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PubMed1988

Gray platelet syndrome in the elderly.

A 68-year-old male who suffered from thrombocytopenia and mild splenomegaly for 18 years was found to present agranular gray platelets on peripheral blood smear. Bone biopsy revealed a mild, diffuse, reticular fibrosis with no collagen, and electron microscopy of the platelets showed an absence of almost all the alpha-granules. Platelet thrombospondin and fibronectin analysed by SDS-polyacrylamide gel electrophoresis and Rocket immunoelectrophoresis were absent. Follow-up of 4 years showed the same parameters with no evidence of active myeloproliferative or dysmyelopoietic disorders. Hemorrhagic diathesis was limited to ecchymoses and postprostatectomy bleeding, necessitating platelet transfusion. This led us to conclude that our patient probably had a constitutional primary alpha-granule deficiency or gray platelet syndrome. This extremely rare defect has been described in less than 10 patients, all of them very young. Our observation shows that these patients may have a long, uneventful survival.

Aged↗
PubMed1989

Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors.

The extrinsic fibrinolytic system and its response to cigarette smoking was studied in five healthy male smokers 35-45 years old. Tissue plasminogen activator (t-PA) release in response to venous occlusion was intact both at 8:00 A.M. and 3:00 P.M. Acutely smoking two cigarettes neither stimulated fibrinolysis nor changed levels of t-PA or plasminogen activator inhibitors. Functional plasminogen activator inhibitor (PA-I) levels and euglobulin lysis times were higher in the smoking group than in a control group matched for age, sex, and body mass. Antigenic levels of PA-I 1, the PA-I derived from vascular endothelial cells and platelets, were similar in both groups. While smoking did not acutely alter fibrinolysis in chronic smokers, these individuals had a high frequency of abnormal fibrinolysis characterized by high levels of PA-I activity. This abnormality is due to either high specific activity of PA-I 1 or to the presence of other antigenically distinct plasminogen activator inhibitors. Abnormal fibrinolysis may be one mechanism contributing to the thrombotic diathesis of cigarette smokers.

Adult↗
PubMed1989

Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review.

Hyperfibrinolytic states are reported to be a cause of bleeding in patients with amyloidosis. We reviewed the literature on excessive fibrinolysis in association with amyloidosis and report our findings from a patient with idiopathic amyloidosis who developed a bleeding diathesis. Coagulation laboratory studies indicated elevated plasminogen activator levels associated with a reduction of plasminogen and alpha 2-plasmin inhibitor (alpha 2-PI) levels. The level of tissue-type plasminogen activator (t-PA) inhibitor and t-PA antigen were normal. However, the patient did have a five- to sevenfold increase in amidolytic activity for the urokinase substrate pyro-Glu-Gly-Arg-pNA (S-2444). This case therefore represents a novel example of a hyperfibrinolytic state associated with amyloidosis caused by elevated urokinase-type plasminogen activator (u-PA). Epsilon-amino caproic acid (EACA) therapy resulted in an increase in alpha 2-PI and plasminogen levels and effectively reduced the blood loss. Hyperfibrinolytic states in amyloidosis have now been reported to be due to elevated t-PA and u-PA and depleted t-PA inhibitor.

Aminocaproic Acid↗
PubMed1992

Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII.

A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling.

Deamino Arginine Vasopressin↗
PubMed1994

Quantitative defect of glycoprotein Ib in severe cirrhotic patients.

A decrease of platelet agglutination induced by ristocetin has been described in cirrhotic patients. In order to investigate the relationship of such phenomenon with a putative defect on platelet membrane glycoprotein Ib, we have studied the quantitative and functional status of Gp Ib in eleven severe alcoholic cirrhotic patients, and the ability of their formalin-fixed platelets to agglutinate in the presence of normal plasma plus ristocetin. Interestingly, we found a significant decrease of immunoreactive GP Ib molecules (9,978 +/- 1,534 vs. 17,064 +/- 404 molecules per platelet) and ristocetin-dependent binding of vWF (9,113 +/- 1,338 vs. 13,992 +/- 1,968 molecules per platelet) (P < 0.01) in comparison to the levels found in a control group of healthy subjects. Immunoblotting analysis of platelet lysates confirmed the reduction of GP Ib level in cirrhotic patients, but showed no modification on the precipitation pattern of this glycoprotein. The ristocetin-induced platelet agglutination (light transmission %) was also significantly lower in patients with cirrhosis (48 +/- 7.6 vs. 92 +/- 3.6, P < 0.01), and correlated with the binding of normal vWF (r = 0.863, P = 0.0013). Patients with bleeding times longer than 7 min and/or clinical history of bleeding episodes showed the lowest values of platelet agglutination and GP Ib level. In conclusion, our present results indicate that liver cirrhosis is associated with a relevant decrease of functional GP Ib molecules on the platelet surface. This reduction might be related to the prolongation of bleeding time and to the bleeding diathesis observed in cirrhotic patients.

Adult↗
PubMed1994

Hemophilic pseudotumor: multicenter experience over a 25-year period.

Pseudotumor is an infrequent manifestation of bleeding diathesis seen in hemophiliacs, the management of which is still controversial. To ascertain the effectiveness of the main therapies of choice, we have reviewed 1,831 patients affected by hemophilias A (1,108) and B (172), von Willebrand's disease (329), and other miscellaneous coagulopathies (222) diagnosed between 1965 and 1990 in a multicentric, retrospective study. Pseudotumor was proven in 21 patients. Replacement therapy was given in 15 cases as the first therapeutic approach, with complete success attained in only two, whereas surgery, which was carried out in 14 patients, completely resolved the process in eight (P = 0.017). Patients over 40 years of age demonstrated worse prognosis than younger patients (P = 0.02), but no other clinical parameters were shown to have influenced the patients' evolution. Surgical management was the most effective treatment for pseudotumor, although more conservative therapies cannot be overlooked in selected cases.

Adolescent↗
PubMed1994

Gray platelet syndrome with splenomegaly and signs of extramedullary hematopoiesis: a case report with review of the literature.

Gray platelet syndrome (GPS) is a rare bleeding disorder characterized by thrombocytopenia, agranular gray platelets in blood films, and almost total absence of platelet alpha-granules and their constituents. We describe here a rare case of GPS with myelofibrosis and splenomegaly indicating extramedullary hematopoiesis. Splenectomy was followed by normalization of platelet count but the bleeding diathesis continued. Based on a follow-up of more than 15 years, the slight myelofibrosis in our patient seems to be non-progressive. We also summarize the major clinical and laboratory features of previously published cases of GPS in order to obtain more comprehensive understanding of this rare disorder. From the clinical point of view, the bleeding tendency in this syndrome generally varies from mild to moderate, and no specific treatment is usually needed. Careful examination of peripheral blood films is necessary for the diagnosis of this rare syndrome.

Adult↗
PubMed1994

Clinical relevance of gestational thrombocytopenia of < 100,000/microliters.

We identified 22 women with thrombocytopenia of < 100,000/microliters found incidentally during pregnancy and prospectively monitored their platelet count and clinical outcome for a minimum of 6 months postpartum. During the study period, four women became pregnant twice, accounting for a total of 26 pregnancies. The lowest platelet count during pregnancy was 65,600/microliters +/- 19,400 (mean +/- SD), and at delivery 84,500/microliters +/- 32,300 (P < 0.02). The thrombocytopenia was virtually asymptomatic in all patients during the pregnancy and delivery, whether vaginal or surgical. Neonatal platelet counts (n = 18) were normal (270,700/microliters +/- 69,900), and none of the newborns (n = 24) had a bleeding diathesis. Normalization of the platelet count (i.e., > 150,000/microliters) was documented in 18 patients within 1 month postpartum, in five within 3 months postpartum, and in two as late as 5 months after delivery. One woman did not recover from the thrombocytopenia and eventually developed other stigmata of an autoimmune disease. Long-term follow-up showed recurrence of thrombocytopenia in four patients: three in the context of a subsequent pregnancy and one who developed idiopathic thrombocytopenic purpura. Retrospective analysis of blood counts obtained from 12 previous pregnancies demonstrated thrombocytopenia of a similar degree to the index pregnancy. We conclude that gestational thrombocytopenia of < 100,000/microliters is clinically a benign phenomenon that can recur in subsequent pregnancies and is not accompanied by neonatal thrombocytopenia. In some cases, however, pregnancy-associated thrombocytopenia may be a manifestation of an autoimmune disease with its attendant implications for the neonate. Since the differential diagnosis between the two conditions may be difficult to establish when first encountered during pregnancy, a conservative approach emphasizing careful surveillance and guarded reassurance is justified as long as the platelet counts are > 50,000/microliters.

Adult↗
PubMed1995

An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide.

We report a new case of severe bleeding diathesis due to an acquired inhibitor of fibrin crosslinking. The patient, an 80-year-old woman, was admitted to the hospital for a massive subcutaneous hematoma, with severe anemia requiring red cell transfusion; a subsequent retroperitoneal hematoma developed 2 weeks later. Coagulation studies were normal except for a thromboelastographic pattern suggestive of FXIII deficiency. Clot solubility test was abnormal even after 1:1 mix with normal plasma. Immunochemical studies confirmed the presence of a monoclonal IgG lambda inhibitor directed against FXIII activity (type II FXIII inhibitor). The patient IgG fraction selectively inhibited FXIII transamidating activity but did not inhibit the thrombin-mediated activation of FXIII. The patient was treated with high doses of FXIII concentrate to overcome the inhibitor and immunosuppressive therapy with cyclophosphamide and discharged in good conditions. High doses of commercially available FXIII appear to be a safe and effective method of controlling acute episodes of bleeding in patients with acquired FXIII deficiency.

Aged↗
PubMed1991

New syndrome: mother and son with hypertelorism, downslanting palpebral fissures, malar hypoplasia, and apparently low-set ears associated with joint and scrotal anomalies.

We report on a mother and son with a similar syndrome of hypertelorism and telecanthus, epicanthal folds, downslanting palpebral fissures, ptosis, broad nasal bridge, malar hypoplasia, thin upper lip, smooth philtrum, and apparently low-set prominent ears. The son also has a hypoplastic shawl scrotum, cryptorchidism, and genu valgum. His language development was delayed at 18 months, but subsequently improved and was normal at age 3. The mother has the additional findings of marked cubitus valgus, hyper-extensible joints, dull normal intelligence and a bleeding diathesis. This pattern of multiple congenital anomalies may represent a new syndrome.

Abnormalities, Multiple↗
PubMed2004

Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.

Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30-50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with downslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene-gene or gene-environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation.

Abnormalities, Multiple↗
PubMed2006

Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder.

Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.

Adult↗
PubMed2006

Lack of association between UBQLN1 and Alzheimer disease.

Alzheimer disease (AD) is heterogeneous and complex with a strong genetic diathesis. It is the most common cause of dementia affecting the elderly. Linkage studies [Kehoe et al., 1999; Hum Mol Genet 8: 237-245]; [Pericak-Vance et al., 2000; Exp Gerontol 35: 1343-1352]; [Myers et al., 2002; Am J Med Genet 114: 235-244]; [Blacker et al., 2003; Hum Mol Genet 12: 23-32] identified chromosome 9q as a region containing a possible AD candidate gene. Functional protein studies [Mah et al., 2000; J Cell Biol 151: 847-862]; [Ko et al., 2002; J Biol Chem 277: 35386-35392] identified the UBQLN1 gene on chromosome 9q that encodes ubiquilin as a likely candidate for a role in late-onset AD pathogenesis. A recent family-based study by [Bertram et al., 2005; N Engl J 352: 884-894] reported genetic association and expression evidence for a putative AD risk allele of an intronic single nucleotide polymorphism (SNP) within the UBQLN1 gene. In this study, we comprehensively assessed whether any of seven polymorphisms located across the UBQLN1 gene are associated with AD in another large family-based data set and an independent case-control data set. We found no significant association of AD risk with any of the seven SNPs genotyped (including those SNPs previously reported by Bertram et al.) in either the family-based or case-control data set. Age-specific analyses and analyses conditional on Apolipoprotein E (ApoE) genotype and sex also revealed no significant associations to AD risk in either data set. Using age at onset (AAO) as a quantitative trait revealed a modest age modifying association; however, the results were inconsistent between the data sets. Our results suggest that UBQLN1 variants do not increase risk for AD in these data.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Characterization of gout in a skeletal population sample: presumptive diagnosis in a Micronesian population.

Characterization of the nature and skeletal distribution of gout was accomplished in a Chamoru (Chamorros) population with predilection to the disease. Uniform excavation by the gouty diathesis produces a punched-out appearance to these predominantly monarticular lesions. The lesion is distinct from that seen in rheumatoid arthritis, spondyloarthropathy, or infection. Reactive new bone formation in some gouty lesions also has an apparently unique, ivory-like discoloration (contrasted with the adjacent bone), which facilitates diagnosis.

Female↗
PubMedDate not supplied

Antecedents of neurosis in a cohort of 30,344 twins in Sweden.

We analyzed questionnaire survey responses in a cohort of 30,344 twins in Sweden, 280 of whom became inpatients due to neurosis within the subsequent 10 years. As a group, they differed substantially in their reported health profile from the survey responders who were not admitted for psychiatric treatment. When subclassified into anxiety, depressive, and other neuroses, these were indistinguishable from each other regarding self-perceived health and personality traits. Women were more likely to be hospitalized for neurosis. These mental and social antecedents for both anxiety and depression are in keeping with the concept of a shared diathesis which is supported by neurophysiological, treatment and genetic epidemiological studies.

Adolescent↗
PubMedDate not supplied

Familial transmission of panic disorder: effect of major depression comorbidity.

This study assesses the effect of major depressive disorder (MDD) comorbidity on familial transmission of panic disorder (PD). The following questions are addressed: (1) is PD familial, i.e., do relatives of patients with PD show an increased risk for PD? (2) do PD and MDD share a common diathesis, i.e., do relatives of patients with PD without MDD show an increased risk for MDD? (3) is lifetime comorbid PD with MDD conjointly familial, i.e., do relatives of patients with PD and MDD show an increased risk for the combined syndrome? Subjects were: (1) 152 relatives of 54 anxiety clinic patients with PD and MDD; (2) 193 relatives of 72 patients with PD without MDD; (3) 231 relatives of 77 not ill controls. Relatives were interviewed by clinicians, and best estimate DSM-III-R diagnoses were formulated by senior staff. Relatives of PD with MDD (13%) and PD without MDD probands (9%) showed significantly higher rates of PD than relatives of controls (3%). Relatives of PD with MDD probands (37%) showed significantly higher rates of MDD than relatives of PD without MDD (24%) and controls (21%), with no difference between the latter two groups. Relatives of PD with MDD probands (9%) showed significantly higher rates of PD with MDD than relatives of PD without MDD (3%) and controls (1%). We conclude that: (1) PD is familial; (2) PD in the absence of MDD does not incur increased risk of MDD to relatives; and (3) PD with MDD may represent a distinct, complex syndrome.

Adolescent↗
PubMed1981

Differences in immunoregulatory T cell circuits between diphenylhydantoin-related and spontaneously occurring systemic lupus erythematosus.

We studied T cell surface markers, concanavalin A-induced, and spontaneously expanded suppressor cell function and the functions of postthymic precursor (Tar) cells in 3 patients with diphenylhydantoin (DPH)-related systemic lupus erythematosus (SLE). The findings were compared with those in 6 patients with spontaneously occurring SLE, 3 with active and 3 with inactive disease as well as with those in 3 normal volunteers. All 4 groups were age and sex matched. Findings were also compared to studies made in a group of 32 untreated idiopathic SLE patients and 32 normal controls. All T cell markers and immunoregulatory functions were normal in the DPH-treated SLE patients whereas all groups of patients with spontaneously occurring SLE had low numbers of t gamma cells, and Tar cells, and decreased concanavalin-A and spontaneously expended suppressor, human feedback inhibition and generation of suppression functions. Since consanguineous relatives of patients with spontaneously occurring SLE have been shown to have decreased suppressor cell function and patients with long-inactive spontaneous SLE continue to have defects in their T cell circuits, our findings may indicate that, in patients who develop SLE upon DPH intake the lupus diathesis uncovered by the drug probably resides in a site of immunoregulation different from that involved in spontaneously occurring lupus.

Adolescent↗
PubMed1983

Familial systemic lupus erythematosus in males.

Several families in which systemic lupus erythematosus predominates in males are presented. The disease primarily manifested itself in the sons and in the male parents. Females in some of the families had other autoimmune diseases such as idiopathic thrombocytopenic purpura or symptoms suggestive of a lupus diathesis. It is suggested that the sons inherited the disease from their fathers in these families. The disease in the patients had some similarity to the disease in BXSB mice.

Adolescent↗