Characteristics
Hemophilia is a rare, genetic disorder in which the blood doesn't clot in the typical way and fails to slow down or stop bleeding. The reason for this inadequate blood clotting lies in the fact that patients don’t have enough clotting factor. Clotting factors are proteins in the blood that interfere with platelets to form blood clots. As a result, low levels of clotting factor increase the bleeding risk. The severity of the hemophilia is determined by the level of clotting factor in the blood.
In patients with a severe form of hemophilia, the main concern consists of bleeding inside the body, especially in the knees, ankles, or elbows. These internal bleeding can lead to severe organ damage and can even be life-threatening.
Based on the clotting factor that is lacking, three different hemophilia subtypes have been described. Hemophilia A is the most common subtype and occurs when there is not enough clotting factor 8 (VIII). In contrast, patients with Hemophilia B don’t have enough clotting factor 9 (IX) in their blood). The rarest of the three hemophilia subtypes is Hemophilia C in which clotting fact 11 (XI) is deficient.
In the majority of cases, hemophilia is inherited. In this, patients inherit a mutation in a gene encoding for a specific clotting factor. As a result of these mutations, not enough clotting factor is produced, or the produced clotting factor is not functioning properly. Both hemophilia A and B are sex-linked disorders, indicating that they are inherited in a recessive X-linked manner. This means that a woman who inherits a faulty X chromosome with abnormal factor gene will carry hemophilia but will likely not experience any symptoms (as she still has a functional factor gene on her 2nd X-chromosome). In contrast, boys who inherit a faulty X-chromosome will likely have more severe hemophilia symptoms (as they only have one X-chromosome). Of note, about 20% of all hemophilia cases develop spontaneous, meaning that someone develops the disease in the absence of a family history of abnormal bleeding.
Symptoms
People with hemophilia bleed longer than other people. These bleeds can occur internally, in joints and muscles, or externally, from minor cuts or injuries. How often a person bleeds, and the severity of these bleeds depends on the level of normal clotting factor a patient still produces.
Patients with hemophilia may suffer from excessive bleeding from cuts or injuries, or after surgery or dental work, have frequent nosebleeds without a clear cause and often present with large or deep bruises. In addition, they may suffer from pain, swelling or tightness in their joints and have blood in their stool or urine.
One of the more serious complications in patients with hemophilia consists of bleeding into the brain. Symptoms of intracranial bleeding include a prolonged headache, repeated vomiting, sleepiness, double vision, sudden weakness, convulsions, and seizures.
Diagnostic tests
The basis for a diagnosis of hemophilia consists of assays that assess how long it takes for the blood to clot. These clotting factor assays will show the type of hemophilia and give an indication on the severity of the disease (i.e., how much clotting factor is the patient still producing).
For people with a family history of hemophilia, genetic testing is often used to identify carriers allowing a more informed decision on becoming pregnant. In addition, it is possible to determine if a fetus is affected by hemophilia during pregnancy. However, this test is not without risk for the fetus and requires careful consideration.
Treatments
The long-standing standard treatment for patients with hemophilia consists of replacement therapy in which the missing clotting factor is replaced regular subcutaneous injections of lab-made (recombinant) clotting factors. In general, replacement therapy is reserved for patients with severe hemophilia. For patients with mild or moderate hemophilia, a short course of replacement therapy can be given when they need to undergo surgery. Unfortunately, some patients develop antibodies to the replacement therapy. These antibodies are called inhibitors and attack the clotting factors that control bleeding. In patients with inhibitors, immune tolerance induction (ITI) is given on a daily basis to bring down inhibitor levels.
In addition to replacement therapy, treatments can be given to stimulate the production of clotting factor (e.g., desmopressin in patients with mild hemophilia), or prevent clots from breaking down (e.g., anti-fibrinolytics). More recently, emicizumab has been introduced in the treatment landscape for patients with Hemophilia A. This agent is able to restore the blood clotting cascade in patients with Hemophila A by mimicking the function of factor VIII.
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