A retrospective analysis of bleeding complications in 438 patients with acute leukaemia during the years 1972-1991.

The incidence and mortality of bleeding complications have been investigated in 438 patients with acute leukaemia consolidated either by chemotherapy (n = 241) or by bone marrow transplantation (n = 197). Bleeding signs on admission were found in 38% of the chemotherapy-treated group. Haemorrhagic deaths during the 1st month were seen in 10%. The majority of the major bleedings were localized intracranial, but gastrointestinal haemorrhages were also common. The platelet count was significantly lower (40 x 10(9)/l versus 69 x 10(9)/l, p < 0.001) and the leukocyte count significantly higher (31.2 x 10(9)/l versus 11.6 x 10(9)/l, p < 0.001) in the group with bleeding complications than in those without. The haemorrhagic mortality in patients consolidated with chemotherapy compared with transplant patients was similar, 23% and 19%. The majority of the lethal haemorrhages in the latter group were observed in patients undergoing allogenic bone marrow transplantation after engraftment. Septicaemia, graft-versus-host and venous occlusive disease were contributing factors.

Bleeding complications and coagulopathy in acute leukaemia.

Factors and inhibitors of coagulation and fibrinolysis were investigated on admission in 57 patients with acute leukaemia and they were correlated to the occurrence of haemorrhage. Coagulation disturbances were found in 98%. Seventeen of the patients with haemorrhagic symptoms had major bleeding. Severe thrombocytopenia (< 20 x 10(9)/l) was found in 16%. Patients with major bleedings had significantly lower concentrations of prothrombin complex, fibrinogen, protein C and platelets. Low levels of antiplasmin and fibrinogen were characteristic of 'bleeders' with promyelocytic and lymphoblastic leukaemia. We found a positive correlation between vWF:Ag and leukaemic cell count especially in lymphoblastic leukaemia (ks = 0.72). Reduced levels of antithrombin indicated a poorer prognosis.

Elastase activity in leukaemic cells and plasma in patients with acute leukaemia.

Proteolysis of coagulation factors and inhibitors resulting in haemorrhage can be mediated by elastase. Indirect signs of this are elevated levels of elastase complexed to its inhibitor in plasma, alpha 1-antitrypsin (E alpha 1-AT). We have measured intracellular elastase activity in leukaemic cells from 60 patients with acute leukaemia. Elastase activity was detected in 92% of the patients with acute nonlymphoblastic leukaemia (ANL), no activity was found in the patients with acute lymphoblastic leukaemia (ALL). High levels were found in cells from patients with promyelocytic leukaemia. Moderate to high total circulating blast elastase activity was measured in 70% of the ANL patients with haemorrhage compared with 36% of the patients without bleeding complications (p < 0.05). The available intracellular elastase activity was correlated to the level of E alpha 1-AT (rs = 0.42, p < 0.01) but not to the elastase specific split product of fibrinogen, B beta 30-43. In complete remission the levels of E alpha 1-AT were normalized. Intracellular elastase activity might be a useful supplement to differentiate ANL and ALL.

Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg.

In an open, randomised controlled study, 101 patients with phlebographically diagnosed deep vein thrombosis of the leg, not extending into more than two thirds of the femoral vein, were randomised to receive Fragmin (a low molecular weight heparin) administered subcutaneously either once or twice daily in doses of 200 U(anti-FXa)/kg/24h or 100 U(anti-FXa)/kg/12h respectively. Prior to Fragmin unfractionated heparin had been administered by continuous iv infusion for not longer than 24h. Warfarin was administered from the first treatment day. Fragmin was administered for at least 5 days or until the prothrombin complex had been within the therapeutic range for at least 2 days. Patients were kept in bed for the first day but thereafter were ambulant. Phlebography was repeated at 5-7 days. Comparison of the phlebograms revealed a similar improvement (reduction in Marder score) in both groups. There were 5 cases of bleeding: 1 major and 3 minor in the twice daily group and 1 minor bleed in the once daily group. There were no cases of clinical pulmonary embolism. It is concluded that Fragmin, administered as a single daily subcutaneous injection, is effective in the treatment of deep vein thromboses, and offers the advantages of reduced costs, despite higher price of the drug, including reduced nursing time.

Elastase activity in leukemic cells.

Elastase, a proteolytic enzyme which digests different clotting factors, has previously been isolated from monocytes, macrophages and granulocytes. In the present work, we have isolated leukemic cells from 1 patient with acute lymphoblastic leukemia (ALL) and from 6 patients with acute nonlymphoblastic leukemia. Detectable elastase activity was found in the cells from all patients with acute nonlymphoblastic leukemia and ranged from 0.016 to 0.619 mukat/l/micrograms DNA. The highest elastase activity was found in 1 patient with promyelocytic leukemia (M3), and no activity was found in the cells from the patient with ALL. It is possible that elastase-mediated proteolysis of coagulation factors is the mechanism responsible for bleeding complications which are frequent in M3.

Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT).

In a prospective, randomized, open study 119 consecutive patients with phlebographically verified deep venous thrombosis (DVT) of the leg (36% distal and 64% proximal) were treated either with a low molecular weight heparin (Fragmin, Kabi-Vitrum) subcutaneously (120 anti-FXa U/kg) twice daily or standard heparin (SH) as continuous intravenous infusion (480 IU kg-1 day-1). The Fragmin doses were adjusted to achieve an anti-FXa activity of 0.2-0.4 U/ml before injection and not greater than 1.5 U/ml 4 h after the morning injection. The SH dose was modified to prolong the APTT 2-3 times. Repeat phlebography after 5-7 days showed improvement in 34/45 patients (76%) in the Fragmin group and in 30/49 patients (61%) in the SH group and progress in 2/45 (4%) and 3/49 (6%), respectively. The mean Marder scores decreased from 18.7 +/- 12.1 to 15.7 +/- 12.7 in the Fragmin group and from 16.9 +/- 12.0 to 14.4 +/- 11.8 in the SH group (ns). Two patients in the SH group and none in the Fragmin group had major bleedings. After 22 +/- 7 months follow up 6 rethromboses had occurred in the SH group and 4 in the Fragmin group. Postthrombotic signs and symptoms were similar in both groups. We conclude that two daily sc Fragmin doses seem as effective and safe as continuous SH in the treatment of DVT of the leg.

Fatal pulmonary embolism caused by streptokinase treatment of deep venous thrombosis of the leg?

During the last 10 years, four of 150 (2.7%) patients with deep venous thrombosis (DVT) treated with streptokinase (SK) at our department have died of pulmonary embolism (PE). A retrospective study of 1393 DVT patients treated with heparin during the period 1973-1986 showed that five (0.36%) of these patients died of PE while still on heparin. In this paper we describe the four patients treated with SK who developed fatal PE. In our opinion this increase in mortality does not warrant the use of SK in routine treatment of DVT of the leg before a proper trial has been conducted to compare the frequencies of pulmonary embolism after both treatments.

Clinical experiences in the administration of a low molecular weight heparin (Fragmin, Kabi-Vitrum) to healthy volunteers and in the treatment of established deep venous thrombosis.

A low molecular weight heparin (Fragmin, Kabi-Vitrum) with a mean molecular weight of 4,000-5,000 D has been investigated in healthy volunteers and in patients with DVT. We found a T 1/2 of 4 hours and a high bioavailability after subcutaneous injection in volunteers. In a randomised study, patients with phlebographically verified DVT, 120 U(anti-FXa)/kg Fragmin injected twice daily was found to be as effective as 240 U/kg, 12 h standard heparin as continuous infusion in preventing DVT progress. No major bleedings were seen in the Fragmin group. We conclude that Fragmin administered subcutaneously twice daily results in adequate anticoagulation and is safe and practical in the treatment of DVT.

A pilot study; desmopressin (DDAVP) in the treatment of deep venous thrombosis.

In a pilot study on 9 patients with acute deep venous thrombosis of the leg the fibrinolytic response and the possible thrombolytic effect of desmopressin (DDAVP), when given supplementary to standard heparin treatment, was examined. Six injections of 0.3-0.4 microgram DDAVP/kg b.w. at 12 hours intervals were given. No serious side effects were observed. The fibrinolytic variables that followed showed that plasma levels of t-PA increased significantly and most pronounced after the first injection. Rephlebography 4-7 days after hospitalization showed partial thrombolysis in 7 out of 9 patients. The phlebographic score according to Marder was reduced from 22.7 +/- 12.1 to 18.4 +/- 10.1 (p = 0.018), corresponding to a thrombus size reduction of 19%. No correlation between the level of the fibrinolytic variables measured and the degree of thrombolysis in the individual patients, could be demonstrated in this small number of patients.

Acute unidentified hepatitis in a hypogammaglobulinaemic patient on intravenous gammaglobulin successfully treated with interferon.

A 59-year-old male with acquired hypogammaglobulinaemia since 1978 developed a fulminant hepatitis. The hepatitis appeared after two years intravenous treatment with Sandoglobulin (Sandoz, Switzerland). No virus markers could be detected in the body fluids or liver tissue. Blood transfusions had not been given within one year before development of the liver disease. There was strong suspicion that the patient had acquired non-A non-B hepatitis from the gammaglobulin infusions. Treatment with alpha-interferon ran parallel to a normalization of the pathological liver enzymes and the histology of the liver. This observation suggests a direct antiviral effect of alpha-interferon, despite the anecdotical and noncontrolled character of these data.

Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers.

The pharmacokinetics of a low molecular weight heparin (LMWH) with a mean mw of 4000-6000 D (KABI 2165, Fragmin) was studied in 6 healthy volunteers after intravenous (iv) and subcutaneous (sc) administration of 120 U (anti FXa)/kg. The half-life in plasma of the anti FXa activity after iv injection was 119 +/- 17 min, the volume of distribution (Vd) 3.4 +/- 0.5 1 and the total clearence 20.5 +/- 2.5 ml/min. The maximal anti FXa activity determined 3 min after iv bolus injection amounted to 2.2 +/- 0.3 U (anti FXa)/ml with a corresponding increase of the APTT from 31 +/- 7 sec to 113 +/- 35 sec. The elimination of the anti FXa activity was a monoexponential first order process. After sc administration the plasma half-life of the anti FXa activity was longer than after iv injection, 228 +/- 40 min, corresponding to the absorption rate thus found to be the rate limiting step. After sc administration the peak was reached after 4 hours (0.6 +/- 0.1 U (anti FXa)/ml; APTT increase 5 sec). The bioavailability after sc injection was calculated to be 87 +/- 6%. As a consequence of the high bioavailability and long T1/2 of the anti FXa activity, Fragmin administered sc seems to induce adequate levels of heparin-like activity making this regimen worth further investigation as an alternative for the treatment of deep venous thrombosis.

Pharmacokinetics of intravenously and subcutaneously administered Fragmin in healthy volunteers.

Studies in 8 healthy volunteers showed that the low molecular weight heparin Fragmin KabiVitrum is eliminated according to first order kinetics without dose dependency after intravenous injection of doses between 40 and 120 anti-Xa U/kg. Fragmin remains in the circulation more than twice as long as unfractionated heparin (UFH). Fragmin administered subcutaneously has a bioavailability which is much greater than that of UFH. Fragmin administered subcutaneously twice a day results in a significant anti-Xa activity and provides an alternative to intravenous infusions.

Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis.

54 patients with venographically verified deep venous thrombosis (DVT) were randomized to treatment with either intravenous infusions of 240 anti-Xa U/kg/12 h unfractionated heparin (UFH) or 240 or 120 anti-Xa U/kg/12 h of the low molecular weight heparin Fragmin. Repeated venographies showed improvement in 48% of the UFH-treated patients and 50 and 77%, respectively, in the Fragmin-treated patients. Progression was seen only in the UFH-treated patients and was observed in 11%. Two bleeding complications were seen in the Fragmin group in 2 patients receiving the very high dose of 240 anti-Xa U/kg/12 h. Anti-Xa activity in plasma and activated partial thromboplastin time (APTT) does not correlate in the Fragmin-treated patients. Fragmin was as effective as UFH in preventing the progress of thrombosis in DVT. In another study 120 anti-Xa U/kg Fragmin given subcutaneously 2 times daily to 13 patients with DVT resulted in adequate anti-Xa activity but with a tendency for accumulation of the Fragmin-induced activity. Subcutaneous injections of Fragmin 2 times daily also appears to prevent the progression of thrombosis effectively.

A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep venous thrombosis.

In order to study whether a low molecular weight heparin (LMWH) of mw 4000 D is effective in the treatment of deep venous thrombosis (DVT), patients with DVT verified by phlebography were randomized to treatment by continuous intravenous infusion of either unfractionated heparin (UFH) or LMWH. The initial dose was 240 U (anti F Xa)/kg/12 h. This study (study I) was stopped because of major bleeding in 2 newly operated patients in the LMWH group after 27 patients had been treated. The heparin activity measured as F Xa inhibition assayed in retrospect, was found to be much higher in the LMWH group (mean 1.6-2.0 anti F Xa U/ml) than in the UFH group (mean 0.5-0.8 anti F Xa U/ml). A second study was therefore initiated in which the DVT patients were randomly given UFH (240 U/kg/12 h) or LMWH only 120 U (anti F Xa)/kg/12 h, as initial doses (study II). In this study 27 patients could be evaluated, the mean heparin activity still being higher in the LMWH group (0.9-1.2 anti F Xa U/ml) than in the UFH group (0.5-0.7 anti F Xa U/ml). A second phlebographic investigation showed progression of thrombus size in 3 (11%) of the UFH patients of studies I and II (n = 29) and improvement in 14 (48%). There was no progression in any LMWH patient, 6 (50%) had improved in study I and 10 (77%) in study II. The mean decrease of thrombus size score (according to Marder) during treatment did not differ between the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors and inhibitors of blood coagulation and fibrinolysis in acute nonlymphoblastic leukaemia.

Factors of coagulation and fibrinolysis have been evaluated in 15 patients with untreated acute nonlymphoblastic leukaemia (ANLL). 10 patients had major bleeding (MB) and 6 had laboratory signs of DIC. 5 patients went into complete remission (CR). Antithrombin III (AT III) was decreased in 7 patients, antiplasmin (AP) in 9, fibronectin (FN) in 6 and factor XIII in 4/12. The ratio between factor VIIIR:Ag and factor VIII:C was over 2.0 in 11 patients, and high values were especially seen in patients with MB and patients with DIC. Spontaneous proteolytic activity, measured with S-2288 was increased in 3 patients who all had MB, and none of whom achieved CR. 2 patients with promyelocytic leukaemia (M3) had low fibrinogen and AP, high FDP and normal AT III, speaking for primary fibrinolysis, which in addition to proteolytic enzymes in the blast cells are important contributing factors regarding MB in ANLL.

A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment.

The pharmacokinetics of a heparin fragment of low molecular weight (LMWH) of 4000-5000 D and unfractioned standard heparin (UFH) have been studied after i.v. injections of different doses and infusions in 8 humans. The heparin activity was significantly higher and the effect on APTT lower after LMWH fragment as compared to UFH in the same doses. The half-life of heparin activity was about 1 hr for UFH and about 2 hr for LMWH. LMWH was found to be eliminated according to first order kinetics and there were no signs of dose dependency.