Hereditary Thrombocytopenia Research Articles

Hereditary Thrombocytopenia due to Reduced Platelet Production

Hereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.

An operation on a follicular dental cyst performed on a patient with hereditary thrombocytopenia

An operation on a follicular dental cyst performed on a patient with hereditary thrombocytopenia

The sebastian platelet syndrome report of the first native Saudi Arabian patient

Sebastian platelet syndrome is an hereditary thrombocytopenia with giant platelets and inclusion bodies in the granulocytes consisting of dispersed filaments, clusters of ribosomes and a few segments of rough and smooth endoplasmic reticulum at the ultrastructural level, similar to those observed in Fechtner syndrome (a variant of the Alport syndrome)--Sebastian platelet syndrome lacks the additional clinical features such as high frequency deafness, congenital cataract, and chronic interstitial nephritis. Here we report the fourth case worldwide and the first of an Arabian ancestry.

Familial macrothrombocytopenia associated with decreased glycosylation of platelet membrane glycoprotein IV

A case of hereditary thrombocytopenia with large platelets (familial macrothrombocytopenia, FM) is reported. Studies on the platelets from the propositus showed decreased glycosylation of platelet membrane glycoprotein IV, which would distinguish the case from other FM previously described.

Hereditary types of thrombocytopenia with giant platelets and inclusion bodies in the leukocytes

Three forms of hereditary thrombocytopenia with giant platelets and inclusion bodies in the leukocytes have thus far been recognized. The May-Hegglin anomaly is characterized by giant platelets and spindle-shaped inclusion bodies in the leukocytes, which consist of 7-10 nm parallel-lying filaments. The Fechtner syndrome is a variant of the Alport syndrome, with inclusion bodies consisting of dispersed filaments, ribosomes and a few segments of rough and smooth endoplasmic reticulum. The Sebastian platelet syndrome shows the same platelet and leukocyte morphology observed in the Fechtner syndrome, but the additional anomalies e.g., the Alport syndrome, are lacking. The clinical signs and symptoms are variable. Most patients show only a mild bleeding tendency or are asymptomatic, but cases of severe postoperative hemorrhage have also been reported. Platelets can vary greatly in number, but are usually in the range of 20,000 to 120,000 platelets/microliters, showing a mean platelet volume of 15-20 fl, unimpaired in vitro function and, in addition to their size and unorganized microtubular system, normal morphology. To date, no platelet membrane defects have been defined. Because the megakaryocyte number and platelet kinetics are normal, the pathogenesis of thrombocytopenia in these giant platelet syndromes is unresolved; this is also true of the leukocyte inclusion bodies. Because of the ubiquity of electronic particle counters, asymptomatic patients are increasingly being identified, but they are often misdiagnosed as having autoimmune thrombocytopenia.

Hereditary thrombocytopenia with excessively prolonged bleeding time, corrected by infusions of platelet poor plasma.

In a family with hereditary thrombocytopenia, transfused normal platelets as well as their own platelets had a shortened survival in the patients' circulation (11). On the other hand, the patients' platelets survived normally when transfused to a normal recipient. Platelet-associated immunoglobulins or circulating platelet antibodies were not detected (immunofluorescence method). About 200 ml platelet poor plasma (PPP) from each of 4 normal donors was infused daily for 5 consecutive d to 1 afflicted family member, causing a rise of platelet count from 65 X 10(9)/l to 163 X 10(9)/l and a decrease of bleeding time from 28 to 11 min 7 d after the PPP was discontinued. The platelet count then gradually decreased and was 65 X 10(9)/l with a bleeding time of 30 min 16 d after the PPP was discontinued. In a repeated PPP infusion experiment a similar response was evoked. It is concluded that the afflicted family members must have a deficiency of some plasma principle necessary to keep platelets fit and circulating.

Inherited Thrombocytopenia, Elevated Serum IgA and Renal Disease: Identification as a Variant of the Wiskott-Aldrich Syndrome

A kindred with X-linked hereditary thrombocytopenia in association with elevated serum IgA and a mild nephropathy is described. Thirteen males with thrombocytopenia were identified in three generations amongst 49 family members who were available for screening. Serious infective sequelae were absent but five patients had suffered from severe eczema since infancy. The platelet volume as measured by an automated counter and electron microscopy was reduced compared with normal and in vitro tests demonstrated minor abnormalities of immune function in three patients. The disorder is identified as a novel variant of the Wiskott-Aldrich syndrome and comparisons are made with previously described kindreds showing different patterns of expression.

Thrombocytopenia Due to Defective Platelet Production

An increasing number of kindreds with thrombocytopenia have been described in the past decade as platelet counts have been done regularly. These patients are delineated from ITP, recognizing that some patients with hereditary thrombocytopenia may benefit from splenectomy. Until more information on platelet biochemical information is available, these disorders have been categorized by platelet size, now quantifiable as mean platelet volume (MPV). The availability of rapid and quantitative measurement of platelet count and MPV allow a better understanding of megakaryocyte proliferation and platelet production. The evolving changes of MPV during treatment and recovery from chemotherapy will now allow a forecast of marrow hypoplasia, since the platelet count and increase in MPV follow the increase in megakaryocyte ploidy to herald marrow regeneration. It is anticipated that the careful plotting of the MPV relationship to the platelet count will allow the physician to evaluate marrow function indirectly, in many cases replacing repeated bone marrow studies.

Neutrophilic phagocytosis in autoimmune thrombocytopenia purpura.

In vivo neutrophil phagocytosis was demonstrated by transmission electron microscopy (TEM) in the peripheral blood of two half-sibs with hereditary thrombocytopenia. These sibs have had a lifetime documented history of thrombocytopenia. Light microscopy morphology and histochemistry studies of blood and marrow were normal, similar studies of blood from available members of the kinship were also normal. Scanning electron microscopy (SEM) of platelets from each member of the kinship showed normal dendritic and spreading formation. In the TEM thin sections of platelet buffy coats, neutrophil ingestion of platelets was common and all stages of the phagocytic process were noted--from platelet-neutrophil intimacy to the formation of myelin bodies in phagosomes. The clinical courses over a 10-year period were mild, requiring rare therapeutic interventions. The chronic thrombocytopenia, lengthy mild course, modestly elevated platelet-associated immune globulin, normal aggregation and survival studies, and autoimmune neutrophil reaction to platelets allowed classification of these patients as hereditary thrombocytopenia purpuras.

Complications after elective splenectomy in children.

Elective splenectomies performed in children aged 0-14 during the period 1968 to 1977 have been reviewed. One hundred and twelve children were splenectomized during the period studied. The indication for splenectomy was usually a haematological disorder e.g. hereditary spherocytosis or idiopathic thrombocytopenia. As splenectomized children run the risk of developing overwhelming sepsis, inquiries have been sent to all children. Two cases of nonfatal pneumococcal septicaemia are reported. Although the incidence of septicaemia is low, spleensaving operations are to be preferred where possible. When splenectomy is performed, pneumococcal antibodies should be determined. If a low titre is found, polyvalent pneumococcal vaccine should be used.

Hereditary autoimmune thrombocytopenic purpura: an immunologic and genetic study.

Excerpt Although numerous cases of hereditary thrombocytopenia have been reported (1), only four families (1, 2) have clinical findings consistent with the diagnosis of autoimmune thrombocytopenic ...

IMMUNE DEFICIENCY IN SEX‐LINKED HEREDITARY THROMBOCYTOPENIA

Eleven thrombocytopenic members of a large family with sex‐linked hereditary thrombocyto‐penia were studied. Routine immunological investigation revealed little evidence of immune deficiency, but abnormal results were obtained in studies of the in vitro blast transformation response of the patients lymphocytes. Impaired responses to microbial antigens were observed in all patients thus studied, whereas a decreased response to mitogens was observed in only one patient. Of the non‐thrombocytopenic family members, approximately half showed subnormal responses to one microbial extract. These results, taken together with the increased incidence of infections in the thrombocytopenic patients, indicate the necessity for immunological scrutiny of patients with hereditary thrombocytopenia, in particular when splenectomy is considered.

Hereditary thrombocytopenia, deafness, and renal disease.

The syndrome of hereditary thrombocytopenia, deafness, and renal disease was manifest in at least eight members in three generations of a family. They had a lifelong history of bleeding, usually as epistaxis, bilateral sensorineural deafness starting in late childhood or the teenage years, and persistent proteinuria with varying degrees of renal dysfunction. Two members died at a young age, one from central nervous system hemorrhage, the other from chronic renal failure. Splenectomy and steroid therapy have been of transient benefit. There was dominant inheritance of the syndrome. Hematologic studies showed thrombocytopenia, large platelets, and megakaryocytic hyperplasia of the bone marrow. In contrast to a previous report, our studies showed that affected members had normal in-vitro platelet function and normal ultrastructural platelet morphology. At autopsy, histologic changes in the kidney of one affected family member were indistinguishable from those reported in classic hereditary nephritis with nerve deafness (Alport's syndrome).

Sex-Linked Hereditary Thrombocytopenia with Immunological Defects

14 cases of severe thrombocytopenia in one family are presented. Case histories, clinical examination, analyses of platelets, haemoglobin, reticulocytes, leucocytes, eosinophilocytes, differential counts of leucocytes, serum immunoglobulin IgA, IgM, IgG, IgE concentrations, complement fixing platelet antibodies, isohaemagglutinins, colour perception, determination of red cell and serum groups as well as HL-A types were obtained from a total of 59 members of the family. The in vitro blast transformation response of blood lymphocytes was studied in 6 patients and 45 relatives. The pattern of transmission of the disease was in full agreement with X-linked recessive inheritance. Investigation of the immune system revealed impaired responses to microbial antigens in the 6 patients so studied. All relatives examined had normal haematological status, whereas approximately half showed a subnormal response to one microbial extract. The low responders were evenly distributed within the family, and it was not possible to correlate low response and presumed carrier state.

Letter: Pulmonary embolism in hereditary thrombocytopenia.

Letter: Pulmonary embolism in hereditary thrombocytopenia.

Platelet membrane function studies on platelets from patients with hereditary thrombopathic thrombocytopenia.

Routine clotting tests, general platelet function tests, platelet Na<sup>+</sup> and K<sup>+</sup> concentrations, the influx and efflux kinetics of <sup>86</sup>Rb<sup>+</sup> (as K<sup>+</sup> analogue) and the osmotic resistance have been studied in platelets from patients with a dominant hereditary macrocytic thrombopathic thrombocytopenia. Calculated on a cell-volume basis the pathological platelets showed no abnormalities in the concentration gradients for Na<sup>+</sup> and K<sup>+</sup>. In all patients a normal active uptake and a strikingly decreased passive efflux rate of <sup>86</sup>Rb<sup>+</sup> from the platelets was observed. Ouabain increased the efflux rate of <sup>86</sup>Rb<sup>+</sup> from control platelets, whereas no or weak efflux-increasing effect was observed in the pathological platelets. The platelets of all patients studied showed a shift towards a more resistant osmotic fragility curve, possibly caused by an increased surface to volume ratio of the cells. The findings are explained in terms of a pathological platelet membrane which is more rigid in structure and which requires more drastic stimuli in order to function properly.

Intrinsic platelet defects in hereditary thrombocytopenia.

SUMMARYNine families with hereditary thrombocytopenia have been described. They have been discussed and classified according to mode of inheritance, the presence or absence of clinical features of the Wiskott‐Aldrich Syndrome, platelet size, and platelet lifespan studies. These features and an assay for serum Antiplatelet Factor help to distinguish hereditary disease from acquired thrombocytopenias such as idiopathic thrombocytopenic purpura. This distinction is important, since response to therapy, particularly splenectomy, is clearly different for hereditary and acquired disease.

Hereditary thrombocytopenia: Relation to Wiskott-Aldrich syndrome with special reference to splenectomy: Report of a family and review of the literature

Two brothers with eczema and congenital thrombocytopenia, thought to be inherited as a sex-linked recessive defect, are presented. Although both had some of the immunologic deficiencies associated with Wiskott-Aldrich syndrome, they could respond in both the humoral and cellular immune systems following antigenic challenge. After splenectomy, the older brother had several serious infections and died. The disorder present in this family raises important questions concerning the relationship of inherited thrombocytopenia, eczema, and immunologic deficiency and the role of splenectomy in the treatment of chronic thrombocytopenia in children. Whereas only 2 to 3 per cent of children develop serious infections following splenectomy for idiopathic thrombocytopenia, the risk is significantly higher in boys than in girls and in patients with sex-linked recessive thrombocytopenia. It seems likely that splenectomy can unmask a latent immunologic deficiency in certain thrombocytopenic males, and hence should be approached with extreme caution in any individual with eczema, a family history of thrombocytopenia, or evidence of immunologic deficiency.

Hereditary Thrombocytopenia with an Intrinsic Platelet Defect

Thrombocytopenia, inherited as a dominant trait, was present in three generations of a kindred. The clinical picture was quite similar to that of idiopathic thrombocytopenic purpura, but thrombokinetic studies clearly distinguished the two diseases. Platelet-survival studies after labeling with 51Cr demonstrated shortened life-spans of the patients' platelets both in themselves and in normal volunteers. Platelets from healthy volunteers, however, survived normally in the patients, showing that the accelerated platelet destruction resulted from an intrinsic platelet defect and not one extrinsic to the cell. Morphologic and biochemical studies have not as yet elucidated the nature of the defect. Splenectomy in two patients was followed by improvement in the thrombocytopenia, but the postoperative platelet survival remained short.

Hereditary thrombocytopenia with excessively prolonged bleeding time.

A report is given of a hereditary bleeding disorder characterized by thrombocytopenia and excessively prolonged bleeding time.The disorder was inherited as an autosomal dominant trait, and segregated independently of the ABO, Rh, MNSs and Duffy blood group systems, and probably of the ABH secretor genes.The patients' own platelets had a shortened survival in the patients' own circulation, indicating an increased destruction. The increased destruction was not due to an intrinsic defect of the patients' platelets, because the platelets survived normally when transfused to a normal recipient. The patients must therefore have some factor or mechanism in their blood or vascular system which shortens the life‐span of their own platelets as well as that of transfused normal platelets.Another striking finding was the unproportionate increase of the bleeding time. The moderately reduced platelet count and normal AHG exclude von Willebrand's disease. The presently reported bleeding disorder did not show the characteristics of the thrombasthenic or the thrombopathic group of disorders.The presently reported haemorrhagic disorder does not fit into any of the previously described ones.