Glanzmann's thrombasthenia, Glanzmann's Research Foundation, blood, blood disorder, blood disease, fibrinogen bridging, prolonged bleeding, autosomal recessive, platelets, hematologists, hemophelia, Haemophilia, nose bleeds

Medical Articles

Sustained Engraftment Post Bone Marrow Transplant Despite Anti-Platelet Antibodies in Glanzmann Thrombasthenia

Veronica M. Flood, MD., F. Leonard Johnson, MD, Lynn K. Boshkov, MD, Gregory A Thomas, MD, Diane J. Nugent, MD, Antony C. Bakke, PhD, H. Stacy Nicholson, MD, MPH, David Tilford, MD, Mary P. Brown, MD, and Kamar T. Godder, MD, MPH.

Background. Patients with Glanzmann thrombasthenia (GT) have normal platelet counts but abnormal platelet aggregation and carry the risk of life-threatening bleeding. We report three patients who received bone marrow transplantation (BMT) for type 1 GT and discuss the risk and management of anti-platelet antibodies. Patients and Results. Diagnosis of GT was made through abnormal platelet aggregation studies or the absence of GPIIb/IIIa by flow cytometry. All patients had severe bleeding requiring multiple red blood cell transfusions. One patient received an unrelated donor transplant and two received matched sibling donor transplants following conditioning therapy with busulfan, cyclophosphamide, and fludarabine. Two patients developed an anti-platelet antibody, treated in one with intravenous immune

globulin (IVIG). Engraftment of white blood cells and platelets was achieved on day +13 to +14 and +17 to +25, respectively. Complete donor chimerism and GPIIb/IIIa+ platelets are sustained at +22 to +30 months post transplant. Conclusions. In summary, patients with GT and history of severe hemorrhage can be cured with BMT, but the presence of anti-platelet antibodies should be sought and platelet transfusions minimized prior to transplant. IVIG may be helpful in cases of refractory immune thrombocytopenia related to anti-platelet antibodies. Improvement in transplant-related complications with current transplant regimens allows consideration of BMT for life-threatening non-malignant disorders such as GT.

Pediatric Blood Cancer 2005; 45;971-975.

INTRODUCTION

Glanzmann thrombasthenia (GT) is an inherited bleeding disorder resulting from either qualitative or quantitative abnormalities in the glycoprotein IIb/IIIa complex located on the platelet membrane. Glanzmann first reported a series of patients with muco-cutaneous bleeding, normal platelet counts, and prolonged bleeding times in 1918. Later, it was discovered that these patients lacked functional GPIIb/IIIa on their platelets. This defect prevents adequate formation of the platelet plug, which then leads to increased bleeding at sites of injury. GT patients can be classified as type I, with less than 5% GPIIb/IIIu and absent clot retraction; or type II. with 10-20% GPIIb/IIIa and minimal clot retraction. Qualitative defects manifest as variants with abnormal function despite normal or near-normal levels of GPIIb/IIIa.

The clinical spectrum of GT is variable, with symptoms ranging from minimal bleeding to significant epistaxis, menorrhagia, and life-threatening hemorrhage. Treatment typically consists of local control measures. Systemic and topical antifibrinolytic therapy may be helpful, while platelet transfusions are reserved for severe bleeding. Although, the infusion of normal donor platelets will initially allow hemostasis, GT patients may develop

antiplatelet antibodies against the GPIIb/IIIa complex, decreasing the efficacy of transfusion and creating the risk of poor response to future transfusions. While aiding in temporary hemostasis, none of the measures described above address the underlying defect. The only curative treatment to date has been bone marrow transplantation (BMT). Four previous transplants for GT have been reported, all with matched sibling donors.
We report three patients who received BMT for GT at our institution. All patients had type I GT and had experienced severe bleeding requiring multiple transfusions. One patient received a transplant from a human

1 Pediatric Stem cell Transplant Program. Division of Pediatric Hematology/Oncology. Oregon Health & Science University, Portland, Oregon

2 Department of Pathology. Oregon Heath& Science University, Portland, Oregon

Division of Hematology, Children's Hospital of Orange County, Orange California

3 Central Oregon Pediatrics, Bend. Oregon

4 Correspondence to: Victoria H. Flood. Kamar T Godder, Division of Pediatric Hematology / Oncology, DCRCP, Oregon Health and Science University. 3181 SW Sam Jackson Park Road, Portland, OR 97239

Glanzmann Thrombasthenia

Disease type: Platelet Disorder
Chromosome: 17

Pathology
Glanzmann Thrombasthenia (GT) is a disorder affecting platelets, and blood clotting. In GT, platelets fail to aggregate following stimulation, failing to form blood clots. GT is an autosomal recessive disorder in one of two genes, either the GPIIb or GPIIIa (GP stands for glycoprotein) In GT one or both of these proteins are mutated in some manner.

GPIIb, and GPIIIa exist together as a dimer (they are joined together, reffered to as: GPIIb/IIIa). GPIIb/IIIa once activated will bind to one end of fibrinogen. Another platelet, with its own GPIIb/IIIa can then bind to the other end of the fibrinogen. This allows the formation of a large collection or aggregation of bound platelets, commonly called a blood clot. In GT the GPIIb/IIIa is defective, the platelets can no longer bind with one another, and the blood clot fails to form.

Aetiology
The genetics underpinning the disease are very diverse,ranging from major deletions in the gene to single point mutations. The disease is very rare, with only about 200 cases in the world (1995), of which only twelve have been solved at the genetic level. Defects seem split equally between GPIIb, and GPIIIa.

Symptoms
Common symptoms include:
Excessive bleeding after skin damage (dentist, surgery, accidents).
Spontaneuos bleeding within the joints.
Spontaneuos bleeding within mucosal tissues.
Mennorhagia - Bleeding more severe during menstruation.

Further reading: Newman P.J., Poncz M (1995) Inherited disoreders of platelets. IN Scriver C.R., Beaudet A.L., William S.S., editors, Molecular and Metabolic basis of disease. McGraw & Hill Inc, 3335-3358

Glanzmann's Thrombasthenia
Dr. Mark Shumate

Glanzmann's Thrombasthenia is a rare genetic bleeding disorder. It is a disorder of platelet function and is caused by a deficiency or abnormality in the membrane glycoprotein (GP) IIb-IIIa which is responsible for the formation of a plug (haemostatic plug) which prevents further bleeding of injured blood vessels. In effect the platelets do not stick together adequately causing prolonged bleeding even from minor injuries. Despite the abnormality of platelet function, the total platelet count is normal and specialised platelet function tests are necessary to make the diagnosis.

Glanzmann's Thrombasthenia may be of variable severity. Some patients (Type 1) are severely affected whilst others are less so (Type 2). The genes for glycoprotein IIb and IIIa are on chromosome 17, but many genetic mutations have already been described. Glanzmann's Thrombasthenia is not always the result of the same mutation.

Normal handling of infants can cause superficial bruises. Epistaxis (nose bleeds) in childhood and menstrual bleeding can cause problems.

Platelet transfusions can be used in cases of serious bleeding. However antibodies against platelets can develop as a result of such transfusions. Anti-platelet drugs such as aspirin should be avoided.

Bone marrow transplantation is the only curative form of treatment. However this is generally considered more hazardous than the condition except in exceptional circumstances.

Inheritance patterns
Autosomal recessive, carriers can now be detected.

Pre-natal diagnosis
This is possible at 18 plus weeks through a fetal blood sample. However where the child is affected the fetal sampling carries a high risk of haemorrhage and may be fatal. Unaffected or carrier fetuses will not undergo any special risk from the testing. Genetic counselling is available.

Medical text last updated August 2001 by Dr R F Stevens, Consultant Haematologist/Oncologist, Royal Manchester Children's Hospital, Manchester, UK.

GLANZMANN'S THROMBASTHENIA CONTACT GROUP
Marilyn Buxton Glanzmann's Thrombasthenia Contact Group 28 Duke Road Newton Hyde
SK14 4JB Tel 0161 368 0219 e-mail: glanzmannsupport@btopenworld.com This is a Contact Group founded in 1990.

Authored by Mark J. Shumate, M.D., M.P.H., Assistant Professor, Hematology/Oncology Division, Emory University

Edited by Christopher D. Hillyer, M.D., Program Director, Transfusion Medicine and Hospital Blood Bank, Associate Professor, Departments of Medicine and Pathology, Emory University School of Medicine; F. Talavera, Pharm.D., Ph.D., Department of Pharmacy, Creighton University; Emmanuel C. Besa, M.D., Professor, Department of Medicine, Section of Hematology and Oncology, Medical College of Pennsylvania Hospital, MCP Hahnemann University; Rajalaxmi McKenna, M.D., Director, Hemophilia Center; Division of Hematology, Clinical Professor of Medicine, Hematology/Oncology Faculty Foundation, Director, Cardeza Special Hematology and Hemostasis Laboratories, Thomas Jefferson University and Hospital; and Michael E. Zevitz, M.D., Director of Echocardiography Lab, Division of Cardiology, Clinical Assistant Professor, Department of Medicine, Finch University of Health Science/The Chicago Medical School

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. This defect leads to defective platelet aggregation and subsequent bleeding. It is rare and is inherited in an autosomal recessive pattern.

Pathophysiology:

Platelet aggregation at sites of vascular injury requires expression of GPIIb/IIIa complex on the surface of the platelets forming the platelet plug.

GPIIb/IIIa complex binds fibrinogen and/or von Willebrand factor (vWF). Adjacent platelets are cross-linked through GPIIb/IIIa - fibrinogen - GPIIb/IIIa complexes. When GPIIb/IIIa complex functions abnormally, platelet aggregation is impaired and bleeding occurs.

GPIIb/IIIa complex is a heterodimer that requires calcium for the GPIIb and GPIIIa to associate normally. Both GPIIb and GPIIIa are required for normal platelet function. A defect in either one can lead to a bleeding disorder.

Platelet counts and platelet functions that do not depend on GPIIb/IIIa are normal in thrombasthenic patients.

Frequency:

Internationally:
The disease is quite rare and inherited in an autosomal recessive manner. It is seen most often in populations with increased consanguinity.

Mortality/Morbidity:

Bleeding problems can be severe, but the prognosis remains good if platelet transfusion is available.

Age:

Thrombasthenia typically presents with mucocutaneous bleeding at birth or early in infancy.

CLINICAL

History:

Bleeding from a condition which could cause bleeding in an otherwise normal individual.
Petechiae and ecchymoses, although spontaneous petechiae are uncommon
Menorrhagia, often worse at menarche
Gingival bleeding worse with poor dental hygiene
Epistaxis
Hemarthroses are rare.

Physical:

Examine the skin and oral mucosa for petechiae, ecchymoses and any current bleeding.

Causes:

The disease is a genetic condition.

DIFFERENTIALS

Other Problems to be Considered:

Afibrinogenemia

Autoantibodies to GPIIa/IIIb

Bernard-Soulier Syndrome and Other Qualitative Platelet Disorders such as Gray Platelet Syndrome; Wiskott-Aldrich Syndrome; Platelet-Type von Willebrand Disease; or Platelet Storage Pool Defects.

WORKUP

Lab Studies:

Complete blood count, prothrombin time and partial thromboplastin time

The platelet count and other coagulation tests should be normal.

Bleeding times should be prolonged
Platelet aggregation studies

The primary platelet aggregation response to platelet agonists such as ADP and epinephrine are decreased while 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:

Platelet morphology on peripheral blood smears is normal

TREATMENT

Medical Care:

Thrombasthenia patients 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 HLA-matched platelets is a further attempt in the prevention of platelet alloimmunization.

Patients should be vaccinated for hepatitis B, due to infectious risks associated with multiple transfusions,
Avoid medications that effect platelet function, such as aspirin and other NSAIDs.
Consider oral contraceptives to control menorrhagia.

Surgical Care:

To prevent excessive bleeding during surgery, platelets should be transfused pre-operatively.
Further platelet transfusions based on maintaining hemostasis

Consultations:

A hematologist confirms the diagnosis and makes transfusion recommendations.

FOLLOW-UP

Further Outpatient Care:

Regular dental care is recommended to avoid gingival bleeding.

Deterrence/Prevention:

Avoid drugs which 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
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.

Patient Education:

Regular dental care is necessary to avoid gingivitis and gingival bleeding.

TEST QUESTIONS

CME Question 1: What is the inheritance pattern of Glanzmann thrombasthenia?

A: Autosomal dominant
B: X-linked recessive
C: Autosomal recessive
D: Y-linked dominant
E: Glanzmann thrombasthenia is not a heritable disease

The correct answer is C: Glanzmann thrombasthenia is due to defects in GPIIb or GPIIIa. Both of these protein`s genes are on chromosome 17. Fifty percent activity of each protein is enough to support normal platelet aggregation. Therefore, the disease is inherited as an autosomal recessive trait.

CME Question 2: Which of the following drugs can be safely given to a patient with thrombasthenia?

A: Aspirin
B: Ticlopidine
C: Heparin
D: Dipyridamole
E: Gentamicin

The correct answer is E: Aminoglycoside antibiotics such as gentamicin do not alter platelet function, all of the other drugs listed alter platelet function.

Pearl Question 1: What are the results of a complete blood count in a Glanzmann thrombasthenia patient?

The correct answer is: The platelet and white blood cell count would be normal. The red count may be decreased due to bleeding and/or concomitant iron deficiency

Pearl Question 2: How do platelets from a Glanzmann thrombasthenia patient appear on microscopic examination of the blood smear?

The correct answer is: The platelets appear normal.

Pearl Question 3: If an adult patient with no family history of thrombasthenia or any previous bleeding disorder develops a thrombasthenic-like condition, what should be considered in the differential diagnosis?

The correct answer is: Autoantibodies against GPIIb/IIIa have been described which result in a thrombasthenic-like syndrome. This suspicion can be confirmed by demonstrating an inhibitor of platelet function through mixing studies using normal plasma and normal platelets.

Pearl Question 4: How can excessive menorrhagia be managed?

The correct answer is: In addition to platelet transfusion for acute bleeding, menorrhagia can be prevented with use of oral contraception.

BIBLIOGRAPHY

George JN, Caen JP, Nurden AT: Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood 1990 Apr 1; PT - REVIEW, ACADEMIC(7): 1383-95.
Malik U, Dutcher JP, Oleksowicz L: Acquired Glanzmann's thrombasthenia associated with Hodgkin's lymphoma: a case report and review of the literature. Cancer 1998 May 1; PT - REVIEW LITERATURE(9): 1764-8.
Vuckovic SA: Glanzmann's thrombasthenia revisited. J Emerg Med 1996 May-Jun; 14(3): 299-303.

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this textbook have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this text do not warrant the information in this text is accurate or complete, nor are they responsible for omissions or errors in the text or for the results of using this information. The reader should confirm the information in this text from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

Last Modified Date : - Thursday, 14 December 2000

From Medhelp.org: GLANZMANN'S THROMBASTHENIA - A form of congenital platelet functional defect that result in prolongation of the bleeding time. Characteristics include mucosal and post-operative bleeding that may be severe.

From Hemodyne: PCF AND GLANZMANN'S THROMBASTHENIA

Glanzmann's thrombasthenia is an inherited, severe abnormality of platelet functionwhich causes significant bleeding problems. The platelets from such patients contained reduced amount or abnormal forms of GP IIb/IIIa. The term "thrombasthenia" means weak platelets. Glanzmann knew that the platelets were "weak" because clots from such patients did not shrink or express serum.

Although they contained normal numbers of platelets, these clots behaved as if they contained no platelets. In the figure below, PCF in samples from three such patients are compared to a group of normals. The decrease in PCF is not subtle. The kinetics of PCF development in Glanzmann's thrombasthenia are similar to those seen in blood treated with GP IIb/IIIa inhibitors. Indeed, treatment with Reopro is thought to induce a "Glanzmann's-type deficit".

From Cornel Vet : Glanzmann's thrombasthenia

Glanzmann's thrombasthenia (also called thrombasthenic thrombopathia) is an autosomal recessive inherited platelet disorder. This has only been recognized in dogs and has been found in Otterhounds and Great Pyrenees. The defect is due to absent or dysfunctional glycoprotein IIb/IIIa on platelets. GPIIb/IIIa is the platelet fibrinogen receptor and is essential for platelet aggregation (mediated by fibrinogen).

Affected dogs have prolonged bleeding from minor wounds, spontaneous epistaxis and readily form hematomas at sites of injury or venipuncture. The dogs have a normal to mildly decreased platelet count, normal to increased mean platelet volume and a prolonged BMBT. Decreased platelet retention, absent platelet aggregation to collagen, ADP, platelet activating factor and thrombin, and decreased granule secretion are characteristic. Shape change does occur in response to platelet agonists. Clot retraction is abnormal which helps differentiate this disorder from Bassett Hound thrombopathia. The defect can be in the gene of either glycoprotein IIb or IIIa, as both molecules are required for proper receptor functioning. In both Otterhounds and Great Pyrenees, the defect is due to a genetic mutation that affects a calcium-binding domain of the extracellular portion of glycoprotein IIb (each breed has a different mutation).

Epistaxis in a Great Pyrenees dog with Glanzmann's thrombasthenia.
(Photograph provided courtesy of Dr. Boudreaux, Auburn University.)

From Adam.com: Congenital platelet function defects

Alternative names:

Bernard-Soulier syndrome; Glanzmann's thrombasthenia; platelet function defects - congenital; storage pool disease

Definition:

A disorder of platelet function, the blood cells essential for the coagulation of the blood, that is present at birth.

Causes, incidence, and risk factors:

Congenital platelet function defects are bleeding disorders characterized by prolonged bleeding time (the time it takes to form clotting mechanisms in the blood) in spite of normal platelet counts. There is usually a family history of a bleeding disorder consisting of prolonged bleeding or easy bruising. Bernard-Soulier syndrome is a congenital disorder where the platelets lack receptors to adhere to the walls of the blood vessels. Bleeding may be severe with this disorder. Glanzmann's thrombasthenia is a condition which causes mucosal and postoperative bleeding and may also be severe. Storage pool disease is a mild bleeding disorder that causes bruising. The risk factor is a family history of a bleeding disorder.

Dr. Richard Stevens

Glanzmann's disease is otherwise known as Glanzmann's Thrombasthenia and was first described in 1918. It is a hereditary condition (autosomal recessive inheritance) and is therefore more common where consanguineous marriages are common. Clinically, it cannot be distinguished from other platelet disorders.

It commonly presents in infancy or early childhood with multiple bruises and petechial spots following minimal or unrecognisable trauma. Nose bleeds and bleeding from the mouth is common and may be severe. Large muscle bleeds and bleeding into joints are uncommon but menorrhagia (heavy periods) can be severe in girls. Serious accidental or surgical trauma can be life threatening. The severity of the condition appears to subside with age, probably as a result of greater discretion.

The essential diagnostic features are a normal platelet count and morphology and a greatly prolonged bleeding time, associated with a complete failure of platelt aggregation with all agents (ADP, adrenaline, thrombin and collagen) except von Willebrand factor. Having demonstrated the aggregation defect, the diagnosis can be confirmed by measuring the amounts of the platelet glycoproteins Gpllb and llla in the platelet surface membrane which are either deficient or functionally abnormal.

A number of different variants of Glanzmann's disease have been described of differing severity. In type 1 there is a severe (<5%) deficiency of the platelet membrane glycoprotein complex whereas in type ll the deficiecy is mild (5 to 20%). Type lll has also been described where the glycoproteins are present in normal or near normal amounts, but are functionally defective. The genes for both glycoproteins llb and llla are contained on chromosome 17. Many different gene abnormalities (in different families) can give rise to the clinical condition.

Carriers (heterozygotes) for Glanzmann's disease usually have no significant bleeding symptoms and have normal platelet function tests. Their platelets, however, express about half the normal number of glycoprotein llb/llla complexes. The condition can be diagnosed pre-natally from foetal blood samples, but carries a high risk to an affected person from continuing haemorrhage. If the molecular defect is known (which is not often the case), diagnosis can be performed at 8 to 10 weeks gestation using chronic villus sampling and the use of DNA probes. It is important to remember that detailed counselling of the parents is necessary before antenatal diagnosis, which is contra-indicated if the parents wish the pregnancy to continue even if the foetus is affected.

The only curative treatment for Glanzmann's disease is bone marrow transplantation. The risks of this procedure are considerable, however, so as to confine its use to patients in which severe bleeding cannot be adequately by more conservative measures. Meanwhile, the management of Glanzmann's disease consists of the avoidance of trauma and medicines such as aspirin, which may further affect platelet function, and the treatment of major bleeding episodes by platelet transfusion. Minor bleeding from accessible sites (eg teeth and gums) can be controlled by local application of thrombin and adrenaline solutions. Severe nose bleeds may require nasal packing and platelet transfusions. Antifibrinolytic drugs, such as Tranexamic acid (Cyclokapron) may help control bleeding and tooth decay. Heavy periods (menorrhagia) may be a problem and may require hormonal therapy for control.

Excessive platelet transfusions should be avoided because of their risk of developing platelet antibodies. These may be antibodies directed against the glycoprotein llb/llla complex or against other more common platelet (HLA) determinants. HLA matched platelets may be necessary. White cell filtration of platelets may reduce the likelihood of developing platelet antibodies.

Dr. Richard Stevens
Royal Manchester Childrens Hospital Pendelbury 1999

Dr. Richard Stevens, Consultant Haematologist/Oncologist, Royal Manchester Children's Hospital, Manchester, UK. August 2001

Normal handling of infants can cause superficial bruises. Epistaxis (nose bleeds) in childhood and menstrual bleeding can cause problems.

Bone marrow transplantation is the only curative form of treatment. However this is generally considered more hazardous than the condition except in exceptional circumstances.

Inheritance patterns
Autosomal recessive, carriers can now be detected.

Medical text last updated August 2001 by Dr R F Stevens, Consultant Haematologist/Oncologist, Royal Manchester Children's Hospital, Manchester, UK.

GLANZMANN'S THROMBASTHENIA CONTACT GROUP

Marilyn Buxton Glanzmann's Thrombasthenia Contact Group
28 Duke Road Newton Hyde
SK14 4JB Tel 0161 368 0219
e-mail: glanzmannsupport@btopenworld.com
This is a Contact Group founded in 1990.