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Some cytokines, i.e. tumor necrosis factor-, interleukin-6 and soluble interleukin-2 receptors are associated with complications of stem cell transplantation. Insulin-like growth factors (IGFs) are a family of peptides essential for the proliferation of normal and malignant cells. Recently increased levels of IGFs have been associated with the development of malignant tumors. In this communication we report on 96 measurements of insulin-like growth factor-I (IGF-1), insulin-like growth factor-II (IGF-2), and insulin-like growth factor-binding protein-3 (IGFBP-3) performed in 19 patients following stem cell transplants. Seventeen patients had allogeneic and 2 patients autologous transplants. Most IGF determinations were made at days 0, 7, 14, 21 and 28, some at other time points. The baseline values (day 0) of IGF-1 and IGFBP-3 were not different from controls. IGF-2 values were slightly lower than controls. Following transplantation, a consistent increase of IGF-1 was observed in 9/16 patients at days 7 and 14. Later the values decreased again. IGF-2 and IGFBP-3 did not change significantly after transplantation. No direct correlation could be established with the severity of graft-versus-host disease, levels of interleukin-6 and the time to hematopoietic recovery. A potential relevance of IGFs following stem cell transplantation may be the early diagnosis of liver damage and the development of second malignancies. More studies are necessary to investigate the pathophysiology and the clinical relevance of the increase of IGF-1 following stem cell transplantation.

Today, more than 40% of all patients who develop a thrombosis are found to have inherited thrombophilia. The most common cause of this is APC resistance, which can usually be traced back to factor V-Leiden. In the commonly heterozygous patients the risk of thrombosis is increased about 7-fold (life-long risk of thrombosis 10 to 15%). In most cases, however, additional thrombogenic stimuli are required (oral contraception, pregnancy, surgery, immobilization). In combination with oral contraceptives, the risk is increased roughly 30-fold. In contrast, APC resistance does not present an increased risk for thrombosis in the arterial system (myocardial infarction, stroke). Four further inherited or acquired disorders of the hemostatic system are known: prothrombin dimorphism, antithrombin, protein C and protein S deficiencies. Prothrombin dimorphism, the second most common form of inherited thrombophilia, has been known only for the past two years and elevates the risk of thrombosis only to a moderate degree. Today, a search for thrombophilic factors should be carried out not only in young patients with spontaneous development of thrombosis, but also in elderly patients, even when an additional risk for the occurrence of thrombosis such as traumatization or immobilization is present. Therapeutic consequences are discussed.

Thrombotic complications are observed in patients undergoing bone marrow transplantation despite thrombocytopenia and impaired coagulation due to liver function disturbances. Endothelial cell damage which is involved in the pathogenesis of major transplant related complications like graft-versus-host disease, veno-occlusive disease, sepsis or microangiopathy may be a contributing factor. Little is known about platelet function in bone marrow transplant recipients. In order to study functional alterations in circulating platelets we investigated unstimulated and ADP-stimulated platelets of 10 bone marrow transplant recipients ex vivo by flow cytometry in a pilot study using a panel of monoclonal antibodies to characterize changes in membrane glycoproteins. Samples were collected before and during conditioning and at three timepoints after engraftment. 10 healthy volunteers served as controls. Platelets of bone marrow transplant recipients showed partly a significant, higher expression of surface bound fibrinogen, activated fibrinogen receptor, and glycoprotein Ib as compared to controls. P-selectin, a marker of platelet degranulation was significantly elevated after ADP-induced stimulation at all timepoints compared to controls. Only marginal differences were found for GP IIb/IIIa surface expression. The data point to an increased platelet activation state in bone marrow transplant recipients which might contribute to the thrombotic phenomena observed in these patients.

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication after bone marrow transplantation (BMT). We previously have described plasminogen activator inhibitor-1 (PAI-1) as a possible marker of VOD. To confirm the significance of this finding, we now determined PAI-1 levels in 31 of 186 consecutive patients undergoing BMT who developed hyperbilirubinemia greater than 3 mg/dL for various reasons. Diagnoses were made by clinical criteria and confirmed by biopsy in 23 of 31 patients. They included VOD (n = 7), acute graft-versus-host disease (GVHD) of the liver (n = 7), and other hepatic injury (n = 17). PAI-1 (mean +/- SD) was significantly (P < .001) elevated in patients with VOD (321.6 +/- 161.2 ng/mL) as compared with patients with GVHD (22.8 +/- 8.4 ng/mL) or other hepatic damage (32.8 +/- 30.8 ng/mL) at the timepoint of bilirubin increase. At the peak bilirubin concentration, the corresponding PAI-1 levels were 426.1 +/- 230.0 ng/mL in patients with VOD, 41.0 +/- 20.6 ng/ mL in patients with GVHD, and 44.6 +/- 32.9 ng/mL in patients with other hepatic injury (P < .001 VOD v GVHD/other hepatic injury). Our results underline the relevance of PAI-1 in the differential diagnosis of hyperbilirubinemia after BMT and its significance as a sensitive and specific marker of severe VOD.

Veno-occlusive disease (VOD) of the liver is one of the most frequent fatal complications after bone marrow transplantation (BMT). A decrease of natural anticoagulants, in particular protein C (PC), has been assumed to be involved in the pathogenesis of the disease. We determined PC and antithrombin III (AT III) levels in two patients undergoing BMT and subsequent liver transplantation due to VOD. Additionally, in one of the patients protein S (PS) levels were also measured. Normal baseline (day-8) PC levels (86 and 89%) were markedly reduced in both patients at the time of VOD manifestation on day 20 and 40, respectively (26 and 31%). PS levels lay within the normal range from day-8 (before myeloablative chemotherapy) until one week after clinical onset of VOD when substitution therapy with fresh frozen plasma (FFP) was initiated. AT III levels decreased moderately during the second and third posttransplant week, but were normal in the patient with a late clinical manifestation of VOD. In both patients PC and PS levels lay within the normal range after liver transplantation which was performed on day 41 and 79, respectively. AT III was substituted several times. Both patients died due to infectious complications on day 141 and 101, respectively. The data confirm previous reports that a decrease of PC is observed in BMT recipients and can be associated with hepatic vein occlusion. Whereas the relevance of AT III is uncertain, PS does not seem to be involved in the pathogenesis of VOD. Liver transplantation lead to normalization of PC levels, but its significance remains to be discussed in terms of ethical justifiability, medical feasibility and costs.

Tumor necrosis factor-alpha (TNF alpha) is a central mediator in the pathogenesis of sepsis. It also interferes with the hemostatic system and exerts and a net procoagulant effect. Since TNF alpha may contribute to thrombotic complications in sepsis patients, we determined markers of thrombin activation, parameters of the fibrinolytic system (D-dimer, tissue plasminogen activator antigen (tPA) urinary type plasminogen activator antigen (uPA), plasminogen activator inhibitor antigen (PAI-1) and von Willebrand factor antigen (vWF) in 30 patients with sepsis or septic shock. All patients were treated with standard therapy, but 14 patients were treated additionally with an anti-TNF alpha monoclonal antibody (MAK 195F); 16 patients served as historical controls. No significant effect of the antibody on the parameters of the hemostatic system could be determined. Our data speak against a modulation of coagulation or the fibrinolytic system by the monoclonal anti-TNF alpha antibody MAK 195F in this cohort of sepsis patients.

Background: Veno-occlusive disease (VOD) leads to obliteration of small intrahepatic venules and is one of three most important complications with fatal outcome after bone marrow transplantation (BMT). The etiology of VOD is not completely understood. Endothelial cell injury induced by the conditioning myeloablative radiochemotherapy with subsequent activation of the coagulation cascade seems to be a crucial step in the pathogenesis of the disease., Patients and Methods: We investigated tissue plasminogen activator (tPA), its main inhibitor (PAI-1) and the natural anticoagulants protein C and S by enzymimmunoassay prospectively in 32 bone marrow transplant recipients., Results: VOD developed in four patients. They presented with extremely elevated levels of PAI-1 after BMT whereas tPA levels remained low. Additionally a transient decrease of protein S was found one week after BMT which was more pronounced in VOD patients. No protein C deficiency was observed., Conclusion: Our data suggest that hypofibrinolysis due to an excess of PAI-1 may be involved in the pathogenesis of VOD. The determination of PAI-1 may be useful to recognize the development of VOD and facilitate the decision for thrombolytic therapy with rtPA. A decrease of protein S may play a role as a cofactor in the early phase after BMT.