Complement inhibition in biomaterial- and biosurface-induced thromboinflammation.

Therapeutic medicine today includes a vast number of procedures involving the use of biomaterials, transplantation of therapeutic cells or cell clusters, as well as of solid organs. These treatment modalities are obviously of great benefit to the patient, but also present a great challenge to the innate immune system, since they involve direct exposure of non-biological materials, cells of non-hematological origin as well as endothelial cells, damaged by ischemia-perfusion in solid organs to proteins and cells in the blood. The result of such an exposure may be an inappropriate activation of the complement and contact/kallikrein systems, which produce mediators capable of triggering the platelets and PMNs and monocytes, which can ultimately result in thrombotic and inflammatory (i.e., a thrombo-inflammatory) response to the treatment modality. In this concept review, we give an overview of the mechanisms of recognition within the innate immunity system, with the aim to identify suitable points for intervention. Finally, we discuss emerging and promising techniques for surface modification of biomaterials and cells with specific inhibitors in order to diminish thromboinflammation and improve clinical outcome.

Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33-overexpressing CMV/IL33 mice.

IL-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous studies emphasized a role for IL-33 in shaping innate and adaptive immune responses. IL-33 was also reported to modulate myelopoiesis and myeloid cell activity. In this article, we describe IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, which display an inflammatory phenotype associated with growth retardation and paw swelling. The phenotype of CMV/IL33 mice is dependent on activation of the ST2 receptor and is characterized by extensive neutrophil infiltration into different organs, including the paws. Local or systemic levels of proinflammatory mediators such as IL-1ß, Cxcl-1, G-CSF, and IL-6 are increased. CMV/IL-33 mice also suffer from anemia, thrombocytosis, and a marked dysregulation of myelopoiesis, leading to an important increase in myeloid cell production or accumulation in bone marrow (BM), spleen, and peripheral blood. Consistently, recombinant IL-33 induced proliferation of myeloid lineage cells in BM-derived granulocyte cultures, whereas IL-33 knockout mice exhibited minor deficiencies in spleen and BM myeloid cell populations. Our observations reveal a neutrophil-dominated inflammatory phenotype in IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, and highlight important regulatory effects of IL-33 on myelopoiesis in vitro and in vivo, where excessive IL-33 signaling can translate into the occurrence of a myeloproliferative disorder.

Hyper IgM Syndrome with low IgM and thrombocytosis: an unusual case of immunodeficiency.

We report a 5 years old male child with low serum IgG, IgA and IgM levels, who presented with recurrent perianal and oral ulcers, intermittent fever, and protracted diarrhea. Despite the lack of typical respiratory symptoms, low serum IgM level and persistent thrombocytosis, an X-linked hyper-IgM syndrome (X-HIGM) was considered. Laboratory investigations revealed a diagnosis of hyper-IgM syndrome caused by CD40L deficiency.

Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms.

The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Excessive expressions of T cell activation markers in pediatric immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated bleeding disorder in children. Activated T cells have been shown to play important roles in ITP. The aims of this study were to evaluate whether these T cell activation markers could be used as indicators to differentiate ITP patients from controls, and to assess whether they could be used as predictors of IVIG response in ITP patients. METHODS: A cohort of 92 hospitalized ITP patients, 49 unrelated healthy children, and 48 thrombocytosis patients were enrolled in this retrospective study between February 2013 and September 2018. Expression of CD25, HLA-DR, and CD69 on the surfaces of CD4+ and CD8+ T cells were detected by flow cytometry. All statistical analyses were performed using SPSS 20.0 software. RESULTS: Compared to the healthy controls, ITP patients had higher percentages of CD4 + CD25+ T cells, CD4 + HLA-DR+ T cells, CD8 + HLA-DR+ T cells, and CD8 + CD69+ T cells. Compared to the thrombocytosis patients, ITP patients had higher percentages of CD4 + HLA-DR+ T cells and CD8 + HLA-DR+ T cells, and lower CD4 + CD69+ T cells and CD8 + CD69+ T cells. Platelet count at admission had a negative correlation with CD4 + CD25+ T cells in ITP. CD4 + CD69+ T cells were decreased in chronic compared to the newly diagnosed and persistent ITP patients. Activated T cell markers had no predictive value for IVIG response in ITP patients. CONCLUSIONS: T cell activation markers were excessively expressed in pediatric ITP, and those markers had no predictive value for IVIG response in ITP patients.

Anti-endothelial cell antibodies in antineutrophil cytoplasmic antibodies negative pauci-immune crescentic glomerulonephritis.

AIM: Pauci-immune crescentic glomerulonephritis (CrGN) is frequently associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA). However, in patients with ANCA-negative pauci-immune CrGN, the pathogenesis is not clear. Anti-endothelial cell antibodies (AECA) have been implicated in the pathogenesis of vasculitis. The purpose of this study is to investigate the prevalence of AECA and their possible clinical significance in ANCA-negative pauci-immune CrGN. METHODS: Sera from 19 patients with ANCA-negative pauci-immune CrGN, 26 patients with ANCA-positive pauci-immune CrGN and 10 healthy blood donors were collected. Soluble proteins extracted from cultured human umbilical vein endothelial cells were used as antigens and western blot analysis was carried out to detect AECA. RESULTS: In ANCA-negative pauci-immune CrGN, 10 of 19 patients were serum IgG-AECA positive and seven bands reactive with endothelial antigens could be blotted. The prevalence of skin rash and thrombocytosis was significantly higher in patients with anti-76 kDa and anti-123 kDa autoantibodies than in patients without, respectively. Birmingham Vasculitis Activity Scores of patients with anti-200 kDa AECA were significantly higher than in patients without. In the sera of 26 ANCA-positive cases, 23 were AECA positive and 11 bands could be recognized. The prevalence of total AECA and anti-90 kDa AECA was significantly lower in patients with ANCA-negative pauci-immune CrGN than in patients with ANCA-positive pauci-immune CrGN. CONCLUSION: Anti-endothelial cell antibodies could be found in sera of patients with ANCA-negative pauci-immune CrGN; some AECA might have some clinical significance. The discrepancies of AECA might be a possible contributor to the differences between ANCA-negative and ANCA-positive pauci-immune CrGN.

Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis.

Platelets are key regulators of vascular integrity; however, their role in anaphylaxis, a life-threatening systemic allergic reaction characterized by the loss of vascular integrity and vascular leakage, remains unknown. Anaphylaxis is a consequence of inappropriate cellular responses triggered by antibodies to generally harmless antigens, resulting in a massive mediator release and rapidly occurring organ dysfunction. Human platelets express receptors for immunoglobulin G (IgG) antibodies and can release potent mediators, yet their contribution to anaphylaxis has not been previously addressed in mouse models, probably because mice do not express IgG receptors on platelets. We investigated the contribution of platelets to IgG-dependent anaphylaxis in human IgG receptor-expressing mouse models and a cohort of patients suffering from drug-induced anaphylaxis. Platelet counts dropped immediately and markedly upon anaphylaxis induction only when they expressed the human IgG receptor FcγRIIA/CD32A. Platelet depletion attenuated anaphylaxis, whereas thrombocythemia substantially worsened its severity. FcγRIIA-expressing platelets were directly activated by IgG immune complexes in vivo and were sufficient to restore susceptibility to anaphylaxis in resistant mice. Serotonin released by activated platelets contributed to anaphylaxis severity. Data from a cohort of patients suffering from drug-induced anaphylaxis indicated that platelet activation was associated with anaphylaxis severity and was accompanied by a reduction in circulating platelet numbers. Our findings identify platelets as critical players in IgG-dependent anaphylaxis and provide a rationale for the design of platelet-targeting strategies to attenuate the severity of anaphylactic reactions.

Platelet Fc receptor. Increased expression in myeloproliferative disease.

The platelet Fc receptor, a membrane receptor for immune complexes or aggregated immunoglobulin (Ig)G, was compared in normal and myeloproliferative platelets. Washed platelets from 11 normal donors and 27 patients were incubated with fluorescein-conjugated ovalbumin-anti-ovalbumin complexes and examined by phase and fluorescence microscopy. Only 3.2+/-1% of the normal platelets stained, whereas 76+/-16% of the myeloproliferative platelets stained with the immune complex. The fluorescent staining was mediated by a platelet Fc receptor, as shown by the absence of platelet staining with immune complex containing antibody preincubated with Staphylococcal protein A to block the Fc region. In addition, no staining occurred with antigen or antibody alone or after preincubation of platelets with aggregated IgG. Platelets from normal or myeloproliferative donors did not stain with the immune complexes when the incubation was performed in plasma. The increased expression of Fc receptors on myeloproliferative platelets was corroborated by studies of [(14)C]serotonin release by immune complexes or aggregated IgG in 8 patients and 17 normal donors. Serotonin uptake was similar in both groups. Myeloproliferative platelets released significantly more serotonin than normal platelets at each concentration of immune complex or aggregated IgG; in addition, myeloproliferative platelets released serotonin in response to much smaller concentrations of immune complex or aggregated IgG. [(14)C]Serotonin release by myeloproliferative platelets was not increased above that of normal platelets when thrombin was used as the stimulus. The results were independent of patient age, sex, therapy, hematocrit, or platelet size. Interaction of circulating immune complexes with platelets bearing increased Fc receptors may contribute to the abnormal hemostasis associated with the myeloproliferative syndromes.

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes.

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.

Thrombocytosis in pediatric patients is associated with severe lower respiratory tract inflammation.

BACKGROUND: Secondary thrombocytosis is associated with a variety of clinical conditions. The aim of this study was to determine the incidence and to analyze the clinical significance and prognostic value of thrombocytosis in lower respiratory tract infection. METHODS: A total of 102 pediatric patients were hospitalized with lower respiratory tract infection during a period of 30 months. RESULTS: Forty nine (48%) of those patients had platelet counts >500 x 10(9)/L. The median age of the thrombocytotic patients was 31 months as opposed to 61 months for the non-thrombocytotic ones. The patients with thrombocytosis had more serious illness. This is indicated by three factors: more severe clinical condition on admission, presence of respiratory distress and longer hospitalization. Sedimentation rate >70 mm/h was observed in 44.4% patients of the thrombocytotic group compared to only 27.7% of the non-thrombocytotic ones. Almost all patients with pleural effusion were thrombocytotic. The children with very high platelet counts >650 x 10(9)/L presented with respiratory distress on admission and required longer hospitalization time. No other significant clinical or laboratory differences were demonstrated between these patients and the remainder of the thrombocytotic patients. CONCLUSIONS: Thrombocytosis is a common finding among patients with lower respiratory tract infection. Thrombocytotic patients have a more severe clinical condition. Importantly, thrombocytosis occurs almost exclusively in patients with pleural effusion. The platelet count may be a useful clinical marker associated with the severity of the lower respiratory tract infection.

Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera.

OBJECTIVE: Circulating polymorphonuclear leukocyte (PMN) activation occurs in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We want to define whether this phenomenon plays a role in the formation of circulating PMN-platelet aggregates in these conditions. METHODS: In 80 patients (46 ET and 34 PV) and 50 control subjects, we conducted a flow cytometric analysis to evaluate the levels of PMN-platelet aggregates (defined as the percentage of CD11b-positive PMN coexpressing a platelet-specific marker, i.e., CD42b or CD62P) and the levels of activated PMN and activated platelets. In addition, the in vitro PMN-platelet aggregate formation in response to N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-induced activation of PMN was studied. RESULTS: Significantly high PMN-platelet aggregates in ET and PV patients were found and were associated with increased PMN surface CD11b and surface platelet CD62P expression. In vitro f-MLP stimulation upregulated PMN-CD11b expression and simultaneously increased CD11b/CD42b and CD11b/CD62P aggregates, without affecting platelet surface antigens. In ET patients receiving aspirin, the increments in f-MLP-induced PMN-CD11b and in PMN-platelet aggregates were significantly lower versus ET subjects not treated with aspirin. CONCLUSION: Our data show that in ET and PV patients PMN activation plays an important role in increasing circulating PMN-platelet aggregates and suggest that aspirin treatment may decrease their formation.

Elevated platelet count before ileal pouch-anal anastomosis for ulcerative colitis is associated with the development of chronic pouchitis.

Acute pouchitis (AP) after ileal pouch-anal anastomosis (IPAA) is common and easily treated. However, chronic pouchitis (CP) remains a difficult management problem and may represent a form of Crohn disease (CD) of the ileal pouch. Because CD patients have higher platelet counts than ulcerative colotis (UC) patients, we prospectively evaluated the association between preoperative platelet count and pouchitis development in 159 patients undergoing IPAA. Reactive thrombocytosis (RT) was defined as a platelet count > 450 x 10(9)/L. Median preoperative platelet count was 312 x 10(9)/L (range, 103 x 10(9)/L to 886 x 10(9)/L). One hundred twenty-five patients (79%) had a normal (150 x 10(9)/L to 450 x 10(9)/L) platelet count (-RT patient group). Twenty-eight patients (18%) had RT. Six patients (3%) had a platelet count below 150 x 10(9)/L. After a median follow-up of 13 months, 45 patients (28%) developed pouchitis. Pouchitis developed in 33 +RT patients (26%) versus 9 -RT patients (32%) (P = NS). UC patients who had +RT had a 25 per cent incidence of CP compared to only 7 per cent of those UC patients who had -RT (P = 0.03). The incidence of CP was significantly higher after IPAA in UC patients having thrombocytosis before surgery compared to UC patients having a normal platelet count before surgery.

[Correlation between platelet count and CA-125 in ovarian cancer]. / Znaczenie kliniczne poziomu plytek krwi w raku jajnika.

OBJECTIVE: To determine whether a correlation between platelet count and CA-125 exists, and to compare the mean levels of CA-125 in groups with normal and elevated platelet counts. DESIGN: A retrospective analysis of the medical records concerning to 31 ovarian cancer inpatients, treated 1998-2002 with primary surgery and subsequent platinum-based chemotherapy at the Division of Gynecology, Department of Perinatology and Gynecology, University Medical School Poznan. MATERIALS AND METHODS: 137 serum and whole blood samples collected from 31 ovarian cancer patients during their consecutive hospital stays. RESULTS: There was a positive, moderate (r = 0.49) and highly significant (p < 0.0000001) correlation between platelet count and CA-125 levels. Thrombocytosis occurred in 45% patients before treatment, and in none when the 6th course of chemotherapy was given. In the thrombocytosis group, an average CA-125 level (913.5 U/ml) was significantly higher (p < 0.00001) then in the group with normal platelet count (103.7 U/ml). CONCLUSIONS: Platelet count and CA-125 levels do correlate in blood samples taken from ovarian cancer patients at the same time.

Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis.

PURPOSE: Evaluate the discriminatory value of plasma interleukin-6 or C-reactive protein levels in clonal thrombocytosis compared with those in reactive thrombocytosis. PATIENTS AND METHODS: A comparative analysis of quantitatively measured laboratory values in a prospectively studied group of consecutive patients. The setting was a tertiary referral center consisting of two hospitals and an outpatient clinic. Plasma interleukin-6 and C-reactive protein levels were measured in 91 consecutive patients with thrombocytosis (platelet count > or = 600 x 10(9)/L). The cause of thrombocytosis was determined by reviewing the medical histories and follow-up data without knowledge of the corresponding laboratory values. Sixty-four patients had reactive thrombocytosis, 20 had clonal thrombocytosis, and 7 had clonal thrombocytosis plus reactive thrombocytosis. Plasma interleukin-6 was measured by an enzyme-linked immunosorbent assay, and C-reactive protein was measured with rate immunonephelometry. RESULTS: Interleukin-6 levels were undetectable in all the patients with clonal thrombocytosis, whereas they were increased in 60% of the patients with reactive thrombocytosis or clonal thrombocytosis plus reactive thrombocytosis. There was a correlation between interleukin-6 and C-reactive protein levels (r = .6), and the median and range values of both levels differed significantly between the clonal thrombocytosis group and the other two groups (P < 0.0001). In 81% of the patients with reactive thrombocytosis, levels of either interleukin-6 or C-reactive protein were elevated. There was no correlation between interleukin-6 and C-reactive protein levels and the platelet count. CONCLUSIONS: An elevated interleukin-6 level is rare in uncomplicated clonal thrombocytosis and suggests reactive thrombocytosis. However, an isolated normal value has little discriminatory value. Measurement of C-reactive protein level may be used as a less expensive surrogate for measurement of interleukin-6. Repeatedly low levels of both interleukin-6 and C-reactive protein are most consistent with clonal thrombocytosis.

Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.

BACKGROUND AND PURPOSE: High platelet counts are occasionally seen in patients suffering from progressive malignant disorders. While granulocyte colony-stimulating factor (G-CSF) has been implicated in paraneoplastic leukemoid reactions, the stimulus for thrombocytosis is unknown. Our purpose in this study was to determine if plasma from cancer patients with thrombocytosis contains a factor or factors with thrombopoietic activity. METHODS: We tested the effects of plasma obtained from 5 individuals with advanced tumors and high platelet counts and from 4 patients with advanced cancer and normal platelet counts on megakaryocytic differentiation of two megakaryoblastic cell lines (Dami and HEL). Differentiation was evaluated by assessing the expression of the platelet-specific cell-surface antigens CD41 (HUPL-mI) and glycoprotein IIb-IIIa using an immunocytochemical staining score. In addition, plasma samples from 7 of the 9 patients and from 5 additional cancer patients with thrombocytosis were assayed for the levels of interleukin (IL)-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and IL-1 beta protein using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of platelet-specific cell-surface antigen was increased in HEL cells after exposure to plasma from all 5 of the cancer patients with thrombocytosis, and in Dami cells after exposure to plasma from 4 of the 5. Similar, but less significant, results were found when these cells were incubated with control combinations of recombinant GM-CSF plus IL-6 or of IL-3 plus IL-6. Platelet-specific cell-surface-antigen expression was not increased in HEL or Dami cells after exposure to the plasma from the 4 cancer patients with normal platelet counts or to normal control plasma. ELISA revealed elevated levels of IL-6 in the plasma from 4 patients with thrombocytosis (38, 40, 63, and 99 pg/mL). In addition, GM-CSF concentration was high in 3 of these 4 patients (33, 47, and 127 pg/mL), and the G-CSF level was elevated in 1 (543 pg/mL). IL-1 beta and IL-3 levels were undetectable. CONCLUSIONS: Our data suggest that the thrombocytosis observed in individuals with advanced malignant disease is mediated by a humoral mechanism. Levels of IL-6, GM-CSF, and G-CSF are elevated in some of these patients, but the plasma concentrations are generally lower than those required for in vitro induction of megakaryocytic differentiation. Plasma from patients with paraneoplastic thrombocytosis may therefore contain thrombopoietins that have not yet been identified, and which might have clinical usefulness.

Autosplenectomy and antiphospholipid antibodies in systemic lupus erythematosus: A pathogenetic relationship?

OBJECTIVES: To describe a systemic lupus erythematosus (SLE) patient with functional asplenia and antiphospholipid syndrome (APS) and to review the literature to better define its pathogenesis and diagnosis, emphasizing a possible relationship with antiphospholipid antibodies (aPL). METHODS: Descriptive report of 1 case and review of the literature by means of a MEDLINE search from 1966 to 2002. RESULTS: A SLE patient presented with cutaneous vasculitis and an unexpected thrombocytosis which resulted from autosplenectomy. Subsequently, she developed full-blown APS. In the literature, autosplenectomy has been described only in 1 other case of APS secondary to SLE. However, clinical or laboratory features linked to aPL occurred in several other cases among the 17 cases reported with functional asplenia. CONCLUSIONS: Autosplenectomy in SLE may be pathogenetically related to aPL. Thrombocytosis, unusual in SLE, may be a diagnostic clue of this condition. Pneumococcal vaccination is warranted to prevent life-threatening infections that frequently complicate this asplenia.

Increased serum level of interleukin-6 in patients with psoriatic arthritis and thrombocytosis.

The role of elevations of serum cytokines in psoriasis is a provocative issue. We report two patients with psoriasis who had episodes of fever, arthritis, and general fatigue. Their symptoms seemed to be associated with increases in serum levels of interleukin (IL)-6, which paralleled the severity of clinical symptoms as well as elevated serum titers of C-reactive protein (CRP) and platelet counts. Since IL-6 is a multipotential cytokine with B-cell activating, T-cell activating, and thrombocytopoietic functions, the symptoms and abnormal laboratory findings in these patients may have been related to their increased serum levels of IL-6. Monitoring the serum level of this cytokine may thus be useful in evaluating the clinical status of patients with psoriatic arthritis.

[Atypical heparin-induced thrombocytopenia (HIT)--"heparin allergy" with thrombocytosis]. / Atypische heparininduzierte Thrombocytopenie (HIT)--"Heparinallergie" mit Thrombocytose.

We report a truck driver with severe soft tissue contusion of both legs who developed atypical heparin-induced thrombocytopenia (HIT) after a thrombosis prophylaxis with unfractionated heparin; despite a thrombosis the patient showed a systemic allergic reaction to heparin in combination with elevation of thrombocytes and positive heparin-dependent antibodies. Six days after the initial trauma deep vein thrombosis of the left lower leg was diagnosed and fasciotomy was performed, preventing an imminent compartment syndrome. Another 5 days later the patient developed exanthema of the trunk and upper extremities and urticaria on his face, as well as severe headache. His platelet count increased from 134,000/microliter to 258,000/microliter. After exclusion of other causes for these symptoms, a reaction to heparin-dependent antibodies (heparin-platelet-factor 4 complex) was demonstrated 2 days later. Thrombosis prophylaxis was changed to hirudin (Refludan) and elevation of thrombocytes to 445,000/microliter was noted. Shortly after rinsing of an intravenous line with less than 50 IE unfractionated heparin at day 36 after trauma the patient developed an anaphylactic shock, which could be managed with cortisone. We suggest that in HIT the thrombocytopenia may represent only one form of an allergic reaction to heparin. The cause of the thromboembolic event is an antigen-antibody reaction to heparin taking place on the surface of the thrombocyte. This is similar in all forms of systemic reaction to heparin application, even though the symptoms may vary. As thrombocytopenia may not be the main symptom of a heparin-induced antibody reaction--in our hospital only 5 of 10 patients with HIT--the disease should rather be named "heparin allergy". We suggest a new classification of different pattern of heparin allergy types I-IV. The new types I and II are similar to HIT types I and II. Type III is the reaction of antibodies without decrease of thrombocytes, and type IV the reaction of antibodies associated with systemic allergic symptoms.

CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis.

Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP) that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7), also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.