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Glanzmann Thrombasthenia

Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Mark J Shumate, MD, MPH, Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, Emory University

Updated: Nov 20, 2008

Introduction

Background

Glanzmann thrombasthenia is a genetic platelet disorder in which the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either deficient or present but dysfunctional. The genes of both of these proteins are on chromosome 17, and 50% activity of each protein is enough to support normal platelet aggregation. Defects in the GP IIb/IIIa complex leads to defective platelet aggregation and subsequent bleeding.1,2,3,4,5,6

Glanzmann thrombasthenia is rare and it is inherited in an autosomal recessive pattern. The disorder was first described by Dr. Eduard Glanzmann in 1918.

Pathophysiology

When an injury occurs, the GP IIb/IIIa receptors play an important role in the adherence of platelets to the endothelium as well as have a role in platelet aggregation.

The GP IIb/IIIa complex binds fibrinogen and/or von Willebrand factor (vWF). Adjacent platelets are cross-linked through GP IIb/IIIa–fibrinogen–GP IIb/IIIa complexes. When the GP IIb/IIIa complex functions abnormally, platelets cannot aggregate. This then leads to increased bleeding.

The GP IIb/IIIa complex is a heterodimer that requires calcium for GP IIb and GP IIIa to associate normally, and both GP IIb and GP IIIa are required for normal platelet function. A defect in either glycoprotein can lead to a bleeding disorder. However, platelet counts do not depend on GP IIb/IIIa, and, therefore, patients with defects in these glycoproteins have normal platelet counts. The morphology of the platelets on a peripheral smear is not unusual.

Frequency

International

Glanzmann thrombasthenia is quite rare, is inherited in an autosomal recessive manner, and is observed most often in populations that have increased consanguinity. Reports of families with a high incidence have been observed from countries such as Iran, Israel, and Jordan, where marriage among close relatives is allowed.

Mortality/Morbidity

Bleeding problems can be severe in patients with Glanzmann thrombasthenia, but the prognosis remains good with appropriate supportive care.

Sex

There may a slightly higher female preponderance for Glanzmann thrombasthenia. 

Age

Patients with thrombasthenia typically present with mucocutaneous bleeding at birth or early in infancy.

Clinical

History

The clinical history of Glanzmann thrombasthenia may include the following:

  • Excessive bleeding after dental extraction (this may often be the first sign of the disease)
  • Petechiae and ecchymoses (although spontaneous petechiae are uncommon)
  • Menorrhagia, often worse at menarche
  • Gingival bleeding (which is worse with poor dental hygiene)
  • Epistaxis
  • Hemarthroses (rare)
  • Family history of a bleeding disorder may or may not exist
  • Gastrointestinal bleeding or hematuria is less common

Physical

  • In patients suspected with of Glanzmann thrombasthenia, examine the skin and oral mucosa for petechiae, ecchymoses, and any current bleeding.
  • The spleen should normally be nonpalpable.

Causes

  • Glanzmann thrombasthenia is a genetic condition. The disease is clinically apparent in patients who are homozygous. Glanzmann thrombasthenia is normally of no clinical significance in patients who are heterozygous for this condition.
  • Rare acquired forms caused by antibodies against GP IIb/IIIa have been described. One such affected patient developed non-Hodgkin lymphoma,2,7 and another had no underlying cause.7

Differential Diagnoses

Platelet Disorders
von Willebrand Disease
Wiskott-Aldrich Syndrome

Other Problems to Be Considered

  • Afibrinogenemia (see also Inherited Abnormalities of Fibrinogen [in the Pediatrics: General Medicine section] and Hemostatic Disorders, Nonplatelet)
  • Autoantibodies to GP IIa/IIIb
  • Bernard-Soulier syndrome and other qualitative platelet disorders (eg, gray platelet syndrome, platelet-type von Willebrand disease, or platelet storage pool defects)

Workup

Laboratory Studies

The workup for Glanzmann thrombasthenia may include the following:

  • Complete blood cell (CBC) count, prothrombin time (PT), and activated partial thromboplastin time (aPTT)
    • The platelet count and other coagulation tests should be normal, although the red blood cell count may be decreased due to bleeding and/or concomitant iron deficiency.
    • The bleeding times should be prolonged.
    • The Platelet Function Analyzer 100 (PFA-100) is a device that may be helpful in determining the cause of bleeding diathesis. Patients with Glanzmann thrombasthenia fail to plug the collagen-based filter.
  • Flow cytometry and monoclonal antibodies confirm the diagnosis of Glanzmann thrombasthenia.
  • Platelet aggregation studies
    • The primary platelet aggregation response to platelet agonists such as adenosine diphosphate (ADP), epinephrine, and collagen are decreased, whereas the response to ristocetin is normal.
    • If the secondary platelet aggregation response is abnormal, suspect a platelet storage pool defect or an abnormality in platelet signal transduction.

Histologic Findings

The platelet morphology on peripheral blood smears is normal in patients with Glanzmann thrombasthenia.

Treatment

Medical Care

  • Patients with Glanzmann thrombasthenia who are bleeding require platelet transfusion.
    • Because patients are likely to require multiple transfusions during their lifetime, take care to avoid platelet alloimmunization.
    • Prevention is best accomplished by using leukocyte-depleted blood products. Leukocyte depletion can be accomplished with mechanical filtration. Only filtered blood products should be given.
    • Use of platelets matched via human leukocyte antigen (HLA) is a further attempt to prevent platelet alloimmunization.
  • Patients should be vaccinated for hepatitis B due to the infectious risks associated with multiple transfusions
  • Avoid medications that affect platelet function, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Consider oral contraceptives to control menorrhagia.
  • Recombinant human-activated factor VII (rFVII) has been used in patients with antibodies to GP IIb/IIIa and/or HLA that render transfusions ineffective. The exact dosing of rFVII for Glanzmann thrombasthenia has not been determined.

Surgical Care

For patients with Glanzmann thrombasthenia who require surgical intervention:

  • To prevent excessive bleeding during surgery, platelets should be transfused preoperatively.
  • Further platelet transfusions are considered, based on maintaining hemostasis.
  • rFVIIa may be useful for preventing or controlling bleeding.

Consultations

A hematologist confirms the diagnosis of Glanzmann thrombasthenia and makes transfusion recommendations.

Medication

The goals of pharmacotherapy are to induce active immunity, reduce morbidity, and prevent complications in patients with Glanzmann thrombasthenia.

Vaccines, Viral

Viral vaccines provide immunity against viral infections.


Hepatitis B immune globulin/vaccine (Hyper-Hep, H-BIG, Recombivax HB, Engerix-B)

Recombinant vaccine used to provide immunization against all the known subtypes of the hepatitis B virus.

Dosing

Adult

0.06 mg/kg or 3-5 mL IM as early as possible (24 h) following a needlestick

1-month boost: 1 mL

6-month boost: 1 mL

Pediatric

0.5 mL IM as early as possible (within 12 h) after birth

<10 years:

Initial dose: Recombivax HB 0.25 mL or Engerix-B 0.5 mL

1-month boost: Recombivax HB 0.25 mL or Engerix-B 0.5 mL

6-month boost: Recombivax HB 0.25 mL or Engerix-B 0.5 mL

>10 years:

Initial dose: Recombivax HB 0.5 mL or Engerix-B 1 mL

1-month boost: Recombivax HB 0.5 mL or Engerix-B 1 mL

6-month boost: Recombivax HB 0.5 mL or Engerix-B 1 mL

Interactions

May decrease the effects of immunosuppressive agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Immunosuppressed patients may require larger doses to respond as well as healthy individuals; the vaccine does not protect against the hepatitis A virus; instances of multiple sclerosis exacerbations following the administration of the hepatitis B vaccine have occurred.

Oral Contraceptives

Estrogen-progestin combinations of oral contraceptives reduce the secretion of LH and FSH from the pituitary by decreasing amount of gonadotropin-releasing hormones (GnRHs).


Ethinyl estradiol and norethindrone (Ovcon 50)

Suggested mechanisms by which hormonal therapy might affect bleeding include improvement in coagulation, alterations in the microvascular circulation, and improvements in endothelial integrity. One active tablet contains ethinyl estradiol 0.05 mg and norethindrone 1 mg.

Dosing

Adult

1 tab PO qd

Pediatric

Not established

Interactions

May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control; progestins may decrease effects of aminoglutethimide; rifampin may reduce levels of norethindrone

Contraindications

Documented hypersensitivity; thrombophlebitis, undiagnosed vaginal bleeding; cerebral apoplexy

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, asthma, depression, or thromboembolic disease

Coagulation Factor VIIa

Coagulation factor agents promote hemostasis.


Factor VIIa (Recombinant) (Novo-Seven)

Vitamin K–dependent glycoprotein that promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.

Dosing

Adult

Not established; 90 mcg/kg q2h until homeostasis achieved is suggested

Pediatric

Not established

Interactions

Contraindications

Documented hypersensitivity to factor VII, mouse, hamster, or bovine protein

Precautions

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, and disseminated intravascular coagulation

Follow-up

Further Outpatient Care

  • Regular dental care is recommended to avoid gingival bleeding in individuals with Glanzmann thrombasthenia.

Deterrence/Prevention

  • Patients with Glanzmann thrombasthenia should avoid drugs that decrease platelet function or coagulation, such as the following:
    • Aspirin or other NSAIDs
    • Heparin
    • Warfarin
    • Ticlopidine or clopidogrel
    • GP IIb/IIIa antagonists, such as abciximab
    • Streptokinase, urokinase, or tissue plasminogen activator (tPA)
    • Volume expanders, such as dextran or hydroxyethyl starch
    • Dipyridamole

Complications

  • Bleeding complications of any type

Prognosis

  • With platelet transfusions for bleeding complications, the prognosis is generally good in those with Glanzmann thrombasthenia.

Patient Education

  • Educate patients with Glanzmann thrombasthenia that regular dental care is necessary to avoid gingivitis and gingival bleeding.

Miscellaneous

Medicolegal Pitfalls

  • Failure to monitor for bleeding complications is a medicolegal pitfall.

References

  1. George JN, Caen JP, Nurden AT. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood. Apr 1 1990;75(7):1383-95. [Medline]. [Full Text].

  2. Malik U, Dutcher JP, Oleksowicz L. Acquired Glanzmann's thrombasthenia associated with Hodgkin's lymphoma: a case report and review of the literature. Cancer. May 1 1998;82(9):1764-8. [Medline]. [Full Text].

  3. Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis. Apr 6 2006;1:10. [Medline]. [Full Text].

  4. Poon MC, Zotz R, Di Minno G, et al. Glanzmann's thrombasthenia treatment: a prospective observational registry on the use of recombinant human activated factor VII and other hemostatic agents. Semin Hematol. Jan 2006;43(1 suppl 1):S33-6. [Medline].

  5. Poon MC. Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann's thrombasthenia. Vasc Health Risk Manag. 2007;3(5):655-64. [Medline]. [Full Text].

  6. Saxena R, Kannan M. Glanzmann's thrombasthenia: an overview. Clin Appl Thromb Hemost. Oct 16 2008;epub ahead of print. [Medline].

  7. Tholouli E, Hay CR, O'Gorman P, Makris M. Acquired Glanzmann's thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder. Br J Haematol. Oct 2004;127(2):209-13. [Medline].

  8. Ali N, Moiz B, Shaikh U, et al. Diagnostic tool for Glanzmann's thrombasthenia clinicopathologic spectrum. J Coll Physicians Surg Pak. Feb 2008;18(2):91-4. [Medline].

  9. Jin PP, Shen WZ, Yang F, et al. [Analysis of clinical features and genotype in three Chinese pedigrees with Glanzmann thrombasthenia]. Zhonghua Xue Ye Xue Za Zhi. Mar 2008;29(3):149-53. [Medline].

  10. Lombardo VT, Sottilotta G. Recombinant activated factor VII combined with desmopressin in preventing bleeding from dental extraction in a patient with Glanzmann's thrombasthenia. Clin Appl Thromb Hemost. Jan 2006;12(1):115-6. [Medline].

  11. Shen WZ, Ding QL, Jin PP, et al. A novel Pro126His beta propeller mutation in integrin alphaIIb causes Glanzmann thrombasthenia by impairing progression of pro-alphaIIbbeta3 from endoplasmic reticulum to Golgi. Blood Cells Mol Dis. Oct 29 2008;epub ahead of print. [Medline].

  12. Vuckovic SA. Glanzmann's thrombasthenia revisited. J Emerg Med. May-Jun 1996;14(3):299-303. [Medline].

Keywords

Glanzmann thrombasthenia, thrombasthenia, Glanzmann disease, Glanzmann's thrombasthenia, platelet glycoprotein GPIIb-IIIa complex, blood platelet disorders, hemorrhagic disorders, genetic platelet disorders, platelet glycoprotein IIB, GP IIb, platelet glycoprotein IIIa, GP IIIa, GP IIa/IIIb, defective platelet aggregation, von Willebrand factor, vWF, bleeding

Contributor Information and Disclosures

Author

Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Zonera Ashraf Ali, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Mark J Shumate, MD, MPH, Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, Emory University
Mark J Shumate, MD, MPH is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Wadie F Bahou, MD, Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook
Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Further Reading

Related eMedicine Topics

  • Alloimmunization From Transfusions
  • Factor VII
  • Hemophilia, Overview
  • Thrombasthenia
  • Transfusion and Autotransfusion
  • Transfusion Reactions
  • Transfusion-Transmitted Diseases
  • von Willebrand Disease

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