You are in: eMedicine Specialties > Pediatrics: General Medicine > Hematology ThrombastheniaArticle Last Updated: Nov 30, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Noah Federman, MD, Department of Pediatrics, Fellow, Division of Pediatric Hematology/Oncology, Mattel Children's Hospital at UCLA, David Geffen School of Medicine at U Noah Federman is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology Coauthor(s): Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine, Division of Hematology-Oncology and Pathology and Laboratory Medicine, University of California at Los Angeles; 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 Editors: J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine Author and Editor Disclosure Synonyms and related keywords: thrombasthenia, Glanzmann thromboasthenia, Glanzmann disease, constitutional thrombopathy, hereditary hemorrhagic thrombopathy, Bernard-Soulier syndrome INTRODUCTIONSection 2 of 10
  BackgroundGlanzmann, a Swiss pediatrician, initially described thrombasthenia in 1918 when he noted purpuric bleeding in patients with normal platelet counts. 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 (Nathan, 2003). 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. PathophysiologyGT 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 cross-linking of platelets and formation of a clot. Specific deficiency The platelet integrin GP IIb-IIIa (also referred to as aIIb-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 (Nurden, 2005). Small deletions, insertions, splicing defects, and nonsense and missense mutations are common. A database of these mutations can be reviewed at the 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 (Lee, 1999). Although granule release still occurs, cross-linking 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 (Lee, 1999). 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 are extremely variable. FrequencyUnited StatesOver 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. InternationalAs 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 (Nurden, 2006). Mortality/MorbidityThe 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. RaceHigh carrier rates of GT mutations have been reported in Jordanian nomadic tribes, Iraqi Jews, French gypsies, and individuals from southern India. A recent 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 (Toogeh, 2004). SexThe disease is inherited as an autosomal recessive disorder. No differences appear to occur based on sex. Men more frequently present with gingival bleeding, while women present more frequently with menorrhagia. AgePatients 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. CLINICALSection 3 of 10
History
Physical
Causes
DIFFERENTIALSSection 4 of 10
Abdominal Trauma Bernard-Soulier Syndrome Birth Trauma Child Abuse & Neglect: Physical Abuse Epistaxis Gastrointestinal Bleeding: Surgical Perspective Head Trauma Hematuria Hemolytic-Uremic Syndrome Meckel Diverticulum Neonatal Sepsis Von Willebrand Disease
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| Drug Name | Aminocaproic acid (Amicar) |
|---|---|
| Description | Synthetic competitive inhibitor of plasminogen activation. Preparations include 250 mg/mL PO syr, 500 mg PO tab, and IV susp. |
| Adult Dose | Loading dose: Infuse 4-5 g IV over 30 min Maintenance dose: 1 g/h PO/IV until bleeding stops; not to exceed 30 g/d |
| Pediatric Dose | 100-200 mg/kg PO initially, followed by 100 mg/kg PO q6h; not to exceed 30 g/d Alternatively, 100 mg/kg (3 g/m2) IV initially, followed by 33 mg/kg/h (1 g/m2/h) IV; not to exceed 18 g/m2/d |
| Contraindications | Documented hypersensitivity; evidence of active intravascular clotting process; DIC; use of IV product in newborns; hematuria (relative contraindication because urinary obstruction may result) |
| Interactions | Coadministration with estrogens may cause increase in clotting factors, leading to hypercoagulable state |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution with impaired liver and kidney function (adjust dose) and coronary artery disease; rapid IV administration may cause hypotension, bradycardia, or arrhythmias; doses used are for vWD, although no studies have determined optimal dosing in thrombasthenia; because aminocaproic acid can be fatal in patients with DIC, differentiate between hyperfibrinolysis and DIC; do not use IV product in newborns (contains benzyl alcohol) |
These agents act like antidiuretic hormone (ADH) to increase factor VIII levels (transiently). They also have direct and local effect on vessel walls that produces increase in platelet adhesion. In part, this local hemostatic action of desmopressin may account for the clinical observation that desmopressin shortens the bleeding time, bleeding episodes, or both.
| Drug Name | Desmopressin (DDAVP, Stimate) |
|---|---|
| Description | Synthetic vasopressin analog used to control severe bleeding. |
| Adult Dose | 0.3 mcg/kg IV over 15-30 min; may repeat once if necessary <50 kg: 150 mcg (1 spray) intranasally as single dose >50 kg: 300 mcg (1 spray each nostril) intranasally as single dose Use high-concentration nasal spray (ie, 150 mcg/spray) |
| Pediatric Dose | <3 months: Not established >3 months: Administer as in adults |
| Contraindications | Documented hypersensitivity; platelet-type vWD |
| Interactions | Coadministration with demeclocycline and lithium decreases effects; fludrocortisone and chlorpropamide increase effects of desmopressin |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in hyponatremia, fluid and electrolyte imbalance, and coronary artery disease; avoid overhydration in patients using desmopressin to gain benefit from its hemostatic effects; doses used are for vWD; no studies have determined optimal dosing in thrombasthenia |
Hemostasis is the physiologic response to bleeding. Injury and factors released by platelets initiate the coagulation cascade, which is mediated by blood clotting factors. This results in formation of an insoluble fibrin clot, reinforcing the initial platelet plug.
| Drug Name | Coagulation factor VIIa, recombinant (NovoSeven) |
|---|---|
| Description | Vitamin K–dependent GP that promotes hemostasis by activating extrinsic pathway of coagulation cascade. Data for refractory severe bleeding in the setting of platelet allosensitization are limited. Reports of efficacy in refractory severe bleeding in pregnancy and in the perioperative period. |
| Adult Dose | 110 mcg/kg IV bolus q90min for 4 doses; then q2h for 24 doses; then q3h for 20 doses Adjust dose to nearest 1.2-mg vial size |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Monitor for signs of thrombosis or activation of coagulation system; thrombotic events may increase in patients with advanced atherosclerotic disease, crush injury, sepsis, or DIC |
These agents are used as an adjunct to achieve hemostasis.
| Drug Name | Gelatin, topical absorbable (Gelfoam, Gelfilm) |
|---|---|
| Description | Used to provide hemostasis in surgery. Can be used for oral and dental surgery and with topical thrombin to stop epistaxis. Available in sponges, dental packs, and sterile powder. |
| Adult Dose | Apply packs or sponges dry or saturated with normal saline; hold in place with direct pressure until hemostasis achieved |
| Pediatric Dose | Administer as in adults |
| Contraindications | Do not use as sole hemostatic agent in patients with severe bleeding or for closure of skin incisions; do not use in menorrhagia, postpartum bleeding, or in presence of infection |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Generally well tolerated; adverse effects may include increased incidence of infection; tissue compression due to fluid absorption, granuloma formation, or fibrosis |
| Drug Name | Thrombin, topical (Thrombostat, Thrombogen, Thrombinar) |
|---|---|
| Description | Used as an adjunct to achieve hemostasis. Topical thrombin catalyzes the conversion of fibrinogen to fibrin. |
| Adult Dose | Profuse bleeding: Apply 1000-2000 U of powder directly to the site of bleeding Mild bleeding: Apply 100 U for mild skin or mucosal bleeding |
| Pediatric Dose | Administer in adults |
| Contraindications | Documented hypersensitivity to drug or material of bovine origin |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Only for external or topical use; do not use as only hemostatic agent in patients with severe bleeding; may develop bovine antibodies |
Article Last Updated: Nov 30, 2006
