The Von Willebrand disease is a frequent disorder in bleeding, and it is an inheritable disorder. Von will stamp the dysfunctions cause illness to the von Will brand factor gene. There is mediation from the plasma protein and meshing of platelets at the injured site which stabilises and binds blood clotting factor. Thus defects in von Willebrand factor result in bleeding due to impairing platelets adhesion or because of reduced blooding clotting factor concentration (Haberichter, 2015, 1755). Therefore there is a prolonged period for flowing to stop and blood to clot. There various types of von will brand disease, and each depends on whether either one or both parents passed dysfunctional genes on someone. However, the linkage is not identified approximately in type 1 case. In von Willebrand type 1 disease, has a strong association and therefore level of von Willebrand factor is lower. Von Willebrand factor is affected by known and unidentified environmental and genetic factors in various standards such as age, thyroid status, blood type, stress, inflammation and hormone stress( Peyvandi et al. 2009 p 351). The mutation that affects the expression may cause von Willebrand type 1. The specific variation that influences functional epitopes has been recognised to cause type 2 disease.
Meanwhile, most of these mutations are in the 134 amino acid segment encoded by exon 28. The mutation leading to type 3 von Willebrand diseases are usually little mutation due to small deletions. The splice site mutations are caused by splice mutation. However, mutations missense are not common.
Von Willebrand disease is a more frequent disorder patients suffer from. This disease infects both the males and the females. Meanwhile, it is a less severe condition compared to other bleeding complications(Dong, 2005, 1714). Many people having this condition might not realise they have this disorder because their bleeding conditions are very mild. VWD cause little or no distraction in people’s lives unless there is serious injury or in case there is a need for surgery. There can be a bleeding problem in all forms of VWD( Ruggeri, 2001, 263)
VWD is associated with the various sign and symptoms. In case a person has this condition they exhibit the following symptoms. In fact, there is injury, little or no injury the person experiences bruising (Catasman & Fedric 2003, 101). This may often occur maybe one to four times per month. The bruise is usually large or has a raised lump. There is also longer than normal bleeding. This is after surgery procedures, injury, dental work, childbirth, and the bleeding occur more than five minutes following a skin cut.
Meanwhile extended or heavy bleeding during or after surgery or surgical bleeding and after dental work occurs. This may stop and eventually start again hours or days later. A person may also experience spontaneously nosebleeds that are usually hard to stop (Catasman & Goodeve, 2013, 669). This bleeding keeps on occurring frequently and often happens five times or more in a year, or it might last longer than ten times a year. In women, a person suffering from VWD, usually have heavy menstrual periods that last more than seven days( Sadler & Bodde,2006, 2013). The symptoms of this condition include clots that are larger than a quarter. Changing menstrual pad tampon more often or use of double sanitary protection to control the menstrual flow. VWD might also result in the diagnosis of anemia whose symptoms includes tiredness, fatigue, and breath shortage. During birth, a person may suffer from massive blood loss.
In some instances, other bleeding events in people having von Willebrand disease might include blood in the stool as a result of stomach or intestine bleeding. Also, the urine might contain blood due to bleeding in the bladder or kidneys. Although it is rare, they might occur bleeding into joints or internal organs.
Von Willebrand disease is brought about a result of abnormality, which is von Willebrand disease quantitative or qualitative factor. It is a huge multimeric glycoprotein necessary for platelets meshing (Sadler 2009, 38). Also, it acts as the protein carrier for element VIII. With this von Willebrand factor have the responsibility in both primary that involves the platelets adhesion and platelets formation plug. Secondly, it consists FVIII that is usually hemostasis. The von Willebrand disease factor primary hemostasis holds to the platelets using its receptor to a glycoprotein of the platelets surface and functions as a link between the injury part in the site of damage and then platelets. The secondary hemostasis, von Willebrand factor shields FVIII against degradation as well as transport in the location of the damaged part. There von Willebrand disease is divided into two categories inherited and the acquired. The inherited forms consist of types 1, 2 and 3. Class 2 is further categorized into 2M, 2N, 2A, and 2B. These types differ regarding intensity and type of defect in von Willebrand factor.
Iron deficiency anemia is a situation in which blood lacks adequate red blood cells. Iron deficiency is caused by lack of enough iron. Leukemia is an example of iron deficiency disease. Leukemia is also known to as a cancer of blood or bone marrow. It is a disease one of the major cancers in childhood although it is occurring frequently in adults. Leukemia is caused when the immature DNA blood cells usually white blood cells are damaged is a certain way. This makes the blood cells to continuously divide as they grow hence they are multiple.
Leukemia is a genetic disease although in most cases are not seen as hereditary. Meanwhile, a wide range of factors can likely make you more prone get the disease. It is believed that various types of leukemia are due to DNA mutations in the blood cells. This mutation in the genetics affects the reproduction of the blood cells in the bone marrow. Also, proper functioning of the blood cells can be modified. The modifications are genetics however they are not hereditary. Thus leukemia is caused by the gene mutations. The abnormalities in genetics often are not inherited from the family. They are therefore referred to as acquired gene mutation. The causes of these mutations are not well known. In some instance, one can be genetically predisposed to leukemia, but risk factors arise from their lifestyle such as smoking cigarette can make you prone to developing leukemia.
It is essential to state various forms of the inherited forms of von Willebrand disease. VWF is altered genetically such as the low factor level. The intracellular transports of the subunits of the glycoprotein have interfered with the mutation in type 1 dominant severe. This represents for 70-80% of the incidents. It is associated with the slow quantitative reduction in qualitative normal von Willebrand disease. Usually, a person suffering von Willebrand type 1 disease experiences severe to moderate of diagnosis symptoms. The von Willebrand factor has a reduced plasma level. This type is passed as the autosomal dominant gene having incomplete penetration. However in a single family may vary widely. The person suffers a spectrum of mucocutaneous bleeding symptoms. This is mostly related to a deficiency in von Willebrand factor (Redoghien & Castman 2007, 117). Other evidence associated argues that the cause of mild von Willebrand reduction is considered to involve the contribution from other genes apart from the ABO blood groups genes and von Willebrand factor (Albanez & Ogiwara, 2016, 957).
The type 2 disease is accountable for 16-21% of the Willebrand disease incidences. Usually is a wide variety of illness consisting the von Willebrand factor qualitative deficiency. The type 2 von Willebrand disease is mostly the autosomal recessive and the autosomal dominant. The type is subdivided further into four which is 2N, 2B, 2M, 2A. This is where the plasma Von Willebrand factor although it appears normal it is structurally and functionally defensive (Dimino & Canaro, 2013, 2015). The 2A von Willebrand disease acts as an inheritable due to the dominant trait of the autosomal and is related to normal and reduced plasma level factorVillic and von Willebrand factor. The analysis reveals that there is a relatively compressed multimeter in the intermediate and multimeter complexes high molecular weight. The multimetric disorders are affected by degradation to proteolytic of von Willebrand factor. The anomalies experienced in the multimetric defects are similar to the ones found in the plasma.
Von Willebrand type 2B diseases are caused by the autosomal trait. This disease is linked with the lowered quantity in the von Willebrand factor multimeters high molecular weight. Increased fragments of low-molecular-weight characterize this. Individuals having type 2B, von Willebrand disease suffer homeostatic defects brought by intermittent thrombocytopenia and the qualitatively abnormal von Willebrand factor. This result to gaining of mutation activity in von Willebrand factor that causes meshing at the platelets spontaneously with von Willebrand factor multimeters and platelets rapid clearance of both high molecular weight (Hampshire, 2001, 476) This unusual Willebrand factor experiences increased affinity platelets glycoprotein Ib. Platelets may lower further at the pregnancy period in conjunction with operational processes, or desmopressin acetate has been administered.
Type 2M is very rare, and the results from the laboratory are same to those people having von Willebrand disease type 2A disease. Type 2M of von Willebrand disease is related with decreasing of platelets the in directed function which is never affected by a high molecular weight multimeter decrease. The von Willebrand factor activity is lowered. However, analysis of the von Willebrand factor FVIII, antigen, multimeters located around the range reference. This is because of impairment occurring to the von Willebrand factor gene which causes absent or decreased platelets glycoprotein ib bindings, and its inheritance is a form of autosomal dominant(Castman & Lethagen 2008, 3533).
Type 2N von Willebrand disease is not universal. However, it is associated with the von Willebrand factor decreasing significant affinity or FVIII because of the mutations of the genes of the factor VIII meshing part of the Willebrand factor. Hence, because of this, FVIII levels are usually lowered to around 5-25% of the range reference. The FVIII-binding defects in the patients are inheritable in the manner of autosomal recessive manner. The type 2N male patient is regularly confused about suffering mild hemophilia A. Due to this condition, the type 2N von Willebrand disease is not supposed to be regarded to individual suffering bleeding disorder and FVIII deficiency and is not transmitted directly as the X-linked disease (Castman & Federic, 2012, 635). Also, this applies to the patients who do not respond completely to hemophilia A therapy.
The type 3 von Willebrand disease is rarest among all categories. It is also the mildest type of the condition. It is autosomal inheritable recessive trait, and patients are combined heterozygous or homozygous. The von Willebrand disease is linked with significant abnormalities of von Willebrand factor and FVIII in the plasma, lack of von Willebrand factor in endothelial cells with the platelets and the DDAVP lacks to respond (Dong 2005, 1714). The type 3 von Willebrand disease is associated to worse bleeding clinical symptoms. This characteristic is found both in the mucous membrane and external bleeding and the muscle and joint bleeds. These conditions are inheritable as the autosomal recessive trait. Kindreds are the most current continuity with this variant.
Von Willebrand acquired disease occurs, because of von Willebrand factor clearance to the plasma forming a complex with its antibody. They may be caused as a result of adhesion to the tumor cells or generated due to the availability of von Willebrand factor that distracts the multimer or even slowing the digestion of the protein and is also observed with patients suffering the aortic stenosis (Albahez & Ogiwara, 2016, 958).
Von Willebrand disease prevalence is 0.6-1.3 %. The autosomal inheritance patterns suggest an equal distribution of female’s patients and male’s patients. However, the disease is diagnosed more in females due to female-homeostatic challenges. These data were collected through laboratory criteria and conservative clinical. However, most people will have only minor bleedings in their lifetime; most of them may likely never be referred to medical assistance. The availability of those related cases to specialized centers for bleeding diagnosis is estimated to be one example for 10000 people with a cumulative incidence of hemophilia B and A are similar (Sadler, 2009, 39). The worse von Willebrand disease is very rare disorder and its occurrence case is one for 1million people and this dependent on ethnic background.
The von Willebrand disease symptoms vary across patients, depending on the residual level of von Willebrand factor functions. The postpartum disease bleeding secondary and primary occurs frequently. Due to this von Willebrand factor physiologic levels rise throughout the life. Those suffering the type 1 von Willebrand factor may have standards that are within the normal range when they become older. Still, it is not recognized whether the rise is because of the reduced bleeding episodes (Topez & Franchini, 2009, 95). The most common von Willebrand disease symptoms in children are epistaxis and bleeding. In adult menorrhagia, hematomas, and bleeding from small injuries are the most common symptoms. Majority of patients experiences bleeding after surgery or dental work. A possible life-threatening and severe well known bleeding complication is the gastrointestinal bleeding from angiodysplasia. Type 2 and 3 von Willebrand disease is frequent in elderly patients. The intraarticular bleeding is the frequent complication in patients with hemophilia.
Meanwhile, there has not been reporting as a severe problem to patients with von Willebrand disease. These conditions might be associated symptoms to type 2N or type 3 infections. Joint bleeding is identified to appear in a wide range of severely affected patients and has a potential of leading to arthropathy and reduced joint function. The level of the residual factor VIII strongly determines the collective bleeding risk, as well as the worsening of the von Willebrand disease (Manucci & Franchini, 2001, 205). Patients in type 3 with the greatest threat are those with deficient factor VIII levels. Lowered health quality of the patient’s life for the people with von Willebrand disease. Most women in the von Willebrand disease suffer from menorrhagia, which damages the life quality.
The von Willebrand disease diagnosis is determined by the personal bleeding history or the family bleeding history, or both, together with the laboratory tests signifying abnormalities in von Willebrand factor, factor VIII or both( Favaloro, 2011, 345 ). Assessment of the bleeding phenotype starts with full history information of the bleeding symptoms of the family members and the patients. The severity rating of the von Willebrand disease has received significant attention in recent years. Numerical scoring symptoms based on a structured questionnaire usually referred to as bleeding assessment. They have developed and endorsed by the ISTH. These tools have less diagnostic use because they depend firmly on the number of previous hemostatic challenges and the age. The method of tools in diagnostic is challenging to use in young children who have not undergone dental intervention or surgery yet. Another problem to bleeding-assessment tools is the application of the cumulative scoring. This means that the patient experienced severe episodes of bleeding earlier and the bleeding score will remain high even though bleeding does not occur again.
The diagnostic approach begins with assessing the person clinically to an individual who has symptoms of bleeding mucocutaneous bleeding. Evaluation initially takes into account family and personal history manifestation of bleeding. These evaluations are aimed at identifying the sign of bleeding such as severity, spontaneity, and localization. Various tools have been invented to assist in the diagnosis of disorders in bleeding. These tools are general while others are symptoms specific.
The von Willebrand factor antigen measurement forms a basis to the diagnosing von Willebrand disease. Platelets adhesion is factor dependent by the level of von Willebrand factor. When von Willebrand factor antigens are unable to detect the type 3 of von Willebrand disease is diagnosed. Meanwhile, usage of a cutoff level of 5 IU shows that the patients with detection 5 strong but shallow, von Willebrand factor antigen levels are supposed to be classified as possessing type 3 disease (Domino & Canaro, 2013, 1496). Measurement of von Willebrand propeptide factor, that includes cleaning product formed during the synthesis by von Willebrand factor. Usually, type 3 disease both propeptide and von Willebrand factor antigen are generally absent or at deficient levels if present (Battle & Topez, 2009, 95). However, in the severe type 1 disease, there is a shallow level of the antigen, but the level of the propeptide is normal or reduced. In instances the von Willebrand factor antigen is measurable. This standard is regarded in relation to the ristocetin von Willebrand factor with the cofactor activity essay.
The proportional reduction in the von Willebrand factor ristocetin cofactor activity and von Willebrand factor antigen fits type 1 von Willebrand disease diagnosis. Disproportional reduction in von Willebrand factor ristocetin cofactor are compared with von Willebrand factor antigen, this indicates the presence of type 2 disease (Federici & Mannucci, 2005, 538). Additional striping tests, such as essays of von Willebrand factor multimeters and ristocetin-induced platelets aggression are supposed to determine the phenotypic characteristics that define type 2M, 2B, and 2A von Willebrand disease. Factor VIII activity is also measured as the first-line test6 because the level is reduced frequently in von Willebrand disease types. A reduction in factor VIII is more significant than the decrease in the von Willebrand factor antigen. Bellow than 0.2 % Willebrand factor antigen indicates that type 2N von Willebrand disease. This situation is confirmed by measuring the meshing of factor VIII and von Willebrand factor of ruling out milder hemophilia A.
The Von Willebrand disease disorder is diverse and is categorized into 3 major categories. Quantitative this includes Type 3 and 1 or qualitative which are type 2B, 2M, 2A, 2N, and the anormalities. Type 1 is differentiated simply from type 3 because of its severe inadequacy that ranges from 21-40 % of the autosomal dominant in the inheritance transmission and most of the mutation and mild bleeding manifestation bleeding (Castman & Lethagen, 2008, 3533). The level below 30% suggests the diagnostic of von Willebrand disease, while from 30-50% are regarded as low von Willebrand factor with major risk of mild bleeding. The type is related with total lack in von Willebrand factor at platelets and plasma. Type 3 victims 80% of them are null allege in the von Willebrand factor. The most people are compound heterozygous or homozygous. The type 2 von Willebrand diseases are autosomal dominant disorders having large intrusive and are as a result of missense mutations. Type 2N and 3 are the inheritable manners in an autosomal recessive.
Von Willebrand is mostly milder in type 1 and severity increases in type 3 and 2. The gravity of the likelihood in bleeding is equal to a deficiency at the primary level of the von Willebrand factor and secondary lack of FVIII. Mucocutaneous bleeding is an eminent and typical manifestation of disease and might influence the life quality. FVIII is mildly lowered and there is the rare manifestation of severe coagulation except in type 3 von Willebrand diseases. Bleeding after dental work is frequently found in bleeding postoperative manifestation. The bleeding after surgical work may occur to patients who are affected severely by type 1 & 2 diseases. Post-delivery bleeding is rare to see in type 1 because FVIII/VWF levels try to adjust at the last stage of pregnancy in the docile type 1 von Willebrand disease.
The type 1 von Willebrand disease is caused by an incomplete quantitative defect generated advanced clearance of von Willebrand factor or reduced secretion. Type 3 is a rare von Willebrand disease disorder with a complete absence of the von Willebrand factor. Type 2 von Willebrand disease is caused by obstruction of von Willebrand factor functioning and it is divided into various variants. Type 2A is due to lofty von Willebrand factor multimeters molecular weight in the plasma and von Willebrand factor reduced meshing to complex glycoprotein. Type 2B von Willebrand disease is indicated with an enhanced accord of von Willebrand factor, though the multimeter plasma distribution is normal. Type 2N von Willebrand disease is affliated with von Willebrand factor multimeter plasma normal distribution but has a reduced FVIII binding capacity.
The monitoring and progression of von Willebrand disease is hard because of its heterogeneity and thus requires laboratory tests panels. Screening essay balances the partial thromboplastin time, platelets function analyser and the bleeding time .essays diagnostic is the FVIII:C, the VWF:RCo, the VWF.Ag and the VWF: CB. The (RIPA) Ristocetin-induced platelets aggression and analysis metric are confirmatory tests. Von Willebrand factor functional essays are under the evaluation of the ability of protein interacting with platelets complex in ristocetin present and the ability of antibiotic to generate agglutination of platelets by VWF, VWF: Rco, and measures agglutination of induced ristocetin of the platelets formalin-fixed in the existence of patients plasma.RIPA assess ristocetin-induced agglutination in the platelets of the patients in the platelet-rich plasma. Also, RIPA is important in type 2B diagnosis.
The von Willebrand disease treatment is usually categorized into two sections which are adjunctive therapies that goals at providing an indirect hemostatic benefit. The treatments aim at increasing the VWF and FVIII of the plasma levels. Adjunctive therapies are used with important advantage in von Willebrand disease especially in situations such as the moments of dental procedures and minor surgeries, and the treatment of menorrhagia (Castman & Lethagen, 2008, 3533). The interventions such as the application of antifibrinolytic agents, for example, the tranexamic acid together with epsilon-aminocaproic acid and the introduction of topical hemostatic preparations that consists of the fibrin glue presence to the exposed site bleeding. However, women suffering menorrhagia hormonal therapy administration occurs inform of combined contraceptives or the progesterone that contains intrauterine systems for example Merina. Often these results have a lot of benefits. Moreover, the iron store replacement in an individual suffering iron deficiency can lead to improved quality of life.
To raise von Willebrand factor and factor VIII instantly to people having von Willebrand disease two approaches are extensively utilized. These approaches are the parental administration of desmopressin and infusing of the plasma-derived factor VIII/ von Willebrand factor concentration. Desmopressin usually is analog synthetic of an antidiuretic hormone vasopressin. More than 25 years treating von Willebrand disease, subcutaneous, intravenous and intranasal routes have been utilized extensively in the clinical experience with desmopressin. Meanwhile, there have been the excellent grouping of the side effects of desmopressin. In many cases, they are seen as transient and are minor. A headache, facial flushing, and mild tachycardia do not occur frequently (Goodeve & Erkenboom, 2007, 117)). This is because some patients have been observed to feel lightheaded immediately after the administration.
Desmopressin plays a significant role in treating or preventing episodes of bleeding in patients having type 2A, 1, 2N, and 2M von Willebrand disease. However, it is not active 3 patients as the thrombocytopenia maybe exacerbate and this rarely occurs in people with type 2B von Willebrand disease. Meanwhile, regarding the unpredictable nature of desmopressin response, persons with von Willebrand disease must go through a therapeutic trial of administration to diagnose the response status in an individual. The approach of treatment can be applied to prevent bleeding related to dental procedures and minor injuries and also in the treatment of severe menstrual bleeding (Tossetto & Rodeghera, 2006, 768). However, if there is required repeated administration in desmopressin, it should not happen daily. The subsequent procedure is likely to lead to a reduced response.
Patients whose desmopressin is contraindicated or ineffective or there are situations where it linked with a major risk of significant bleeding, and the hemostatic duration support required lasts more than 2-3 days. Through the coagulation of the plasma-derived concentrates the Factor VIII and levels of von Willebrand factor regains. Due to lack of ability to inactivate cryoprecipitate and absence of any licensed recombinant von Willebrand factor concentrate has led an extensive application of several plasmas derived factor VIII products von Willebrand factor (Rodeghiero& Castman, 2005, 2669).
Substitution therapy is another method of treating this disease and consists of infusing of ready of concentrated blood-clotting factors containing factor VIII and von Willebrand factor. These therapies can be applied to all types of diseases. This can is recommended when the DDAVP is not an option or it was not effective. Another replacement therapy for treating adults who are 18 years and beyond is genetically engineered von Willebrand factor product. This is because the recombinant factor made in the absence of plasma might reduce the risk of allergies reaction or infection.
Contraceptives in women can be important in regulating heavy bleeding at the menstrual bleeding. The estrogen can boost the von Willebrand factor and factor VIII activity. However, it is usually done control birth and further study is required. Also, there are closing-stabilizing medications. They include anti-fibrinolytic medicines like aminocaproic acid and the tranexamic acid. These medications can assist to deter bleeding by reducing the breaking down of blood clots. The drugs are prescribed before and after tooth extraction and surgical work.
Von will brand disease is the more well-known bleeding disorder. In an investigation case study was conducted in the von Willebrand diagnosis in the developing countries had several findings. The aim of the case investigation was to establish whether von Willebrand is still a major threat to developing as it is in the western countries. These data was as a result of the laboratory. The following data concerning the information gathered in the laboratory test on individuals are as follows.
Laboratory finding related with various types of von Willebrand disease.
|
Type 1 |
Type 2A |
Type 3 |
Type 2M |
Type 2B |
Type 2N |
|
|
VWF: Ag |
↓ or ↓ ↓ |
absent (<0.06 U/mL) |
↓ |
↓ |
↓ |
normal or ↓ |
|
Multimers |
↓ or ↓ ↓ |
absent (<0.04 U/mL) |
↓ ↓ or ↓↓↓ |
↓ ↓ |
↓ ↓ |
normal or ↓ |
|
VWF:RCo / VWF:Ag ratio |
normal or ↓ |
0.01-0.08U/mL |
normal or ↓ |
normal or ↓ |
normal or ↓ |
↓ ↓ or ↓↓↓ |
|
VWF:RCo / VWF:Ag ratio FVIII:C |
>0.5 |
not used |
<0.5 |
<0.5 |
<0.5 |
<0.4 |
|
VWF: RCo |
normal |
Not present |
loss of high molecular weight multimers |
high molecular weight multimers loss |
Normal |
normal |
Also, assessment of von Willebrand related disorders were conducted. The prevalence of the disease was as follows.
|
Clinical spectrum |
Count |
Percentage |
|
Gum bleeding |
22 |
30.7 |
|
Circumcision |
16 |
25.1 |
|
Hematoma |
16 |
25.2 |
|
Menorrhagia |
14 |
22.1 |
|
Bleeding after trauma |
13 |
18.1 |
|
Hemarthrosis |
11 |
19.1 |
|
Bruises |
04 |
14.7 |
|
Hematuria |
03 |
4.4 |
|
Epistaxis |
02 |
2.9 |
|
Umbilical cord bleeding |
03 |
4.4 |
The bleeding disorders incidences vary according to ethnic origin and country. The research illustrated that von Willebrand is the frequent inherited disorder in western countries. Meanwhile, the studies conducted in India and Iran reported the low prevalence on von Willebrand factors. There is a broad spectrum of clinical characteristics of bleeding on the people in which the research was conducted. The data also outlined that women had a high prevalence of menorrhagia all population at general.
It is essential to point out that new pathological insights in the past decades have emerged into von Willebrand disease treatment and diagnostic approaches. Meanwhile, this can be further improved by introducing more reproducible and rapid assays of von Willebrand factor function. The mutation identification in von Willebrand factor will be facilitated by sequencing. More use of prophylactic treatment for patients who are affected severely patients is warranted, considering the beneficial effects reported. A further study is needed because there is low information in the finite in the countries that are developing. This will, in turn, assist accurate diagnosis of bleeding disorders thus proper treatment and management.
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