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Korrektur zu 10.1038/s41375-020-0826-9

Zusammenfassung Es wird uber zwei Falle von Afibrinogenamie beim Hund berichtet. Im einen Fall (11jahrige Schaferhundin) lag eine Verbrauchskoagulopathie (Fibrinogenmangel zufolge intravasaler Gerinnung) mit Verminderung von Faktor 1, II, V, VII und VIII und der Thrombozyten vor. Das Tier hatte ein metastasierendes Mamma-Karzinom. Beim zweiten Patienten (6jahriger Durrbachler-Rude) fehlte selektiv das Fibrinogen. Obwohl er an einer generalisierten Retikulo-Histozytose litt, wird — auf Grund des Gerinnungsstatus und der Familienanamnese — auch das Vorliegen einer hereditaren Afibrinogenamie diskutiert. Summary Afibrinogenaemia in the dog Two cases of absence of fibrinogen in the blood in the dog are reported. In one case (11-year-old Alsatian bitch) there was a usage coagulopathy (lack of fibrinogen as a result of intravascular clotting), with reduction of factors 1, 2, 5, 7 and 8 and of platelets. The animal had a metastasising mammary carcinoma. The second case was a 6-year-old Durrbach male with selective failure of fibrinogen. Although the animal had a generalised reticulo-histiocytosis, the question of a hereditary afibrinogenaemia is discussed on the basis of the clotting status and the family history. Resume Afibrinogenemie chez le chien On rapporte deux cas d'afibrinogenemie chez le chien. Dans un des cas, (une chienne berger de 11 ans), on observe une coagulopathie de consommation (deficience en fibrinogene a la suite d'une coagulation intravasculaire), avec diminution des facteurs I, II, V, VII et VIII et des thrombocytes. L'animal presentait un carcinome mammaire a metastases. Dans le deuxieme cas, (un chien de Durrbach mâle de 6 ans), le fibrinogene faisait defaut de maniere selective. Bien que l'animal fut atteint d'une reticulo-histiocytose generalisee, on discute cependant l'eventualite d'une afibrinogenemie hereditaire, en vertu des resultats de la coagulation et de l'anamnese familiale. Resumen Afibrinogenemia en el perro Informase sobre dos casos de afibrinogenemia en perros. En un caso (perra pastor de 11 anos de edad) se hallo una coagulopatia de consumo (carencia de fibrinogeno como consecuencia de coagulacion intravasal) con disminucion de los factores I, II, V, VII y VIII y de los trombocitos. El animal tenia un carcinoma mamario que producia metastasis. En el paciente segundo (macho Durrbach de 6 anos de edad) faltaba selectivamente el fibrinogeno. Aunque padecia una reticulo-histocitosis gene-ralizada, se discute — en virtud de la situacion de coagulacion y de la anamnesis familiar — tambien la presencia de una afibrinogenemia hereditaria.

The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. Of 31 patients, 20 had tuberculosis, 8 had atypical MBI, and 3 had diagnoses based on histological findings only. Five patients (16%) died, all of whom had received an allogeneic SCT. Because of the increased numbers of unmatched donors and transplantation programs in countries with a high prevalence of tuberculosis, constant vigilance is required to early detect MBI in SCT recipients.

The use of granulocyte colony-stimulating factor (G-CSF) has been established to improve hematological recovery after allogeneic bone marrow transplantation (BMT). The optimal timing to start with G-CSF has not been determined. This study investigates whether delayed use of G-CSF starting on day 6 is as safe and efficient as starting treatment with G-CSF immediately after BMT. Thirty-eight patients undergoing allogeneic BMT were randomized to either receive post-transplant G-CSF treatment starting at day 1 or at day 6. The time to hematological recovery was monitored and the groups were compared with respect to peritransplant morbidity and mortality. Recovery of the neutrophil granulocyte counts (PMN) to100/microl,500/microl and1000/microl was comparable in both groups. The nadir of the PMN counts after stopping G-CSF was also similar. There was no difference in the recovery of red blood cells and platelet counts and no difference between the two groups with respect to the number of febrile episodes, number of days with antibiotics or number of documented bacterial, fungal or viral infections. Delayed treatment with G-CSF resulted in a reduction of G-CSF treatment from 19 days to 14 days (P = 0.0017). Reducing the length of treatment by 5 days lowered G-CSF treatment costs by 26.3%. Therefore, postponing treatment with G-CSF has no influence on the hematological recovery after allogeneic BMT. There is an economical benefit of postponing G-CSF use without any clinical disadvantages.

The best treatment of CMV gastrointestinal disease has been controversial, with some centers adding intravenous (i.v.) Ig to antiviral chemotherapy. The aim of this retrospective survey was to compare the outcome of antiviral chemotherapy with or without i.v. Ig. A questionnaire was sent to centers belonging to the EBMT. Thirty-three patients with CMV gastrointestinal disease were reported, 22 patients were given antiviral chemotherapy alone and 11 patients a combination of antiviral chemotherapy and i.v. Ig. Eighteen of 33 (55%) patients responded to therapy, 13 of those treated with antiviral chemotherapy alone and five (45%) of those treated with the combination (P = NS). Patients with acute GVHD of grades II-IV had significantly worse outcomes than patients with acute GVHD grades 0-I. In a Cox proportional hazards model corrected for acute GVHD there was no difference in outcome of CMV gastrointestinal disease with or without addition of Ig. Survival at 100 days after diagnosis of CMV gastrointestinal disease was 64%. There was no difference in survival in patients treated with or without i.v. Ig. The results of this retrospective survey indicate that addition of i.v. Ig to antiviral chemotherapy might not improve outcome in patients with biopsy-proven CMV gastrointestinal disease.

We describe the phenomenon of waning of focal hepatic and/or splenic lesions on abdominal computed tomographic (CT) scan during neutropenia in patients with chronic disseminated candidiasis. After observation of the phenomenon in one patient, a total of five cases were prospectively monitored with serial CT scans. After the diagnosis of disseminated candidiasis, hepatic lesions decreased in size and conspicuousness in three patients, while in two others they disappeared completely during a subsequent chemotherapy-induced neutropenia. After recovery of the neutrophils, the lesions reappeared or increased in conspicuousness in all five patients. Of three patients treated with a second cycle of myeloablative chemotherapy, lesions again decreased in two patients during neutropenia and increased again in one patient after neutrophil recovery. In all five patients, candidiasis eventually resolved after prolonged antifungal treatment. In chronic disseminated candidiasis, hepatic or splenic lesions may transiently disappear during neutropenia. Thus, antifungal therapy should not be discontinued on the basis of radiologic findings alone.

Intravenous immunoglobulins (IvIgG) are often used in patients receiving a basic immunosuppressive therapy with CsA either for prevention of infectious complications or as an additional prophylaxis of graft versus host disease in clinical bone marrow transplantation. As far as we know, the combined in vitro immunosuppressive effects of these 2 drugs have not been investigated yet. In this study, we compared the effect of CsA, IvIgG, and CsA combined with IvIgG on the proliferative capacity of peripheral blood mononuclear cells in a mixed lymphocyte culture system. The concentration-dependent inhibition of peripheral blood mononuclear cell proliferation in the mixed lymphocyte culture system by CsA is a well established phenomenon. By adding IvIgG to the cultures (n=20) containing CsA, we were able to show a significantly (P

Effective granulocyte transfusion (GT) therapy has been hampered by the low yield of neutrophil granulocytes (PMN) obtainable from normal donors even by use of corticosteroid prestimulation, hydroxyethyl starch (HES), and modern leukapheresis (LA) techniques. To increase the PMN yield we performed LA in 22 healthy volunteer donors after a single subcutaneous administration of 300 micrograms of granulocyte colony- stimulating factor (G-CSF) 12 to 16 hours before LA. Five to 7 L of blood was processed within 1.9 to 3 hours using the standard CS- 3000Plus (Baxter, Deerfield, IL) LA protocol including HES. The mean number of PMN harvested was 44.32 +/- 15.5 x 10(9), corresponding to 6.88 +/- 2.1 x 10(9)/L of blood processed. In the final product PMN functions (in vitro: chemotaxis, phagocytosis, chemiluminescence, superoxide anion production; in vivo: chemiluminescence, half-life) were at least normal. In all donors G-CSF induced a consistent increase of white blood cell (mean 16.46 +/- 3.8 x 10(9)/L) and PMN counts (15.94 +/- 3.6 x 10(9)/L). No G-CSF-related side effects were observed and LA was well tolerated. G-CSF prestimulation allows to harvest three to five times higher numbers of functionally normal PMN by LA compared with corticosteroid pretreatment. This may help to overcome one of the major limitations of an effective PMN support.

Transient pure red cell aplasia (PRCA) in three consecutive patients receiving ATG for management of kidney graft rejection prompted a systematic study of the effects on erythropoiesis of the ATG preparation used at our institution. We found that 90% of patients treated with rabbit anti-T lymphoblast globulin developed reticulocytopenia (less than 17,000 reticulocytes/mm3), with complete disappearance of reticulocytes in 65% of patients and increased requirement for red cell transfusion. PRCA, with selective aplasia of erythroblasts was confirmed by bone marrow aspiration in 4 patients volunteering for aspiration, and by the kinetic of the disappearance of blood reticulocytes in relation to the beginning of ATG treatment. The nadir of thrombocytes and lymphocytes, blood cells directly destroyed by ATG in circulation, followed the start of ATG treatment within 1 to 4 days. In contrast the nadir of reticulocyte counts occurred later, between day 7 and 13 after ATG was begun, reflecting the fact that toxicity was directed against red cell precursors rather than mature circulating cells. In agreement with these clinical findings ALG was found to be cytotoxic in vitro for erythroid precursors. Analogously to autoimmune PRCA caused by autoantibodies to erythroblasts, this type of PRCA could be viewed as "heteroimmune disease."

The major risk factor associated with repeated platelet transfusions is alloimmunization. Its management represents one of the greatest remaining clinical and research challenges in the field of platelet transfusion therapy. This is particularly true because current approaches to the treatment of leukemias and various solid tumors are now focussed on the administration of intensive, repetitive courses of postremission chemotherapy necessitating successful platelet support for a prolonged time. Moreover, once alloimmunization has supervened and histocompatible donors cannot be identified there are no proven approaches for the management of bleeding complications in thrombocytopenic patients. Thus, any practical means by which the rate or the speed of alloimmunization could be minimized would be of considerable clinical importance.

In 3 of 15 consecutive patients receiving a human leukocyte antigen (HLA)-identical but major ABO incompatible bone marrow transplant (BMT), pure red cell aplasia (PRA) lasting 5 to 8 months was observed. Titers of the incompatible anti-A agglutinin before infusion of the red blood cell (RBC)-depleted BMT was very high in one, and in the usual range in two patients. Decrease of agglutinin titers during the first 4 weeks after BMT were comparable between PRA patients and those of ABO- incompatible BMT recipients with timely RBC recovery. However, in PRA patients, agglutinin titers rose again and remained elevated for 19 to 28 weeks. RBC engraftment and reticulocyte recovery ultimately occurred spontaneously and coincided with the decrease of agglutinin titers below 16. These observations indicate that PRA is antibody-dependent in this setting. Furthermore, it is conceivable that cyclosporine facilitates recipient-derived antibody synthesis after major ABO- incompatible BMT.

The threshold for prophylactic platelet transfusions in patients with hypoplastic thrombopenia generally recommended in the standard literature is 20,000 platelets/μL. A more restrictive transfusion policy may be indicated in patients with chronic severe aplastic anemia (SAA) in need of long-term platelet support. We evaluated the feasibility and safety of a policy with low thresholds for prophylactic transfusions (≤5,000 platelets/μL in stable patients; 6,000 to 10,000 platelets/μL in cases with fever and/or hemorrhagic signs) combined with progressive lengthening of transfusion intervals (up to at least 7 days irrespective of the interim course of platelet counts). The study was based on a retrospective analysis of a total of 18,706 patient days with platelet counts ≤10,000/μL in patients with chronic SAA treated (for more than 3 months) on an outpatient basis. Altogether, 1,135 platelet transfusions were given, 88% at counts ≤10,000/μL and 57% at counts ≤5,000/μL. The mean transfusion interval was 10 days. During the period of observation, three major nonlethal bleeding complications occurred, which could be well controlled. We conclude that the restrictive policy with low transfusion thresholds and prolonged transfusion intervals proved feasible and safe in chronic SAA patients.

Refsum's disease (Heredopathia atactica polyneuritiformis) is caused by accumulation of phytanic acid in all body tissues due to an inherited failure of alpha-oxidation of branched chain fatty acids. Plasmapheresis has been reported to be beneficial by removal of phytanic acid from the blood. We describe a patient with Refsum's disease in whom long-term plasmapheresis did not improve clinical, biochemical or electrophysiological parameters.

Severe hemolysis occurred in a 51-year-old female after a 17-day course of intravenous amoxicillin. A strongly positive direct antiglobulin test (anti-IgG titer 1:2,000) ensued which disappeared after withdrawal of the drug. Both the patient's serum and eluate obtained from the patient's red cells contained an IgG antibody which reacted with red blood cells coated in vitro with amoxicillin, but not with uncoated cells. In addition, high-titer antipenicillin, antiampicillin and antiamoxicillin IgG antibodies could be demonstrated in her serum by a RAST-based solid-phase radioimmunoassay. The patient's hemolysis gradually subsided within 1 week after discontinuing the drug. This is the first report of amoxicillin-induced immune hemolytic anemia.

Twenty-four thrombocytopenic patients refractory to random-donor platelet support were given 106 platelet transfusions obtained from 57 different HLA-typed single donors. For critical evaluation of the transfusion responses, “fullhouse” HLA typing of donors and a precise measurement of the number of infused platelets were performed. Posttransfusion platelet increments were related to the HLA matching of donor-recipient pairs and to leukocyte crossmatch tests in vitro. The transfusion response displayed a striking difference depending on the absence (type-0 match) or presence (type-1 or-2 match) of donor HLA antigens differing from the recipient. Whereas 95% of transfusions from type-0 match donors resulted in a compatible platelet increment, only 20% successful transfusion responses could be achieved with type-1 or -2 match donors. In 77% of type-1 or -2 match transfusions with poor posttransfusion platelet increments, the lymphocyte cytotoxicity test (incubation time 180 min at room temperature) was positive. This test therefore seems to be a useful tool in predicting the outcome of transfusion responses in type-1 and -2 match pairs. In contrast, the lymphocyte cytotoxicity tests were of no predictive value in type-0 match pairs. The influence of specific antigranulocyte antibodies on type-0 match platelet transfusions was assessed in four recipients. Although severe transfusion reactions were observed, no detrimental influence on platelet increments could be observed, at least following the initial transfusion.

A 26-year-old man with severe aplastic anemia was treated with high-dose Cyclophosphamide followed by the infusion of bone marrow cells from his HLA-identical sister. After initial intake of the graft, rejection ensued by day 46 which was followed by a permanent complete aplasia. After 4 months, bone marrow retransplantation with the same donor was attempted after a more intensive conditioning regimen. This led to permanent engraftment with rapid normalization of the blood counts lasting now for over 12 months. The patient has since remained in excellent clinical condition without signs of graft-versus-host disease.

A randomized study was performed in 54 thrombocytopenic patients with acute leukemia. Alloimmunization of recipients of random multiple-donor platelet concentrates (MD group) was compared to that of patients receiving random single-donor platelets (SD group). In the SD patients, formation of alloantibodies (mostly anti-HLA) occurred less frequently (p less than 0.002), after a longer time period (p less than 0.002), and after a higher number of transfusions (p less than 0.005) as compared to MD patients. SD patients also became refractory to random platelets less frequently (p less than 0.005), after a longer time period, and after a higher number of transfusions (p less than 0.02). In SD patients, the increments after the first and the last transfusion were in the same range, whereas in MD patients, the 1-hr (p less than 0.001) and the 24-hr (p less than 0.025) increments decreased from the first to the last transfusion. Thus, the use of random SD platelet transfusions postponed alloimmunization.

A 17-year-old woman with severe aplastic anemia was treated with high-dose cyclophosphamide followed by infusion of bone marrow cells from her HLA-identical, ABO-incompatible brother. The marrow graft failed to take. Subsequently, the patient revealed an autologous marrow reconstitution leading to a near-complete hematologic recovery which is now persisting for over 20 months.

ZusammenfassungEs wurde die Blutgerinnung und Fibrinolyse in dem durch Punktion der Nabelschnurvene gewonnenen Blut von 140 Neugeborenen untersucht und die Resultate denjenigen zahlreicher früherer Arbeiten gegenübergestellt.1. Fibrinogen- und Faktor-V-Spiegel lagen praktisch immer im Erwachsenen-Normalbereich.2. Die Thrombinzeit war bei 85% der Neugeborenen verlängert. Eine Erhöhung des endogenen Heparins konnte als Ursache ausgeschlossen werden. Die Thrombinzeit-verlängerung der meisten Neugeborenen dürfte auf eine fibrinolytische Alteration des Fibrinogens zurückzuführen sein. Bei einigen Neugeborenen konnte aber die Existenz eines funktionell andersartigen, »fetalen« Fibrinogens nicht sicher ausgeschlossen werden.3. Die fibrinolytische Aktivität – bestimmt durch die Euglobulinlysezeit, die bovine, nicht erhitzte Fibrinplatte und die Immunelektrophorese auf Fibrinogenabbaupro-dukte – war bei rund 60% der Neugeborenen erhöht. Die Vollblutfibrinolyse und die Parakoagulation durch Protaminzugabe im Serum erwiesen sich hingegen als zu wenig empfindliche Methoden zur Erfassung der Fibrinolyse im Nabelschnurblut.

Splenic function was evaluated after subcutaneous epinephrine injection (0.5 mg/m2) in 15 bone marrow transplant (BMT) recipients, 10 healthy volunteers and 5 healthy asplenic men. Healthy volunteers and BMT recipients with minor primary induction chemotherapy (mRx) showed similar rise in platelet (plt) and neutrophil granulocyte (PMN) counts and similar contraction of spleen. Patients with intensive primary induction chemotherapy (MRx), however, had significantly smaller spleens and spleen contraction (p less than 0.02) and no plt increase (p less than 0.05) when compared with healthy volunteers. 2 patients with MRx even exhibited a decrement of plt count after epinephrine, similar to that observed in all 5 healthy asplenic subjects tested. Our results suggest that mRx and conditioning for BMT including total body irradiation (TBI) does not alter the splenic function, but that the combination of MRx and conditioning regimen including TBI may cause functional hyposplenism, sensitively revealed by reduction in plt count after epinephrine stimulation.

In bone marrow transplantation the main reasons for treatment failure within the first months posttransplant were infection, interstitial pneumonia, GvHD and rejection (in SAA). A significant association with 6-month-mortality has been established for: 1) the use of high-dose-rate TBI, 2) the occurrence of moderate to severe GvHD, 3) more advanced disease, 4) patients of older age, 5) infection at the time of BMT and 6) high number of pre transplant transfusions and/or refractoriness to random platelets (1,2).

To study prognostic factors 38 consecutive patients with aplastic anemia were evaluated until death or over a follow-up period of at least 4 years. A prognostic formula was devised by multivariate analysis for prediction of short-term survivors at diagnosis of aplastic anemia: Using the initial percentage of nonmyeloid cells in the marrow aspirate and the neutrophil count in peripheral blood, survival of less than 4 months is predicted with a probability of 89% (sensitivity 80%). The lowest blood counts during the course of the disease are useful to predict the outcome in more chronic courses of aplastic anemia: A reticulocytopenia below 5 X 10(9)/1, a neutropenia below 0.1 X 10(9)/1 or a thrombocytopenia below 5 X 10(9)/1 all resulted in an ultimate mortality of over 90%. However, if none of these threshold values were reached, a 4 year survival of 71% was observed. Thus, 5 X 10(9) reticulocytes/1, 0.1 X 10(9) neutrophils/1 and 5 X 10(9) platelets/1 form a group of risk factors to predict a fatal or favorable outcome throughout the course of the disease.