and/or Invasive Procedure in Adult and Pediatric patients
  • Dosage: Pre-operative dose of 75 IU VWF:RCo/kg body weight; subsequent doses of 50-75 IU VWF:RCo/kg body weight at 8-12 hour intervals post-operative as clinically needed.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Von Willebrand factor in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Von Willebrand factor in pediatric patients.

Contraindications

Alphanate is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components.

Warnings

Anaphylaxis and Severe Hypersensitivity Reactions

Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with Alphanate should be discontinued, and emergency treatment should be administered.

Neutralizing Antibodies

Development of procoagulant activity-neutralizing antibodies (inhibitors) has been detected in patients receiving FVIII-containing products. Carefully monitor patients treated with AHF products for the development of FVIII inhibitors by appropriate clinical observations and laboratory tests. No studies have been conducted with Alphanate to evaluate inhibitor formation. Therefore, it is not known whether there are greater, lesser or the same risks of developing inhibitors due to the use of this product than there are with other FVIII preparations. If expected plasma FVIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay that measures FVIII inhibitor concentration should be performed. Patients with these inhibitors may not respond to treatment with Antihemophilic Factor/von Willebrand Factor Complex (Human), or the response may be much less than would otherwise be expected; therefore, larger doses of Antihemophilic Factor/von Willebrand Factor Complex (Human) are often required. The management of bleeding in patients with inhibitors requires careful monitoring, especially if surgical procedures are indicated.mDepending on the level of the inhibitor and/or clinical response, it may be appropriate to use an alternative ‘bypass’ therapeutic agent.

Reports in the literature suggest that patients with Type 3, severe von Willebrand Disease, may develop alloantibodies to von Willebrand factor (VWF) after replacement therapy. The risk of developing alloantibodies in patients with von Willebrand disease due to the use of this product is not known.

Thromboembolic Events

Thromboembolic events have been reported in von Willebrand Disease patients receiving AHF/VWF Complex (Human) replacement therapy, especially in the setting of known risk factors for thrombosis. In addition, endogenous high levels of FVIII have also been associated with thrombosis but no causal relationship has been established. In all VWD patients in situations of high thrombotic risk receiving coagulation factor replacement therapy, caution should be exercised and antithrombotic measures should be considered.

Intravascular Hemolysis

Massive doses of AHF/VWF Complex (Human) have resulted in a few cases of acute hemolytic anemia, increased bleeding tendency or hyperfibrinogenemia as reported in the literature, which subside after cessation of the commercial factor infusion. Alphanate contains blood group specific isoagglutinins and, when large and/or frequent doses are required in patients of blood groups A, B, or AB, the patient should be monitored for signs of intravascular hemolysis and falling hematocrit. Should this condition occur, thus leading to progressive hemolytic anemia, the administration of serologically compatible Type O red blood cells should be considered, the administration of Alphanate should be discontinued, and alternative therapy should be considered.

Vasomotor Reactions

Rapid administration of a FVIII concentrate may result in vasomotor reactions. Alphanate should not be administered at a rate exceeding 10 mL/minute.

Transmissible Infectious Agents

Because Alphanate is made from pooled human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob Disease (CJD) agent. Stringent procedures designed to reduce the risk of adventitious agent transmission have been employed in the manufacture of this product, from the screening of plasma donors and the collection and testing of plasma, through the application of viral elimination/reduction steps such as solvent detergent and heat treatment in the manufacturing process. Despite these measures, such products can still potentially transmit disease; therefore, the risk of infectious agents cannot be totally eliminated.

Adverse Reactions

Clinical Trials Experience

Respiratory System
Gastrointestinal Effects
Dermatological Effects
Neurological Effects
General Symptoms
Musculoeskeletal Effects
Hematological and Lymphatic Effects
Urogenital Effects
Special Senses

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Alphanate (A-SD/HT). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Among patients treated with Alphanate (A-SD/HT), cases of allergic/hypersensitivity reactions (including urticaria, rash, pruritus, chest tightness, shortness of breath, wheezing, flushing, palpitations, nausea, and vomiting) have been reported.

The following represents the most frequently reported adverse reactions: fever, chills, headache, joint pain, and fatigue. In addition, one case was reported for swelling of the parotid gland, pulmonary embolus, femoral venous thrombosis, seizure, and brief cardiorespiratory arrest.

Drug Interactions

None known.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Pregnancy Category C. Animal reproduction studies have not been conducted with Alphanate. It is also not known whether Alphanate can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Alphanate should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Von Willebrand factor in women who are pregnant.

Labor and Delivery

No human or animal data. Use only if clearly needed.

Nursing Mothers

No human or animal data. Use only if clearly needed.

Pediatric Use

Hemophilia A in Pediatric Population

Clinical trials for safety and effectiveness in pediatric hemophilia A patients 16 years of age and younger have not been conducted.

VWD Indication in Pediatric Population

The hemostatic efficacy of Alphanate has been studied in 20 pediatric subjects with VWD 18 years of age and under. Based on the data from a subset of these subjects, age had no effect on the pharmacokinetics of VWF:RCo. There were no clinically important differences between pediatric patients and adults.

Geriatic Use

No human or animal data. Use only if clearly needed.

Gender

There is no FDA guidance on the use of Von Willebrand factor with respect to specific gender populations.

Race

There is no FDA guidance on the use of Von Willebrand factor with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Von Willebrand factor in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Von Willebrand factor in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Von Willebrand factor in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Von Willebrand factor in patients who are immunocompromised.

Administration and Monitoring

Administration

Hemophilia A

Doses administered should be titrated to the patient's clinical response, including individualized needs, severity of the deficiency, severity of the hemorrhage, presence of inhibitors, and FVIII level desired. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Alphanate. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial FVIII activity assays be performed.

Dosing requirements and frequency of dosing is calculated on the basis of an expected initial response of 2% FVIII:C increase per IU FVIII:C/kg body weight (i.e., 2% per IU/kg) and an average half-life for FVIII:C of 12 hours. If dosing studies have determined that a particular patient exhibits a lower than expected response and shorter half-life, the dose and the frequency of dosing should be adjusted accordingly. Failure to achieve the expected plasma FVIII:C level or to control bleeding after an appropriately calculated dosage may be indicative of the development of an inhibitor (an antibody to FVIII:C). Its presence should be documented and the inhibitor level quantitated by appropriate laboratory procedures. Treatment with AHF in such cases must be individualized.

Von Willebrand Disease

The following table provides dosing guidelines for pediatric and adult patients with von Willebrand Disease.

How to Administer

Alphanate is for intravenous use only after reconstitution. Use plastic disposable syringes. Do not refrigerate after reconstitution. Reconstituted Alphanate may be stored at room temperature (not to exceed 30 °C) prior to administration, but administer intravenously within three hours. Discard any unused contents into the appropriate safety container. Do not administer Alphanate at a rate exceeding 10 mL/minute.

Monitoring

There is limited information regarding Von Willebrand factor Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Von Willebrand factor and IV administrations.

Overdosage

There is limited information regarding Von Willebrand factor overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Mechanism of Action

Antihemophilic Factor/von Willebrand Factor Complex (Human) contains Antihemophilic Factor (FVIII) and von Willebrand Factor (VWF), constituents of normal plasma, which are required for clotting. The administration of Alphanate temporarily increases the plasma level of FVIII, thus minimizing the hazard of hemorrhage in patients with hemophilia A. FVIII is an essential cofactor in activation of factor X leading to formation of thrombin and fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein FVIII.

Structure

There is limited information regarding Von Willebrand factor Structure in the drug label.

Pharmacodynamics

There is limited information regarding Von Willebrand factor Pharmacodynamics in the drug label.

Pharmacokinetics

Hemophilia A

Following the administration of Alphanate during clinical trials, the mean in vivo half-life of FVIII observed in 12 adult subjects with severe hemophilia A was 17.9 ± 9.6 hours. In this same study, the in vivo recovery was 96.7 ± 14.5% at 10 minutes postinfusion. Recovery at 10 minutes post-infusion was also determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body weight.

Von Willebrand Disease (VWD)

A pharmacokinetic crossover study was conducted in 14 non-bleeding subjects with VWD (1 type 1, 2 type 2A, and 11 type 3) comparing the pharmacokinetics of Alphanate (A-SD/HT) and an earlier formulation, Alphanate (A-SD). Subjects received, in random order at least seven days apart, a single intravenous dose of each product, 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg in subjects younger than 18 years of age). Pharmacokinetic parameters were similar for the two products and indicated that they were biochemically equivalent. Pharmacokinetic analysis of Alphanate (A-SD/HT) in the 14 subjects revealed the following results: the median plasma levels (% normal) of VWF:RCo rose from 10.00 IU/dL [mean, 11.86 ± 4.97 IU/dL; range: 10.00 to 27.00 IU/dL] at baseline to 206.00 IU/dL [mean, 215.50 ± 101.70 IU/dL; range: 87.00 to 440.00 IU/dL] 15 minutes post-infusion; median plasma levels of FVIII:C rose from 5.00 IU/dL [mean, 21.00 ± 33.83 IU/dL; range: 2.00 to 114.00 IU/dL] to 206.00 IU/dL [mean, 215.29 ± 94.26 IU/dL; range: 110.00 to 421.00 IU/dL]. The median bleeding time (BT) prior to infusion was 30 minutes (mean, 28.8 ± 4.41 minutes; range: 13.5 to 30 minutes), which shortened to 10.38 minutes (mean, 10.4 ± 3.20 minutes; range: 6 to 16 minutes) 1 hour post-infusion.

Following infusion of Alphanate (A-SD/HT), the median half-lives for VWF:RCo, FVIII:C and VWF:Ag were 6.91 hours (mean, 7.67 ± 3.32 hours, range, 3.80 to 16.22 hours), 20.92 hours (mean, 21.58 ± 7.79 hours; range: 7.19 to 32.20 hours), and 12.80 hours (mean, 13.06 ± 2.20 hours: range: 10.34 to 17.45 hours), respectively. The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12 (IU/dL)/(IU/kg) [mean, 3.29 ± 1.46 (IU/dL)/(IU/kg); range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [mean, 2.13 ± 0.58 (IU/dL)/(IU/kg); range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII

Nonclinical Toxicology

There is limited information regarding Von Willebrand factor Nonclinical Toxicology in the drug label.

Clinical Studies

VWD: Prophylaxis for Elective Surgery – Prospective Study

In a prospective, multi-center clinical study, 37 subjects with VWD (6 Type 1, 16 Type 2A, 3 Type 2B, 12 Type 3) underwent 59 surgical procedures that included 20 dental, 7 orthopedic, 8 gastrointestinal, 6 gastrointestinal (diagnostic), 9 vascular, 3 gynecologic, 2 genitourinary, 2 dermatologic and 2 head and neck procedures for which Alphanate (A-SD) or Alphanate (A-SD/HT) was administered [21 subjects were administered with Alphanate (A-SD) and 18 were administered with Alphanate (A-SD/HT), 2 received both products] for bleeding prophylaxis (see TABLE 7). Prior to each surgical procedure, the investigators provided an estimation of the expected blood loss during surgery for a normal person of the same sex and of similar stature and age as the subject undergoing the same type of surgical procedure. An initial preoperative infusion of 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for patients less than 18 years of age), was administered one hour preoperatively. A sample was obtained 15 minutes after the initial infusion for the determination of the plasma FVIII:C level. The level had to equal or exceed 100% of normal for an operation to proceed. No cryoprecipitate or alternative FVIII product was administered during these surgical procedures. Platelets were required in only two subjects. The protocol permitted intra-operative infusions of Alphanate (A-SD) and Alphanate (A-SD/HT) at 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for patients less than 18 years of age) to be administered as required according to the judgment of the investigator.

Postoperative infusions at doses of 40 to 60 IU VWF:RCo/kg (50 to 75 IU VWF:RCo/kg for pediatric patients) was administered at 8- to 12-hour intervals until healing had occurred. After achieving primary hemostasis, for maintenance of secondary hemostasis the dose was reduced after the third postoperative day. See Dosage and Administration (2.2). Overall, in 55 surgical procedures undertaken with a prolonged BT pre-infusion, the BT at 30 minutes post-infusion was fully corrected in 18 (32.7%) cases, partially corrected in 24 (43.6%) cases, demonstrated no correction in 12 (21.8%) cases, and was not done in one case (1.8%). The mean blood loss was lower than predicted prospectively. Bleeding exceeding the predicted value did not correlate with correction of the BT. Three patients had bleeding which exceeded by more than 50 mL the amount predicted prospectively. Among the latter subjects, the BT 30 minutes post-infusion was normal in one and only slightly lengthened in two cases.

Additionally, the surgeries were categorized as major, minor or invasive procedures according to definitions used in the study. The outcome of each surgery was evaluated according to a clinical rating scale (excellent, good, poor or none) and was considered successful if the outcome was excellent or good. The study results were also evaluated independently by two referees with clinical experience in this field in the same way (surgery categorization and outcome of each surgery according to a clinical rating scale). The results for the effect of treatment on surgical prophylaxis (Referee Evaluation) per treated subject are summarized in TABLE 10. There is a high level of agreement between the referee evaluations and the analyzed outcome data, with a decrease of only a single success (21/24 vs. 22/24).

VWD: Prophylaxis for Elective Surgery – Retrospective Study

A retrospective, multi-center study was performed to assess the efficacy of Alphanate (A-SD/HT) as replacement therapy in preventing excessive bleeding in subjects with congenital VWD undergoing surgical or invasive procedures, for whom DDAVP® was ineffective or inadequate. The study was performed between September 2004 and December 2005, and 61 surgeries/procedures (in 39 subjects) were evaluated. Of the 39 subjects, 18 had Type 1 VWD (46.2%); 12 subjects (30.8%) had Type 2 VWD, and 9 subjects (23.1%) had Type 3 VWD. The median age for subjects overall was 40 years; approximately one-half of the subjects overall were male.

The primary efficacy variable was the overall treatment outcome for each surgical or invasive procedure, as rated by the investigator using a 4-point verbal rating scale (VRS): “excellent,” “good,” “poor,” or “none (no indication of efficacy).” The categorization of the replacement treatment outcome according to the proposed scale was based upon the investigator's clinical experience.

The secondary efficacy variables were:

  • Daily (Day 0 and Day 1) treatment outcome for each surgical or invasive procedure, rated by the investigator using the same 4-point VRS used for the primary efficacy variable. Day 0 was the day of surgery, and Day 1 was the day following surgery.
  • Overall treatment outcome for each surgical or invasive procedure, rated by an independent referee committee using the same 4-point VRS used for the primary efficacy variable.

In addition, an independent referee committee was convened to evaluate the efficacy outcomes. The committee was composed of 2 physicians with demonstrated clinical expertise treating subjects with similar medical characteristics to those of the study population. The committee was blinded to the investigator ratings; and each referee evaluated the outcomes independent of one another. More than 90% received an investigator and referee's overall and daily rating of “effective” (“excellent” or “good”). The results of the primary efficacy analysis are in TABLE 11.

The majority of ratings were “excellent” (≥ 81.3% in each VWD type). Nine Type 3 subjects underwent 1 major and 15 minor procedures. Two procedures (1 major and 1 minor) in 1 subject with Type 3 VWD received an overall efficacy rating of “none,” and 1 procedure (minor) in 1 subject with Type 2 VWD received an overall efficacy rating of “poor.” The total dose of Alphanate received over the entire perioperative period of the retrospective study is summarized in TABLE 15.

How Supplied

lphanate is supplied in sterile, lyophilized form in a single dose vial with a vial of diluent (Sterile Water for Injection, USP) and a Mix2Vial filter transfer set. IU activity of FVIII and VWF:RCo are stated on the carton and label of each vial. Alphanate is available in the following potencies and color coded based upon assay on the carton and label as follows:

Storage

Alphanate is stable for three years, up to the expiration date printed on its label, provided that the storage temperature does not exceed 25 °C (77 °F). Do not freeze.

Images

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Patient Counseling Information

  • Inform patients of the early signs of hypersensitivity reaction, including hives, generalized urticaria, chest tightness, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Have epinephrine available in case of severe immediate hypersensitivity reactions. If allergic symptoms occur, discontinue treatment immediately and seek emergency treatment.
  • Inform patients that inhibitors to FVIII and VWF have been detected in patients receiving FVIII or AHF/VWF Complex (Human). If expected levels are not obtained or if bleeding is not controlled with adequate dose, contact your physician.
  • Inform patients that thromboembolic events may be associated with AHF/VWF Complex (Human). For patients with high thrombotic risk, antithrombotic measures should be considered. See Warnings and Precautions.
  • Inform patients that despite stringent procedures designed to reduce risk, the risk of transmitting infectious agents cannot be totally eliminated. Ask patients, especially pregnant women and immunocompromised individuals, to report any signs and symptoms of fever, rash, joint pain, or sore throat, to their physician immediately.

Precautions with Alcohol

Alcohol-Von Willebrand factor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Von Willebrand factor Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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Von Willebrand factor
PDB rendering based on 1ao3.
Identifiers
Symbols VWF ; F8VWF; VWD
External IDs Template:OMIM5 Template:MGI HomoloGene466
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]


Overview

Von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome.[1]

Biochemistry

Synthesis

vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively in endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.[1]

Structure

The basic vWF monomer is a 2050 amino acid protein. Every monomer contains a number of specific domains with a specific function; elements of note are:[1]

Monomers are subsequently N-glycosylated, arranged into dimers in the endoplasmic reticulum and into multimers in the Golgi apparatus by crosslinking of cysteine residues via disulfide bonds. With respect to the glycosylation, vWF is one of the few proteins that carry ABO blood group system antigens.[1]

Multimers of vWF can be extremely large, >20,000 kDa, and consist of over 80 subunits of 250 kDa each. Only the large multimers are functional. Some cleavage products that result from vWF production are also secreted but probably serve no function.[1]

VWF monomer and multimers

Function

Von Willebrand factor is not an enzyme and therefore has no catalytic activity. Its primary function is binding to other proteins, particularly Factor VIII and it is important in platelet adhesion to wound sites.[1]

vWF binds to a number of cells and molecules. The most important ones are:[1]

  • Factor VIII is bound to vWF while inactive in circulation; Factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin.
  • vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel.
  • vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress (i.e., rapid blood flow in narrow blood vessels, see below).
  • vWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).

vWF appears to play a major role in blood coagulation. vWF deficiency or dysfunction (von Willebrand disease) therefore leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets.[1]

Catabolism

The biological breakdown (catabolism) of vWF is largely mediated by a protein cryptically termed ADAMTS13 (acronym of "a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13"). It is a metalloproteinase which cleaves vWF between tyrosine at position 842 and methionine at position 843 (or 1605-1606 of the gene) in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other peptidases.[2]

Role in disease

Hereditary or acquired defects of vWF lead to von Willebrand disease (vWD), a bleeding diathesis of the skin and mucous membranes, causing nosebleeds, menorrhagia, and gastrointestinal bleeding. The point at which the mutation occurs determines the severity of the bleeding diathesis. There are three types (I, II and III), and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms.[3] Most cases of vWD are hereditary, but abnormalities to vWF may be acquired; aortic valve stenosis, for instance, has been linked to vWD type IIA, causing gastrointestinal bleeding - an association known as Heyde's syndrome.[4]

In thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), ADAMTS13 either is deficient or has been inhibited by antibodies directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of vWF and microangiopathic hemolytic anemia with deposition of fibrin and platelets in small vessels, and capillary necrosis. In TTP, the organ most obviously affected is the brain; in HUS, the kidney.[5]

Higher levels of vWF are more common among people that have had ischaemic stroke (from blood-clotting) for the first time. Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group.[6]

History

vWF is named after Dr. Erik von Willebrand (1870-1949), a Finnish doctor who in 1924 first described a hereditary bleeding disorder in families from the Åland islands, who had a tendency for cutaneous and mucosal bleeding, including menorrhagia. Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease (vWD) from haemophilia and other forms of bleeding diathesis.[7]

In the 1950s, vWD was shown to be caused by a plasma factor deficiency (instead of being caused by platelet disorders), and, in the 1970s, the vWF protein was purified.[1]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Sadler JE (1998). "Biochemistry and genetics of von Willebrand factor". Annu. Rev. Biochem. 67: 395–424. doi:10.1146/annurev.biochem.67.1.395. PMID 9759493.
  2. Levy GG, Motto DG, Ginsburg D (2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
  3. Sadler JE, Budde U, Eikenboom JC; et al. (2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". J. Thromb. Haemost. 4 (10): 2103–14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557.
  4. Vincentelli A, Susen S, Le Tourneau T; et al. (2003). "Acquired von Willebrand syndrome in aortic stenosis". N. Engl. J. Med. 349 (4): 343–9. doi:10.1056/NEJMoa022831. PMID 12878741.
  5. Moake JL (2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Semin. Hematol. 41 (1): 4–14. PMID 14727254.
  6. Bongers T, de Maat M, van Goor M, et. al (2006). "High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability". Stroke. 37 (11): 2672–7. PMID 16990571 PMID 16990571 Check |pmid= value (help).
  7. von Willebrand EA (1926). "Hereditär pseudohemofili". Fin Läkaresällsk Handl. 68: 87–112. Reproduced in Von Willebrand EA (1999). "Hereditary pseudohaemophilia". Haemophilia. 5 (3): 223–31, discussion 222. doi:10.1046/j.1365-2516.1999.00302.x. PMID 10444294.

See also

ar:عامل فون ويليبراند de:Von-Willebrand-Faktor sv:Von Willebrands faktor


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