Glanzmann Thrombasthenia
Overview
Glanzmann Thrombasthenia, or Thrombasthenia of Glanzmann and Naegeli is an extremely rare inherited disorder in which there is abnormal function of a component of the blood called the platelets, leading to abnormalities in blood clotting and increased bleeding.
Symptoms
Most people with TGN will have a major bleeding event before the age of five. Common manifestations of the disease include nose bleeds, bleeding from the gums, or skin rashes caused by bleeding into the skin (known as purpura or petechiae). Larger amounts of bleeding into underlying tissue may result in diffuse black bruises, usually seen on the arms and the legs. Normal handling of infants can cause superficial bruises and may be mistaken for abuse. As a result of chronic bleeding, patients may have lower amounts of red blood cells in their blood (anemia) and suffer from iron deficiencies. Rarely, there may be bleeding into the joints, causing disfiguration. Bleeding after traumatic accidents or after surgical operations and dental procedures may be profuse and require vigorous medical treatment. Prolonged untreated or unsuccessfully treated bleeding associated with TGN may be life-threatening. For reasons which are unclear, severity of bleeding events appears to decrease with increasing age. There are other concerns when TGN is diagnosed in a woman. Because of the platelet disorder, women may experience particularly heavy menstrual bleeding. In fact, the first occurrence of menstrual bleeding in a young woman may be so severe that it requires prompt medical attention and treatment. Further, pregnancy and delivery represent severe bleeding risks and may not always be manageable with medical treatment.
Diagnosis
TGN is diagnosed through a combination of medical history, physical examination, and laboratory testing. Bleeding episodes and physical manifestations of the disease (as described above) may prompt an investigation for the underlying cause. The presence of a bleeding disorder in more than one close or distant relative is especially important, as it may indicate that a genetic cause of the condition is involved. Blood tests will reveal normal amounts of platelets. Tests performed with substances that stimulate platelet clumping though GP IIb/IIIa will show minimal effects as a result of the platelet defect. Conversely, tests performed using a different substance, ristocetin, which causes platelet clumping through different mechanisms, will provoke a brisk and appropriate platelet response. Other blood tests will reveal a longer than normal bleeding time, poor clot retraction, and may demonstrate low numbers of red blood cells and iron deficiency. The diagnosis of TGN is ultimately confirmed by investigating the GP IIb/IIIa glycoprotein complex. Antibodies that are specifically designed to distinguish between normal and abnormal GP IIb/IIIa can be used in a technique known as immunofluorescence (in which the antibody is attached to a fluorescent dye) or a test called a Western blot (in which proteins are first separated by size and then exposed to antibodies). These methods can also be used to detect people who are carriers of a mutant gene for TGN by demonstrating only half-normal amounts of GP IIb/IIIa. Prenatal diagnosis may also be possible but is not recommended as sampling of the blood in an affected fetus may lead to uncontrollable bleeding that could prove fatal.
Prognosis
Although there is no cure, the prognosis for people with TGN is quite good. Despite the fact that the majority of people with this disorder will require medical treatment to control bleeding, patients rarely die of massive blood loss. Interestingly, the severity of bleeding appears to decrease with increasing age. Barring any catastrophic accident which results in uncontrollable bleeding, life span is approximately the same as the general population.
Treatment
Several medications can aid in the treatment of TGN, while others should be avoided. Some patients will demonstrate shortening of their bleeding time with DDAVP, a medication that improves the function of platelets. Women who have heavy bleeding may benefit from birth control pills to prevent their menstrual periods. Nutritional iron supplements may alleviate or prevent the development of iron deficiency and will aid in restoring normal levels of red blood cells. Medications to be avoided are those which interfere with platelet function and predispose to bleeding, including aspirin, ibuprofen and ibuprofen-like drugs, heparin, warfarin, ticlopidine, clopidogrel, abciximab, streptokinase, urokinase, or tissue plasminogen activator. The treatment of choice for stopping active bleeding is through transfusion of normal platelets that are obtained from donors without the disease. Studies have shown that most people (approximately 85%) with the disorder will require platelet transfusions during their lifetime. For individuals with TGN, transfusion with one unit of platelets for every 11-22 lbs (5-10 kg) of body weight will correct the defect in blood clotting and may be life-saving. Pre-emptive transfusions are especially important before surgical operations or dental procedures. Transfusions should be continued until wound healing is complete. Over time, platelet transfusion may become less effective. Platelets obtained from donors and given to a patient with TGN are recognized by the immune system as foreign cells. The immune system, in turn, generates antibodies that attach to the donor platelets and impair their function, ultimately leading to their destruction. Because of this unfortunate effect, platelet transfusions are best reserved for life-threatening bleeding or before procedures in which bleeding is likely. Using platelets from donors closely related to the patient may delay the immune response and extend the benefits of transfusion therapy. Patients with TGN should be followed closely by a hematologist and should be vaccinated against the hepatitis B virus, because of the high risk of exposure to the virus with ongoing blood-product transfusions. Patients should also been seen regularly by a dentist to prevent gum disease that could result in profuse bleeding. Genetic counseling can be offered to affected individuals or couples with a family history of the disorder. Bone marrow transplantation is currently the only curative form of treatment for patients with TGN. However this is generally considered more hazardous than the disease itself, except in exceptional circumstances. In 2000, a multidisciplinary team of scientists, led by a researcher at the Medical College of Wisconsin, was able to correct the GP IIb/IIIa defect in bone marrow cells taken from patients with TGN using advanced gene therapy techniques. The researchers are now focusing on applying the technique to lab animals with a form of TGN, but these positive early results give hope for an eventual cure in humans.