eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thrombasthenia

Author: Noah C Federman, MD, Assistant Professor of Pediatrics, Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine; Director, Pediatric Bone and Soft Tissue Sarcoma Program, University of California at Los Angeles
Coauthor(s): Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA; Mark E Green, MD, Chief, Department of Emergency Medicine, Emergency Medicine, Gateway Medical System; Lawrence S Frankel, MD, Director of Pediatric Hematology/Oncology, Scott and White Clinic; Professor, Department of Pediatrics, Division of Hematology/Oncology, Texas A&M University School of Medicine
Contributor Information and Disclosures

Updated: Nov 18, 2008

Introduction

Background

Glanzmann, a Swiss pediatrician, initially described thrombasthenia in 1918 when he noted purpuric bleeding in patients with normal platelet counts.¹ The term thrombasthenia means weak platelets. Glanzmann thrombasthenia (GT) is one of several inherited disorders of platelet function, which also include Bernard-Soulier syndrome, as well as deficiencies of platelet adhesion, aggregation, and secretion.² Each of these disorders is characterized by a lifelong bleeding tendency.

As in most individuals with hereditary hematologic disorders, thrombasthenia is typically diagnosed at an early age. Pediatricians must be aware of its existence and, when confronted with a complicating coagulopathy, consider thrombasthenia in the differential diagnosis.

Pathophysiology

GT is a rare autosomal recessive disorder whereby the production and assembly of the platelet membrane glycoprotein (GP) IIb-IIIa is altered, preventing the aggregation of platelets and subsequent clot formation.

Review of platelet function

Platelets adhere to sites of endothelial injury and then activate, aggregate, and secrete various chemicals designed to promote further platelet recruitment and aggregation. von Willebrand factor (vWF) binds the exposed collagen and binds GP Ib-IX-V complex on the surface of the platelet. This binding adheres platelets to the site of injury. Fibrinogen and vWF bind to the GP IIb-IIIa complex exposed on the activated platelet's surface. This allows crosslinking of platelets and formation of a clot.

Specific deficiency

The platelet integrin GP IIb-IIIa (also referred to as a IIb-b) is a calcium-dependent heterodimer complex that can bind fibronectin, fibrinogen, vWF, and vitronectin. Approximately 80,000 GP IIb-IIIa receptors are present on the surface of each platelet. GP IIb and GP IIIa have their own separate genes on the long arm of chromosome 17. Abnormalities in either gene or in the assembly of the complex result in an abnormal or deficient receptor and, consequently, in disease. Specific genetic abnormalities of each GP include missense mutations, nonsense mutations, splice site mutations, deletions, and point mutations. More than 70 mutations have been described. These mutations are widely distributed over the 2 genes that encode GP IIb and IIIa present at chromosome band 17q.21-23.³ Small deletions, insertions, splicing defects, and nonsense and missense mutations are common. A database of these mutations can be reviewed at the Samuel Bronfman Department of Medicine's Glanzmann Thrombasthenia Database.

GT is an autosomal recessive disorder and heterozygous individuals are asymptomatic. Typically, one of the GPs is not properly formed, leaving the other unpaired in the endoplasmic reticulum, where it is degraded. Platelet aggregation, which requires the entire complex, is therefore deficient or completely absent. Binding sites for thrombin are preserved in thrombasthenic platelets, allowing the platelets to be activated for aggregation.⁴ Although granule release still occurs, crosslinking as described is disabled.

The deficiency is uniformly present throughout the platelet population and is present in endothelial cells and precursor megakaryocytes. Patients with GT are classified as having type 1, type 2, or variant type based on the degree of GP IIb-IIIa deficiency, fibrinogen binding, and clot retraction.⁴ Patients with type 1, the most severe form of the disease, have less than 5% of the normal amount of GP IIb-IIIa present on their platelets. Additionally, they have absent fibrinogen binding and clot retraction. Individuals with type 2 have 10-20% of GP IIb-IIIa, can bind fibrinogen, and have normal–to–moderately deficient clot retraction capability. Persons with the variant type of thrombasthenia have more than 50% of the normal amount of GPIIb-IIIa; however, fibrinogen binding and clot retraction widely vary.

Frequency

United States

Over 500 cases of thrombasthenia have been reported in the international literature. Although GT predominates among certain ethnic groups, an estimate of worldwide incidence and prevalence has not been reported.

International

As stated above, international frequency data are unknown. However, particularly high carrier rates have been reported in certain ethnic groups, such as Arab populations, specifically Jordanian nomadic tribes, Iraqi Jews, French gypsies, and individuals from southern India. The incidence rate also appears to be increased in families in which marriage to close relatives is accepted.⁵

Mortality/Morbidity

The probability of death following bleeding is estimated at approximately 5-10%. Most of these cases are related to occurrence of severe unprovoked intracranial or GI hemorrhages.

Race

High carrier rates of GT mutations have been reported in Jordanian nomadic tribes, Iraqi Jews, French gypsies, and individuals from southern India. A report of 382 patients with GT in Iran may suggest that this hereditary hemorrhagic disorder may be more common than initially believed in the Arab population.⁶

Sex

The disease is inherited as an autosomal recessive disorder. No differences appear to occur based on sex. Men present more frequently with gingival bleeding, whereas women present more frequently with menorrhagia.

Age

Patients with GT are typically diagnosed in infancy or early childhood. However, age of diagnosis can range from birth to adulthood. Neonatal purpura typically suggests type 1 thrombasthenia. Epistaxis and GI bleeding are frequent presenting signs of GT and are more severe in children, especially those aged 4-10 years. Menorrhagia may be a presenting sign of GT in adolescent females and can be a critical problem. The severity and frequency of bleeding usually decreases with age.

Clinical

History

• Initially, patients present with mucocutaneous bleeding in the neonatal period or with bleeding following circumcision.
• Children with thrombasthenia may have purpura, epistaxis, gingival bleeding, GI bleeding, and menorrhagia.
• The occurrence of most minor bleeding decreases with age.
• Severe menorrhagia is a common problem that requires careful observation and treatment with oral contraceptive pills. It is usually associated with an excessively proliferative endometrium that reflects estrogen dominance.⁵
• Additional presenting symptoms include GI bleeding and hematuria.
• Excessive bleeding following parturition and postsurgical bleeding represent a significant risk.
• Although uncommon, hemarthrosis and deep hematomas more characteristic of hemophilias can occur.
• Posttraumatic bleeding may be severe in patients not prepared with normal platelets.
• Clinical bleeding does not always correlate with the amount of GP IIb-IIIa present.
• Because the Glanzmann thrombasthenia (GT) trait is recessive, the absence of a family history should not delay a workup for thrombasthenia.

Physical

• Most patients with thrombasthenia present with signs of purpura or bleeding.
• The initial physical examination should focus on assessing hemodynamic stability.
• The diagnosis is made in patients with refractory hemorrhage and appropriate findings on the diagnostic laboratory studies (see Laboratory Studies).
• Other than identification of hemorrhage, physical examination findings are of limited use.

Causes

• Trauma is the most frequent cause of bleeding in persons with thrombasthenia. This includes surgical procedures (eg, dental extractions) in which bleeding can be severe. Pregnancy and delivery are also common causes of severe bleeding in this disorder.
• Spontaneous bleeding typically decreases in adolescence and adulthood.
• GI bleeding requires an investigation as to cause.
• Unprovoked intracranial and GI bleeding can occur and is, for the most part, responsible for the 5-10% mortality in GT.

• Search for CME/CE on This Topic »

• Glanzmann Thrombasthenia (Hematology)
• Platelet Disorders (Hematology)

• Recent Developments in the Perioperative Management of Adult Patients with Chronic Kidney Disease