Introduction to von Willebrand Disease..and Other Coagulation Disorders.

The bleeding disorder now called haemophilia A or factor VIII deficiency has been known since biblical times. Physicians referred to it in medical literature in 1793. Haemophilia B or factor IX deficiency, on the other hand, was not recognized as a distinct entity until 1952. It is now known account for 20% of all cases of haemophilia. At least eight other coagulation disorders have been identified, most of them in the 20th century and some only within the past 25 years

Von Willebrand Disease

It may surprise some in the haemophilia community to learn than von Willebrand’s disease is believed to be the most common inherited bleeding disorder in humans, estimated to occur in up to 3% of the population. It was first described in 1926 by Erik von Willebrand, a Finnish physician, who reported a new type of bleeding disorder among the inhabitants of some islands between Sweden and Finland. Von Willebrand observed that these patients had an abnormality in their blood platelet function. Years later it was found that some people with von Willebrand’s disease also have a low level of factor VIII.

What is the most common inherited bleeding disorder, the one that affects many millions of people around the world?

You may be surprised to hear that it is not haemophilia. It is von Willebrand disease, a related disorder that few people have heard of, unless they have it or know someone who does.

Why is such a common illness such a secret? Perhaps because the disease is usually less severe than haemophilia, it has not generated the kind of publicity, educational efforts and support that other chronic illnesses have. In fact, it is often so mild, it is not diagnosed at all. Some people live with the disease for many years before getting an accurate diagnosis. For more severely affected patients, this lack of knowledge has caused real suffering.

Fortunately, substantial progress has been made in recent years. The von Willebrand gene has been identified and research is underway to develop gene therapy. As research continues, however, the challenge continues to educate healthcare professionals and the public about this disorder. That is the best way to assure those with von Willebrand that they will receive proper diagnoses and treatment.

The Basics of von Willebrand

Von Willebrand disease is not a type of haemophilia. Like haemophilia, von Willebrand disease does make it difficult to stop bleeding when an injury occurs. But the two disorders have different causes, different symptoms an many cases, different patterns of inheritance and different treatments.

Normal In Haemophilia In von Willebrand
Bleeding starts Bleeding starts Bleeding starts
Step 1 Blood vessels constrict Blood vessels constrict Blood vessels constrict
Step 2 Platelet plug forms Platelet plug forms Incomplete platelet plug; bleeding continues
Step 3 Fibrin clot forms; bleeding stops Incomplete fribrin clot; bleeding continues Incomplete or delayed fibrin clot; bleeding continues
The factor that is missing or deficient in haemophilia (factor VIII in haemophilia A; factor IX in haemophilia B) is essential to the formation of a fibrin clot, the tough threads that hold the platelet plug in place. The factor that is missing, deficient or abnormal in von Willebrand disease, von Willebrand factor, is essential to the formation of the platelet plug itself.

While haemophilia affects a person’s ability to complete the final step in blood clot formation, von Willebrand disease affects an earlier step in the clotting process (see above box — “The Blood Clotting Process”).

Platelets are tiny particles in the blood that clump together at the site of the injury to prepare for the formation of a blood clot. Von Willebrand factor causes them to bind to areas of a blood vessel that are damaged. If there is too little von Willebrand factor, or the factor is defective, platelets do not gather properly when a blood vessel is injured.

Some people with von Willebrand disease also have too little factor VIII. This happens because the von Willebrand protein serves as a carrier for factor VIII and when there is too little von Willebrand factor, factor VIII may also be reduced. In people with haemophilia A, who have little or no factor VIII, the level of von Willebrand factor is usually normal.

Unlike people with haemophilia, most people with von Willebrand disease do not usually bleed into joints and muscles. Because it is a disorder of the platelets, von Willebrand disease causes what is called mucosal bleeding, or bleeding into mucous membranes of the mouth, nose, intestine or uterus. This can lead to nose bleeds, unusually heavy menstrual bleeding and internal (gastrointestinal) bleeding. The severity of symptoms varies among people with von Willebrand disease, even among family members. Although the type of disease does not change, the severity of symptoms can change throughout a person’s life.

Types of von Willebrand Disease

Researchers have identified many variations of the disease, but most fall into the following classifications:

Type I: Most common and mildest form of von Willebrand disease. Levels of von Willebrand factor are lower than normal. Levels of factor VIII may also be reduced.

Type II: In these people, the von Willebrand factor itself has an abnormality. Depending on the abnormality, they may be classified as having Type IIA or Type IIB. In Type IIA, the level of von Willebrand factor is reduced as is the ability of platelets to clump together. In Type IIB, although the factor itself is defective, the ability of platelets to clump together is actually increased.

Type III: Severe von Willebrand disease. These people may have a total absence of von Willebrand factor and factor VIII levels are often less than 10%.

Pseudo (or platelet-type) von Willebrand disease: This disorder resembles Type IIB von Willebrand disease, but the defects appears to be in the platelets, rather than the von Willebrand factor

An Equal Opportunity Disorder

This disease, like haemophilia, is passed down through the genes. Unlike haemophilia, however, which usually affects only males, von Willebrand disease occurs in men and women equally. A man or woman with the disease has a 50% chance of passing the gene on to his or her child (see box). Types I and II are usually inherited in what is known as a “dominant” pattern. This means that if even one parent has the gene and passes it onto a child, the child gets the disease. Whether the child has no symptoms, mild symptoms, or, less commonly, severe symptoms, he or she definitely has the disease. Regardless of the severity of the symptoms, the child can still pass the gene on to his or her own offspring.

Type III von Willebrand disease, however, is usually inherited in a “recessive” pattern. This type occurs when the child inherits the gene from both parents. Even if both parents have mild or asymptomatic disease, their children are likely to be severely affected.

These patterns of inheritance differ from that of haemophilia, which is caused by a defect in one of the “sex-linked” chromosomes. A man with haemophilia cannot pass the gene on to a son, because the abnormality is carried on the X chromosome, and a man contributes only a Y chromosome to his male offspring.

Research concerning the inheritance of von Willebrand disease is still underway to clarify a great deal of information that is not yet understood about the disease.

“Acquiring” von Willebrand Disease

Once in a while, people develop what appears to be von Willebrand disease later in life. When this occurs in those who have no family history of the disease, it is thought that they are probably producing antibodies that destroy or decrease the amount of von Willebrand factor. Some other people have “acquired” a form of the disease in association with another disorder, such as rheumatoid arthritis, systemic lupus erythematosus, kidney and certain cancers.

A Difficult Diagnosis

Despite progress in understanding this disorder, it is still sometimes difficult to diagnose. A physician may mistake its mild symptoms for those of other illnesses. For example, a woman with heavy menstrual bleeding might be advised to have a hysterectomy when the real cause of her disorder eventually proves to be von Willebrand disease. When a healtcare practitioner hears of recurrent nosebleeds, easy bruising, heavy menstrual periods, or longer than usual bleeding after such routine operations as tonsillectomy or tooth extraction, diagnostic tests should be performed to rule out the possibility of von Willebrand disease. Specific tests for von Willebrand factor must be conducted because people with a mild form of the disease may have normal results on the usual screening tests for bleeding disorders. The tests listed under section ‘Laboratory Tests for von Willebrand Disease‘ are considered the most useful.

Although the results of these tests can determine whether a person has von Willebrand disease, there are a few considerations that must be noted to make sure the diagnosis is correct. In certain situations, the amount of von Willebrand factor is temporarily increased; this could skew the results of laboratory tests. Examples include: newborns, people under stress (including a child who is crying), women who are pregnant or using birth control pills and individuals who have just had surgery or a blood transfusion. People who have recently taken aspirin or certain other medication can have an alteration in the function of their platelets. In these situations, laboratory tests may need to be repeated to assure the right diagnosis.

Various treatments are available for von Willebrand disease. Once a proper diagnosis has been made, the treating physician will decide whether therapy is required and, if so, will tailor the therapy to the case at hand.

Hemostasis / Platelets

In 1926, Erik von Willebrand, a Finnish internist, reported his studies of a family living on the Aland Islands, in the Gulf of Bothnia between Finland and Sweden. The proband was a 5-year-old girl with severe spontaneous bleeding. Three of her sisters had died before age 4 of severe bleeding. Both parents and many relatives had mild bleeding histories, and the disease clearly differed from both haemophilia and Glanzmann thrombasthenia. Severe disease was transmitted through males and females, among whom some were mildly symptomatic and others were asymptomatic. During the ensuing 70 years, our understanding of von Willebrand disease (VWD) has advanced to the point that we can discuss its pathogenesis in molecular detail. Nevertheless, VWD remains a clinical diagnostic problem for many of the reasons that were evident from the earliest reports. Chief among these are that no bleeding symptoms are specific for VWD, and heterozygous transmitters of VWD may be phenotypically normal. This presentation will consider the classification of VWD and some practical problems associated with its diagnosis.

Von Willebrand factor (VWF) is a large, multimeric protein that circulates in the blood plasma. VWF also is stored in granular of endothelial cells and platelets, and can be secreted from these sites in response to appropriate stimuli. VWF performs two major roles in hemostasis; it mediates the adhesion of platelets to sites of vascular injury, and it is a carrier protein for factor VIII. Defects in VWF, therefore, may cause bleeding by impairing either platelet adhesion or blood clotting.

This increasingly complex basic information has led to a simplified classification for VWD (Table 1). This includes three major categories: partial quantitative deficiency (type 1), qualitative deficiency (type 2), and total deficiency (type 3). Qualitative type 2 VWD is divided further into four variants – 2A, 2B, 2M, and 2N – based upon the nature of the phenotype. These six categories correspond to distinct pathophysiologic mechanisms with distinct clinical features and therapeutic requirements.

Classification of VWD
1. All VWD is caused by mutations at the VWF locus.
2. Type 1 VWD refers to partial quantitative deficiency of VWF.
Type 2 VWD refers to qualitative deficiency of VWF.
Type 3 VWD refers to virtually complete deficiency of VW
3. Type 2A VWD refers to qualitative variants with decreased platelet-dependent function that is associated with the absence of high-molecular-weight VWF multimers.
4. Type 2B VWD refers to qualitative variants with increased affinity for platelet GPIb..
5. Type 2M VWD refers to qualitative variants with decreased platelet-dependent function that is not caused by the absence of high-molecular-weight VWF multimers.
6. Type 2N VWD refers to qualitative variants with markedly decreased affinity for factor VIII.
7. When recognised, a mixed phenotype caused by compound heterozygosity is indicated by separate classification of each allele, separated by a slash (/).
8. For the description of mutations, numbering systems are suggested for amino acids and nucleotides.
Unlike haemophilia, von Willebrand disease is not gender-related. So the effect is the same regardless of whether the defective von Willebrand factor (vWF) is passed down from the mother or father. It also makes no difference whether the child is a boy or girl; the disease shows up in the same way.

If one parent has a defective gene: If both parents have a defective gene:
Each parent contributes one of his/her genes for vWF to his/her child. As shown, there are four possible genetic combinations than can result from this union./td> Again, there are four possible genetic combinations.
Odds: Odds:
2 out of 4 children (50%) will be genetically normal.
2 out of 4 children (50%) will have the defective vWF gene.
1 out of 4 children (25%) will be genetically normal.
2 out of 4 children (50%) will have one defective vWF gene.
1 out of 4 children (25%) will have two defective vWF genes, which will result in severe von Willebrand disease.
gene AA gene BB
gene C Von Willebrand types I and II have a “dominant” inheritance pattern.
That means that in a child with one normal gene and one gene for either of these von Willebrand types, the defective gene in “stronger. So the child will actually have the disease.
gene C Von Willebrand type III has a recessive inheritance pattern.
In a child with one normal gene and one gene for von Willebrand type III, the defective gene is “weaker”, so the child will be a carrier for the disease, but will not have it.
gene D In order to have von Willebrand type III, the child must have two genes for the disease.

Bleeding time

How long does it take to stop bleeding? This finding is related to both the number and function of platelets and the amount of von Willebrand factor.

Factor VIII clotting activity

This measurement, which is low or nonexistent in people with haemophilia A, is usually normal or only slightly lowered in people with von Willebrand disease. The measurement takes into account not just the level of Factor VIII, but also its ability to function.

vWF antigen

This measures the amount of von Willebrand factor. Those with mild disease usually have 25-35% of the normal amount. Those with severe disease have less than 5%. A person’s blood type may affects these levels.

Ristocetin cofactor activity

A measurement of how well the von Willebrand factor is working.

vWF multimers

Evaluates the structure of the von Willebrand factor molecule. Helps in correctly classifying the type of von Willebrand disease.

Platelet function tests

Measure how well platelets work. Helps identify the type of von Willebrand disease or other disorder.

Included under this heading are several rare coagulation disorders known as congenital fibrinogen defects. They include afibrinogenemia and hypofibrinogenemia, and dysfibrinogenemia. The first two are called quantitative abnormalities because they have to do with an absent or low quantity of fibrinogen. The third is called a qualitative abnormality because the fibrinogen does not work well.

Fibrinogen, also known as Factor I, is needed for most types of platelet aggregation. People who have a Factor I deficiency have a combined bleeding disorder, meaning that both platelets and clotting are abnormal. Afibrinogenemia is the complete absence of fibrinogen. Hypofibrinogenemia is a low level of fibrinogen – less than 100mg in 1dL of blood. Both conditions are inherited in an autosomal fashion and can affect males and females.

The severity of the disorder is related to the amount of fibrinogen. Afibrinogenemia is usually discovered in newborns and can cause bleeding from the umbilical cord, genitourinary tract, or central nervous system. People with hypofibrinogenemia may have little, moderate, or severe bleeding.

Dysfibrinogenemias are due to variations in the Factor I molecule. More than 70 different types of dysfibrinogenemia have been identified. Few people who have any of these disorders suffer symptoms, although some are predisposed to form blood clots (thrombosis).

Many people with hypofibrinogenemia or dysfibrinogenemia need no treatment. Those who require treatment may be given cryoprecipitate or fresh frozen plasma. Anticoagulants are sometimes prescribed to reduce the risk of thrombosis.

Only 30 cases of this hereditary clotting factor defect have been identified in the whole world. It may take the form of a deficiency of prothrombin or an abnormal Factor II molecule. Either form may lead to severe bruising, excessive menstrual bleeding, postoperative hemorrhage, and occasionally muscle hematomas.

Mild cases may be treated with plasma infusion. Severe Factor II deficiencies may be treated with prothrombin complex concentrates (PCCs).

Factor V deficiency is also known as Owren’s disease or parahaemophilia. This deficit was identified in Norway in 1943. Since then about 150 cases have been reported, occurring in both men and women.

The role of Factor V is to accelerate the activity of thrombin. When levels of Factor V are low, clotting is delayed or progresses slowly. People with this deficiency may have occasional nosebleeds, excessive menstrual bleeding, and bruising, although many have no symptoms. The first sign of this condition may be bleeding following surgery. The treatment is administration of fresh frozen plasma is not given because Factor V deteriorates rapidly.

Factor V deficiency has to be distinguished from a combined deficiency of Factors V and VIII, which is entirely separate disorder.

This disorder is rare, occurring in one in 500,000 males and females. Diagnosis is made by testing for Factor VII in the blood. Congenital Factor VII deficiency should be distinguished from acquired Factor VII deficiency that may result from liver disease, vitamin K deficiency, or other malabsorption conditions.

When levels of the factor are less than 1% of normal, bleeding can be severe. The trauma of birth may cause bleeding in the head of a newborn. Circumcision may cause heavy bleeding. Children and adults may suffer bleeding from nose, gums, or gastrointestinal tract, and women may suffer excessive menstrual bleeding.

Severe bleeding may be treated with fresh frozen plasma or PCCs. Because the half-life of infused Factor VII is very short, patients may require treatment every 4 or 6 hours for severe bleeding or surgery.

Factor X deficiency ranks with Factor II as one of the rarest inherited clotting disorders, with only about 50 reported cases. Some cases are due to reduced or absent synthesis of the molecule; in other cases, the number of molecules is normal, but they don’t work properly. Several genetic variations of Factor X deficiency of varying severity have been described.

People with factor activity that is less than 1% of normal are susceptible to severe bleeding; those with 10% or more are only mildly affected. Symptoms include frequent bruising, gastrointestinal bleeding, and nosebleeds. Muscle and intracranial bleeding may be severe. Women with Factor X deficiency may have excessive menstrual bleeding and are susceptible to first-trimester miscarriage. Bleeding episodes are usually managed by infusion of fresh frozen plasma or PCCs.

This hereditary disorder occurs primarily in Jews of eastern European ancestry, resumably because intermarriage within this closed group, generation after generation, allowed the defective gene to surface more frequently. In the United States, for example, most cases are found in New York and Los Angeles. Approximately 200 cases of Factor XI deficiency have been reported since it was identified in 1953.

Most patients with Factor XI deficiency have little or no bleeding. Often there is no correlation between bleeding episodes and the level of factor.

If you have factor XI deficiency, chances are your symptoms are milder than those of either haemophilia A or haemophilia B and there may be no strong relationship between your factor XI levels and bleeding complications. You may be prone to bruising, nose-bleeds, or blood in your urine. Prolonged bleeding after childbirth can occur. But you are not likely to bleed spontaneously, and haemorrhage is usually a problem only after an injury or surgery. Joint bleeds are uncommon, but delayed bleeding (starting an unexpectedly long time after an injury) may be a problem.

A hallmark of this rare inherited deficiency is poor wound healing and abnormal scar formation. The reason is that Factor XIII – fibrin stabilisation factor – is necessary for clot formation and wound healing.

The most common clinical symptom, seen in over 80% of cases, is bleeding from umbilical stump after birth. Bleeding episodes are usually lifelong and include severe bruising, hematomas, and prolonged bleeding after trauma. Characteristically, bleeding is delayed for several hours or days after trauma. Haemorrhage into the brain or spinal cord area is more common than in other inherited coagulation disorders and can be life-threatening. Plasma replacement is given to pregnant women to prevent spontaneous abortions.

Deficiency of Factor XIII can be corrected with infusions of fresh frozen plasma or factor XIII concentrates. Because of the high incidence of intracranial bleeding and spontaneous abortions, prophylaxis is often recommended.

Antifibrinolytic Inhibiting the breakdown of fibrin, the blood component that forms the essential portion of a blood clot
Autosomal Relating to any chromosome that is not a sex chromosome
Afibrinogenemia The absence of fibrinogen from the blood
Coagulopathy A disorder that prevents normal clotting of the blood
Dysfibrinogenemiac Malfunction of fibrinogen in the blood
Fibrinogen Factor I, a protein in the blood that is converted to fibrin by the action of thrombin
Glycoprotein A protein compound that also contains carbohydrate
Hypofibrinogenemia A low or deficient level of fibrinogen in the blood
Platelet A component of blood that contributes to coagulation
Prothrombin Factor II, a protein in the blood that is converted to thrombin in the coagulation process
Thrombin An enzyme derived from prothrombin that converts fibrinogen to fibrin