Acquired factor VIII inhibitors in nonhemophilic patients.

Antibodies against factor VIII occur in about 15-35% of hemophilia A patients and induce refractoriness to factor VIII substitution. In most cases, these antibodies are of the IgG class. Strategies to avoid or to treat such inhibitors are controversial. In very rare cases, factor VIII inhibitors also develop in nonhemophilic patients. Although there are anecdotal reports that these antibodies may disappear spontaneously without occurrence of bleeding tendencies, in the majority of patients the clinical course is characterized by severe hemorrhages. From 1980 to 1995, we observed ten nonhemophilic patients with acquired factor VIII inhibitors at our hospital. In most cases, a sudden bleeding tendency was observed shortly after an injury or surgery. Coagulation tests showed a prolonged aPTT and a decreased F VIII level. Other deficiencies of blood-clotting factors and acquired or hereditary von Willebrand's disease were excluded. Therapy with F VIII concentrates did not produce the expected increase. Measurement of F VIII inhibitor levels in Bethesda units/ml (BU/ml) revealed maximal values in the range of 2-128 BU/ml. Immunosuppressive therapy with azathioprine or cyclophosphamide in combination with methylprednisolone led to complete disappearance of the inhibitor, normalization of the coagulation tests, and complete remission of the bleeding tendency in seven treated patients within 6 weeks. Although the clinical course is not predictable and inhibitors may disappear spontaneously, combined therapy with methylprednisolone and azathioprine or cyclophosphamide is recommended for patients with bleeding tendency. In pregnancy, therapy should be started only with methylprednisolone; post-partum, azathioprine should be used additionally if methylprednisolone as a single drug does not lead to complete remission. In emergency situations, therapy with high doses of human factor VIII concentrate may be used. When bleeding does not cease, the additional use of activated prothrombin-complex concentrates or porcine factor VIII is indicated. Possible side effects may include hepatitis and short-lived intravascular thrombin production.

[T-helper (CD4+) cytopenia and HLA-A1, -B8, -C27, -DR3]. / T-Helfer(CD4+)-Zytopenie und HLA-A1, -B8, -Cw7, -DR3.

HLA antigen frequencies have been evaluated in a group of 99 AIDS patients who died with low T-helper cell counts. 34 patients also had HIV-associated Kaposi's sarcoma (KS). HLA-A1, Cw7, B8, DR3 has been postulated to be associated with rapid decline of T-helper cells in AIDS patients and with fast disease progression of AIDS. The results of this study support this hypothesis. However, significant elevations of these HLA antigens solely have been found in the group of patients with opportunistic infections, but not in patients with KS.

[Resuscitation necessitated by a transfusion reaction after HLA mismatched platelets substitution]. / Reanimationsbedürftige Transfusionsreaktion nach HLA-unangepasster Thrombozytensubstitution.

A severe nonhemolytic transfusion reaction occurred to a polytransfused leukemic patient as a life-threatening anaphylactic shock with cardio-pulmonary arrest following the transfusion of HLA-nonadapted/mismatched platelets. As the only potential causative agent a lymphocytotoxic antibody with the specificity anti-HLA-A2 has been found. The HLA antibody reacted up to a dilution of 1:2,048. The recipient was negative for the corresponding antigen, but HLA-2 was present on donor's platelets. This observation demonstrates again the clinical value of HLA-matched platelet transfusion in patients who need long-term support.

[Ex-vivo bleeding time as a control for platelet transfusion]. / Ex-vivo-Blutungszeit zur Kontrolle der Thrombozytentransfusion.

Thrombocytopenia is the most common cause of bleeding tendency and, if due to impaired platelet production, is best treated by platelet transfusion. For patients with acute leukemia prophylactic platelet transfusion should be considered if platelet count is below 20 x 10(9)/l. This will be underlined by a retrospective analysis at our clinic of 231 patients suffering from acute myelocytic leukemia (AML FAB M1-7) and showing an early-death rate of 7.7% by bleeding complications. To estimate the effectiveness of platelet transfusions, not only stopping of bleeding symptoms and corrected count increment (CCI) should be taken into account but also whether the patient has fever, sepsis, hepato-splenomegaly or has taken special drugs. Measuring the in vivo bleeding time is of little use for low reproduction and is stressing for patients. In 1985 Kratzer described a new and sensitive method for the evaluation of platelet function. After modifying this method it is now possible to test platelet function even with platelet counts below 50 x 10(9)/l.

[Plasminogen activator inhibitor 1--a new thrombosis risk marker]. / Plasminogenaktivator-Inhibitor 1--ein neuer Thromboserisiko-Marker.

The plasma activity of plasminogen activator inhibitor 1 (PAI-1) was measured in 278 clinically healthy subjects (98 men, 180 women; mean age 26 [18-50] years). In 198 of them there were factors increasing the risk of thrombosis, such as smoking, over-weight and/or oral contraceptives. PAI-1 activity was within normal range (less than 4 U/ml) in male nonsmokers of normal weight and in female nonsmokers not taking oral contraceptives. In male smokers (5.76 +/- 1.93 U/ml) and in overweight subjects of both sexes (7.49 +/- 1.87 U/ml) PAI-1 was increased up to 10.6 U/ml as an indication of decreased fibrinolysis capacity. Nonsmoking females on oral contraceptives had lower PAI-1 levels (2.72 +/- 0.86 U/ml) than nonsmokers without hormonal intake (3.21 +/- 1.03 U/ml; P less than 0.001). Apparently the increased risk of thrombosis that occurs on oral contraceptives is not due to increased PAI-1 activity.

[Prevention of HLA-alloimmunization of recipients of platelet concentrates]. / Prophylaxe von HLA-Alloimmunisierung bei Empfängern von Plättchen-Konzentraten.

Over a period of twelve months 7163 HLA-matched, single-donor platelet concentrates were prepared for 557 thrombocytopenic patients with hematologic or neoplastic disorders. 80% of the platelet recipients remained HLA-antibody-negative. Patients who developed HLA-antibodies received random platelets and/or leukocyte-contaminated blood-components simultaneously. Thus, HLA-matching, single-donor-preparations and removal of contaminating leukocytes may prevent HLA-alloimmunisation, and therefore improve the efficacy of platelet-transfusion.

Three cases of acquired factor VIII: C inhibitors in non-hemophilic patients.

During the last ten years we observed three non-hemophilic patients with factor(F) VIII: C inhibitors (2 women aged 68 and 80 and a man aged 51). In all three cases, a sudden bleeding tendency was observed shortly after an injury or surgery. Coagulation tests showed a prolonged aPTT and a decreased F VIII: C level. Other deficiencies of blood-clotting factors and acquired or hereditary von Willebrand's disease could be excluded. Therapy with F VIII: C concentrate, cryoprecipitate, or fresh-frozen plasma did not produce the expected increase in F VIII: C. Measurement of F VIII: C inhibitor levels (Bethesda Units, BU) revealed values in the range between 9 and 64 BU. The two patients subjected to long-term therapy with a combination of prednisone (initially 2-3 mg/kg BW) and azathioprine (2-3 mg/kg BW) responded positively; the F VIII: C concentration increased. The third patient, treated only with a low dose of prednisone (30 mg/day), did not show any reaction at all. Since hereditary hemophilia A could be excluded, the inhibitors apparently were acquired. Malignant tumors did not appear. In conclusion, long-term therapy of an acquired F VIII: C inhibitor with a combination of prednisone and azathioprine may lead to complete disappearance of the inhibitor, normalization of the coagulation tests, and complete remission of the bleeding tendency.

[Clinical and serological characterization of Chlamydia-induced arthritis]. / Klinische und serologische Charakterisierung der Chlamydien-induzierten arthritis.

Chlamydia-induced arthritis was diagnosed in 32 patients (18 men and 14 women; mean age 33 [17-54] years). 13 were HLA-B27 positive. In 19 patients the arthritis was largely confined to one joint. Enthesopathies occurred in 14 patients, and in 13 sacroiliitis was diagnosed radiologically. The most frequent extra-articular changes affected the urogenital system (26 cases). The full Reiter syndrome was present in seven patients (four men, three women). All patients had serum antibodies against Chlamydia. In 16 patients Chlamydia was diagnosed as the causative organism by urogenital swab. Chlamydia-induced arthritis differs from other arthritides in the high proportion of HLA-B27 negative patients.

[The immunologically-caused early abortion]. / Der immunologisch bedingte Frühabort.

Recent advances in the understanding of immunological events during pregnancy offer new diagnostic and therapeutic approaches to couples suffering from unexplained recurrent spontaneous abortion. In terms of immunology the success of pregnancy means, that the fetus as a semi-allogeneic graft is not rejected by the mothers/recipients immune system. Beside a variety of specific and non-specific mainly locally acting substances a process of active tolerance induction is responsible for fetal survival. In response to paternally inherited fetal antigens the maternal immune system produces so-called blocking factors. In most women with unexplained recurrent spontaneous abortion these blocking factors cannot be detected. By immunization with paternal or third party lymphocytes the maternal immune system can be stimulated to produce blocking factors and therefore to protect a conceptus from rejection.

Time-dependent variation of HLA-antigen-frequencies in HIV-1-infection (1983-1988).

In a 5-year-study of HLA-phenotypes in 411 HIV-1-infected individuals, a progressive decrease of the formerly elevated frequency of HLA-DR5 has been observed. HLA-DR3 seems to have a protective effect. These results are discussed with respect to the mimicry-hypothesis of HLA and disease associations. Further preliminary results indicate that HIV-associated Kaposi's sarcoma could be associated with HLA-A28, and therefore might be a different etiologic entity than HIV-infection alone.

[Severe aplastic anemia and pregnancy]. / Schwere aplastische Anämie und Schwangerschaft.

Severe aplastic anaemia was diagnosed in a 24-year-old woman in the 16th week of her pregnancy. She was delivered by cesarean section in the 35th week of a healthy boy, treatment in the intervening period having been exclusively by supportive measures. Allogenic bone marrow transplantation, planned after delivery, had to be cancelled owing to the sudden death of the female donor. Immunosuppressive treatment with antithymocyte globulin, corticosteroids and cyclosporin A failed to improve the haematological picture and the patient died one year after the delivery of intracerebral haemorrhage.

[Immunologically-induced abortion--diagnosis and therapy]. / Der immunologisch bedingte Abort--Diagnose und Therapie.

As etiological factors responsible for repeated miscarriages disturbances of the maternal-fetal immunoregulation are involved. Diagnostic aspects of the immunobiology of abortion and the clinical management of habitual abortion by immunotherapy are discussed.

[Significant association of HLA-B8 with systemic lupus erythematosus and with specific serological markers]. / Signifikante Assoziation des HLA-B8 zum systemischen Lupus erythematodes und zu bestimmten serologischen Markern.

Analysis of the HLA antigens of the A, B and C locus of 87 patients with systemic lupus erythematosus (SLE) revealed a significant elevation for HLA-B8 of 64% as compared to 22% in a healthy control group (n = 1850) (P less than 0.000001). Owing to the known linkage disequilibrium of this genetic marker with the HLA-A1 antigen, the HLA phenotype A1, B8 was found in 55% of the SLE patients (P less than 0.000001). Moreover, a significant association of the HLA-B8 in 82% (P less than 0.025) of Ro antibody-positive SLE patients (n = 22) and in 84% (P less than 0.025) of Ha antibody-positive patients (n = 19) was striking. A more frequent occurrence of this HLA antigen could also be detected in patients with a persistent nDNA antibody elevation and in patients with manifestation of the disease before the 40th year of life as compared to patients who manifested it later. An association of the HLA-B8 antigen with a raised disease activity of SLE can be inferred.

[Cimetidine and ranitidine in intensive care patients. Double-blind randomized cross-over study on intravenous administration: hemodynamics, plasma coagulation, blood gases and acid-base status]. / Cimetidin und Ranitidin bei Intensivpatienten. Doppelblinde randomisierte Cross-over-Studie zur intravenösen Gabe: Hämodynamik, plasmatische Gerinnung, Blutgase und Säure-Basen-Status.

Intravenous cimetidine 200 mg, and ranitidine 50 mg were administered as 2 minute infusions to 50 intensive-care patients. Cimetidine and ranitidine differed significantly in their effect on systolic arterial blood pressure measured during the second minute (alpha = 0.01). In the case of cimetidine the haemodynamic parameters measured over 10 minutes revealed a clearly defined fall in systolic, diastolic and mean arterial blood pressure as well as a rise in heart rate. The initial values were regained 5 minutes after drug application. Adverse effects of ranitidine on haemodynamics were much less than those of cimetidine. Neither drug produced any essential change in clotting parameters (partial thromboplastin time, plasma thrombin time, thromboplastin time and fibrinogen) measured before and 5 minutes after application, nor had they any effect on blood-gases or acid-base status.

[Pulmonary function during a 10-day successful extracorporeal CO2 elimination in acute respiratory failure. Case report]. / Lungenfunktion während 10-tägiger erfolgreicher extrakorporaler CO2-Elimination bei schwerem akuten Lungenversagen. Fallbricht.

Extracorporeal CO2-removal (ECCO2-R) with low-frequency positive-pressure ventilation (LFPPV) may relieve the acutely injured lung from the burden and the risks of excessively high ventilatory minute volumes and airway pressures. It was the purpose of this study to document the evolution of lung function during clinical ECCO2-R with special emphasis on extravascular lung water. ECCO2-R was applied in a 21-year-old female patient suffering from severe post-traumatic infectious adult respiratory distress syndrome. The indication for ECCO2-R was based on the following findings: total static lung compliance 25 cm X cm H2O-1; arterial pO2 50 mm Hg with an inspiratory oxygen concentration of 100%; intrapulmonary right-to-left shunt over 50% of the cardiac output; and extravascular lung water 24 ml X kg-1 (normal 4.5-7 ml X kg-1). ECCO2-R was shown to provide satisfactory conditions for improving the above-mentioned abnormal parameters of pulmonary function. Pressure-limited low-frequency mechanical ventilation allowed successful management of several pneumothoraces with bronchopleural fistulas which occurred during the procedure. It is concluded that these complications of positive airway pressure would have led to the patient's death under the conditions of conventional mechanical ventilation.