Rare Glanzmann Thrombasthenia Critical for the Understanding of ... - ASH Publications

Fast Facts: Glanzmann thrombasthenia

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Swiss pediatrician Eduard Glanzmann published the original clinical description of Glanzmann thrombasthenia (GT) in 1918.¹ In 1973, GT went on to play a pivotal role in hematology when it was proposed that the clinical presentation of GT resulted from missing glycoproteins (GP) on platelets. Alan T. Nurden, PhD, emeritus research director of Centre Nationale de la Recherche Scientifique in Paris, and Jacques Caen, MD, emeritus professor at the Académie Nationale de Médecine in Paris, made this discovery by applying electrophoretic procedures to the platelets of patients with GT.

Their work stimulated worldwide investigations that shed light on the complexity of the platelet surface constituents and revealed that, once activated, the GP IIb/IIIa complex (now known as the αIIbβ3 integrin) becomes the receptor for fibrinogen. As such, it forms the basic link between platelets and the fibrin network that forms around a clot. The platelets of patients with GT lack the αIIbβ3 integrin and are thus unable to adequately form a hemostatic plug. This accounts for the bleeding diathesis of patients with GT.

Studies of the mutations of αIIbβ3 that cause the clinical presentation of GT have resulted in critical insights into integrin structure and function and have paved the way for an understanding of platelet aggregation. This year marks the 50th anniversary of the seminal discovery by Drs. Nurden and Caen. Dr. Nurden explained that "Glanzmann has been a landmark disease for hematologists. It's the most studied rare platelet disorder."

Development and Presentation

An extremely rare coagulopathy, GT can present with hemorrhage, normal full blood count, and a significantly prolonged bleeding time. It can be classified as type I, type II, or type III. In the type I subgroup, patients have less than 5% of the normal GP IIb/IIIa receptor levels, whereas 5% to 20% of the receptors are present in type II. Patients with type III have expressed but nonfunctional αIIbβ3.

GT occurs primarily as the result of a spontaneous gene mutation that can be inherited in an autosomal recessive manner. It is genetically heterogeneous, caused by hundreds of mutations that can have different presentations. "Some of the patients will have enough integrin to allow the platelets to function, at least partially," said Dr. Nurden, explaining it is difficult to predict the bleeding tendency simply by the gene mutation.

Experts estimate GT affects one in one million individuals worldwide. In populations or regions with high consanguinity, however, the prevalence may be one in 200,000 or higher. Iran, Pakistan, and the Canadian province of Newfoundland and Labrador are some of the areas with a higher prevalence. Of note, because some patients have mild symptoms and therefore may never be diagnosed, the actual prevalence may be higher than reported.

GT can also be acquired when patients develop antibodies to GP IIb/IIIa.² In some rare cases, GT is acquired as an accompaniment to immune thrombocytopenic purpura (ITP) and may become more obvious post-splenectomy as destruction of antibody-bound platelets is inhibited and it becomes technically easier to assess platelet function. Autoimmune platelet dysfunction without thrombocytopenia is also possible and is likely underrecognized and may be underdiagnosed. Patients may also develop acquired GT in association with autoimmune disorders or malignant lymphoid disorders such as Hodgkin or non-Hodgkin lymphoma. In addition, therapeutic monoclonal antibodies to αIIbβ3, such as abciximab, can have a bleeding risk, while blood transfusion or pregnancy can give rise to allo-antibodies that bind to GP IIb/IIa.

Patients with GT present with normal platelet counts but abnormal bleeding, often in the mouth and nose. The increased mucosal bleeding can include heavy menstrual bleeding, easy bruising, and nosebleeds. The bleeding tendency is variable, with some patients having minimal bruising and others having frequent severe, potentially fatal hemorrhages. Unlike in hemophilia, patients with GT do not experience bleeding in their joints. Donald Arnold, MD, professor of medicine at McMaster University, in Hamilton, Ontario, explained that patients with GT often present from birth with excessive bruising simply from moving around in the cradle, and noted that bruising tends to lessen as patients age.

Diagnosis

The clinical expression of disease can be varied and, unfortunately, the diagnosis of GT can be easily missed, Dr. Arnold noted. The gold standard for diagnosis is light transmission aggregometry to assess platelet function. If a patient lacks platelet aggregation to adenosine diphosphate, epinephrine, collagen, and thrombin, the findings are highly specific for GT. Unfortunately, there are no readily available tests to evaluate bleeding risk under the flow conditions of the microcirculation.

Patients typically present at childhood with bleeding, and hematologists will note that routine coagulation test results are normal and that the patient's platelet count number does not fit with the bleeding profile. "Other investigations have to be done deliberately because they aren't routine," Dr. Arnold said. He explained that the platelet aggregation test can also be paired with flow cytometry for even more information about the platelets.

Dr. Arnold noted that certain symptoms should raise the index of suspicion for GT. These include nosebleeds that continue for minutes, large and painful bruises, significant bleeding after trauma, and menstruation that is so heavy that it limits activities outside of the house. He emphasized that the clinical presentation can vary a great deal, however, and some patients may just have nosebleeds. "If something is not feeling right about a patient's bleeding history," said Dr. Arnold, "if that sense is tingly and the regular hematology tests are normal, do additional investigations."

Treatment

Although there is no cure for GT, diagnosis can "alleviate a whole bunch of anxiety on the part of the patient," Dr. Arnold said. Once diagnosed, patients can take advantage of resources, such as those provided by Glanzmann's Research Foundation (GRF; curegt.org) in the U.S. GRF not only works to increase awareness of GT, but it also provides a network of support for families navigating a GT diagnosis and raises funding to find a cure.

Therapy for GT involves both preventive measures and treatment of specific bleeding episodes. Lawrence Leung, MD, the Maureen Lyles D'Ambrogio Professor of Medicine at Stanford University School of Medicine in Palo Alto, California, cautions patients to be careful and avoid the normal antiplatelet therapies such as aspirin and non-steroidal anti-inflammatory drugs. Because most patients with GT lack platelet GP IIb/IIIa, they are prone to making an antibody response to transfused platelets. Platelet transfusion should thus be minimized, and patients should be monitored for both antiplatelet and antibodies against human leukocyte antigens (HLA). Likewise, patients with autoimmune GT are likely to be resistant to straightforward platelet transfusion. Fortunately, autoimmune GT often remits spontaneously and may respond to conventional immunosuppressive treatment.

When patients with GT require surgery, the surgical team should be informed in advance that the patient has a bleeding disorder, and a multidisciplinary approach should be taken to optimize platelet function, Dr. Arnold explained. This could include use of aminocaproic acid to enhance hemostasis when fibrinolysis contributes to bleeding. In addition, recombinant coagulation factor VIIa can also be used to prevent or treat bleeding. Factor VIIa has a U.S. Food and Drug Administration indication for people of all ages with hemophilia A or B with inhibitors, congenital factor VII deficiency, GT when platelets don't work, and adults with acquired hemophilia. It was introduced in the U.S. in March 1999 and is approved for use before, during, and after surgery. Factor VIIa promotes platelet-fibrin interaction on the activated platelet surface in a tissue-factor-independent manner, and Dr. Arnold suggested that factor VIIa be kept on reserve for elective surgeries and possibly even used preventively. He noted, however, that its effects are short-lived, lasting perhaps two hours.

Dr. Nurden explained that patients with life-threatening bleeding can also receive human allogeneic hematopoietic cell transplants to restore hemostasis.³ Such transplants were first performed in Paris in the early 1980s, first in a brother and later his sister, both of whom had severe type I GT and antibodies to αIIbβ3, which made them refractory to transfusion. Both brother and sister received bone marrow transplants from an asymptomatic sibling; the transplants restored platelet function and αIIbβ3 expression, and the results have been stable for years.

In January, Hemab Therapeutics dosed its first patient in its phase I/II study of the bispecific antibody HMB-001 to be used as a prophylactic treatment for GT.⁴ The phase I/II open-label study was designed to evaluate safety, tolerability, and biomarkers such as factor VII levels and bleeding time before and after HMB-001 treatment. The antibody binds endogenous factor VIIa with one antibody arm and TLT-1 on activated platelets with the other arm. It is expected to stabilize endogenous factor VIIa and recruit it to the site of vascular injury. Preclinical data have shown that HMB-001 potentiates fibrin formation at hemostatic lesions in patients in GT and brings factor VIIa to levels that are considered therapeutically effective. If clinically effective, HMB-001 would be the first prophylactic treatment option for patients with GT.

Prognosis

The Glanzmann phenotype can change over a patient's lifetime as the whole homeostatic system adapts to the mutation. That, in combination with the rarity of the disease, means it is difficult to describe a typical prognosis. Nevertheless, many patients worldwide have been followed for decades and their stories may provide insights into what can be expected during the clinical journey.

For example, Dr. Leung has spent 30 years following one of the first patients in the U.S. to be diagnosed with GT.⁵ The patient has type I GT as confirmed by flow cytometry, with a platelet-specific expression of GP IIb and GP IIIa that is 0% to 0.1% of normal. He has survived both ankle surgery and arterial valve replacement.

Dr. Leung's patient underwent open aortic valve replacement with cardiopulmonary bypass to treat his severe aortic valve stenosis secondary to bicuspid valve disease. The surgery was performed without perioperative bleeding complications, and Dr. Leung and colleagues published the roadmap in a case study. They wrote that, because the patient had significant anti-HLA antibodies, the treatment team preoperatively collected 51 plateletpheresis units from selected matched donors as directed units for the patient. The patient received 35 apheresis platelet units: 10 units on the day of surgery and 25 units postoperatively over the ensuing four days. The team used thromboelastograms (TEG) in conjunction with traditional hematologic laboratory analysis to optimize clinical management but found that the patient experienced persistent microvascular bleeding despite a normal-appearing TEG. Thus, they administered 5 mg of recombinant factor VIIa in divided doses over 30 minutes and were able to achieve hemostasis. They chose a dose of factor VIIa that was less than that approved for the treatment of hemophilia to minimize potential thrombotic complications in the postoperative setting.

Dr. Nurden has also published the description of a patient studied by David Wilcox, PhD, and his group at the Medical College of Wisconsin in Milwaukee.6 The patient was a boxer in his mid-40s who was diagnosed with a mild form of GT at the age of five. The patient had a novel mutation of F153Sβ3, which permits fibrinogen binding and receptor-mediated endocytosis. This rare gain-of-function mutation in the β1-domain of αIIbβ3 resulted in a constitutively active conformation that nevertheless results in significantly altered normal integrin/platelet function.

Even with the diagnosis of GT, the Milwaukee patient engaged in life-long strenuous physical activities and contact sports without serious bleedings. He underwent dental procedures without preventive therapy and did not bleed excessively. His diagnosis of GT did mean, however, that during major trauma and surgeries he received platelet transfusion, recombinant factor VIIa, and antifibrinolytics.

Conclusion

Although GT remains rare, its existence continues to advance hematology. "Investigating why GT platelets don't aggregate did lead to enormous insight and understanding of the mechanism of platelet aggregation in the 1980s that has translated into an effective therapeutic and a new class of antiplatelet agents (GP IIb/IIIa antagonists)," Dr. Leung said. Hopefully, if HMB-001 is safe and effective, patients will also have a much-needed treatment option.

References

1. Nurden AT. The GPIIb-IIIa defect of platelets in Glanzmann thrombasthenia. Haematologica. 2023;108(4):937-938.
2. Tholouli E, Hay CRM, O'Gorman P, Makris M. Acquired Glanzmann's thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder. Br J Haematol. 2004;127(2):209-213.
3. Nurden A. Profiling the genetic and molecular characteristics of Glanzmann thrombasthenia: can it guide current and future therapies? J Blood Med. 2021;12:581-599.
4. Hemab Therapeutics. Hemab Therapeutics announces first patient dosed in phase 1/2 study of HMB-001 to treat bleeding disorder Glanzmann thrombasthenia. January 10, 2023. Accessed July 1, 2023. https://www.prnewswire.com/news-releases/hemab-therapeutics-announces-first-patient-dosed-in-phase-12-study-of-hmb-001-to-treat-bleeding-disorder-glanzmann-thrombasthenia-301717243.html.
5. Sheikh AY, Hill CC, Goodnough LT, et al. Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion. 2014;54(2):300-305.
6. Koukouritaki SB, Thinn AMM, Ashworth KJ, et al. A single F153Sβ3 mutation causes constitutive integrin αIIbβ3 activation in a variant form of Glanzmann thrombasthenia. Blood Adv. 2023;7(13):3180-3191.

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