Patients with systemic sclerosis and low CD4 numbers after autologous stem cell transplantation have a favorable outcome.

BACKGROUND: Treatment with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) is an intensive treatment option for patients with severe forms of systemic sclerosis (SSc). Even though associated with a high treatment related mortality, the results in this high-risk population are generally favourable. The knowledge on the potential mechanism of action of this therapy and how it can improve patients with SSc is crucial to better select the right patients for aHSCT. METHODS: This is a monocentric retrospective study from Tübingen, Germany, including 32 patients who underwent aHSCT. Peripheral blood samples were analysed for different lymphocyte subsets at various timepoints before and after aHSCT. Patients were divided into responders and non-responders according to the modified Rodnan skin score and lung function test in the three years following aHSCT. RESULTS: Responders showed significantly lower levels of cluster of differentiation (CD)4 positive T cells in the first months after aHSCT (month 1 and 3), B cells (month 3 and 6 after aHSCT) and natural killer cells (month 1). Mantel-cox test showed a significant deviation of the probability curves, i.e. patients with lower CD4 + T cells and natural killer cells one month and B cells after 3 months after stem cell transplantation had a higher probability to belong to the responder group. CONCLUSIONS: Taken together, this study supports the theory that a profound CD4 + T cell and B cell lymphopenia is important for patients with SSc to achieve a sustained response after aHSCT.

Detection of IgE-autoantibodies to nuclear antigens in patients with systemic sclerosis and analysis of their clinical relevance.

OBJECTIVES: Antinuclear antibodies (ANA) of the IgE-type have been described in several connective tissue disorders (CTD) but not yet in systemic sclerosis (SSc). Aim of the study was, therefore, to establish an ELISA for the demonstration of IgE-autoantibodies to topoisomerase-I (topo-I) and the centromeric proteins A and B (CENP-A/B), to assess their prevalence and reactivity in SSc and to analyse their clinical relevance. METHODS: One hundred fifty-one patients with SSc and 88 with CREST-syndrome, 291 patients with other CTD, and 23 patients with fibromyalgia syndrome (FM) as a control collective were included into the study. Patients' sera were analysed by an in-house-ELISA for IgE autoantibodies against topo-I and CENP-A/B using recombinant antigens. Patients were assessed for median Rodnan skin score(mRSS), different organ and cutaneous manifestations. RESULTS: Of the patients with CREST syndrome, 67% had IgE-anti-CENP-A- and 77% IgE-anti-CENP-B-antibodies. IgE-anti-topo-I antibodies were found in 56% of patients with SSc. Prevalence and reactivity were significantly higher in CREST and SSc, respectively, than in other CTD or FM. IgE-reactivity strongly correlated with IgG-antibody reactivity. In CRESTsyndrome, IgE-anti-CENP-A (but not CENP-B)-antibodies were significantly higher and more prevalent in patients with skin ulcers, high mRSS, and more than four organ manifestations. They did not correlate with blood eosinophil counts. In contrast, for IgE-anti-topo-I antibodies no correlation with clinical manifestations was observed. CONCLUSIONS: IgE-autoantibodies against CENP-A/B and topo-I occur in SSc underlining the concept that SSc may be a T helper cell type 2 mediated disease. IgE-anti-CENP-A-antibodies correlated with disease activity, but this has to be confirmed in larger studies.

Anemia and iron deficiency in pregnant women with rheumatic diseases.

INTRODUCTION: Anemia and iron deficiency are the most common pathologies in pregnancy and associated with adverse pregnancy outcome. As patients with rheumatic diseases are also at high risk for anemia, we aimed to investigate the frequency of anemia and iron deficiency during pregnancy in this group and whether anemia is a risk factor for adverse maternal or child outcome. METHODS: We analyzed 368 pregnancies from a German registry for pregnancies in patients with rheumatic diseases (TURIRE) from 2014-2022. Anemia and iron deficiency were defined according to the World Health Organization. Main outcome measures were prevalence of anemia, iron deficiency, and adverse outcomes. RESULTS: From the 368 patients 61% were diagnosed with a connective tissue disease, 16% with rheumatoid arthritis or juvenile idiopathic arthritis, 14% with spondyloarthritis, 3% with vasculitis and 7% with other. Prevalence of anemia/iron deficiency was 18%/28% in the first, 27%/51% in the second and 33%/62% in the third trimester. Low hemoglobin levels (OR 0.52) or iron deficiency (OR 0.86) had a negative impact on child outcome. However, lower hemoglobin levels were associated with a lower risk for maternal complications (OR 1.47). CONCLUSION: Prevalence of anemia and iron deficiency is high in pregnant women with rheumatic diseases. Compared to previously published cohorts of the general population from different countries, the prevalence of anemia and iron deficiency is distinctly higher. Furthermore, patients with rheumatic diseases already start with impaired iron storage and/or hemoglobin levels. Thus, iron supplementation should be initiated early on in this vulnerable in this patient group.

Pregnancies in women with antineutrophil cytoplasmatic antibody associated vasculitis.

PURPOSE OF REVIEW: Antineutrophil cytoplasmatic antibody associated vasculitis (AAV) usually manifests after age fifty, thus making it very rare during reproductive age. Although rare, AAV, particularly eosinophilic granulomatosis with polyangiitis, can manifest at a younger age. AAV can also appear for the first time during pregnancy. RECENT FINDINGS: Data from pregnant patients with AAV mostly derive from case reports or retrospective studies, with an absolute number of <100 published cases. Therefore, numbers of results of pregnancy outcome vary widely. SUMMARY: As with other chronic autoimmune diseases, patients and infants seem to be at a higher risk for preterm delivery, intrauterine growth retardation and preeclampsia. Possible treatment for AAV in pregnancy depends upon gestational age and include glucocorticosteroids, azathioprine, intravenous immunoglobulins, and in severe cases rituximab and even cyclophosphamide. Plasma exchange might be an option in selected patients. Aside from cyclophosphamide these medications can also be used during breastfeeding. Acetylsalicylic-acid 100-150 mg/day reduces the risk of preeclampsia, also in this population. Patients should be counseled prior to conception and medication that is suitable for pregnancy should be established early on. During pregnancy, we recommend close monitoring of disease activity, blood pressure and ideally to co-consult with a gynecologist in an interdisciplinary approach.

CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome.

Importance: Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome. Objective: To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement. Design, Setting, and Participants: This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity. Exposure: Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion. Main Outcomes and Measures: The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes. Results: Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%). Conclusions and Relevance: CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium.

G protein-coupled receptors (GPCR) are involved in various physiological and pathophysiological processes. Functional autoantibodies targeting GPCRs have been associated with multiple disease manifestations in this context. Here we summarize and discuss the relevant findings and concepts presented in the biennial International Meeting on autoantibodies targeting GPCRs (the 4th Symposium), held in Lübeck, Germany, 15-16 September 2022. The symposium focused on the current knowledge of these autoantibodies' role in various diseases, such as cardiovascular, renal, infectious (COVID-19), and autoimmune diseases (e.g., systemic sclerosis and systemic lupus erythematosus). Beyond their association with disease phenotypes, intense research related to the mechanistic action of these autoantibodies on immune regulation and pathogenesis has been developed, underscoring the role of autoantibodies targeting GPCRs on disease outcomes and etiopathogenesis. The observation repeatedly highlighted that autoantibodies targeting GPCRs could also be present in healthy individuals, suggesting that anti-GPCR autoantibodies play a physiologic role in modeling the course of diseases. Since numerous therapies targeting GPCRs have been developed, including small molecules and monoclonal antibodies designed for treating cancer, infections, metabolic disorders, or inflammatory conditions, anti-GPCR autoantibodies themselves can serve as therapeutic targets to reduce patients' morbidity and mortality, representing a new area for the development of novel therapeutic interventions.

Functional autoantibodies in systemic sclerosis: influence of autologous stem cell transplantation and correlation with clinical outcome.

OBJECTIVES: To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I (topo-I) in SSc-patients and to analyse their prognostic relevance. MATERIAL AND METHODS: Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients' sera were tested for anti-AT1R and anti-topo-I antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4-217 months, median 28 months). Anti-topo-I antibodies were also analysed for their capacity to inhibit enzyme function. RESULTS: A total of 70% of the SSc patients had anti-topo-I- and 51% anti-AT1R antibodies in the ELISA before aSCT. In all instances, anti-topo-I antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2 patients than in group 1 patients (P < 0.001), while there was no difference between both groups for anti-AT1R antibodies detected by ELISA. Stimulatory anti-AT1R antibodies detected by LA were confined to group 1-patients. CONCLUSIONS: Reactivity of functionally active anti-AT1R antibodies was not influenced by aSCT, while anti-topo-I antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.

Optimal management of ANCA-associated vasculitis before and during pregnancy: current perspectives.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis characterized by autoantibodies against neutrophil cytoplasmic antigens (proteinase 3 PR3-ANCA and myeloperoxidase MPO-ANCA) and inflammation of small vessels. AAV include the diagnosis Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), which share many clinical and pathological features. Immunomodulatory therapies have significantly improved prognosis during the last decade. Nevertheless, especially in undiagnosed and thus uncontrolled AAV mortality due to renal impairment or pulmonary haemorrhages is still high. AAV are rare in fertile women, as the typical age of manifestation is above 50 years but there are women with AAV who are or want to become pregnant. This review focusses on how to manage patients with AAV planning to become pregnant and during their pregnancy.

Mobilization with reduced cyclophosphamide for autologous stem cell transplantation is feasible in patients with systemic sclerosis.

OBJECTIVES: To assess the feasibility of reduced cyclophosphamide dosing in the setting of mobilization chemotherapy prior to high dose chemotherapy and autologous stem cell transplantation in patients with SSc. The primary end point was the occurrence of 'poor mobilization' when using different cyclophosphamide dosing. The second end point was to analyse potential risk factors for difficult stem cell mobilization in this cohort of patients with SSc. METHODS: This single-centre study retrospectively reviewed 32 patients with SSc who underwent autologous stem cell transplantation. We analysed the occurrence of 'poor mobilization' (defined as CD34+ progenitor cell count <2 × 106/kg body weight, the use of increasing G-CSF dose, the use of plerixafor, or leukapheresis on >2 consecutive days) in different cyclophosphamide mobilization regimens: We herein compared low dose (2 × 1-1.5 g/m2) cyclophosphamide vs high dose (2 × 2 g/m2) for mobilization. RESULTS: Higher dosing of cyclophosphamide seems not to be beneficial regarding stem cell collection as there was no significant difference in stem cell yield between high dose and reduced dose cyclophosphamide (6.2 vs 5.2 × 106/kg bodyweight after CD34+ enrichment). Furthermore, higher doses of cyclophosphamide might be associated with more side effects; this difference was, however, not statistically significant. Lower bodyweight and BMI (P < 0.001) as well as rituximab pre-therapy (P < 0.05) and cardiac involvement (P < 0.01) might negatively impact stem cell collection independently from the chosen regimen. CONCLUSION: Our data demonstrate that a reduced cyclophosphamide mobilization regimen seems to be feasible. Risk factors for poor mobilization might be low bodyweight, prior rituximab therapy and cardiac involvement.

iNKT cells can effectively inhibit IL-6 production by B cells in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease with poorly understood pathogenesis and limited treatment options. Patient mortality is rooted predominantly in the development of pulmonary and cardiac complications. The overactivated immune system is assumed to sustain the inflammatory signature of this autoimmune disease. Here, we investigate the potential of immunoregulatory invariant natural killer T (iNKT) cells to inhibit proinflammatory B cell responses in an in vitro model of inflammation. METHODS: B cells from healthy volunteers (n = 17) and patients with SSc (n = 15) were used for functional testing upon lipopolysaccharide (LPS) stimulation in a co-culture system with third-party iNKT cells. Cytokine production was measured with antibody-based immunoassays (ELISA) and intracellular cytokine staining. RESULTS: iNKT cells strongly inhibited the production of proinflammatory interleukin-6 by B cells upon stimulation with LPS in both healthy volunteers and patients with SSc. In a Transwell assay, cell contact between B cells and iNKT cells proved necessary for this inhibitory effect. Similarly, blocking of CD1d on the surface of B cells abolished the immunoregulatory effect of iNKT cells on B cells. B cell subsets with higher expression of CD1d, namely unswitched memory B cells, were more susceptible to iNKT cell inhibition. CONCLUSION: Our in vitro data underline the potential of iNKT cells in the control of SSc and provide a rationale for the use of novel iNKT cell-based therapeutic strategies in the context of autoimmune diseases.

Functionally Active Antibodies to the Angiotensin II Type 1-Receptor Measured by a Luminometric Bioassay Do Not Correlate With Clinical Manifestations in Systemic Sclerosis: A Comparison With Antibodies to Vascular Receptors and Topoisomerase I Detected by ELISA.

Objectives: 1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT1R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ETA1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance. Methods: Sera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT1R. Patients' sera were also tested by commercially available ELISA for anti-AT1R, -ETA1- and by an in-house ELISA for anti-topo-I-abs. Results: Fifty-two percent of the SSc-patients had functionally active anti-AT1R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT1R-, -ETA1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT1R-, and -ETA1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT1R-, -ETA1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT1R, and ETA1 were associated with digital ulcers, pulmonary- and esophageal manifestation. Conclusions: Functionally active anti-AT1R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.

Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients.

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41%) suffered from ESs, seven sADs occurred in six patients (27%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen's d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50% vs. 60.00%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES.

Inhibition of effector B cells by ibrutinib in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease with a significant morbidity and reduced survival of patients. Effective treatment and clinical control of the disease remain challenging. In particular, the development of pulmonary and cardiac fibrosis and pulmonary hypertension are severe complications responsible for excessive mortality. Currently available treatment strategies only alleviate symptoms and slow disease progression. Here, we investigated the therapeutic potential of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor used in B cell malignancies, to alter B cell pathology in SSc in an in vitro model of autoimmunity. METHODS: PBMCs and sorted B cells of 24 patients with SSc were used for functional testing after stimulation with hypomethylated DNA fragments (CpG) to induce an innate immune response. The effects of ibrutinib on cytokine production, autoantibody release, and activation of the transcription factor NFκB were evaluated. RESULTS: Ibrutinib was able to reduce the production of the profibrotic hallmark cytokines IL-6 and TNF-α mainly from the effector B cell population in patients with SSc. Importantly, small doses of ibrutinib (0.1 µM) preserved the production of immunoregulatory IL-10 while effectively inhibiting hyperactivated, profibrotic effector B cells. In a flow cytometry analysis of phosphorylated NFκB, an important transcription factor in the induction of innate immune responses in B cells, significantly less activation was observed with ibrutinib treatment. CONCLUSION: Our data could pave the avenue for a clinical application of ibrutinib for patients with SSc as a novel treatment option for the underlying pathogenetic immune imbalance contributing to disease onset and progression.

Disease progression and defects in primary hemostasis as major cause of bleeding in multiple myeloma.

BACKGROUND AND OBJECTIVES: In patients with multiple myeloma (MM), unexpected bleeding complications remain a major issue. Since routine coagulation parameters are often inconspicuous, diagnosis and treatment of the underlying coagulation disorders are challenging. PATIENTS AND METHODS: In our single-center observational study, we analyzed 164 patients with MM for coagulation disorders and bleeding complications. RESULTS: Prolonged closure times (CTs), measured by PFA-100, were the most common, abnormal coagulation test, found in 66% of bleeding patients vs 5% in non-bleeding, followed by qualitative defects of von Willebrand factor (VWF:CB/VWF:Ag ratios), found in 34% vs 1% in the non-bleeding group. Increased serum free light chains (SFLC) and SFLC ratios were significantly associated with prolonged CTs and acquired von Willebrand syndrome (AVWS). Prolonged CTs and AVWS were associated with disease progression, determined by dynamics of SFLC ratios (P < .001), serum creatinine level (P = .013), Beta-2 microglobulin (P = .03), LDH (P = .016), and bone marrow infiltration (P < .001). Of note, response to myeloma therapy was frequently correlated with normalization of coagulation parameters. CONCLUSIONS: Bleeding complications in MM are predominantly caused by defects in primary hemostasis and associated with disease progression. In a peri-interventional workup, determination of CTs and VWF:CB/VWF:Ag ratios are of significant importance to assess bleeding risk.

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers.

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

Low plasma protein Z levels are associated with an increased risk for perioperative bleedings.

BACKGROUND AND OBJECTIVES: Protein Z (PZ) deficiency has been implicated both in bleeding diatheses and in thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low PZ on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding. PATIENTS AND METHODS: After exclusion of other coagulation disorders, 154 Patients were stratified into quartiles according to PZ plasma concentrations to evaluate the relation between PZ and bleeding complications. RESULTS: Low PZ levels were associated with increased blood loss (P < .001), increased need for blood transfusions (P < .001), and a higher rate of surgical revisions (P = .009) in a concentration-dependent fashion. Low PZ caused earlier (within 24 hours) and repetitive bleedings (P = .005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (P < .05). Finally, ROC analyses confirmed the predictive value of low PZ for bleeding complications and PZ-thresholds for clinical practice were determined. CONCLUSIONS: Low PZ appears to be an underestimated risk factor for perioperative bleeding. Determination of PZ plasma concentrations might be useful in the preoperative workup in patients with a bleeding history, when detailed clotting analyses remain inconclusive.