Thrombasthenia of Glanzmann and Naegeli

Definition

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.

Description

Blood clotting, or coagulation, is the process by which several factors in the blood stick together to form a physical barrier that prevents bleeding. In response to a disruption in blood flow or bleeding because of injury, several factors in the blood stick together at the site of injury, sealing off the blood vessel and stopping blood loss in a process called hemostasis. If any of the factors that contribute to the process of coagulation and hemostasis are abnormal, dangerous bleeding conditions can result.

One of the factors involved in hemostasis is called the platelet. Platelets are small disc-shaped structures that circulate in the blood stream in an inactive state. When an injury occurs, platelets become activated and stick to fibrous proteins, called fibrinogen, that are also circulating in the blood stream. Because there are multiple sites on the fibrinogen proteins for platelets to bind and vice versa, a cross-linked net or mass called a "platelet plug" is formed which seals off the injury and prevents further bleeding. Next, the platelet mass actively contracts to form an even more solid mass in a process called "clot retraction." Over time, repair cells can use this mass as a scaffolding to lay down new tissue and thereby effect a permanent repair of the injury.

Platelets attach to fibrinogen through the use of specialized sugar-proteins (glycoproteins) that are present on the platelet surface. There are two specific glycoproteins that form a complex responsible for the platelet-fibrinogen interaction: glycoprotein IIb, and glycoprotein IIIa.

The platelet disorder thrombasthenia of Glanzmann and Naegeli (TGN) results from an inherited defect in the glycoprotein IIb/IIIa complex (GP IIb/IIIa). As a result of this glycoprotein defect, platelets fail to stick to fibrinogen, leading to defective hemostasis and prolonged bleeding. TGN is sometimes subdivided into different groups: type I, in which there is no functional GP IIb/IIIa; type II, in which small amounts of working GP IIb/IIIa can be detected; and variant thrombasthenia, in which the amount of working GP IIb/IIIa may vary. Thrombasthenia of Glanzmann and Naegeli has also been referred to by other names, including: Glanzmann's thrombasthenia, diacyclothrombopathia IIb-IIIa, Glanzmann disease, and glycoprotein complex IIb/IIIa deficiency.

TGN was first described by the Swiss physician Edward Glanzmann in 1918. Glanzmann used the term, "thrombasthenia," meaning "weak platelets," because clots from patients with the disorder did not retract well. Although the disease is exceedingly rare, platelets taken from people with the disease have been very useful in the research that first discovered how normal platelets function.

Genetic profile

TGN is a genetic condition and can be inherited or passed on in a family. The disorder results from any number of different mutations that can occur in either the gene for glycoprotein IIb or the gene for glycoprotein IIIa (both located on chromosome 17, locus 17q21.32), with defects split equally between the two genes.

In the majority of cases, it appears that the genetic abnormality for the disorder is inherited as an autosomal recessive trait, meaning that two abnormal genes are needed to display the disease. A person who carries one abnormal gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to his or her children, who must inherit one abnormal gene from each parent to display the disease. People who are carriers of the abnormal gene appear to have only half-normal amounts of working GP IIb/IIIa, which is still sufficient for normal platelet function.

There are reports of a few families in which the defect is inherited in an autosomal dominant fashion. In this pattern of inheritance , only one abnormal gene is needed to display the disease, and the chance of passing the gene to offspring is 50%.

Demographics

TGN is exceedingly rare, with less than 1,000 cases identified between 1962 and 2000. There are several groups in which the majority of cases of thrombasthenia have been discovered, including Iraqi Jews, Arabs living in Israel and Jordan, populations of south India, and French Gypsies of the Manouche tribe.

Signs and 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.

Treatment and management

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.

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, lifespan is approximately the same as the general population.

Resources

BOOKS

Cotran R. S. Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders, 1999.

"Disorders of the Platelet and Vessel Wall." In Harrison's Principles of Internal Medicine, edited by A.S. Fauci. New York: McGraw-Hill, 1998.

"Disorders of the Platelets and the Blood Vessels." In Nelson Textbook of Pediatrics, edited by R.E. Behrman. Philadelphia: W.B. Saunders, 2000, pp 1520-1525.

"Hereditary Disorders of Platelet Function." In Wintrobe's Clinical Hematology, edited by R. Lee. Philadelphia: Lippincott Williams & Wilkins, 1999, pp 1662-1669.

PERIODICALS

French, D.L., and U. Seligsohn. "Platelet Glycoprotein IIb/IIIa Receptors and Glanzmann's Thrombasthenia." Arteriosclerosis Thrombosis and Vascular Biology 20 (March 2000): 607-610.

Tomiyama, Y. "Glanzmann Thrombasthenia: Integrin Alpha IIb Beta 3 Deficiency". International Journal of Hematology 72 (December 2000): 448-454.

ORGANIZATIONS

Glanzmann's Thrombasthenia Support Group. 28 Duke Rd., Newton, Hyde, SK14 4JB. UK 0161-368-0219

WEBSITES

"Glanzmann Thrombasthenia." Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=187800>.

Oren Traub, MD, PhD