Von Willebrand disease
Encyclopedia
von Willebrand disease (vWD) is the most common hereditary coagulation
abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor
(vWF), a multimeric
protein that is required for platelet
adhesion. It is known to affect humans and dogs (notably Doberman Pinschers), and rarely in swine, cattle, horses, and cats. There are three forms of vWD, inherited, acquired and pseudo or platelet type. There are three types of hereditary vWD, vWD Type I, vWD Type II and vWD III. Within the three inherited types of vWD there are various subtypes. Platelet type vWD is also an inherited condition.
vWD Type I is the most common type of the disorder and those that have it are typically asymptomatic
or may experience mild symptoms such as epistaxis although there may be severe symptoms in some cases. There are various factors that affect the presentation and severity of symptoms of vWD such as blood type.
vWD is named
after Erik Adolf von Willebrand
, a Finnish
pediatrician who first described the disease in 1926.
and blood loss during childbirth
.
Severe internal
or joint bleeding
is uncommon (which mostly occurs in type 3 vWD).
of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a glycoprotein
(GP)Ib binding assay, a collagen
binding assay or, a ristocetin
cofactor activity (RiCof) or ristocetin induced platelet agglutination
(RIPA) assays. Factor VIII
levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most medical laboratories
. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay
(PFA) will give an abnormal collagen/adrenaline closure time and in most cases (but not all) a normal collagen/ADP
time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection
, pregnancy
and stress
.
Other tests performed in any patient with bleeding problems are a complete blood count
(especially platelet
counts), APTT (activated partial thromboplastin time), prothrombin time
, thrombin
time and fibrinogen
level. Testing for factor IX
may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.
The testing for vWD can be influenced by laboratory procedures. There are numerous variables in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted out to an outside facility and the specimen is frozen and transported long distances.Diagnostic errors are not uncommon, and there is a varying rate of testing proficiency amongst laboratories with error rates ranging from 7% to 22% in some studies to as high as 60% in cases of misclassification of vWD sub-type. To increase the probability of a proper diagnosis testing should be done at a facility with immediate on-site processing in their own specialized coagulation laboratory.
's (ISTH) classification depends on the definition of qualitative and quantitative defects.
Many patients are asymptomatic or may have mild symptoms and not have clearly impaired clotting
which might suggest a bleeding disorder. Often times the discovery of vWD occurs incidentally
to other medical procedures requiring a blood work-up. Most cases of Type 1 vWD are never diagnosed due to the asymptomatic or mild presentation of Type I and most people usually end up leading a normal life free of complications many unaware they have the disorder.
Trouble may however arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia
(heavy periods
). There are also a minority of cases of Type I which may present with severe symptoms.
may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.
but a pedigree suggesting autosomal, rather than X-linked, inheritance.
that they have occasional hemarthroses
(joint bleeding), as in cases of mild hemophilia.
. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
A form of vWD occurs in patients with aortic valve stenosis
, leading to gastrointestinal bleeding
(Heyde's syndrome
). This form of acquired vWD may be more prevalent than is presently thought. In 2003 Vincentelli et. al noted that patients with acquired vWD and aortic stenosis who underwent valve replacement experienced a correction of their hemostatic abnormalities but that the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match with the patient.
Thrombocythemia is another cause of acquired von Willebrand disease, due to sequestration of von Willebrand factor via the adhesion of vast numbers of platelet
s.
Acquired vWD has also been described in the following disorders: Wilms' tumour
, hypothyroidism
and mesenchymal dysplasias.
. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract
and the uterus
. In angiodysplasia
, a form of telangiectasia
of the colon
, shear stress is much higher than in average capillaries
, and the risk of bleeding is increased concomitantly.
In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant
. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology
in addition to polymorphism
s of the vWF gene alone. The individual's ABO blood group
can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.
The vWF gene is located on chromosome twelve
(12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.
of vWD is about 1 in 100 individuals. However the majority of these people do not have symptoms. The prevalence of clinically significant cases is 1 per 10,000. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation
. It may be more severe or apparent in people with blood type
O.
concentrates complexed to vWF (antihemophilic factor, more commonly known as Humate-P) Mild cases of vWD can be trialled on desmopressin
(1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, Stimate), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies
in the endothelial cells.
In the 1950s, it became clear that a "plasma factor," antihemophilic factor (FVIII), was decreased in these persons and that Cohn fraction I-0 could correct both the plasma deficiency of FVIII and the prolonged bleeding time. Since this time, the factor causing the long bleeding time was called "von Willebrand factor" in honor of Dr. Erick von Willebrand.
Variant forms of VWF were recognized in the 1970s, and we now recognize that these variations are the result of synthesis of an abnormal protein.
During the 1980s, molecular and cellular studies distinguished hemophilia A and vWD more precisely. Persons who had vWD had a normal FVIII gene on the X chromosome, and some had an abnormal vWF gene on chromosome 12. Gene sequencing identified many of these persons as having a vWF gene mutation. The genetic causes of milder forms of low vWF are still under investigation, and these forms may not always be caused by an abnormal vWF gene.
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor
Von Willebrand factor
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...
(vWF), a multimeric
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
protein that is required for platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
adhesion. It is known to affect humans and dogs (notably Doberman Pinschers), and rarely in swine, cattle, horses, and cats. There are three forms of vWD, inherited, acquired and pseudo or platelet type. There are three types of hereditary vWD, vWD Type I, vWD Type II and vWD III. Within the three inherited types of vWD there are various subtypes. Platelet type vWD is also an inherited condition.
vWD Type I is the most common type of the disorder and those that have it are typically asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
or may experience mild symptoms such as epistaxis although there may be severe symptoms in some cases. There are various factors that affect the presentation and severity of symptoms of vWD such as blood type.
vWD is named
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
after Erik Adolf von Willebrand
Erik Adolf von Willebrand
Erik Adolf von Willebrand was an internist from Finland.The son of a district engineer in Vaasa, von Willebrand got his medical degree in the University of Helsinki. He graduated in 1896, and did his doctoral thesis on the changes that occurred in blood following significant blood loss...
, a Finnish
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
pediatrician who first described the disease in 1926.
Signs and symptoms
The various types of vWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual periodsMenorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
and blood loss during childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
.
Severe internal
Internal bleeding
Internal bleeding is bleeding occurring inside the body. It can be a serious medical emergency depending on where it occurs , and can potentially cause death and cardiac arrest if proper medical treatment is not received quickly....
or joint bleeding
Hemarthrosis
Hemarthrosis is a bleeding into joint spaces.-Causes:It usually follows injury but occurs mainly in patients with a predisposition to hemorrhage such as those being treated with warfarin and patients with hemophilia.It can be associated with knee joint arthroplasty.-Treatment:In hemophilia it may...
is uncommon (which mostly occurs in type 3 vWD).
Diagnosis
When suspected, blood plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
(GP)Ib binding assay, a collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
binding assay or, a ristocetin
Ristocetin
Ristocetin is an antibiotic, obtained from Amycolatopsis lurida, previously used to treat staphylococcal infections. It is no longer used clinically because it caused thrombocytopenia and platelet agglutination. It is now used solely to assay those functions in vitro in the diagnosis of conditions...
cofactor activity (RiCof) or ristocetin induced platelet agglutination
Ristocetin induced platelet agglutination
The ristocetin induced platelet aggregation is an in vitro assay for von Willebrand factor activity used to diagnose von Willebrand disease. It has the benefit over the ristocetin cofactor activity in that it can diagnose type 2B vWD and Bernard-Soulier syndrome.In an unknown fashion, the...
(RIPA) assays. Factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most medical laboratories
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...
. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay
PFA-100
The PFA-100 is a platelet function analyser that aspirates blood in vitro from a blood specimen into disposable test cartridges through a microscopic aperture cut into a biologically active membrane at the end of a capillary...
(PFA) will give an abnormal collagen/adrenaline closure time and in most cases (but not all) a normal collagen/ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
.
Other tests performed in any patient with bleeding problems are a complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(especially platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
counts), APTT (activated partial thromboplastin time), prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
, thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
time and fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
level. Testing for factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.
The testing for vWD can be influenced by laboratory procedures. There are numerous variables in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted out to an outside facility and the specimen is frozen and transported long distances.Diagnostic errors are not uncommon, and there is a varying rate of testing proficiency amongst laboratories with error rates ranging from 7% to 22% in some studies to as high as 60% in cases of misclassification of vWD sub-type. To increase the probability of a proper diagnosis testing should be done at a facility with immediate on-site processing in their own specialized coagulation laboratory.
Classification
There are inherited and acquired forms of vWD. The four hereditary types of vWD described are - type 1, type 2, type 3, and pseudo or platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and HaemostasisInternational Society on Thrombosis and Haemostasis
The International Society on Thrombosis and Haemostasis is a body of experts in the field of blood coagulation and its disorders, such as thrombosis and hemophilia. Founded in 1969, it currently has about 3000 members worldwide...
's (ISTH) classification depends on the definition of qualitative and quantitative defects.
Type 1
Type 1 vWD (60-80% of all vWD cases) is a quantitative defect which is heterozygous for the defective gene. Decreased levels of vWF are detected at 10-45% of normal, i.e. 10-45 IU.Many patients are asymptomatic or may have mild symptoms and not have clearly impaired clotting
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
which might suggest a bleeding disorder. Often times the discovery of vWD occurs incidentally
Incidental findings
Incidental findings are previously undiagnosed medical or psychiatric conditions that are discovered unintentionally and are unrelated to the current medical or psychiatric condition which is being treated or tests being performed...
to other medical procedures requiring a blood work-up. Most cases of Type 1 vWD are never diagnosed due to the asymptomatic or mild presentation of Type I and most people usually end up leading a normal life free of complications many unaware they have the disorder.
Trouble may however arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia
Menorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
(heavy periods
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
). There are also a minority of cases of Type I which may present with severe symptoms.
Type 2
Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Four subtypes exist: 2A, 2B, 2M and 2N.Type 2A
This is an abnormality of the synthesis or proteolysis of the vWF multimers resulting in the presence of small multimer units in circulation. Factor VIII binding is normal. It has a disproportionately low ristocetin co-factor activity compared to the von Willebrand's antigen.Type 2B
This is a "gain of function" defect leading to spontaneous binding to platelets and subsequent rapid clearance of the platelets and the large vWF multimers. A mild thrombocytopeniaThrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.
Type 2M
Type 2M von willebrands disease is a qualitative deficit in von Willebrand factor. Normal antigen levels are seen, decreased function is observed (reduced RICOF) and, differentiating it from 2A, the functional deficit is not a result of an absence of high molecular weight multimers.Type 2N (Normandy)
This is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably led to some 2N patients being misdiagnosed in the past as having hemophilia A, and should be suspected if the patient has the clinical findings of hemophilia AHaemophilia A
Haemophilia A is a deficiency in clotting factor VIII.Haemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild haemophilia A has been described in heterozygous females, presumably due to extremely unfavourable lyonization...
but a pedigree suggesting autosomal, rather than X-linked, inheritance.
Type 3
Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIIIFactor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
that they have occasional hemarthroses
Hemarthrosis
Hemarthrosis is a bleeding into joint spaces.-Causes:It usually follows injury but occurs mainly in patients with a predisposition to hemorrhage such as those being treated with warfarin and patients with hemophilia.It can be associated with knee joint arthroplasty.-Treatment:In hemophilia it may...
(joint bleeding), as in cases of mild hemophilia.
Platelet-type
(also known as pseudo-vWD or platelet-type [pseudo] vWD) Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor (GPIb). This protein is part of the larger complex (GPIb/V/IX) which forms the full vWF receptor on platelets. The ristocetin activity and loss of large vWF multimers is similar to type 2B, but genetic testing of vWF will reveal no mutations.Acquired von Willebrand disease
Acquired vWD can occur in patients with autoantibodiesAutoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
A form of vWD occurs in patients with aortic valve stenosis
Aortic valve stenosis
Aortic valve stenosis is a disease of the heart valves in which the opening of the aortic valve is narrowed. The aortic valve is the valve between the left ventricle of the heart and the aorta, which is the largest artery in the body and carries the entire output of blood.-Pathophysiology:The...
, leading to gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...
(Heyde's syndrome
Heyde's syndrome
Heyde's syndrome is a syndrome of aortic valve stenosis associated with gastrointestinal bleeding from colonic angiodysplasia. It is named after Dr. Edward C. Heyde, who first described the association in 1958...
). This form of acquired vWD may be more prevalent than is presently thought. In 2003 Vincentelli et. al noted that patients with acquired vWD and aortic stenosis who underwent valve replacement experienced a correction of their hemostatic abnormalities but that the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match with the patient.
Thrombocythemia is another cause of acquired von Willebrand disease, due to sequestration of von Willebrand factor via the adhesion of vast numbers of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s.
Acquired vWD has also been described in the following disorders: Wilms' tumour
Wilms' tumor
Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon who first described this kind of tumor....
, hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
and mesenchymal dysplasias.
Pathophysiology
vWF is mainly active in conditions of high blood flow and shear stressShear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...
. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
and the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
. In angiodysplasia
Angiodysplasia
In medicine , angiodysplasia is a small vascular malformation of the gut. It is a common cause of otherwise unexplained gastrointestinal bleeding and anemia. Lesions are often multiple, and frequently involve the cecum or ascending colon, although they can occur at other places...
, a form of telangiectasia
Telangiectasia
Telangiectasias /tɛ.læn.dʒiː'ɛk.teɪ.ʃi:ə/ are small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. They can develop anywhere on the body but are commonly seen on the face around the nose, cheeks, and chin...
of the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, shear stress is much higher than in average capillaries
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
, and the risk of bleeding is increased concomitantly.
In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
in addition to polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
s of the vWF gene alone. The individual's ABO blood group
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.
Genetics
Chromosome 12 (human)
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 143 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
(12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.
Epidemiology
The prevalencePrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of vWD is about 1 in 100 individuals. However the majority of these people do not have symptoms. The prevalence of clinically significant cases is 1 per 10,000. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
. It may be more severe or apparent in people with blood type
Blood type
A blood type is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells . These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system...
O.
Therapy
Patients with vWD normally require no regular treatment, although they are always at increased risk for bleeding. For women with heavy menstrual bleeding, the combined oral contraceptive pill may be effective in reducing bleeding or in reducing the length or frequency of periods. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity factor VIIIFactor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
concentrates complexed to vWF (antihemophilic factor, more commonly known as Humate-P) Mild cases of vWD can be trialled on desmopressin
Desmopressin
Desmopressin is a synthetic replacement for vasopressin, the hormone that reduces urine production. It may be taken nasally, intravenously, or as a tablet...
(1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, Stimate), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies
Weibel-Palade body
Weibel-Palade bodies are the storage granules of endothelial cells, the cells that form the inner lining of the blood vessels and heart. They store and release two principal molecules, von Willebrand factor and P-selectin, and thus play a dual role in hemostasis and inflammation...
in the endothelial cells.
History
In 1924, a 5-year-old girl who lived on the Åland Islands was brought to Deaconess Hospital in Helsinki, Finland, where she was seen by Dr. Erik von Willebrand. He ultimately assessed 66 members of her family and reported in 1926 that this was a previously undescribed bleeding disorder that differed from hemophilia. Dr von Willebrand recognized the autosomal inheritance pattern, and noted that the bleeding symptoms were greater in children and in women of childbearing age. Thus, he stated that patients with this syndrome had (1) mucocutaneous bleeding, (2) normal clotting time, (3) autosomal inheritance rather than being linked to the X chromosome, and (4) prolonged bleeding times by the Duke method (ear lobe bleeding time). He subsequently found that blood transfusions were useful not only to correct the anemia but also to control bleeding.In the 1950s, it became clear that a "plasma factor," antihemophilic factor (FVIII), was decreased in these persons and that Cohn fraction I-0 could correct both the plasma deficiency of FVIII and the prolonged bleeding time. Since this time, the factor causing the long bleeding time was called "von Willebrand factor" in honor of Dr. Erick von Willebrand.
Variant forms of VWF were recognized in the 1970s, and we now recognize that these variations are the result of synthesis of an abnormal protein.
During the 1980s, molecular and cellular studies distinguished hemophilia A and vWD more precisely. Persons who had vWD had a normal FVIII gene on the X chromosome, and some had an abnormal vWF gene on chromosome 12. Gene sequencing identified many of these persons as having a vWF gene mutation. The genetic causes of milder forms of low vWF are still under investigation, and these forms may not always be caused by an abnormal vWF gene.
Sources
- Harrison's textbook of Internal Medicine, Chapter 177.
- Williams Hematology, 7th edition, Grune and Stratton, chapters112 (p. 1806) and118 (p. 1937)
See also
- Bernard-Soulier syndromeBernard-Soulier syndromeBernard–Soulier syndrome , also called hemorrhagiparous thrombocytic dystrophy, is a rare autosomal recessive coagulopathy that causes a deficiency of glycoprotein Ib , the receptor for von Willebrand factor, which is important in clot formation.The incidence is estimated to be less than 1 in 1...
, caused by a deficiency in the vWF receptor, GPIb - Blood diseases
- Purpura secondary to clotting disordersPurpura secondary to clotting disordersPurpura secondary to clotting disorders are purpura which occur due to hereditary disorders of blood coagulation in which there is a deficiency or qualitative abnormality of a single coagulation factor, as in hemophilia or von Willebrand's disease....
External links
- GeneReviews/NCBI/NIH/UW entry on von Willebrand Disease
- Sheffield.ac.uk, International repository on vWF mutations (University of SheffieldUniversity of SheffieldThe University of Sheffield is a research university based in the city of Sheffield in South Yorkshire, England. It is one of the original 'red brick' universities and is a member of the Russell Group of leading research intensive universities...
) - Hemophilia.org
- Haemophilia.org.uk
- WFH.org, World Federation of Hemophilia
- Ukhcdo.org UK Haemophilia Centre Directors Organisation
- NIH.gov, Clinical Practice Guidelines by the U.S. National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood InstituteThe National Heart, Lung, and Blood Institute is a division of the National Institutes of Health, located in Bethesda, Maryland...