[Sickle cell disease]. / Sichelzellkrankheit.

The term "sickle cell disease" covers a group of genetic blood disorders caused by sickle hemoglobin (HbS) alone or in combination with other variants of the ß­globin locus. Sickle cell disease occurs frequently in sub-Saharan Africa, but is also common in Turkey, Greece, Sicily, the Middle East, India, and the Americas. Polymerization of deoxygenated sickle hemoglobin leads to decreased deformability of red blood cells. These altered erythrocytes can obstruct small blood vessels and cause acute episodes of pain, hemolytic anemia, and organ damage. Complications can vary between the different genotypes and it is important to be aware of the special features of the disease. Hydroxycarbamide has been shown to reduce the morbidity and mortality of patients with sickle cell disease. New drugs and novel treatment approaches such as gene therapy are currently being tested.

[Hemoglobin disorders]. / Hämoglobinkrankheiten.

Hemoglobin disorders such as the thalassemias and sickle cell disease have been present in Germany since the arrival of immigrants from the eastern Mediterranean region, Africa, and Asia in the 1950s. These hereditary diseases not only require very complex treatment, but also render screening for asymptomatic carriers necessary, in order to prevent the birth of an affected child in the next generation. Pediatricians, internists, general practitioners, and gynecologists have to rise to this challenge.

[Anemia and hemoglobin diseases in patients with migration background]. / Anämien und Hämoglobinkrankheiten bei Patienten mit Migrationshintergrund.

Among the German population with migration background there are probably 150 000-200 000 carriers of thalassemia (α und ß) and sickle cell disease, respectively, who have no or little symptoms. Compared to neighboring countries the number of sickle cell (1000-1500) and thalassemia patients (500-600) in Germany is rather low. This may explain the fact that hemoglobin diseases are not yet considered a public health problem in Germany. With optimal care 85-90 % of children with sickle cell disease and 100 % of children with thalassemia reach adulthood. In order to increase awareness for patients with hemoglobin diseases we discuss the most pertinent disease manifestations of adult patients and point out possibilities to obtain information. Specialists in regional centers should be addressed for acute management problems. Up to now it is difficult for many adult sickle cell and thalassemia patients to find a physician well enough informed and experienced to take over the care of their complex disease. Many adult patients are still taken care of by pediatricians. Urgently needed are reference centers with experience in management of hemoglobin diseases who are qualified for training hematologists and who can assure the transition of these patients from pediatrics to adult medical care.

Newly diagnosed immune thrombozytopenia--German guideline concerning initial diagnosis and therapy.

Newly diagnosed immune thrombocytopenia occurs in 3-5/100 000 children < 14 y per year. Bleeding symptoms do not correlate with platelet count. Diagnostic approach includes history, clinical examination and analysis of blood count with blood smear by experienced hematologist. Additional investigations are only necessary in atypical cases and cases with additional symptoms or inadequate response to therapy. The decision to treat ITP should be made cautiously and not entirely be based on the platelet count. Decisions based on clinical symptoms and progress of the illness are more reasonable. There is no evidence, that therapy at the time of diagnosis influences the further course and can avoid intracerebral hemorrhage.

Haemoglobinopathies and newborn haemoglobinopathy screening in Germany.

Germany has been an immigration country since the early 1950s. In December 2007, 6.7 million non-German citizens lived in the country. However, the total number of citizens with a migration background is 15-20 million, about 9 million of whom come from countries where sickle cell disease and thalassaemias are frequent. In a country with 82 million inhabitants health authorities are not worried by the presence of probably 1000-1500 sickle cell and 450 transfusion-dependent thalassaemia patients, and therefore no screening or preventive measures have been taken so far on a national scale. There are plans for a pilot project (1 year) to screen all newborns for sickle cell disease in obstetric hospitals in 4-5 cities with more than 20% migrants. Funding and lack of an infrastructure to provide counselling are major problems.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

[Sickle cell disease in Germany -- disease manifestations, therapeutic options and possibilities for improvement of care]. / Sichelzellkrankheit in Deutschland -- Krankheitsmanifestationen, Therapieoptionen und Möglichkeiten der Optimierung der Betreuung.

The number of sickle cell patients in Europe is steadily increasing due to continuing immigration and increase of average life expectancy. In 2005 probably up to 1,000 sickle cell patients were living in Germany, most of them in former West-Germany. Precise figures are not available as registration of sickle cell patients into a German surveillance study register that was initiated 1987 is on a voluntary basis. In December 2005 the register included a total of 514 patients, with 273 patients (208 children, 65 adults) still actively participating in the study. They were followed at 92 different institutions all over the country. We report on data regarding the origin of these patients, their genotypes, disease manifestations, social integration, therapy and causes of death. We discuss difficulties in the delivery of care and make suggestions for improvement.

Osteosarcoma after allogeneic bone marrow transplantation. A report of four cases from the Cooperative Osteosarcoma Study Group (COSS).

Osteosarcoma, one of the most frequent secondary malignancies after the treatment of young patients with cancer, has only very rarely been observed in association with hematopoietic stem cell transplantation (HSCT). We report four patients who were identified by searching the database of the Cooperative Osteosarcoma Study Group (COSS) for patients whose osteosarcoma arose following HSCT. Transplant indications had been acute lymphoblastic leukemia (3). and sickle cell disease (1). and the stem cell source was bone marrow in all cases (three allogeneic, one syngeneic). All four had received chemotherapy with alkylators as part of their conditioning regimen and/or first line therapy. The conditioning regimen included total body irradiation in three patients. The osteosarcomas arose at the age (adolescence) and sites (around the knee) typical for the disease. All four patients received chemotherapy as part of multimodal osteosarcoma treatment, and all four are currently alive, three in continuous remission at 5 7/12, 2 11/12, and 0 6/12 years and one with relapsed osteosarcoma at 4 1/12 years. One of the osteosarcoma-free survivors suffered a third malignancy, myelodysplastic syndrome. Osteosarcoma should be included among the secondary malignancies that can arise following HSCT. Multi-modal therapy according to guidelines for de novo osteosarcoma can lead to long-term survival in selected patients.

[Splenic sequestration in patients with sickle cell disease. ]. / Milzsequestrationen bei Patienten mit Sichelzellerkrankungen - Eigene Erfahrungen, Epidemiologie, Klinik, Prävention und Therapie.

Splenic sequestration is a potentially life threatening event that is characteristic for sickle cell disease. For reasons unknown a fraction of or even the entire blood volume is trapped in the splenic sinuses within a few hours and thus is no longer available for circulation. The result is splenomegaly, hypovolemia, anemia and extreme reticulocytosis. If the sequestered blood volume is very large the patient goes into fatal hypovolemic shock unless transfused instantly. If the sequestered volume is small there is a chance of spontaneous resolution. The etiology of splenic sequestration is not known. Children with homozygous sickle cell disease (HbSS) are at risk until age 6 years while individuals with compound heterozygous disease (HbSbetaThal, HbSC, HbSD) may develop splenic sequestration even in adulthood. Parents of infants and toddlers with sickle cell disease need to learn how to palpate the spleen in order to detect splenomegaly as early as possible and take the child to the hospital. Splenic sequestration with a drop in hemoglobin of more than 3 g/dl below the patient's usual hemoglobin level is a clear indication for splenectomy regardless of the patient's age as splenic sequestration tends to recur.

The nontreatment of childhood ITP (or "the art of medicine consists of amusing the patient until nature cures the disease").

The management of childhood acute idiopathic thrombocytopenic purpura is controversial, with recent guidelines highlighting the lack of suitable evidence upon which to base management decisions. Three European centers have used an expectant policy and results over the past decade demonstrate that this is safe and convenient for the majority of children. Adequate parental education about the condition from an experienced specialist is essential, together with open access for children should they develop any problems. A clinical stratification of such patients must be incorporated into any future trials, together with quality of life assessment to discover the impact of restrictions on lifestyle, particularly in adolescents with chronic ITP who may need a different approach.

The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment.

OBJECTIVE: To demonstrate the result of watchful waiting without specific therapy in unselected children with acute immune thrombocytopenic purpura (ITP). STUDY DESIGN: Between May 1992 and October 1999, 55 consecutive children (aged 2 months to 16 years; 28 boys and 27 girls) with acute ITP did not receive intravenously administered immune globulin G (IVIG) or sustained prednisone treatment. Patients with extensive mucosal bleeding were given prednisone, 2 mg/kg/d, for 3 days. RESULTS: In 37 of 55 patients the initial platelet count was <10,000/microL. Ten of these patients had active mucosal bleeding. Five additional patients with bleeding had platelet counts between 10,000 and 20,000/microL. Four patients were given a 3-day course of prednisone. Chronic ITP occurred in 7 (13%) of the patients; 29 patients achieved remission within 6 weeks, and 19 patients, between 6 weeks and 6 months. No life-threatening bleeding occurred, and no patient died. CONCLUSION: Most children with severe thrombocytopenia do not have active mucosal bleeding. This management approach, which did not administer specific therapy, avoided side effects, reduced cost, and was effective.

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease.

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)

[Manifestations of sickle cell disease in adolescents and young adults. Clinical aspects and therapy references]. / Manifestationen der Sichelzellerkrankung bei Adoleszenten und jungen Erwachsenen. Klinik und Therapiehinweise.

In Germany about 300 sickle cell patients are being seen at more than 100 different hospitals. One third of these patients are adolescents and young adults. Since this is a congenital chronic disease, the majority of these teenagers and young adults are being cared for by pediatricians. Sickle cell disease in patients older than 15 years is characterized by the development of chronic organ damage, in addition to the occurrence of acute manifestations of disease such as pain crises, splenic sequestration, aplastic crises and Acute Chest Syndrome. Pediatricians who care for older sickle cell patients have to handle not only internal medicine problems but also to answer questions concerning pregnancy and contraception. In this paper the specific problems of adolescents and young adults with sickle cell disease are presented and suggestions are offered for the care of this group of patients.

[Pain crises in patients with sickle cell diseases. Pathogenesis, clinical aspects, therapy]. / Schmerzkrisen bei Patienten mit Sichelzellerkrankungen. Pathogenese, Klinik, Therapie.

About 70% of all patients with sickle cell disease suffer from pain crises. Pain crises are recurrent episodes of pain that range in severity from mild to severe, usually occur very abruptly and are often localized around joints. Pain crises are caused by vaso-occlusions in the vascular bed of the bone marrow, leading to necrosis, edema and increased pressure. For effective analgesia morphine or morphine analogues are often required. When treating a pain crisis the patient's complaints need to be taken seriously and analgesic therapy should be started promptly with analgesics in proportion to the severity of the patient's pain. With mild pain oral non-opioid analgesics are sufficient, in moderate pain they are given in combination with oral codeine. Severe pain requires IV morphine, also combined with a non-opioid analgesic. Intravenous morphine makes a thorough monitoring of ventilation and level of consciousness mandatory. Sickle cell patients do not become drug dependent if given morphine for adequate analgesia. While bone marrow transplantation has become an accepted treatment modality for sickle cell patients with severe pain crises, treatment with hydroxyurea to increase HbF levels and reduce incidence and severity of pain crises, however, is still experimental.

Association of Hb S/Hb lepore and delta beta-thalassemia/Hb lepore in Sicilian patients: review of the presence of Hb lepore in Sicily.

The hemoglobin (Hb) lepore-Boston is a beta-globin structural variant, produced in a reduced amount and formed from the fusion of N-terminus delta-(residues 1-87) and C-terminus beta-chains (residues 116-146). This type of fusion protein is quite common in Southern Italy (Campania, Calabria, and Sicily). We report here the hematological and hemoglobin data on 96 unrelated Sicilians with Hb lepore trait. Particularly interesting are the subjects where Hb lepore occurs with Hb S or Sicilian type delta beta-thalassemia. In these individuals, striking features are clinical variability and different hematological pictures. These observations underscore the importance of thalassemia screening in these geographic areas, such as Southern Italy, principally Sicily, where the mutations in globin gene clusters are especially prevalent. Moreover, as from the second half of the last century, owing to high migratory flux from Sicily to Northern Europe, North and South America, and Australia, the Hb lepore, as well as other hemoglobin variants, have become prevalent, making the identification of the heterozygotes a problem of general interest.

Enumeration of platelets by multiparameter flow cytometry using platelet-specific antibodies and fluorescent reference particles.

The correct enumeration of platelets is still an elusive matter. This is mainly due to the fact that commercial instruments which are used for platelet counting cannot discriminate platelets from other cellular particles and precipitates that cause similar signals. Visual (chamber counting) methods are still frequently used in routine laboratories to verify low automated platelet counts (< 50 x 10/l) despite obvious technical and statistical drawbacks. The following report shows how platelet counts can be measured by multiparameter flow cytometry with the help of reference particles (fluorescent latex beads) and platelet-specific antibodies i.e. anti-GPIIb/IIIa(CD41a), anti-GP Ib-alpha (CD42b) and anti-GP IIIa (CD61). The linearity of this method was highly satisfactory and the observed imprecision was within acceptable limits. At a platelet concentration of 10 x 10(9)/l the coefficient of variation (CV, n = 10) ranged from 5.3% (PCV = 0.456) to 5.6% (PCV = 0.148). Accuracy was evaluated by comparing results to the ICSH-selected method for platelet counting. The correlation of both methods was significant (P < 0.005) and Passing-Bablok's linear regression analysis showed no systematic differences between the two methods. Comparisons of this new platelet counting technique were also performed with routine visual methods, automated blood analysers (Technicon H-1, Sysmex E-5000) and a different flow cytometric method using only forward and side light scatter properties of platelets for their discrimination. The linear correlation of all methods was significant (P < 0.01) at platelet concentrations above 50 x 10(9)/l. At lower platelet concentrations, our new platelet counting technique correlated significantly only with the visual and the forward/side scatter methods.(ABSTRACT TRUNCATED AT 250 WORDS)

[Immune thrombocytopenia in childhood--how much diagnosis and therapy is reasonable?]. / Die ITP (Immunthrombozytopenie) im Kindesalter--Wieviel Diagnostik und Therapie ist sinnvoll?

Acute and chronic ITP in childhood are both relatively mild diseases that only rarely result in live threatening complications. In most cases diagnostic measures can be limited to a detailed history, thorough physical examination, a complete blood count and evaluation of platelet size on smear. A bone marrow aspirate is only necessary if the diagnosis of ITP is not straightforward. Because of large platelet size and vascular stability bleeding tendency in childhood ITP is mild even with very low platelet counts. 90% of children with acute IPT recover spontaneously within 12 months. Therefore therapy can safely be limited to a few situations: necessary surgical intervention during thrombocytopenia, live threatening bleeding, major trauma. In most instances optimal management of ITP consists in a "wait and see" approach in addition to giving detailed and thorough information to patients or parents about the benign nature of the disease, the likelihood of spontaneous recovery and the importance of avoiding aspirin and contact sports. Controversies in regards to diagnosis and therapy of ITP in childhood are discussed and the various therapeutic possibilities are presented.