Heparin-induced thrombocytopenia with thrombosis (HITT) can lead to serious morbidity and may be potentially fatal. We reviewed our experience with this entity over a 4-year period, to determine the following: 1) incidence and type of thrombosis in patients with heparin-induced thrombocytopenia (HIT), 2) clinical consequences of thrombosis, i.e., amputation, cerebrovascular accidents and death, 3) risk factors associated with development of thrombosis, and 4) impact of therapy on clinical outcomes in patients with HITT. Between 1991-1994, 108 patients were diagnosed to have HIT by heparin-induced platelet aggregation test. Thirty-two (29%) of these developed thrombotic complications, of which 20 were venous, 8 arterial, and 4 both. Five of the 32 died, 3 underwent amputations , and 3 had cerebrovascular accidents. The patients who developed thrombotic complications, when compared to those with HIT alone, were older (68.7 ± 11.5 vs. 63.3 ± 16 years, P = .05), had more severe thrombocytopenia (platelet count 46,300 ± 30,400/mm 3 vs. 62,500 ± 34,400/mm 3 , P = .02), and developed it earlier (6.0 ± 2.9 vs. 7.4 ± 3.1 days, P = .03). Multivariate analysis showed that severity of thrombocytopenia and early fall in platelet count were independent risk factors for development of thrombotic complications. We did not find an association between development of thrombosis and clinical events (myocardial infarction, cardiac procedures or surgery, noncardiac surgery, and sepsis) that occurred immediately prior to onset of thrombocytopenia. Heparin was stopped in all 32 patients with HITT. Six received no additional therapy, and one received a single dose of aspirin. Three of these 7 died. The other 25 received anticoagulant or multiagent therapy, with 2 deaths. The death rate was lower in those who were treated with anticoagulant or multiagent therapy (P = .05). We conclude that: 1) Thrombotic complications occur in about 29% of hospitalized patients who develop HIT. 2) Early, severe fall in platelet count in elderly patients receiving heparin appears to be associated with development of thrombotic complications. 3) Our data do not show an association between development of thrombotic complications and clinical events immediately preceding the diagnosis of HIT. 4) In addition to discontinuation of heparin, anticoagulant or thrombolytic therapy should be considered in patients with HITT. Am.

Binding of interferon alpha (IFN alpha) to its receptor induces activation of the Tyk-2 and Jak-1 tyrosine kinases and tyrosine phosphorylation of multiple downstream signaling elements, including the Stat components of the interferon-stimulated gene factor 3 (ISGF-3). IFN alpha also induces tyrosine phosphorylation of IRS-1, the principle substrate of the insulin receptor. In this study we demonstrate that various Type I IFNs rapidly stimulate tyrosine phosphorylation of IRS-2. This is significant since IRS-2 is the major IRS protein found in hematopoietic cells. The IFN alpha-induced phosphorylated form of IRS-2 associates with the p85 regulatory subunit of the phosphatidylinositol 3'-kinase, suggesting that this kinase participates in an IFN alpha-signaling cascade downstream of IRS-2. We also provide evidence for an interaction of IRS-2 with Tyk-2, suggesting that Tyk-2 is the kinase that phosphorylates this protein during IFN alpha stimulation. A conserved region in the pleckstrin homology domain of IRS-2 may be required for the interaction of IRS-2 with Tyk-2, as shown by the selective binding of glutathione S-transferase (GST) fusion proteins containing the IRS-2-IH1PH or IRS-1-IH1PH domains to Tyk-2 but not other Janus kinases in vitro.

The tyrosine kinase Tyk-2 is physically associated with the Type I interferon (IFN) receptor complex and is rapidly activated during IFN alpha stimulation. We report that Tyk-2 forms stable complexes with the SH2-containing hematopoietic cell phosphatase (HCP) in several hematopoietic cell lines in vivo, and that the IFN alpha-induced tyrosine-phosphorylated form of Tyk-2 is a substrate for the phosphatase activity of HCP in in vitro assays. Furthermore, treatment of cells with the phosphatase inhibitor sodium orthovanadate induces tyrosine phosphorylation of Tyk-2 and an associated 115-kDa protein. Altogether, these data suggest that HCP regulates tyrosine phosphorylation of the Tyk-2 kinase, and thus its function may be important in the transmission of signals generated at the Type I IFN receptor level.