International Forum: The Turkish perspective on apheresis activity: The Turkish apheresis registry report.

Therapeutic apheresis is an extracorporeal treatment that selectively removes abnormal cells or harmful substances in the blood that are associated with or cause certain diseases. During the last decades the application of therapeutic apheresis has expanded to a broad spectrum of hematological and non-hematological diseases due to various studies on the clinical efficacy of this procedure. In this context there are more than 30 centers performing therapeutic apheresis and registered in the apheresis database in Turkey. Herein, we, The Turkish Apheresis Registry, aimed to analyze some key articles published so far from Turkey regarding the use of apheresis for various indications.

Plasma exchange in acute hemolytic reaction due to ABO-incompatible erythrocyte concentrate transfusions: Single center experience.

OBJECTIVES: Acute hemolytic transfusion reaction (AHTR) due to ABO-incompatible erythrocyte concentrate (EC) is one of the most catastrophic complications of transfusion. Since the hemolysis is intravascular; hemoglobinemia and hemoglobinuria result in disseminated intravascular coagulation (DIC), acute renal failure, shock, and sometimes death. BACKGROUND: Treatment of AHTR is mostly supportive measures. Today there are no clear suggestions about plasma exchange (PE) in these patients. METHODS/MATERIALS: Here we report our experience with six patients diagnosed with AHTR due to ABO-incompatible EC transfusion. RESULTS: We performed PE in 5 of these patients. Although all of our patients were geriatric and most of them had significant comorbidities four out of five patients recovered without an incident. CONCLUSION: Although PE is considered a last-chance treatment when other measures fail in the literature, our experience above indicates that it must be evaluated in every patient with AHTR early in the course. If the patient has cardiac and renal comorbidities, large volume EC is transfused, DAT is negative, plasma color is red and there is macroscopic hemoglobinuria, we suggest performing PE.

Menorrhagia due to uterine amyloidosis in familial Mediterranean fever: case-based review.

Amyloidosis is described by the deposition of misfolded proteins in the tissues. Amyloidoses are classified into two as systemic and localized. Out of the systemic forms, AL (light chain) amyloidosis is the most prevalent type; however, amyloid A (AA) amyloidosis is more frequently encountered in the rheumatology practice. AA amyloidosis stands out as a major complication of familial Mediterranean fever (FMF). Splenic and renal involvement is more likely in FMF-associated systemic amyloidosis. The involvement of thyroid and adrenal glands has also been described, although infrequently. Amyloidoses have a heterogeneous plethora of clinical manifestations, with certain phenotypes associated with specific amyloid forms. Gynecological amyloidosis is a rare condition. Uterine involvement may occur in a localized fashion or may also arise as a part of systemic involvement, albeit at a lesser ratio. Several cases of uterine AL amyloidosis have been documented so far as an organ involvement in systemic AL amyloidosis. On the other hand, uterine amyloidosis associated with AA amyloidosis has been described merely in one case with rheumatoid arthritis (RA). Here, we presented a 40-year-old female patient with FMF known for 38 years who underwent splenectomy and hysterectomy due to massive splenomegaly, deep anemia, and persistent menometrorrhagia. Histological examinations of materials revealed uterine and splenic AA amyloidosis. This case report is first-of-its-kind to describe FMF-associated uterine AA amyloidosis and also provides a discussion of possible mechanisms of amyloidosis-induced uterine bleeding.

Indications for bone marrow examinations in rheumatology.

Hematologic involvement or hematologic malignancies are frequently encountered during the course of rheumatic diseases. Bone marrow (BM) aspiration and/or biopsy examinations may have a diagnostic role in explaining hematologic findings detected in rheumatology clinical practice. Our aim was to describe the indications for BM examinations and to share our BM aspiration/biopsy results. We analyzed 140 BM aspiration/biopsy results of patients conducted at the Department of Rheumatology from 2010 to 2018. Demographics, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values, serum biochemistry test results including lactate dehydrogenase (LDH), organomegaly, indications for BM examinations and BM examination results for each patient, and mortality rates were recorded. Out of the 140 patients, 63.6% were female, and the median (Q1-Q3) age was 53 (39.5-65) years. One hundred fifteen (82.1%) patients were diagnosed as having primary rheumatic disease, and 25 (17.8%) were admitted due to musculoskeletal symptoms. Rheumatoid arthritis (RA) (n = 34, [29.5%]), and systemic lupus erythematosus (SLE) (n = 21, [18.2%]) were the most common rheumatic diseases. Cytopenia was the most common indication for BM aspiration/biopsy (n = 83, [59.3%]). Thirty-nine (47%) of 83 patients had drug-induced cytopenia. A pathology was detected in 40 (28.5%) of the 140 BM examinations. Patients with pathologic BM results had either a hematologic malignancy (n = 38, [95%]) or metastasis to a solid organ (n = 2, [5%]). The group of patients with pathologic BM biopsy results had significantly higher rates of lymphadenopathy, splenomegaly, and monoclonal gammopathy compared with the group with non-pathologic results (p = 0.001, p = 0.011, and p = 0.023, respectively). Likewise, LDH concentrations of those with pathologic results were higher than in patients with non-pathologic results [737 (range 577-1420) IU/L vs. 541 (range 306-840) IU/L, p = 0.019]. In this study, cytopenia or CBC abnormalities accompanied by elevated LDH values or anemia along with increased ESR were the most common indications for BM aspiration/biopsy. Further prospective studies are needed to determine the indications of BM aspiration/biopsy and establish the parameters that predict abnormal BM results in rheumatology practice.

Etanercept-induced leukemia: could increased mean corpuscular volume be a predictor of hematologic malignancy?

In rheumatology practice, anti-tumor necrosis factor (TNF) alpha agents are frequently used medications, more so in ankylosing spondylitis (AS). There are case reports, besides their adverse effects, such as infection and injection site reaction, suggesting these agents may cause solid or hematologic malignancies. Acute leukemia secondary to anti-TNF alpha agents has been rarely reported in patients with AS. In this case report, based on a patient who developed acute leukemia while on the treatment with etanercept, we will discuss whether it is possible to predict acute leukemia by monitoring the mean corpuscular volume in light of the literature.

Cardiac and pulmonary thrombosis during multidrug treatment in an idiopathic thrombocytopenic purpura patient.

Glucocorticosteroids, intravenous immunoglobulins, vincristine, danazol, and eltrombopag are used in refractory chronic idiopathic thrombocytopenic purpura (ITP). All those treatment modalities are susceptible for thrombosis generation. There is an increased risk of thrombosis in the diseases' natural course. The case we present is a resistant chronic ITP patient who developed pulmonary and intracardiac thrombosis during multidrug treatment. Risk of concomitant usage of drugs and rapid increase in platelet count are discussed.

Serum Level of Lactate Dehydrogenase is a Useful Clinical Marker to Monitor Progressive Multiple Myeloma Diseases: A Case Report.

To follow the progression of multiple myeloma (MM) disease, serum lactate dehydrogenase (LDH) levels are as useful markers as beta-2 microglobulin and monoclonal immunoglobulin. With this study, we have presented a case of a patient with a multiple myeloma which was fulminant course, whose LDH levels were normal at the onset of diagnosis increasing as 27 times more than normal as the disease progressed and who showed the development of extramedullary plasmacytomas. The patient, an 80-year-old female, was diagnosed with stage IIIA IgA type multiple myeloma and melphalan-prednisolon (MP) treatment was started. Although the LDH levels were low during the diagnosis and chemotherapy, the LDH levels increased up to 7557 U/L following the progression and occurrence of extramedullary plasmacytomas and the patient died. During the observation of the patient with MM, if the LDH levels are abnormally high, the progression of the disease should be considered after eliminating the other causes. Bone marrow aspiration and biopsy should be examined and the progression or relapse should be shown. On the other hand, the patients with LDH levels are high should be considered to have added plasmacytomas, the whole body should be examined at an early stage before the development of clinical symptoms and early treatment should be started.

Abnormality of regulatory T-cells in remission and non-remission idiopathic thrombocytopaenic purpura patients.

Primer immunologic defect in patients with idiopathic thrombocytopaenic purpura (ITP) result from autoreactive B-lymphocytes secreting antiplatelet antibodies. Dysfunctional cellular immunity has also great importance in ITP pathogenesis. CD4(+)CD25(+) regulatory T-cells have immunoregulatory features and it is able to inhibit CD4(+)CD25(-) and CD8(+) responses. ITP is also an autoimmune disease; the CD4(+)CD25(+) T-cell levels of the patients decrease during the active state. According to our findings, immunosuppressive treatments increase the CD4(+)CD25(+) Treg cell levels in the non-remission ITP patients. However, this level is not enough to overcome the resistance. CD4(+)CD25(-)Foxp3(+) and CD4(+)Foxp3(+) Treg cells are responsible for the pathogenesis of the non-remission ITP patients and other factors exist, which are responsible for the resistance of ITP treatment.

Regulatory T cells in Behçet's disease: is there a correlation with disease activity? Does regulatory T cell type matter?

The aim of this study was to investigate the percentage of regulatory T cells and the correlation with clinical activity in Behçet's disease. Forty Behçet's disease (BD) patients, 18 males and 22 females, were included in the study. The patients were diagnosed according to the published BD criteria. Twenty age- and sex-matched volunteer healthy donors were also included. At the time of sampling, clinical activity was assessed for activity signs and symptoms according to the BD Current Activity Form. We considered active those patients with a clinical activity index equal to and/or above 2. Eleven patients had active disease and the remaining were considered as clinically inactive. We have studied the percentages of CD4+CD25+FOXP3+, CD4+CD25+ and CD4+FOXP3+regulatory T cells by flow cytometry and investigated the correlation with disease activity. Percentage of CD4+CD25+FOXP3+Treg in active patients was lower than clinically inactive patients and healthy controls. Percentage of CD4+CD25+Treg was not different between active and inactive patients and healthy controls. Percentage of CD4+FOXP3+Treg was lower than healthy controls in clinically active patients but was not different for inactive group and healthy controls. Patients were active when CD4+CD25+FOXP3+Treg was ≤1.19 %, CD4+CD25+Treg was ≤2.68 %, and CD4+FOXP3+Treg was ≤2.60. CD4+CD25+FOXP3+Treg and CD4+FOXP3+Treg were found negatively correlated with disease activity. Peripheral blood regulatory T cells are decreased in clinically active Behçet's disease patients. The advances in our understanding of the interactions between distinct subsets of Treg and clinical activity might help in modulating BD treatment.

Acquired Hemophilia A In Adults: A Multicenter Study from Turkey.

Acquired hemophilia A (AHA) is a rare disease caused by autoantibodies inhibiting factor VIII (FVIII) activity. Although the conditionis usually idiopathic, there may be other underlying diseases. Treatment consists of two steps: treatment of acute bleeding and immunosuppression. In this multicenter study, we aimed to demonstrate the clinical characteristics, management details, and survival of AHA patients in Turkey. Data was collected from eleven centers in Turkey. aPTT, FVIII, FVIII inhibitor, and hemoglobin (HB) levels, mixing test results, and demographics at diagnosis, treatment information, adverse events, bleeding episodes during follow-up, relapses, and outcome were analyzed. Twenty-nine patients were analyzed (58.6% female). No underlying disorder could be detected in 14 patients. The most prevalent etiologies were pregnancy, malignancy and infections. The median FVIII activity and FVIII inhibitor titer at diagnosis were 0.7% (0.0-29.4%) and 32.6 BU (0.6-135.6 BU) respectively. Bleeding was severe in 44.8% of patients. The HB value was significantly lower in patients with severe bleeding. Most of the patients (n = 25, 86.2%) had only one bleeding episode without relapse, three patients (10.3%) had two bleeding episodes, and one patient had more than three bleedings. 21 (75%) patients received hemostatic therapy. The use of recombinant FVIIa was slightly higher than activated prothrombin complex concentrate (15 versus 10 patients). Immunosuppressive treatment was initiated in 26 (93%) patients. Regimens containing steroid, cyclophosphamide, and rituximab in different combinations were the most preferred. The median follow-up period was 13 months (2-156 months). Median overall survival was 154.97 months. Four and six-year survival were 90.9 ± 0.8% and 77.9 ± 14.1% respectively. This is a unique study that investigated the demographic characteristics, treatment approaches, and patient survival of AHA in Turkey.

Incidence of red-cell alloimmunization due to non-anti-D antibodies during pregnancy: an experience from Turkey.

Antigen D incompatibility between mother and fetus is the most frequent cause of red-cell alloimmunization. However there are surface antigens capable of producing hemolytic disease other than antigen D. Populational antigen frequencies may be country specific. The aim of this retrospective study was to evaluate the incidence of red-cell alloimmunization due to non-anti-D antibodies during pregnancy. We evaluated the indirect antiglobulin test results of 535 pregnant women performed between March 2003 and 2009. The incidence of non-anti-D antibodies was found 1.21%, similar with reported in literature, but the spectrum of non-anti-D antibodies was different from other countries.

How should we manage low-dose methotrexate-induced pancytopenia in patients with rheumatoid arthritis?

Low-dose methotrexate (ld-MTX) that is administered during rheumatoid arthritis (RA) treatment has hematological adverse effects such as pancytopenia, although rare. Although well-established and widely used for hematological adverse effects caused by high-dose MTX, leucovorin (folinic acid) treatment does not have an agreed-upon administration for ld-MTX-induced pancytopenia. Here, we aimed to figure out whether there was any difference in response time between the regimens with and without folinic acid prescribed to our patients who developed pancytopenia while on MTX therapy, and to identify risk factors for its development. Our cases were collectively assessed together with other rare cases available in the literature that were reported in a similar manner with an explicitly indicated response time, in days. Thereupon, we looked for any difference in response time between the regimens with and without folinic acid. In total, ten of our patients experienced pancytopenia while on ld-MTX treatment. Mean day on which hematological response was achieved was as follows: 7 days in one patient on folic acid monotherapy, 6 days in three patients on granulocyte-colony stimulating factor (G-CSF) monotherapy, 4.5 days in two patients on leucovorin monotherapy, and 4 days in the remaining three patients who were treated with G-CSF + folinic acid/leucovorin. When we collectively evaluated our patients and the patients with an explicitly stated response duration in the literature (15 patients) and compared regimens including folinic acid to those without folinic acid, duration until response/recovery from pancytopenia was significantly shorter in folinic acid group than that in the group without folinic acid (5.47 ± 2.9 days vs 10 ± 3.77 days, p = 0.002). Treatment modalities including folinic acid (leucovorin) either with or without G-CSF result in a shorter recovery/response time compared to other agents. Leucovorin should definitely be considered and applied in rescue therapy for ld-MTX-associated side effects.

Can we predict thrombotic tendency in rheumatoid arthritis? A thromboelastographic analysis (with ROTEM).

The higher incidence of arterial and venous events is well established in patients with rheumatoid arthritis (RA). Our aim here was to investigate whether there is a prothrombotic state in RA patients by using rotational thromboelastometry (ROTEM) method and to demonstrate whether the disease variables play a role in this process. A total of 85 patients who met the 2010 RA classification criteria were consecutively included in the study. The patients with RA who have been using antiaggregant, anticoagulant, or nonsteroidal anti-inflammatory drugs (NSAIDs) and had a history of arterial or venous thromboembolism were excluded from the study. Their complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer, and lipid profiles were measured, DAS-28 disease activation scores were calculated, and simultaneous ROTEM analysis was performed to determine the predisposition to thrombosis. Of the ROTEM parameters, clotting time (CT, seconds (s)), clot formation time (CFT, s), and maximum clot firmness (MCF) were evaluated. Having a shorter CT and/or CFT in intrinsic (I) or extrinsic (E) pathway and/or a longer MCF compared to the healthy controls was considered as "predisposition to hypercoagulability". The mean age of the 85 RA patients were 54.12 ± 13 years, and 77.6% of the patients were female (n = 66). Of the patients, 52.9% (n = 45) were using methotrexate (MTX) ± hydroxychloroquine (HCQ) ± corticosteroid (CS), while 43.5% (n = 37) were using anti-tumor necrosis factor (TNF) ± MTX. Active steroid usage was ongoing in 64.7% of the patients (n = 55). When evaluated according to DAS-28, in those with higher disease activity, a shorter I-CFT and greater I-MCF were determined (p = 0.020 and p = 0.033, respectively). In those with higher disease activity based on the correlation analysis, I-CFT and E-CFT were shorter and I-MCF and E-MCF were longer, indicating a higher predisposition to thrombosis. Using linear regression, variables with a major effect on ROTEM parameters were identified as DAS-28, CRP, and platelet count. As the first study in the literature, we identified that disease activation is the most important risk factor for prothrombotic state in RA patients irrespective of the drugs used. ROTEM can be used in clinical practice to predict thrombotic events in RA patients.

Detailed features of hematological involvement and medication-induced cytopenia in systemic lupus erythematosus patients: single center results of 221 patients.

OBJECTIVE: Systemic lupus erythematosus (SLE) may affect a number of systems, with the hematological system being one of the most common. Our aim is to determine the existence of cytopenia at diagnosis or during follow-up of our SLE patients as well as the associated factors. MATERIAL AND METHODS: A cohort of SLE patients that had been followed-up in the Department of Rheumotology from 1998 to 2015 was retrospectively assessed. Clinical and laboratory findings about the patients were recorded. RESULTS: Out of 221 patients composing the cohort, cytopenia was already present in 83.3% (n=184) at the time of diagnosis. Anemia was detected in 56.1% (n=124), leukopenia in 28.9% (n=64), lymphopenia in 76% (n=168), neutropenia in 4.5% (n=10), and thrombocytopenia in 17.2% (n=38) of patients. The proportion of patients with cumulative cytopenia was 90% (n=199). Cumulative cytopenia was disease-related in 83.4% (n=166) and medication-related in 16.6% (n=33) of the patients. In cases of drug-induced cytopenia, azathioprine was the most frequently prescribed drug. In patients with cytopenia at the time of diagnosis, erythrocyte sedimentation rates (ESR) were higher, C3 and C4 hypocomplementemia was more prevalent, and they were positive for anti-ds-DNA at a greater proportion (p<0.001, p=0.015, p=0.028, and p=0.019, respectively). Moreover, photosensitivity, renal involvement, and antiphospholipid syndrome (APS) were detected more frequently in patients with cytopenia at the time of diagnosis. There was no difference between the two patient sets in terms of other organ involvement (p>0.05). CONCLUSION: The most common hematological disorders in SLE patients are lymphopenia and anemia, and patients must be further examined for APS and renal involvement if they suffer cytopenia.

A rare cause of cytopenia in a patient with systemic lupus erythematosus: Autoimmune myelofibrosis.

Hematological abnormalities are very common in the course of systemic lupus erythematosus (SLE). Myelofibrosis is a bone marrow disorder in which there is excessive fibrous tissue formation in the bone marrow. Various benign and malignant disorders can cause or be associated with a diffuse increase in the bone marrow reticular tissue. Some diseases such as infections, neoplasms, and autoimmune diseases may also induce bone marrow fibrosis (secondary myelofibrosis). Cytopenia from autoimmune myelofibrosis (AIMF) in SLE is a rare condition. Here we present a case of AIMF associated with SLE and aim to emphasize on the other cause of cytopenia in SLE.

Transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is related to the transfusion of blood components. Typically, it is a clinical syndrome, characterized by the sudden onset of dyspnea, hypoxemia and bilateral non-cardiogenic pulmonary edema. A 83-year-old female patient with a history of AML developed TRALI after receiving 6 units of platelets. TRALI symptoms was started 10 min later the transfusion. AML is a risky group for TRALI. While giving transfusion to the risky groups of TRALI one must be more careful. The mortality rate caused by TRALI will decrease if the patient who is thought to have TRALI or who has bilateral pulmonary edema without any other reason showing the existance of TRALI is given ventilatory support at the right time.