Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.     

Percutaneous cholecystostomy in critically ill patients

Sixteen critically ill patients underwent percutaneous cholecystostomy because of suspected acute cholecystitis. The procedure was technically successful, although 11 of 16 patients died subsequently because of various complications of their underlying primary disorders. We reviewed this series to reassess the value of percutaneous cholecystostomy. Four of 11 patients with definite acute cholecystitis (group 1) were cured by this technique, but three required surgery because of gallbladder wall necrosis. Two of these were among four cases which had demonstrated pericholecystic fluid collections on computed tomography (CT) or ultrasound of the abdomen. There were also five patients (group 2) in whom acute cholecystitis or its relationship to patients' symptoms were not fully determined, and four of them did not improve after percutaneous cholecystostomy. We conclude that this technique has a lower success rate in critically ill patients than reported previously.     

Echocardiography and connective tissue diseases

The aim of this study is to show the clinical value of the echocardiography in the heritable disorders of connective tissue, within a series of 10 cases, from 7,500 echocardiograms reviewed between 1978 and 1985. Echocardiography visualized an aneurysm of the ascending aorta in three patients, a dilatation of the pulmonary artery in one case, a mitral valve prolapse in six patients associated with an aortic and tricuspid valve prolapse in two cases, and a tricuspid valve prolapse and aortic regurgitation in one case. In two patients, an aortic valve prolapse was isolated. Other echocardiographic features were intracardiac calcifications (4 cases), septal hypertrophy (2 cases) and an incompetent foramen ovale (2 cases). Echocardiographic examination must be performed in all connective tissue diseases because cardiovascular complications are responsible for the vast majority of deaths. Conversely, all the patients with valvular prolapse, dilatation of the great vessels, aneurysm of the sinuses of Valsalva or congenital heart defects type incompetent foramen ovale should be suspected of connective tissue disorders. Such diagnosis is crucial when a surgical intervention is being considered because of the fragility of the tissues.     

Upper gut motility of Hirschsprung's disease and its allied disorders in adults

BACKGROUND/AIMS: To clarify the significance of upper gut motility for Hirschsprung's disease and its allied disorders in adults, we studied the upper esophagogastroduodenal motility of adult patients with Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia. METHODOLOGY: Twelve patients (7 men and 5 women, aged between 20 and 55 years with a mean age of 39.6 years) with Hirschsprung's disease (2 cases) or its allied disorders (8 cases of hypoganglionosis and 2 cases of intestinal neuronal dysplasia) were studied. As a control, 15 healthy volunteers (8 men and 7 women aged between 27 and 69 years with a mean age of 49.0 years) were also examined. To obtain the upper gut motility in Hirschsprung's disease, hypoganglionosis, and intestinal neuronal dysplasia, we performed gastrointestinal transit time study, esophageal manometry, and gastroduodenal manometry. RESULTS: On gastrointestinal transit time, barium stagnated in the upper jejunum in 2 cases of hypoganglionosis, in the terminal ileum in one case of hypoganglionosis and intestinal neuronal dysplasia, and in the colon in the remaining patients. In two of the 12 cases of Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia, abnormal esophageal motilities, and absence of interdigestive migrating motor complex, phase III from the stomach were observed. These findings suggested that the entire digestive tract might have been affected in these two cases, i.e., these 2 patients had total gut involvement type of hypoganglionosis. CONCLUSIONS: Gastrointestinal transit time and upper esophagogastroduodenal manometry should be performed because of the relatively frequent association of upper gut dysmotilities with these disorders.     

Rheumatologic aspects of lysosomal storage diseases

Lysosomal storage diseases are rare metabolic disorders, some of which can now be treated using enzyme replacement therapies. Because the time point of treatment initiation significantly influences the outcome in Gaucher disease, Fabry disease, and mucopolysaccharidosis type I, early diagnosis is of utmost importance. All three disorders can present with musculoskeletal symptoms in early stages, therefore, the rheumatologist may be the first to be contacted by these patients. Here, we present three characteristic lysosomal storage disease cases to increase awareness in the rheumatological community of the typical symptom constellations associated with these rare but treatable disorders.     

Hereditary Disorders of Platelet Function

The most common hereditary disorders of platelet function are those in which there is decreased platelet aggregation in response to more than one of the commonly used aggregating agents, collagen, ADP, adrenaline and arachidonic acid. When measured, there is usually also a reduction in the extent of the platelet release reaction and often also thromboxane production. In a proportion of these cases it is possible to demonstrate that there is a decrease in or absence of the contents of the dense storage granules which accounts for the decrease in platelet responsiveness. In most other cases the primary cause of the decreased responsiveness has not been determined, although in some cases deficiency of cyclooxygenase or thromboxane synthetase has been demonstrated. Investigation of patients with these disorders is often difficult because the tests involved are difficult to subject to adequate quality control, their sensitivity and specificity has not been adequately defined, and lack of reproducibility renders it difficult in less severe cases to be certain of abnormality even after repeat tests. Much less common but of great interest are the disorders in which the primary abnormality is in one of the glycoproteins on the platelet surface. In Glanzmann's thrombasthenia glycoprotein IIb.IIIa is absent or greatly decreased leading to failure of activated platelets to bind fibrinogen to their surface. In contrast to the decrease in aggregation seen in the above disorders, the platelets do not aggregate at all in response to the usual aggregating agents. In Bernard-Soulier syndrome there are severe deficiencies of three glycoproteins, particularly lb, leading to inability to bind von Willebrand's factor and consequent inability of the platelets to aggregate in response to ristocetin. Study of the disorders of platelet function will continue to contribute to our ability to detect and treat these disorders and to our knowledge of platelet physiology and biochemistry.     

Hereditary disorders of platelet function

The most common hereditary disorders of platelet function are those in which there is decreased platelet aggregation in response to more than one of the commonly used aggregating agents, collagen, ADP, adrenaline and arachidonic acid. When measured, there is usually also a reduction in the extent of the platelet release reaction and often also thromboxane production. In a proportion of these cases it is possible to demonstrate that there is a decrease in or absence of the contents of the dense storage granules which accounts for the decrease in platelet responsiveness. In most other cases the primary cause of the decreased responsiveness has not been determined, although in some cases deficiency of cyclooxygenase or thromboxane synthetase has been demonstrated. Investigation of patients with these disorders is often difficult because the tests involved are difficult to subject to adequate quality control, their sensitivity and specificity has not been adequately defined, and lack of reproducibility renders it difficult in less severe cases to be certain of abnormality even after repeat tests. Much less common but of great interest are the disorders in which the primary abnormality is in one of the glycoproteins on the platelet surface. In Glanzmann's thrombasthenia glycoprotein IIb.IIIa is absent or greatly decreased leading to failure of activated platelets to bind fibrinogen to their surface. In contrast to the decrease in aggregation seen in the above disorders, the platelets do not aggregate at all in response to the usual aggregating agents. In Bernard-Soulier syndrome there are severe deficiencies of three glycoproteins, particularly lb, leading to inability to bind von Willebrand's factor and consequent inability of the platelets to aggregate in response to ristocetin. Study of the disorders of platelet function will continue to contribute to our ability to detect and treat these disorders and to our knowledge of platelet physiology and biochemistry.     

Depression in adult untreated celiac subjects: diagnosis by the pediatrician

Untreated celiac disease can lead to serious behavioral disorders. We describe three adult patients with undiagnosed or untreated celiac disease without particular intestinal signs, causing persistent depressive symptoms in three of the parents of our pediatric patients. In two of the three cases, the pediatrician suspected the diagnosis when taking the family history of the children. In fact, a diagnosis of celiac disease was made during childhood, when they had intestinal symptoms, but the gluten-free diet was spontaneously interrupted during the teenage period because of the disappearance of the typical intestinal signs. In the third case the mother was tested for antiendomysium antibodies (EmA), as she had a diagnosed celiac child. In all three patients, the depressive symptoms improved quickly with a gluten-free diet. In conclusion, celiac disease should be taken into consideration in the presence of behavioral and depressive disorders, particularly if they are not responsive to the usual antidepressive therapy.     

Increased frequency of somatic mutations at glycophorin A loci in patients with aplastic anaemia, myelodysplastic syndrome and paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH), aplastic anaemia (AA) and myelodysplastic syndrome (MDS) are haemopoietic stem cell disorders. These disorders have some features in common, and a percentage of cases progress to acute leukaemia. We speculated that changes in gene stability are involved in the pathogenesis of these haemopoietic stem cell disorders. Therefore we investigated in vivo mutation frequencies in these disorders by erythrocyte glycophorin A (GPA) mutation assay. The assay enumerates NO or NN variant cells in 10⁶ erythrocytes of the MN type using a flowcytometric technique. Patients undergoing chemotherapy known to be at risk of hypermutageneity were also studied. Events exceeding the 95th percentile of healthy donors (≧ 32 and 34 events, respectively for NO and NN variants) were defined as abnormal. Abnormal events in the NO variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, two out of seven patients with MDS, and four out of nine patients with PNH. Abnormal events in the NN variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, one out of seven patients with MDS, and two out of nine patients with PNH. These results suggest that not only PIG-A, but also other genes including the GPA gene, are hypermutable in haemopoietic stem cell disorders, and that mutagenic pressure and/or gene instability can contribute to the pathogenesis of these disorders.     

精神障碍伴发肺结核病118例临床分析

目的探讨精神障碍患者伴发肺结核病的临床特征。方法分析118例精神障碍患者伴发肺结核病的临床资料。结果 (1)社会人口学资料:男性111例(占94.1%)。(2)精神科资料:精神分裂症97例(占82.2%),精神分裂症病程≥20年者103例(占87.3%)。(3)结核病资料:病灶范围≥3个肺野103例(占87.3%);痰抗酸杆菌涂片阳性39例(阳性率33.1%,39/118),痰分枝杆菌培养阳性者34例(阳性率28.8%);24例患者的药敏试验结果提示耐药(耐药率20.3%,24/118)。(4)其它资料:躯体合并症以糖尿病为主,19例(发生率16.1%);死亡18例(死亡率15.3%)。结论精神分裂症是最常见的伴发肺结核病的精神障碍,精神障碍伴发肺结核病具有病灶范围大、耐药率高、躯体合并症多、死亡率高等特征。     

Grenzen der Anästhesie

The demographic development and ongoing improvement of surgical techniques result in an increasing number of high risk elderly patients undergoing surgery. The anesthesiologist has an important role within the management of these patients, because apart from the present illness resulting in a surgical intervention the anesthesiologist has to assess and treat the pre-existing medical disorders in the perioperative period. In many cases the pre-existing medical disorders and the medications needed for their treatment are more important within the anesthesiological management than the operation to be performed. Apart from the preoperative assessment of the patients risk in combination with a possible optimization of the therapy of the comorbidities, the intra- and postoperative management of these high risk patients has an important influence on the postoperative rehabilitation of these patients. The adequate perioperative anesthesiological management can result in the avoidance of intensive care treatment. A very often underestimated topic is the sufficient perioperative pain treatment of these high risk elderly patients.     

以精神异常为首发表现肺癌的临床分析

目的提高临床医生对以精神异常为首发表现肺癌的认识。方法分析以精神异常为首发表现的4例肺癌患者资料。结果 4例患者病初都出现不同程度的精神异常。其中3例有病理结果,腺癌2例,小细胞肺癌1例。结论以精神异常为首发表现的肺癌,因其临床表现不典型,易误诊、漏诊,提高对本病的认识有利于早期诊断及治疗。     

Three patients with structurally abnormal X chromosomes, each with Xq13 breakpoints and a history of idiopathic acquired sideroblastic anemia

Structural abnormalities of the X chromosome are rarely found in neoplastic disorders. We describe three patients with a history of idiopathic acquired sideroblastic anemia (IASA); each one had an abnormal clone of cells in the bone marrow, characterized by a structurally abnormal X chromosome. In two of these patients, the predominant karyotype was 47,X,2idic(X)(q13); in the other patient, it was 46,X,t(X;11)(q13;p15). Inasmuch as all three of these cases involved chromosome band Xq13, as did two previously published cases, we suggest that band Xq13 may be more prone to structural rearrangement than other X chromosome bands in hematologic disorders. The common Xq13 chromosome breakpoint and clinical presentation (IASA) among these three patients and the occurrence of an X-linked type of sideroblastic anemia may suggest that an association exists between X chromosome abnormalities and IASA. Perhaps alteration of a gene or chromosome structure in or near band Xq13 predisposes to development of IASA. The fact that two of these patients had preleukemia and the third had overt acute leukemia may imply that patients with IASA and X chromosome abnormalities have a poor prognosis. Cases of IASA without associated X chromosome abnormalities are known; thus, if an association between IASA and an abnormal X chromosome does exist, most likely it involves only some patients with IASA.     

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.     

The adult respiratory distress syndrome associated with miliary tuberculosis

Miliary tuberculosis is an unusual cause of acute, catastrophic pulmonary failure. In this report, we describe three patients with miliary tuberculosis who developed the adult respiratory distress syndrome. The diagnosis of tuberculosis was suspected early, appropriate therapy was initiated, and two patients survived. The experience with these cases serves to reemphasize the importance of maintaining a high index of suspicion for treatable precipitating disorders in patients with acute respiratory failure.     

Over-expression of cyclin D1 in chronic B-cell malignancies with abnormality of chromosome 11q13

Accurate identification of B-cell chronic malignancies is sometimes uncertain, despite careful cytologic and immunophenotypic evaluation. Cytogenetics and molecular biology studies may therefore prove useful, because some of these disorders are associated with nonrandom abnormalities, such as the t(11;14)(q13;q32) translocation and bcl-1 rearrangement mainly observed in mantle-cell lymphoma (MCL). We studied the expression of cyclin D1 in malignant lymphoid cells from the peripheral blood of 32 patients with various B-cell chronic lympho-proliferative disorders, using Northern blot (NB) and RNA in situ hybridization (ISH). Cytogenetic analysis was informative in 18 cases, and most of the missing karyotype data were from typical B-CLL cases where a t(11;14) is unlikely to be found. Over-expression of cyclin D1 mRNA was observed by both NB and ISH in four samples (MCL: two cases; lymphoplasmacytic lymphoma: one case, unclassified B-cell chronic disorder: one case). In each of these cases there was an abnormality of chromosome 11q13, either a t(11;14)(q13;q32) translocation (three cases) or a del(11)(q13) without evidence of chromosome 14 involvement (one case). Cytogenetic and gene rearrangement studies are not available in all institutions and have some technical pitfalls. Because of its close association with bcl-1 rearrangement and/or t(11;14), the demonstration of cyclin D1 mRNA over-expression either by NB, or, more conveniently, by ISH, may represent additional information which could be of help for the identification of B-cell malignancies.     

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation: a report of three cases

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorders (PT-LPD) are a well-known complication of organ transplantation. Their incidence after liver transplantation in adults ranges from 1.8 to 4%. Reduction of immunosuppression led to remission in a few cases. Other treatments include chemotherapy, interferon alpha therapy and/or intravenous-immunoglobulins, or antiviral drugs. However, monoclonal antibodies directed against B-cell specific antigens have rarely been used in those patients. Our aim was to study the feasibility and efficacy of Rituximab, a new, promising human chimeric antibody that recognizes the CD20 antigen, for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation. METHODS: Rituximab (IDEC-C2HB8; Roche Laboratories, Neuilly-sur-Seine, France) was administered at a 375 mg/m2 dose on days 1, 8, 15, and 22, in an outpatient setting, in three patients with PT-LPD. The tumor was classified as polymorphic PT-LPD in two cases and PT-LPD with features of large cell lymphoma in one case. All the tumors expressed the CD20 antigen and were EBV-related, and the clonality was confirmed in all three cases. The 4 injections of the anti-CD20 monoclonal antibody were associated with reduced immunosuppression in the three patient. RESULTS: The treatment with Rituximab was well tolerated without any side effects. The two patients with polymorphic PT-LPDs underwent rapid complete remission, whereas the treatment modalities were ineffective in the patient with the large-cell non-Hodgkin-lymphoma. CONCLUSION: These results must be confirmed in a larger cohort of liver transplant recipients suffering from lymphoproliferation. However, they indicate rapid efficiency of Rituximab in association with reduced immunosuppression in these disorders.     

Voluntary lithium salt poisoning; risks of slow release forms

Lithium carbonate has been an invaluable drug in the treatment of manic-depressive illness. At the present time slow-release forms are available for better stability of circulating drug level with one daily take. However the better stability of lithiemia with these forms has to be balanced with a higher toxic risk in cases of lithium carbonate overdose because of continuous release. We report three cases of overdose with sustained-release lithium salts reaching life threatening complications. Two hemodialysis sessions were necessary to control plasma lithium levels. In two cases, lithiemia rebond was observed after the first hemodialysis session, and was associated with severe neurological disorders. This publication pointed out the therapeutic rule of at least two hemodialysis sessions in cases of severe slow release lithium carbonate salts intoxication.     

Celiac disease in a rheumatology unit: a case study

The objective of the study is to present a series of 20 patients who have been attending a rheumatology unit and were diagnosed with celiac disease in adult life. The record-charts of 20 Italian not consanguineous patients affected by celiac disease (1 man and 19 women, mean age of 46.7), diagnosed at >16 years of age, followed by a rheumatology unit were reviewed (group 1). Any other autoimmune disease diagnosed in the patients were given was recorded; moreover, the reason for rheumatologist evaluation was registered as well as the presence of symptoms suggestive of celiac disease and the obstetric history. The clinical features were compared with those of a group of 40 celiac patients (8 men and 32 women, mean age of 43.1) followed by a medicine department (group 2); even in these cases the diagnosis of celiac disease was performed in adult life. Sixteen out of 20 patients in Group 1 were diagnosed as suffering from celiac disease by the rheumatologist. Seventeen concomitant autoimmune disorders among which nine were connective tissue diseases were found in 15 patients. The main reason for rheumatologist evaluation was arthromyalgias. Ten patients showed one or more clinical features suggestive of celiac disease; moreover, eight patients had a history of sideropenic anemia. After the adoption of a gluten-free diet there were three pregnancies that all ended with alive newborns, differently from the obstetric history before celiac disease diagnosis, characterized by a relevant number of miscarriages and foetus deaths. In Group 2, a total of ten autoimmune diseases concomitant with celiac disease were found in eight patients; autoimmune thyroid disorders represented the most frequent cases. No connective tissue diseases were recognized. Celiac disease may coexist with connective tissue diseases; the recognition of this association is difficult because celiac disease may present with atypical or even symptomless forms or in some cases may resemble a multisystem disorder or may mimic a rheumatologic condition; on the other hand, the variety of symptoms of rheumatic disorders may make difficult the diagnosis of celiac disease in association with a systemic autoimmune disease. These confounding factors often lead to a delay in performing the right diagnostic formulation.     

Primary mucociliary transport failure

Among the disorders associated with male infertility and chronic sinopulmonary infections, primary ciliary dyskinesia or cystic fibrosis is characterized by ciliary dysfunction or abnormality of mucus secretion. In addition, Young's syndrome differs from the former because of the absence of ultrastructural cilia disorders and from the latter because of normal sweat and pancreatic functions. However, a number of manifestations seen in these disorders appear to overlap each other, e.g., male infertility and chronic sinopulmonary infections which often develop bronchiectasis. Therefore, I would like to propose that the term 'muco(secretion)ciliary transport failure' is used for illnesses in patients with primary impairment of mucosecretion and/or ciliary transport in organs containing the mucociliary transport system. Primary mucociliary transport failure encompasses three hereditary disorders, that is, primary ciliary dyskinesia, cystic fibrosis and Young's syndrome. Ciliary activity is closely associated with mucus production. For a better understanding of the relationship between ciliary activity and mucus production, further basic and clinical studies should be attempted.