Acquired Glanzmann's Thrombasthenia Associated with Hodgkin Lymphoma: Rapid Reversal of Functional Platelet Defect with Chemotherapy Despite Persistence of a Glycoprotein Iib/Iiia Auto-Antibody

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4656-4656
Author(s):  
Vinod Raman ◽  
Karen Quillen ◽  
John Mark Sloan
Keyword(s):  
Platelet Aggregation ◽  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Bone Marrow Aspiration ◽  
Bleeding Tendency ◽  
Glanzmann’S Thrombasthenia ◽  
Normal Platelet ◽  
Glanzmann's Thrombasthenia ◽  
Functional Defect ◽  
Platelet Antibody

Abstract Abstract 4656 Background: Acquired Glanzmann's Thrombasthenia (GT) is a rare hemorrhagic disorder characterized by the impairment of platelet function caused by inhibition of GpIIb/IIIa signaling, often by an autoantibody. This disorder has been associated with lymphoproliferative and autoimmune disease. Case: A previously healthy 44 year old male presents with severe spontaneous nasal, gingival, and gastrointestinal bleeding with mildly elevated INR and aPTT and normal platelet count in the setting of newly diagnosed stage IVB classical Hodgkin lymphoma, Nodular Sclerosis type. At presentation, platelet aggregation studies showed no aggregation with ADP, epinepherine, and arachidonic acid, with preserved ristocetin aggregation. An anti-platelet antibody was detected. Bone marrow aspiration showed megakaryocytes that were increased in number with occasional atypical forms. Patient was started on ABVD chemotherapy for Hodgkin lymphoma with immediate resolution of bleeding diathesis. Repeat platelet aggregation after cycle 2 of ABVD showed normalization of platelet aggregation. Despite the clinical resolution of bleeding tendency and functional platelet defect, a persistent anti-platelet antibody directed against GPIIb/IIIa receptor was detected. Conclusion: Acquired Glanzmann thrombasthenia is a rare disorder of hemostasis associated with lymphoma and autoimmune conditions. The prompt reversal of the functional defect with chemotherapy in this patient, as well as the persistence of the GpIIb/IIIa antibody, suggest that there may be additional additional lymphoma-specific factors that modify the effect of the autoantibody. Disclosures: No relevant conflicts of interest to declare.

First Report of Transheterozygosity in a Patient with An Inherited Platelet Bleeding Disorder Due to Mutations in the Thromboxane A2 Receptor (TBXA2R) and cyclooxygenase1 (PTGS1),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3260-3260
Author(s):  
Kathleen Freson ◽  
Chantal Thys ◽  
Christel Van Geet
Keyword(s):  
Platelet Aggregation ◽  
Autosomal Recessive ◽  
Conflicts Of Interest ◽  
Autosomal Recessive Disorder ◽  
Bleeding Disorder ◽  
Bleeding Complications ◽  
Normal Platelet ◽  
First Case ◽  
Functional Defect ◽  
Sequencing Platforms

Abstract Abstract 3260 Platelet aggregation by thromboxane (TBXA2) stimulation of its G protein-coupled receptor TXA2R is initiated after conversion of arachidonic acid (AA) into prostaglandin H2 (PGH2) by cyclooxygenase1 (PTGS1) and subsequently by conversion of PGH2 into TXA2 by thromboxane synthase (TBXAS1). Hirata et al (JCI, 1994) reported the first TBXA2R mutation that resulted in reduced platelet responses to U46619 and low AA concentrations in subjects with a heterozygous R60L mutation. This functional defect in combination with mild clinical bleeding problems was only described for the one patient that was homozygous for this mutation. A second TBXA2 patient with an obvious bleeding diathesis carried a heterozygous D304N mutation but it was reported that this variant by itself could not explain the bleeding phenotype as other family members heterozygous for D304N presented with abnormal aggregation responses but no bleeding problems (Mumford, Blood, 2010). Functional SNPs in PTGS1 were described in pharmacogenetic studies including the L237M variant with 50% reduced COX1 metabolic activity but its effect on platelet function was not studied (Lee CR, Pharmacogenet Genomics, 2007). We here describe a 6-year old patient with ecchymosis, easy bruising and important post-traumatic bleeding complications after adenotonsillectomy and circumcision. The boy presents with normal coagulation parameters, normal platelet count and MPV, structurally normal platelets, normal ATP secretion by collagen, and the PFA100 closure time was normal for Col/Epi and mildly prolonged for Col/ADP. Platelet aggregation studies further showed an absent response to 1 mM AA as determined on different occasions, a reduced but not absent response to U46619 and a normal activation with ADP, ristocetin and Horm collagen. His parents and sister presented with increased sensitivity for ecchymoses but none had severe clinical bleeding problems and their platelets showed normal aggregation responses except for the father and sister with a reduced though not absent response to AA. Thromboxane B2 formation was determined and found to be normal in basal (plasma) and maximal stimulated (serum) conditions. In contrast, TXB2 levels were decreased after activation with U46619 for the patient but also for the father and sister compared to the control or mother. Activation with AA also resulted in reduced TXB2 levels for the patient and mildly reduced levels for all other family member compared to controls. This strongly suggests the presence of an autosomal recessive disorder. The TBXAS1, PTGS1 and TBXA2R genes were sequenced for the patient and we identified two heterozygous mutations in separate genes being R60H in TXBA2R and the functional L237M variant in PTGS1. Interestingly, his mother carried the L237M variant while R60H was present in father and sister with similar functional platelet defects as earlier described for the other heterogenous TBXA2R mutations but no clinical bleeding symptoms. To our knowledge, this is the first case of transheterozygosity for mutations explaining an autosomal recessive bleeding disorder. We hypothesize that this pattern of inheritance might be more common than expected and therefore this possibility should be taken into account when analyzing patients in the future using exome or genome wide sequencing platforms. Disclosures: No relevant conflicts of interest to declare.

GLANZMANN'S THROMBASTHENIA IN PREGNANCY: CLINICAL FEATURES AND PLATELET SEROLOGY

1987 ◽  
Author(s):  
M Picó ◽  
A Ribera ◽  
C Martin ◽  
J Zuazu ◽  
J Monasterio
Keyword(s):  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Antigenic Site ◽  
Type I ◽  
Glanzmann’S Thrombasthenia ◽  
Negative Results ◽  
Normal Platelet ◽  
Glanzmann's Thrombasthenia ◽  
Neonatal Thrombocytopenia ◽  
Platelet Antibody

A 24-year-old woman with a diagnosis of Glanzmann's Thrombasthenia (GT) type I (confirmed in our Hemostasis Section by sodium dodecyl sulphate-polyacrylamide gel electrophoresis) and with a history of several transfusions, was seen in our Service since the second month of her first pregnancy.In the first visit a strong anti-Rh(D) antibody was found in her serum. In 28th week an ammiocentesis was done. Seventy two hours later, she was hospitalized because of disminution of foetal movements. Then, a platelet-allo-antibody, IgG+IgM type (title IgG 1/512, IgM 1/2) was detected in her scrum by immunofluorescence test, as well as an anti-HLA antibody (by lymphocytotoxicity test) which reacted with her husband lyin-phocites.The platelet antibody wasn't EDTA or Paraformaldehide (PFA) dependent and reacted with all normal platelets of a panel of known platelet phenotypes and, also although significantly weakly, with GT type II platelets. The negative results were only observed with GT type I platelets. Therefore, it seemed to recognize an antigenic site located in GP IIb-IIIa. Besides, this antibody inhibited the normal platelet aggregation.A caesarian was advised because of foetal suffering an was performed without immediate complications. The patient was protected by our hemotherapy established support and delivered a boy with a severe hemolytic disease (Hematocrit: 6%, bilirrubine: 1,9 mgs./lOCimls., platelets: 40.000/ mm3), who died 48h. later. His platelets had a direct positive test IgG type and in his serum the platelet antibody as in his mother's was detected.We discuss the specificity of the antibody detected and also, its possible implication in the neonatal thrombocytopenia.

Antigenic Properties And Structure Of Membrane Glycoprotein Receptors

1981 ◽  
Author(s):  
T J Kunicki
Keyword(s):  
Platelet Aggregation ◽  
Platelet Adhesion ◽  
Membrane Glycoproteins ◽  
Glanzmann’S Thrombasthenia ◽  
Normal Platelet ◽  
Glanzmann's Thrombasthenia ◽  
Antigenic Properties ◽  
Normal Hemostasis ◽  
Triton X

Membrane glycoproteins (GP) IIb and IIIa are not detectable on the platelets of a majority (Type 1) of patients with Glanzmann’s thrombasthenia, a hereditary disorder of platelet function characterized by an absence of platelet-platelet adhesion. These platelets also do not express the human platelet alloantigen, PlA1, a finding which led to the demonstration that the PlA1 alloantigen is associated with GPIIIa, but not with GPIIb. Alloantibodies directed against the PlA1 determinant or certain other determinants associated with GPIIb and/or GPIIIa appear to be capable of inhibiting normal platelet- platelet adhesion, suggesting that these glycoproteins function as key mediators of this process, an obligate step in normal hemostasis. Subsequent studies have supported this hypothesis by demonstrating that fibrinogen, which is known to be a key cofactor in normal platelet aggregation, does not bind to thrombasthenic platelets.We have used crossed immunoelectrophoresis of Triton X-100 soluble membrane glycoproteins against a multispecific rabbit antibody to quantitate levels of GPIIb and GPIIIa on normal and thrombasthenic platelets and to study the interaction of these two glycoproteins in a soluble nondenatured state. These studies have provided information on 1) the inheritance of PlA1 and the glycoprotein IIb/IIIa defect in Glanzmann’s thrombasthenia, and 2) reversible Ca++-dependent changes in the orientation of GPIIb and GPIIIa, which may contribute to understanding of the function of these glycoproteins in normal platelet aggregation. In the presence of sufficient Ca++, glycoproteins IIb and IIIa were found to exist only in heterogenous complexes, whether within isolated membranes, or in solution. Chelation of Ca++ by EDTA or EGTA resulted in the dissociation of these glycoproteins; reassociation could be induced by readdition of excess Ca++.

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

scholarly journals "Impotent" Platelets in Albinos With Prolonged Bleeding Times

Blood ◽  
1972 ◽  
Vol 39 (4) ◽  
pp. 490-499 ◽  
Author(s):  
Harold M. Maurer ◽  
James A. Wolff ◽  
Sue Buckingham ◽  
Arthur R. Spielvogel
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Bleeding Tendency ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Tryptophan Metabolites ◽  
History Of

Abstract Functional, biochemical, and morphologic platelet abnormalities are reported in four children with the syndrome of albinism, mild bleeding tendency, prolonged bleeding time, and normal platelet count. In these children, primary platelet aggregation with adenosine diphosphate occurred normally, but secondary aggregation was impaired. Collagen and norepinephrine produced almost no platelet aggregation. Platelet content of serotonin (5-HT) was markedly reduced, and uptake and retention of 5-HT by the platelets in vivo and in vitro was poor. In one child who was given a tryptophan load, urinary tryptophan metabolites were normal, suggesting that there was no evidence of a block in the 5-HT synthetic pathway in the gastrointestinal tract. Electron microscopy revealed an absence of densely osmophilic granules in 5-HT poor platelets. Platelets from other albinos with no history of bleeding contained normal amounts of 5-HT and densely osmophilic granules.

Acquired Glanzmann's thrombasthenia: Diagnosis aided by platelet aggregation mixing study

Haemophilia ◽  
2020 ◽  
Vol 26 (2) ◽  
Author(s):  
Frances Compton ◽  
Ravi Sarode ◽  
Cynthia Rutherford ◽  
Brian Curtis ◽  
Nicole De Simone
Keyword(s):  
Platelet Aggregation ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

Glanzmann’S Thrombasthenia: Pregnancy And Parturition

1981 ◽  
Author(s):  
S B Sundqvist ◽  
I M Nilsson ◽  
L Svanberg ◽  
S Cronberg
Keyword(s):  
Platelet Rich Plasma ◽  
Specific Treatment ◽  
Coagulation System ◽  
Drug Induced ◽  
Glanzmann’S Thrombasthenia ◽  
Normal Platelet ◽  
Biparietal Diameter ◽  
Glanzmann's Thrombasthenia ◽  
Tissue Antigens ◽  
Gestational Week

A 35-y-old patient with severe Glanzmann's thrombasthenia became pregnant. Only four such cases are so far known. Two of them were treated successfully with platelet concentrates. Our patient, who had received multiple transfusions, had antibodies against tissue antigens. These were of IgG type. PIPA-test (Kekomäki, R. Medical Biology 54:112, 1977) verified the presence of platelet antibodies. The second wave of aggregation induced by ADP in normal platelet-rich plasma was inhibited by her IgG fraction. Transfusion of HLA matched platelets did not result in any survival of the transfused platelets in her circulation, as revealed by the absolutely absence of aggregability even after the transfusion. Thus no specific treatment was available.During the 24-32 weeks there were signs of activation of the coagulation and the fibrinolytic systems in the form of a decreasing number of platelets and the presence of FDP and fibrin monomers. VIII:C and VIIIR:Ag were remarkably low throughout the pregnancy and the fibrinogen content did not reach the upper limit of the reference area. The oestriol content in plasma and the biparietal diameter as measurements of the condition of the foetus, remained normal during this period, but there was an unexplainable decrease of the plasma oestriol content during the last month of pregnancy.When signs of activation of the coagulation system had disappeared, tranexamic acid was given as prophylaxis (Astedt and Nilsson, Br Med J 1:756, 1978). Apart from transient haematuria in the 24th week of gestation, no complications were seen during the rest of the pregnancy.In the 42nd gestational week the patient delivered a boy, spontaneously per vaginam. No abnormal bleeding occurred either during or after the delivery. Intense and prolonged drug induced contraction of the uterus might have helped to decrease the bleeding. No transfusion of platelets or blood was given.

Bortezomib In Combination with Dexamethasone and Liposome- Adriamycin Chemotherapy Regimen for Relapsed and Refractory Hodgkin Lymphoma: A Case Report

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4829-4829
Author(s):  
Yi Li ◽  
Gaofeng Zheng ◽  
Xiaoyan Han ◽  
Jimin Shi ◽  
Jingsong He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hodgkin Lymphoma ◽  
Radiation Treatment ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Bone Marrow Aspiration ◽  
Salvage Chemotherapy ◽  
New Combination ◽  
Dependent Manner ◽  
Line Therapy

Abstract Abstract 4829 Bortezomib is effective in multiple myeloma, but also in other malignancies, particularly in lymphoma. Here we present a-23-year-old-male patient who complained of a progressive chest pain for 2 years. The CT scan of local hospital showed a mass that measured 5×14cm in the anterior mediastinum. He also had multiple lymphadenopathies in other areas. Tissue biopsy verified Classical Hodgkin lymphoma, nodular sclerosis (NDHL) IIIA. Then he had 12 cycles of ABVD, 1 cycle of MINE and CHOPE, 2 cycles of Hyper-CVAD regimen as prior treatments. Initial therapies induced good responses, but his disease progressed before he was transferred to hospital on December 29, 2009. His blood counts showed that WBC 30×10E9/L, with 89% neutrophils, Hb 99g/L, platelet 452 ×10E9/L. Bone marrow aspiration with immunophenotyping, analysis of TCR/IgH and the chromosome were normal. Biopsy reconfirmed the diagnosis of Hodgkin lymphoma. Lymphoma masses in his right neck, and severe edema with his right arm. He was treated with 2 cycle of IGVP regimen (ifosfamide, gemzar, vindesine, prednsone) and 2 cycles of GIP regimen (ifosfamide, gemzar, prednsone). With more progression, he subsequently received methotrexate and Ara-c with minimal response. Two weeks later, CT showed lung infection and pleural effusion, multiple lymphadenopathy. Lymph nodes decreased mildly and edema disappeared temporary after 3 cycles of R-CHOP. He was then treated with Bortezomib, dexamethasone and L-ADM. Four days after the first cycle, lymphoma masses decreased and significantly and his edema resolved. Due to the severe periphery neuropathy, he declined bortezomib, so 2 weeks later, the symptoms back again, and the FMD regimen (fludarabine, mitoxantrone, dexamethasone) was given. He then chose palliative radiation treatment and eventually died of pneumonia. Nearly 30%-40% of Hodgkin lymphoma relapsed after first line therapy even responds well at the initial stage. To these relapsed ones, the second line therapy including salvage chemotherapy and ASCT (autologous stem cell transplantation) act as the major treatment, but only a minority patients benefit from it. Treatment is limited to relapse and refractory ones hence they deserved more focus. The Bortezomib + L-ADM regimen exhibiting its efficacious after two cycles and the condition changed obviously. Our case is showing more antitumor activity of the new combination relative to either single agent alone. The new regimen responded well and with milder bone marrow suppression. Further study is still needed to demonstrate the relationship between the effective duration and treatment cycles. Some results showed that bortezomib inhibited cell proliferation and induced apoptosis in HL cell lines in a dose-dependent manner. At the same time, it is imperative to be aware of the adverse effects, such as peripheral neuropathy, thrombocytopenia and herpes zoster. As the patient mentioned above, the new regimen may work more optimally if more cycles were carried out, and he would have eventually responded if the complication was well controlled. Disclosures: No relevant conflicts of interest to declare.

Diagnosis of Heterozygotes in Glanzmann’s Thrombasthenia

1982 ◽  
Vol 48 (02) ◽  
pp. 217-221 ◽  
Author(s):  
H Stormorken ◽  
G O Gogstad ◽  
N O Solum ◽  
H Pande
Keyword(s):  
High Reliability ◽  
Type I ◽  
Bleeding Tendency ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Immunochemical Methods

SummaryA study of a family with a propositus suffering from classical thrombasthenia type I has shown that the new immunochemical methods detect heterozygotes with high reliability. There was no overlapping between heterozygotes and normals, and the concentration of the glycoprotein IIb-IIIa-complex is remarkably constant around 50–60% in the heterozygotes. Furthermore, heterozygotes as a group show an increased bleeding tendency.

A New Dysfibrinogenemia: Fibrinogen Oslo IV

1983 ◽  
Vol 49 (02) ◽  
pp. 120-122 ◽  
Author(s):  
H Stormorken ◽  
F Brosstad ◽  
H Seim
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Normal Value ◽  
Normal Platelet ◽  
Fibrinogen Binding ◽  
Successive Generations

SummaryA family with dysfibrinogenemia is described. The abnormal fibrinogen occurred in three successive generations indicating a dominant hereditary pattern. Thrombin and reptilase times were about twice the normal value. This was shown to be caused by a polymerization defect, fibrinopeptide release being normal. Platelet aggregation was undisturbed, indicating normal platelet-fibrinogen binding. The bleeding time was normal and there was no bleeding tendency. However, an obscure recurrent pulmonary ailment may, or may not, be related to the dysfibrinogenemia. The abnormal fibrinogen was tentatively termed Oslo IV.

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