- Hemophilia is a group of hereditary genetic disorders that impair the body’s ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Hemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births. Hemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births.
- Like most recessive sex-linked, X chromosome disorders, hemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and hemophilia is rare, the chance of a female having two defective copies of the gene is very remote, so females are almost exclusively asymptomatic carriers of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Although it is not impossible for a female to have hemophilia, it is unusual: a female with hemophilia A or B would have to be the daughter of both a male hemophiliac and a female carrier.
- Hemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A hemophiliac does not bleed more intensely than a person without it, but can bleed for a much longer time. In severe hemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.
Complications of Hemophilia
Severe complications are much more common in severe and moderate hemophiliacs. Complications may be both directly from the disease or from its treatment:
- Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
- Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
- Transfusion transmitted infection from blood transfusions that are given as treatment.
- Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
- Intracranial hemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.
Management of Hemophilia
Commercially produced factor concentrates such as “Kogenate”, “Advate”, or “Benefix”, a recombinant Factor VIII and IX, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection.
Though there is no cure for hemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in hemophilia A or factor IX in hemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some hemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.
If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII (NovoSeven), which is registered for this indication in many countries.
In early 2008, the US Food and Drug Administration (FDA) approved Xyntha (Wyeth) anti-hemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 (Dr. Mary Nugent) recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.
In Western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with hemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin. This study resulted in the first (October 2008) FDA approval to label any Factor VIII product to be used prophylactically. As a result, the factor product used in the study (Bayer’s Kognate) is now labelled for use to prevent bleeds, making it more likely that insurance carriers in the US will reimburse consumers who are prescribed and use this product prophylactically. Despite Kognate only recently being “approved” for this use in the US, it and other factor products have been well studied and are often prescribed to treat Hemophilia prophylactically to prevent bleeds, especially joint bleeds.
On 10 December 2011, a team of British and American investigators reported the successful treatment of hemophilia B using gene therapy. The investigators inserted the F9 gene into an adeno-associated virus-8 vector, which has a propensity for the liver, where factor 9 is produced, and remains outside the chromosomes so as not to disrupt other genes. The transduced virus was infused intravenously. To prevent rejection, the patients were primed with steroids to suppress their immune response.
It is recommended that people affected with hemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles. Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems. Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.
While not a replacement for traditional treatments, preliminary scientific studies indicate that hypnosis and self-hypnosis may be effective at reducing bleeds and the severity of bleeds and thus the frequency of factor treatment. Herbs which strengthen blood vessels and act as astringents may benefit patients with hemophilia, however there are no peer reviewed scientific studies to support these claims.
Anticoagulants such as Heparin and Warfarin are contraindicated for people with hemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have “blood thinning” side effects. For instance, medications which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.
Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugbyshould be avoided by people with hemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.
Von Willebrand Disease
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 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 nosebleeds 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.
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 periods and blood loss during childbirth.
Severe internal or joint bleeding is uncommon (which mostly occurs in type 3 vWD).
The prevalence 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.
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 VIII concentrates complexed to vWF (antihemophilic factor, more commonly known as Humate-P). Mild cases of vWD can be trialled ondesmopressin (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 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.
Classification and types
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 Haemostasis’s (ISTH) classification depends on the definition of qualitative and quantitative defects.
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 which might suggest a bleeding disorder. Oftentimes 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.
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.
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.
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 thrombocytopenia 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 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 A but a pedigree suggesting autosomal, rather than X-linked, inheritance.
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 VIII that they have occasional hemarthroses (joint bleeding), as in cases of mild hemophilia.
(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 autoantibodies. 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 platelets.
Acquired vWD has also been described in the following disorders: Wilms’ tumour, hypothyroidism and mesenchymal dysplasias.