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{{DrugProjectFormSinglePage
{{Infobox_gene}}
|authorTag={{AP}}
|genericName=Coagulation Factor VIII Complex
|aOrAn=a
|drugClass=plasma derivate
|indicationType=treatment
|indication=[[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
|adverseReactions=facial [[edema]], [[pruritus]], [[rash]], [[urticaria]], [[nausea]], [[dizziness]], [[headache]], [[paresthesia]], [[pharyngitis]], [[pain]], [[shivering]] and factor VIII disorder
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======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=====
'''von Willebrand factor''' ('''VWF''') ({{IPAc-en|ˌ|f|ʌ|n|ˈ|v|ɪ|l|ᵻ|b|r|ɑː|n|t}}) 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]].<ref name=Sadler>{{cite journal|authorlink1=J. Evan Sadler | vauthors = Sadler JE | title = Biochemistry and genetics of von Willebrand Factor | journal = Annual Review of Biochemistry | volume = 67 | issue = | pages = 395–424 | year = 1998 | pmid = 9759493 | doi = 10.1146/annurev.biochem.67.1.395 }}</ref> Increased plasma levels in a large number of cardiovascular, neoplastic, and connective tissue diseases are presumed to arise from adverse changes to the [[endothelium]], and may contribute to an increased risk of [[thrombosis]].{{citation needed | date=August 2011}}
*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.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Von Willebrand factor in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Von Willebrand factor in adult patients.
|fdaLIADPed======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.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Von Willebrand factor in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Von Willebrand factor in pediatric patients.
|contraindications=*Von Willebrand factor 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 Von Willebrand factor should be discontinued, and emergency treatment should be administered.


=====Neutralizing Antibodies=====
== Biochemistry ==
*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 Von Willebrand factor 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. Depending 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=====
=== Synthesis ===
*[[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.
VWF is a large multimeric [[glycoprotein]] present in [[blood plasma]] and produced constitutively as ultra-large VWF in [[endothelium]] (in the [[Weibel-Palade body|Weibel-Palade bodies]]), [[megakaryocyte]]s (α-granules of [[platelet]]s), and subendothelial [[connective tissue]].<ref name=Sadler/>


=====Intravascular Hemolysis=====
=== Structure ===
*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. Von Willebrand factor 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 Von Willebrand factor should be discontinued, and alternative therapy should be considered.
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:<ref name=Sadler/>
* the D'/D3 domain, which binds to [[factor VIII]] ([[von Willebrand Factor type D domain]])
* the A1 domain, which binds to:
** [[platelet]] GPIb-receptor
** [[heparin]]
** possibly [[collagen]]
* the A2 domain, which must partially unfold to expose the buried cleavage site for the specific [[ADAMTS13]] protease that inactivates VWF by making much smaller multimers.  The partial unfolding is affected by shear flow in the blood, by calcium binding, and by the lump of a sequence-adjacent "vicinal disulfide" at the A2-domain C-terminus.<ref name=Jakobi>Jakobi AJ, Mashaghi A, Tans SJ, Huizinga EG. Calcium modulates force sensing by the von Willebrand Factor A2 domain. Blood. 2011 April 28, 117:17.Nature Commun. 2011 Jul 12;2:385.  [http://www.nature.com/ncomms/journal/v2/n7/full/ncomms1385.html]</ref><ref>{{cite journal | vauthors = Luken BM, Winn LY, Emsley J, Lane DA, Crawley JT | title = The importance of vicinal cysteines, C1669 and C1670, for von Willebrand Factor A2 domain function | journal = Blood | volume = 115 | issue = 23 | pages = 4910–3 | date = June 2010 | pmid = 20354169 | pmc = 2890177 | doi = 10.1182/blood-2009-12-257949 }}</ref>
* the A3 domain, which binds to collagen ([[Von Willebrand Factor type A domain]])
* the C1 domain, in which the [[RGD motif]] binds to platelet [[integrin]] α<sub>IIb</sub>β<sub>3</sub> when this is activated ([[Von Willebrand Factor type C domain]])
* the "[[cystine knot]]" domain (at the C-terminal end of the protein), which VWF shares with [[platelet-derived growth factor]] (PDGF), [[transforming growth factor]]-β (TGFβ) and β-[[human chorionic gonadotropin]] (βHCG, of [[pregnancy test]] fame). ([[Von Willebrand Factor type C domain]])
Monomers are subsequently [[glycosylation|N-glycosylated]], arranged into dimers in the [[endoplasmic reticulum]] and into multimers in the [[Golgi apparatus]] by crosslinking of [[cysteine]] residues via [[disulfide bond]]s. With respect to the glycosylation, VWF is one of only a few proteins that carry [[ABO blood group system]] antigens.<ref name=Sadler/>


=====Vasomotor Reactions=====
Multimers of VWF can be extremely large, &gt;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.<ref name=Sadler/>
*Rapid administration of a [[FVIII]] concentrate may result in vasomotor reactions. Von Willebrand factor should not be administered at a rate exceeding 10 mL/minute.
[[Image:VWF.png|none|framed|VWF monomer and multimers]]


=====Transmissible Infectious Agents=====
=== Function ===
*Because Von Willebrand factor 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.
[[image:VWF-GP1ba.png|thumb|300px|right|The interaction of VWF and GP1b alpha. The GP1b receptor on the surface of platelets allows the platelet to bind to VWF, which is exposed upon damage to vasulature. The VWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).]]
|clinicalTrials======Respiratory System=====
Von Willebrand Factor's primary function is binding to other proteins, in particular [[factor VIII]], and it is important in [[Platelet#Adhesion and aggregation|platelet adhesion]] to wound sites.<ref name=Sadler/> It is not an [[enzyme]] and, thus, has no catalytic activity.
*[[Respiratory distress]]  
*[[Cough]]
*[[Pharyngitis]]  
*[[Rhinitis]]


=====Gastrointestinal Effects=====
VWF binds to a number of cells and molecules. The most important ones are:<ref name=Sadler/>
*[[Dyspepsia]]
* 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]]. In the absence of VWF, factor VIII has a half-life of 1-2 hours; when carried by intact VWF, factor VIII has a half-life of 8-12 hours.
*[[Hepatitis]]  
* VWF binds to collagen, e.g., when it is exposed in [[endothelium|endothelial cells]] due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
*[[Nausea]]  
* 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).
*[[Tooth disorder]]
* VWF binds to other platelet receptors when they are activated, e.g., by [[thrombin]] (i.e., when coagulation has been stimulated).
*[[Vomiting]]  


=====Dermatological Effects=====
VWF plays a major role in blood coagulation. Therefore, VWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow [[Shear (fluid)|shear]] in narrow vessels. From studies it appears that VWF uncoils under these circumstances, decelerating passing platelets.<ref name=Sadler/> Recent research also suggests that von Willebrand Factor is involved in the [[angiogenesis|formation of blood vessels themselves]], which would explain why some people with von Willebrand disease develop vascular malformations (predominantly in the [[digestive tract]]) that can [[gastrointestinal bleeding|bleed excessively]].<ref>{{cite journal | vauthors = Randi AM, Laffan MA | title = Von Willebrand Factor and angiogenesis: basic and applied issues | journal = Journal of Thrombosis and Haemostasis | volume = 15 | issue = 1 | pages = 13–20 | date = January 2017 | pmid = 27778439 | doi = 10.1111/jth.13551 }}</ref>
*[[Pruritus]]  
*[[Rash]]  
*[[Urticaria]]  
*[[Face edema]]
*[[Acne]]
*[[Dry skin]]
*[[Sweating]]


=====Neurological Effects=====
===Catabolism===
*[[Paresthesia]]
The biological breakdown ([[catabolism]]) of VWF is largely mediated by the enzyme [[ADAMTS13]] (acronym of "''a'' ''d''isintegrin-like ''a''nd ''m''etalloprotease with ''t''hrombo''s''pondin type 1 motif no. ''13''"). It is a [[metalloproteinase]] that [[proteolysis|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 [[peptidase]]s.<ref>{{cite journal | vauthors = Levy GG, Motto DG, Ginsburg D | title = ADAMTS13 turns 3 | journal = Blood | volume = 106 | issue = 1 | pages = 11–7 | date = July 2005 | pmid = 15774620 | doi = 10.1182/blood-2004-10-4097 | url = http://bloodjournal.hematologylibrary.org/cgi/content/full/106/1/11 }}</ref>
*[[Insomnia]]
*[[Somnolence]]  


=====General Symptoms=====
== Role in disease ==
*[[Pain]]
{{main article|Von Willebrand disease}}
*[[Headache]]
*[[Asthenia]]
*[[Cellulitis]]
*[[Chest pain]]
*[[Flu syndrome]]
*[[Fever]]
*[[Chills]]
*[[Fatigue]]


=====Musculoeskeletal Effects=====
[[Genetic disorder|Hereditary]] or acquired defects of VWF lead to [[von Willebrand disease]] (vWD), a [[bleeding diathesis]] of the skin and mucous membranes, causing [[nosebleed]]s, [[menorrhagia]], and [[gastrointestinal bleed]]ing. 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.<ref>{{cite journal | vauthors = Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB | title = Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor | journal = Journal of Thrombosis and Haemostasis | volume = 4 | issue = 10 | pages = 2103–14 | date = October 2006 | pmid = 16889557 | doi = 10.1111/j.1538-7836.2006.02146.x | url = http://www.blackwell-synergy.com/doi/full/10.1111/j.1538-7836.2005.01681.x }}</ref> Most cases of vWD are hereditary, but abnormalities of 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]].<ref>{{cite journal | vauthors = Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, Bauters A, Decoene C, Goudemand J, Prat A, Jude B | title = Acquired von Willebrand syndrome in aortic stenosis | journal = The New England Journal of Medicine | volume = 349 | issue = 4 | pages = 343–9 | date = July 2003 | pmid = 12878741 | doi = 10.1056/NEJMoa022831 | url = http://content.nejm.org/cgi/content/full/349/4/343 }}</ref>
*[[Joint pain]]
*[[Bone disorder]]
*[[Bone necrosis]]


=====Hematological and Lymphatic Effects=====
In [[thrombotic thrombocytopenic purpura]] (TTP) and [[hemolytic uremic syndrome]] (HUS), ADAMTS13 either is deficient or has been inhibited by [[antibody|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.<ref>{{cite journal | vauthors = Moake JL | title = von Willebrand Factor, ADAMTS-13, and thrombotic thrombocytopenic purpura | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 4–14 | date = January 2004 | pmid = 14727254 | doi = 10.1053/j.seminhematol.2003.10.003 }}</ref>
*[[Anemia]]
*[[Ecchymosis]]


=====Urogenital Effects=====
Higher levels of VWF are more common among people that have had [[Stroke#Ischemic|ischemic stroke]] (from blood-clotting) for the first time.<ref>{{cite journal|last1=Denorme|first1=F|title=The VWF-GPIb axis in ischaemic stroke: lessons from animal models|journal=Thrombosis and Haemostasis|volume=116|issue=4|pages=597–604|doi=10.1160/TH16-01-0036|pmid=27029413|year=2016}}</ref> Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's [[Blood type|blood]] group. High plasma VWF levels were found to be an independent predictor of major bleeding in anticoagulated atrial [[Atrial fibrillation|fibrillation]] patients.<ref>{{cite journal | vauthors = Roldán V, Marín F, Muiña B, Torregrosa JM, Hernández-Romero D, Valdés M, Vicente V, Lip GY | title = Plasma von Willebrand Factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients | journal = Journal of the American College of Cardiology | volume = 57 | issue = 25 | pages = 2496–504 | date = June 2011 | pmid = 21497043 | doi = 10.1016/j.jacc.2010.12.033 }}</ref>
*Abnormal [[ejaculation]]
*Cutaneous [[moniliasis]]  


=====Special Senses=====
== History ==
*[[Eye disorder]]
{{See also|Erik Adolf von Willebrand#Von Willebrand disease}}
|postmarketing=<i>The following adverse reactions have been identified during post-approval use of Von Willebrand factor (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.</i>
VWF is named after [[Erik Adolf von Willebrand]], a Finnish physician who in 1926 first described a hereditary bleeding disorder in families from the [[Åland islands]]. Although Von Willebrand did not identify the definite cause, he distinguished von Willebrand disease (vWD) from [[hemophilia]] and other forms of [[bleeding diathesis]].<ref>{{cite journal| vauthors = von Willebrand EA | title = Hereditär pseudohemofili | trans-title = Hereditary pseudo haemophilia | language = Swedish | journal = Fin Läkaresällsk Handl | year = 1926 | volume = 68 | pages = 87–112}} Reproduced in {{cite journal | vauthors = Von Willebrand EA | title = Hereditary pseudohaemophilia | journal = Haemophilia | volume = 5 | issue = 3 | pages = 223–31; discussion 222 | date = May 1999 | pmid = 10444294 | doi = 10.1046/j.1365-2516.1999.00302.x }}</ref>


*Among patients treated with Von Willebrand factor (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.
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.<ref name=Sadler/>
*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]], [emoral [[venous thrombosis]], [[seizure]], and brief [[cardiorespiratory arrest]].
|drugInteractions=*None known.
|FDAPregCat=C
|useInPregnancyFDA=*Animal reproduction studies have not been conducted with Von Willebrand factor. It is also not known whether Von Willebrand factor can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Von Willebrand factor should be given to a pregnant woman only if clearly needed.
|useInLaborDelivery=*No human or animal data. Use only if clearly needed.
|useInNursing=*No human or animal data. Use only if clearly needed.
|useInPed======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=====
== Interactions ==
*The hemostatic efficacy of Von Willebrand factor 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.
|useInGeri=*No human or animal data. Use only if clearly needed.
|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 Von Willebrand factor. 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.


[[file:HAwer.png|thumb|none|500px]]
von Willebrand Factor has been shown to [[Protein-protein interaction|interact]] with [[Collagen, type I, alpha 1]].<ref name="pmid3490481">{{cite journal | vauthors = Pareti FI, Fujimura Y, Dent JA, Holland LZ, Zimmerman TS, Ruggeri ZM | title = Isolation and characterization of a collagen binding domain in human von Willebrand Factor | journal = The Journal of Biological Chemistry | volume = 261 | issue = 32 | pages = 15310–5 | date = November 1986 | pmid = 3490481 | doi =  }}</ref>


*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.  
Recently, It has been reported that the cooperation and interactions within the Von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates.<ref>{{cite journal | vauthors = Heidari M, Mehrbod M, Ejtehadi MR, Mofrad MR | title = Cooperation within von Willebrand Factors enhances adsorption mechanism | language = en | journal = Journal of the Royal Society, Interface | volume = 12 | issue = 109 | pages = 20150334 | date = August 2015 | pmid = 26179989 | pmc = 4535404 | doi = 10.1098/rsif.2015.0334 | url = http://rsif.royalsocietypublishing.org/content/12/109/20150334 }}</ref>


=====Von Willebrand Disease=====
== See also ==
*The following table provides dosing guidelines for pediatric and adult patients with von Willebrand Disease.
*[[von Willebrand disease]]
[[file:TablaVW1.png|thumb|none|500px]]
*[[Bernard-Soulier syndrome]]
[[file:TablaVW2.png|thumb|none|500px]]


=====How to Administer=====
== References ==
*Von Willebrand factor is for intravenous use only after reconstitution. Use plastic disposable syringes. Do not refrigerate after reconstitution. Reconstituted Von Willebrand factor 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 Von Willebrand factor at a rate exceeding 10 mL/minute.
{{reflist|33em}}


[[file:Captura de pantalla 2014-12-26 a la(s) 12.33.02.png|thumb|none|500px]]
== External links ==
|drugBox=[[file:VWDB2.png|thumb|none|600px]]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=von-willebrand GeneReviews/NCBI/NIH/UW entry on von Willebrand Factor Deficiency. Includes: Type 1 von Willebrand Disease, Type 2A von Willebrand Disease, Type 2B von Willebrand Disease, Type 2M von Willebrand Disease, Type 2N von Willebrand Disease, Type 3 von Willebrand Disease]
|mechAction=*[[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 Von Willebrand factor 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]].
|PK======Hemophilia A=====
*Following the administration of Von Willebrand factor 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)=====
{{Coagulation}}
*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 Von Willebrand factor (A-SD/HT) and an earlier formulation, Von Willebrand factor (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 Von Willebrand factor (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 Von Willebrand factor (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
|clinicalStudies======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 Von Willebrand factor (A-SD) or Von Willebrand factor (A-SD/HT) was administered [21 subjects were administered with Von Willebrand factor (A-SD) and 18 were administered with Von Willebrand factor (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 Von Willebrand factor (A-SD) and Von Willebrand factor (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.


[[file:Table7.png|thumb|none|500px]]
{{PDB_Gallery|geneid=7450}}


*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.
{{DEFAULTSORT:Von Willebrand Factor}}
 
[[Category:Blood proteins]]
[[file:Table8.png|thumb|none|500px]]
[[Category:Coagulation system]]
 
[[Category:Glycoproteins]]
*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).
 
[[file:Able10.png|thumb|none|500px]]
 
=====VWD: Prophylaxis for Elective Surgery – Retrospective Study=====
*A retrospective, multi-center study was performed to assess the efficacy of Von Willebrand factor (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.
 
[[file:12y13masna.png|thumb|none|500px]]
 
*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 Von Willebrand factor received over the entire perioperative period of the retrospective study is summarized in TABLE 15.
 
[[file:15masnaqui.png|thumb|none|500px]]
|howSupplied=*Von Willebrand factor 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. Von Willebrand factor is available in the following potencies and color coded based upon assay on the carton and label as follows:
[[file:Potency.png|thumb|none|600px]]
|storage=*Von Willebrand factor 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.
|packLabel=[[file:Tabladecolores1.png|thumb|none|600px]]
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|fdaPatientInfo=*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.
|alcohol=Alcohol-Von Willebrand factor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*[[Humate-P]]
*[[Alphanate]]
*[[Wilate]]
*[[Wilstart]]
}}
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Latest revision as of 20:02, 3 January 2019

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von Willebrand factor (VWF) (/ˌfʌnˈvɪlɪbrɑːnt/) 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] Increased plasma levels in a large number of cardiovascular, neoplastic, and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may contribute to an increased risk of thrombosis.[citation needed]

Biochemistry

Synthesis

VWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF 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 only a 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

File:VWF-GP1ba.png
The interaction of VWF and GP1b alpha. The GP1b receptor on the surface of platelets allows the platelet to bind to VWF, which is exposed upon damage to vasulature. The VWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).

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

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. In the absence of VWF, factor VIII has a half-life of 1-2 hours; when carried by intact VWF, factor VIII has a half-life of 8-12 hours.
  • VWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
  • 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 plays a major role in blood coagulation. Therefore, VWF deficiency or dysfunction (von Willebrand disease) 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] Recent research also suggests that von Willebrand Factor is involved in the formation of blood vessels themselves, which would explain why some people with von Willebrand disease develop vascular malformations (predominantly in the digestive tract) that can bleed excessively.[4]

Catabolism

The biological breakdown (catabolism) of VWF is largely mediated by the enzyme ADAMTS13 (acronym of "a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13"). It is a metalloproteinase that 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.[5]

Role in disease

Main article: Von Willebrand 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.[6] Most cases of vWD are hereditary, but abnormalities of 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.[7]

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.[8]

Higher levels of VWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time.[9] Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group. High plasma VWF levels were found to be an independent predictor of major bleeding in anticoagulated atrial fibrillation patients.[10]

History

See also: Erik Adolf von Willebrand § Von Willebrand disease

VWF is named after Erik Adolf von Willebrand, a Finnish physician who in 1926 first described a hereditary bleeding disorder in families from the Åland islands. Although Von Willebrand did not identify the definite cause, he distinguished von Willebrand disease (vWD) from hemophilia and other forms of bleeding diathesis.[11]

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]

Interactions

von Willebrand Factor has been shown to interact with Collagen, type I, alpha 1.[12]

Recently, It has been reported that the cooperation and interactions within the Von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates.[13]

See also

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". Annual Review of Biochemistry. 67: 395–424. doi:10.1146/annurev.biochem.67.1.395. PMID 9759493.
  2. ↑ Jakobi AJ, Mashaghi A, Tans SJ, Huizinga EG. Calcium modulates force sensing by the von Willebrand Factor A2 domain. Blood. 2011 April 28, 117:17.Nature Commun. 2011 Jul 12;2:385. [1]
  3. ↑ Luken BM, Winn LY, Emsley J, Lane DA, Crawley JT (June 2010). "The importance of vicinal cysteines, C1669 and C1670, for von Willebrand Factor A2 domain function". Blood. 115 (23): 4910–3. doi:10.1182/blood-2009-12-257949. PMC 2890177. PMID 20354169.
  4. ↑ Randi AM, Laffan MA (January 2017). "Von Willebrand Factor and angiogenesis: basic and applied issues". Journal of Thrombosis and Haemostasis. 15 (1): 13–20. doi:10.1111/jth.13551. PMID 27778439.
  5. ↑ Levy GG, Motto DG, Ginsburg D (July 2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
  6. ↑ Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB (October 2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". Journal of Thrombosis and Haemostasis. 4 (10): 2103–14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557.
  7. ↑ Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, Bauters A, Decoene C, Goudemand J, Prat A, Jude B (July 2003). "Acquired von Willebrand syndrome in aortic stenosis". The New England Journal of Medicine. 349 (4): 343–9. doi:10.1056/NEJMoa022831. PMID 12878741.
  8. ↑ Moake JL (January 2004). "von Willebrand Factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Seminars in Hematology. 41 (1): 4–14. doi:10.1053/j.seminhematol.2003.10.003. PMID 14727254.
  9. ↑ Denorme, F (2016). "The VWF-GPIb axis in ischaemic stroke: lessons from animal models". Thrombosis and Haemostasis. 116 (4): 597–604. doi:10.1160/TH16-01-0036. PMID 27029413.
  10. ↑ Roldán V, Marín F, Muiña B, Torregrosa JM, Hernández-Romero D, Valdés M, Vicente V, Lip GY (June 2011). "Plasma von Willebrand Factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients". Journal of the American College of Cardiology. 57 (25): 2496–504. doi:10.1016/j.jacc.2010.12.033. PMID 21497043.
  11. ↑ von Willebrand EA (1926). "Hereditär pseudohemofili" [Hereditary pseudo haemophilia]. Fin Läkaresällsk Handl (in Swedish). 68: 87–112. Reproduced in Von Willebrand EA (May 1999). "Hereditary pseudohaemophilia". Haemophilia. 5 (3): 223–31, discussion 222. doi:10.1046/j.1365-2516.1999.00302.x. PMID 10444294.
  12. ↑ Pareti FI, Fujimura Y, Dent JA, Holland LZ, Zimmerman TS, Ruggeri ZM (November 1986). "Isolation and characterization of a collagen binding domain in human von Willebrand Factor". The Journal of Biological Chemistry. 261 (32): 15310–5. PMID 3490481.
  13. ↑ Heidari M, Mehrbod M, Ejtehadi MR, Mofrad MR (August 2015). "Cooperation within von Willebrand Factors enhances adsorption mechanism". Journal of the Royal Society, Interface. 12 (109): 20150334. doi:10.1098/rsif.2015.0334. PMC 4535404. PMID 26179989.

External links

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