Tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 are proteins with proteinase-inhibiting and cytokine properties. TIMP-1 is active primarily in B cells and B-cell lymphomas, whereas TIMP-2 expression is restricted to T cells. The expression of TIMP-1 and TIMP-2 in lymph nodes from patients with Hodgkin disease (HD) and in Hodgkin-derived cell lines was investigated. In situ hybridization showed TIMP-1 RNA expression in 3% to 80% of Hodgkin/Reed-Sternberg (H/R-S) cells from 14 of 15 patients, with results in one patient being at the lowest detection limit; no expression of TIMP-2 in H/R-S cells; and only weak expression of TIMP-2 in reactive lymphoid tissue. Production of TIMP-1 protein by H/R-S cells was accordingly found on immunohistochemical analysis of lymph nodes from patients with HD. There was only low expression of matrix metalloproteinase (MMP)-2, which is mainly inhibited by TIMP-2; no expression of MMP-1 and MMP-3 in reactive lymphoid tissue; and no expression of these MMPs in H/R-S cells. Thus, TIMP-1 expression in lymph nodes was not correlated with metalloproteinase expression. Five of 7 Hodgkin-derived cell lines expressed TIMP-1 at the protein level. Only one of these cell lines expressed TIMP-2, at the lowest detection limit. TIMP-1 levels in plasma from patients with HD were within the same range as those in plasma from healthy controls. Recombinant human TIMP-1 inhibited induced cell death in Hodgkin-derived cell lines in vitro. TIMP-1 and TIMP-2 inhibited T-cell cytotoxicity against autologous cells presenting tumor-associated antigens and in allogeneic mixed lymphocyte cultures. Thus, TIMP-1, aside from its role in proteinase equilibrium, is an autocrine and paracrine survival factor for H/R-S cells and an immunosuppressive protein expressed in Hodgkin lymphomas.
Recommendations for vitamin K supplementation were recently changed to 3 x 1 mg orally in healthy term neonates and 0.2 mg parenterally in prematures and high-risk neonates. Prothrombin times (PT) at reduced vitamin K doses (120 patients, 170 samples) during the first 6 weeks of life were below 40% in 6 patients only; all low PTs were unrelated to vitamin K. In the remaining patients, median PT was 100%; 79% of patients had values above 70%. PT was related to birthweight, gestational age and age. There was no decrease over the observation period. Following reduced oral and parenteral vitamin K regimens PTs were well within published reference values for neonates given larger amounts of vitamin K.
Thrombotic thrombocytopenic purpura (TTP) is a clinically
heterogeneous syndrome associated with thrombocytopenia,
microangiopathic hemolytic anemia, neurologic changes, renal impairment,
and fever. The outcome was almost universally fatal until
the use of plasma exchange therapy which has dramatically altered
the course of disease. Case Report: Here, we report on a 30-year-old
female patient suffering from TTP who experienced apheresis treatment
resistance. Non-responding thrombocytopenia after initial improvement
of neurological symptoms was noted while the patient
continued to receive daily plasma exchange therapy (Sartorius
Haemoprocessor™). Neither increased volume of plasma exchange
nor using cryosupernatant plasma instead of solvent detergent (SD)
plasma nor high-dose glucocorticoids lead to a persisting platelet
increment. Because of a positive anti-heparin/PF4 antibody gel test
we suspected a heparin-induced thrombocytopenia type II (HIT II)
developed during plasma exchange therapy. A subsequent non-heparin
plasma exchange therapy (COBE Spectra™) with centrifugation
technique and citrate as anticoagulant was consequently applied,
followed by an increment of the platelet count to normal levels.
Additional investigations of the serum with HIT-specific ELISA
tests and heparin-induced platelet activation assay (HIPA) turned
out to be negative. Eventually it remains unclear to what extent the
therapeutical plasma exchanges potentially reduced HIT antibodies
and consequently sophisticated the test results. Obviously, the
switch to a centrifugal plasmapheresis system using heparin-free
anticoagulation was followed by therapeutical success. Conclusion:
Platelet loss due to the applied plasmapheresis system as well as
potential drug-induced immune thrombocytopenia due to heparin
administration during plasma exchange may cause persistent
thrombocytopenia in patients with TTP. This may be incorrectly interpreted
as continuing active disease, potentially leading to inappropriate
additional treatments.
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