[Future requirements for hematologists]. / Fremtidig behov for spesialister i blodsykdommer.

Today there are not enough specialists in haematology in Norway. During the period 1990-1995 2.5 specialists in haematology qualified per year. In order to meet future requirements for haematologists at Norwegian municipal and university hospitals, it has been estimated by the Norwegian Society for Haematology that the number of specialists qualifying per year should be increased to ten for the next ten years.

[Is there a role for general practitioners in future medicine?]. / Har generalisten noen plass i fremtidens medisin?

Changes in the type and frequency of diseases towards the end of the century will result in a larger number of elderly and chronically ill patients. At the same time, functional changes in the health services will lead to greater centralisation of complicated medical services. The general practitioner offers continuity, care and security in the patient's local environment. In the years to come the growing number of patients will put new pressures on the organisation of public health services. It is to be expected that general practitioners will have to take care of a larger number of more seriously ill patients than they do today. Therefore, general practitioners must examine the possibility of saying no to some of the many tasks they have accepted since the 1960s. Moreover, the hospitals must give priority to making their services more accessible and to improving the cooperation with the general practitioners so that the latter can use the specialists to a greater extent as advisers, and the hospitals as centers of expertise.

[Treatment with growth factors and cytokines in hematologic diseases]. / Behandling med vekstfaktorer og cytokiner ved hematologiske lidelser.

The Norwegian Society of Haematology has worked out guidelines for the use of granulocyte-colony stimulating factor and granulocyte-monocyte colony stimulating factor and interferon alpha in clinical haematological practice. We recommend not using growth factors as a routine to prevent or to treat fever in patients with granulocytopenia induced by cytostatics, or patients with myelodysplastic syndromes. At present such treatment should be restricted to clinical trials. The same conclusion was reached in regard to use of erythropoietin in the case of myelodysplastic syndromes. Harvesting of stem cells from peripheral blood is a well documented indication for administration of growth factors. Interferon alpha as maintenance treatment for cases of multiple myeloma and low grade malignant lymphoma delays progression of the disease but does not improve chance of survival. There is no documentation of improved quality of life. Use of interferon alpha is not justified as a routine treatment for multiple myeloma. In chronic myelogenous leukemia, interferon alpha seems to be equal to or better than hydroxyurea, and may be considered for patients who cannot undergo allogeneic bone marrow transplantation.

Activation of coagulation and deep vein thrombosis after bone marrow harvesting and insertion of a Hickman-catheter in ABMT patients with malignant lymphoma.

Evidence of activation of coagulation was sought in serial plasma samples from 25 ABMT candidates with malignant lymphoma admitted for bone marrow harvesting: 10 females and 15 males, median age 41 years (range 27-58 years). Nineteen patients had non-Hodgkin's lymphoma (NHL) and six had Hodgkin's disease. Of those with NHL, 14 had high-grade and five low- grade disease. The plasma levels of markers of activation (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, fibrinopeptide A and fibrinmonomers) increased significantly (P < 0.001) in association with harvesting. Except for fibrinopeptide A, the indicators of activation were still significantly elevated 24 h after marrow aspiration. Beta-thromboglobulin, a marker of the platelet release reaction, also increased significantly (P < 0.01). Four out of nine patients in whom a long-term central venous catheter was inserted just after marrow aspiration, developed catheter-related deep vein thrombosis, verified venographically, shortly after harvesting. These results suggest that patient with malignant lymphoma undergoing marrow harvesting develop a hypercoagulable state, and that insertion of a central intravenous catheter immediately after marrow harvesting should be avoided to prevent the development of symptomatic deep vein thrombosis.

Disseminated intravascular coagulation (DIC) in adult patients with acute leukaemia.

In 71 patients with acute leukaemia admitted for remission induction, disseminated intravascular coagulation (DIC) was looked for in 50 patients and diagnosed in 10 (20%). Of 10 patients with acute lymphoblastic leukaemia, 3 had DIC, and of 40 patients with acute myeloblastic leukaemia, 7 had DIC. The presence of DIC was related to bleeding manifestations within the first 2 weeks. A haemorrhagic diathesis was present in all DIC patients: 4 had minor and 6 had major bleeding, i.e. WHO grade > or = 2. In addition to blood product support, most DIC patients were treated with low doses of heparin and tranexamic acid. In all DIC patients the haemorrhagic symptoms preceded the heparin administration. Among 40 screened patients without DIC, 17 patients had minor and 3 had major haemorrhagic manifestations. Thus, the proportion of patients with major bleeding was significantly greater among the DIC patients (6/10 vs 3/40, p < 0.001). In conclusion, DIC at presentation was associated with a significantly increased risk for severe haemorrhagic complications and should be looked for in adults with acute leukaemia.

[Etiology and pathogenesis of spontaneous venous thromboembolism]. / Etiologi og patogenese ved spontan venøs tromboembolisme.

Thromboembolic disease is a major clinical problem. This article reviews the etiology and pathogenesis of spontaneous venous thromboembolism. There is an association between thromboembolism and hereditary deficiency of antithrombin III, protein C or protein S. In young patients, impaired fibrinolytic activity may represent the most common haemostatic abnormality associated with thrombosis. Dysfibrinogenaemia has been related to thrombotic disease in some patients. Moreover, the presence of phospholipid directed antibodies is associated with thrombosis in patients with connective tissue disorders. Therefore, for young patients with spontaneous thromboembolic disease, a thorough laboratory investigation is recommended.

[Role of phospholipids in hemostasis]. / Fosfolipidenes rolle i hemostasen.

This article reviews the significance of phospholipids in the haemostatic process. The plasma membranes of activated human blood platelets provide a catalytic phospholipid surface on which the "tenase" complex (factor IXa-factor VIIIa) and the "prothrombinase" complex (factor Xa-factor Va) can be assembled. The formation of a procoagulant platelet surface involves the exposure of anionic phospholipids e.g. phosphatidylserine, and is associated with shedding of microvesicles from the membranes of activated platelets. Moreover, tissue-factor, which plays a key role in blood coagulation by initiating the extrinsic coagulation pathway, requires the presence of phospholipids for optimal biological activity. The phospholipid dependency of the coagulation system explains the prolongation of phospholipid dependent clotting tests in patients with phospholipid directed antibodies such as lupus anticoagulants.

[Phospholipid antibodies (lupus anticoagulant and cardiolipin antibodies). Detection and clinical significance]. / Fosfolipidantistoffer (lupusantikoagulant og kardiolipinantistoffer). Påvisning og klinisk betydning.

Phospholipid antibodies may be detected by their ability to prolong phospholipid dependent coagulation tests, and are then called lupus anticoagulants. When ELISA tests with cardiolipin as coating antigen are used, the term anticardiolipin antibodies is employed. The association with thrombosis is best documented in patients with systemic lupus erythematosus. However, the "antiphospholipid syndrome", i.e. repeated thrombotic episodes and/or foetal loss in combination with a high positive anticardiolipin antibody test and/or an unequivocally positive lupus anticoagulant test, may be seen in individuals without any known underlying disease. The article describes techniques for the detection of antiphospholipid antibodies and adequate processing and handling of plasma samples.

A quantitative, semi-automated and computer-assisted test for lupus anticoagulant.

We describe the design of a quantitative test for lupus anticoagulants (LA), based on the Activated Partial Thromboplastin Time (APTT) and the Russell Viper Venom Time (RVVT). In this assay system, test plasmas mixed 1:1 with a pooled normal plasma (NP) are tested at a low as well as a high cephalin concentration, using an ACL 3000 automated clot timer. The ratio of these two clotting times, divided by the corresponding ratio for the NP, was defined as the Lupus Ratio (LR) and calculated by means of a computer program. The frequency distribution of the LR in a reference population of 150 healthy individuals was determined, and the 97.5 percentile was defined as the upper reference limit and allocated the value one Lupus Anticoagulant Unit (LA-U). Using dilutions of one strong LA positive plasma, standard curves for LA-U determination were constructed for the APTT as well as the RVVT based test, and fitted with a log-logit computer model. The sensitivity of the tests was comparable to that of the Kaolin Clotting Time (KCT). Plasma samples from warfarin treated patients were uniformly negative, while most heparin-containing plasmas were positive in both tests. Plasmas deficient in Factors V, VIII and IX were negative, whereas one Factor VIII-inhibitor containing plasma was positive in the APTT and negative in the RVVT. The present work shows that it is possible to adapt the APPT as well as the RVVT for LA quantification. With an automated clot timer and computer based calculation of results, the assays are simple and reproducible and have a high sensitivity and specificity.

Preparation of plasma for the detection of lupus anticoagulants and antiphospholipid antibodies.

The effect of different methods of plasma preparation on the results of 1) a clotting assay for lupus anticoagulant (LA) detection (the dilute activated partial thromboplastin time, dAPTT), and of 2) an ELISA test for anticephalin antibody (aCEPHA) detection, was evaluated. It is well known that platelet disintegration resulting from freeze-thawing of plasma samples may release procoagulant phospholipid--"LA-bypassing" activity. Even with fresh plasma, the dAPTT of LA positive samples was sensitive to the presence of residual blood platelets. This effect was accentuated by freezing and thawing: with test plasma that had been prepared by a centrifugation force of 3,000 g or less for 15 min at 4 degrees C, freeze-thawing caused a significant shortening of the dAPTT. This phenomenon could not be demonstrated with filtered test plasma, which was platelet free. Surprisingly, ultracentrifugation also led to a substantial shortening of the dAPTT compared to filtered plasma, and should not be recommended as a method of plasma preparation for LA detection. The ELISA test was less sensitive to residual platelets than the dAPTT. Thus, plasma prepared by a centrifugation force of at least 1,500 g may be stored at -20 degrees C before performance of the ELISA test. For the dAPTT, filtering of test plasma and control plasma after centrifugation is recommended for maximum sensitivity, regardless of whether they are to be examined in the fresh state or after freezing and thawing.

Antiphospholipid antibodies in pre-eclamptic women: relation to growth retardation and neonatal outcome.

The significance of antiphospholipid antibodies in pre-eclamptic women has not been thoroughly elucidated. The purpose of this study was to determine the proportion of pre-eclamptic women who were antiphospholipid antibody positive, and to elucidate the significance of these antibodies regarding growth retardation and neonatal outcome. Positive levels of anticephalin antibodies, which are antiphospholipid antibodies, were detected in 7 (19%) out of 37 pre-eclamptic women, as compared with none of 40 in a control group of normotensive women at similar stage of pregnancy (p = 0.004). The birthweight percentiles of the neonates of anticephalin antibody positive women were significantly lower than those of the neonates of anticephalin antibody negative women (p = 0.018). Four of 7 infants of anticephalin antibody positive women were growth retarded (less than 2.5th percentile). This was a significantly larger proportion than that for anticephalin antibody negative women (3/30) (p = 0.004). The 95% confidence interval for the difference between the two proportions was 0.10 to 0.85. Two of the 7 neonates of anticephalin antibody positive women died during the neonatal period, compared with none of the 30 neonates of anticephalin antibody negative women (p = 0.003). Thus, our study suggests that positive levels of anticephalin antibodies in pre-eclamptic women increase the risk for growth retardation and neonatal death.

Antiphospholipid antibodies after myocardial infarction and their relation to mortality, reinfarction, and non-haemorrhagic stroke.

Antiphospholipid antibodies have been suggested as markers for a high risk of recurrent cardiovascular events in young survivors of an acute myocardial infarction. However, there are few data to confirm or refute this hypothesis. In a cohort study, we have measured anticephalin (aCEPHA) and anticardiolipin (aCL) antibodies in a group of patients surviving an acute infarct. Of 597 patients studied, 13.2% were IgG or IgM aCEPHA positive compared with 4.4% of a reference population (n = 158; p = 0.002). In a multivariate analysis, adjusted for major cardiovascular risk factors, neither aCEPHA (IgG or IgM) nor a CL (IgG or IgM) was an independent risk factor for mortality, reinfarction, or non-haemorrhagic stroke. Although an increased proportion of survivors of a myocardial infarction have antiphospholipid antibodies, the presence of such antibodies is not a risk factor for subsequent coronary or cerebrovascular thrombosis.

Shared idiotypic determinant in mono- and polyclonal anti-phospholipid antibodies with lupus anticoagulant activity.

Of 42 purified human myeloma proteins tested, two (IgG3 Her and IgM Mag) were found to possess strong lupus anticoagulant (LA) and anti-cephalin activity, as assessed by a dilute activated partial thromboplastin time (dAPTT) and ELISA test, respectively. For these proteins, we confirmed the observation reported by others that LA activity is present in the antigen-binding (Fab) portion of the immunoglobulin molecule. Rabbit anti-idiotype antibodies against IgG3 Her inhibited the anti-cephalin activity of this protein, suggesting that the anti-cephalin activity of IgG3 Her depends on the hypervariable part of the immunoglobulin and thus most probably is a true antigen-antibody reaction. The anti-Her idiotype antibodies were also able to bind to and inhibit the anti-cephalin activity of IgM Mag. ELISA binding and inhibition experiments showed that the anti-idiotype antiserum contained at least two sets of anti-idiotypes; one set that recognizes a cross-reactive idiotype shared by IgG3 Her and IgM Mag, and another set that seems to be unique to the immunizing protein IgG3 Her. Both sets of anti-idiotype antibodies also bound weakly to polyclonal (patient) IgG, indicating an idiotypic cross reaction.

Quantitation of anticephalin antibodies in a computer-assisted enzyme-linked immunosorbent assay (ELISA): relation to lupus anticoagulant.

Lupus anticoagulants (LA) are IgG or IgM antibodies which prolong phospholipid-dependent coagulation tests. For the detection and quantitation of such antibodies, we have developed an ELISA with cephalin as the coating antigen. The sensitivity of this assay was compared to the activated partial thromboplastin time (APTT). LA was defined as greater than or equal to 5 sec prolongation of the APTT with standard cephalin dilution, or greater than or equal to 10 sec prolongation with a high cephalin dilution, on a 1:1 mixture of patient and control plasma. Plasma samples from 158 healthy individuals were tested for anticephalin antibodies. The 97.5 percentile was chosen as the upper reference limit and allocated a value of 1 ELISA unit. A "four-parameter logistic" model was used for transformation of the absorbances to ELISA units. Of 314 plasma samples referred for LA screening, positive results were found in 62 by both APTT and ELISA. Twenty-three samples were ELISA positive and APTT negative; this finding may be explained by greater sensitivity of the ELISA, which gave positive results in a four-fold greater dilution than the APTT. Prolongation of the APTT without antibody activity was found in 8 samples of which 2 had an inhibitor of factor VIII:C, the remaining 6 probably had true LA. In conclusion, our computer-assisted ELISA is a sensitive and reliable test method for quantitation of anticephalin antibodies. This assay has a high concordance with LA as detected with the APTT.

[Splenectomy in hematologic diseases]. / Splenektomi ved hematologisk sykdom.

We present the results of splenectomy in 45 patients with haematological diseases during the period 1975-85. Of 16 patients with immunologic thrombocytopenia, splenectomy resulted in a satisfactory and sustained platelet elevation in 11 (69%). Splenectomy corrected anaemia in all five patients with hereditary spherocytosis. Of seven patients with autoimmunohaemolytic anaemia, four responded satisfactorily. Postoperative complications occurred in ten of 45 patients (22%). There was no post-operative mortality. Only 49 per cent of the patients had received antipneumococcal vaccination. This is not satisfactory, and all unvaccinated, splenectomized patients should be offered vaccine. If possible, the vaccination should be performed before operation.