Antiphospholipid antibodies in convalescent plasma of donors recovered from mild COVID-19 infection.

BACKGROUND AND OBJECTIVES: Passive immunization by the infusion of convalescent plasma (CP) obtained from patients who have recently recovered from COVID-19, thus having antibodies to severe acute respiratory syndrome coronavirus 2, is a potential strategy to reduce the severity of illness. A high prevalence of antiphospholipid antibodies (APLA) in patients with COVID-19 has been reported during the pandemic, raising a concern whether the use of CP could increase the risk of thrombosis in transfused patients. We aimed to evaluate the prevalence of APLA in COVID-19 CP (CCP) in order to assess the potential prothrombotic influence of transfused CCP to COVID-19 patients. MATERIALS AND METHODS: We studied the prevalence of APLA in 122 CCP samples collected from healthy donors who recovered from mild-COVID-19 at two time periods: September 2020-January 2021 (defined as 'early period' samples) and April-May 2021 (defined as 'late period' samples). Thirty-four healthy subjects unexposed to COVID-19 were used as controls. RESULTS: APLA were present in 7 of 122 (6%) CCP samples. One donor had anti-ß2-glycoprotein 1(anti-ß2GP1) IgG, one had anti-ß2GP1 IgM and five had lupus anticoagulant (LAC) using silica clotting time (SCT), all in 'late period' donors. In the control group, one subject had anti-ß2GP1 IgG, two had LAC using dilute Russell viper venom time (dRVVT) and four had LAC SCT (both LAC SCT and LAC dRVVT in one subject). CONCLUSION: The low prevalence of APLA in CCP donors reassures the safety of CCP administration to patients with severe COVID-19.

Should patients treated with oral anti-coagulants be operated on within 48 h of hip fracture?

To investigate if patients treated with oral anticoagulants (OAC) have delayed surgical intervention (more than 48 h) compared to patients without OAC therapy, and if there is an impact to surgery timing on hospitalization length and mortality. A retrospective cohort study of all patients aged over 65 registered with a new diagnosis of hip fracture who underwent surgery in one of the general hospitals run by Clalit, Israel between 01/01/2014 and 31/12/2017. Data was retrieved for patient demographics, OAC treatment, and Charlson comorbidity index. 5828 patients were operated for hip fractures, mean age was 82.8 years (65-108), 4013 (68.8%) were female. 415 were treated with direct oral anticoagulants (DOACs) (7.1%) and 311 with warfarin (5.3%) prior to their hospitalization. Patients taking OAC were less likely to be operated within 48 h from arrival to the hospital compared to patients not receiving OAC. The 30 day mortality was 4.2% among patients not receiving OAC, 6.0% among patients taking DOACs and 10.0% among patients receiving warfarin (p < 0.001). Adjusted odds ratio for mortality at 30 day among patients taking DOACs was similar to patients who didn't take OAC. (OR 1.0, CI 0.7, 1.6). The 30 day mortality rate of patients who were receiving OAC (either DOACs or warfarin) was not significantly different whether patients were operated within 48 h or not. Mortality rate was highest among patients taking warfarin. For patients who received DOACs, operation within 48 h wasn't associated with lower mortality rate. In these patients it seemed reasonable to adjust surgery time according to patients' characteristics and needs.

[TREATMENT OF IMMUNE THROMBOCYTOPENIC PURPURA IN ADULTS: UPDATE].

INTRODUCTION: Primary immune thrombocytopenic purpura (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia (platelet count less than 100X109/L), caused by IgG autoantibodies which bind to platelets and megakaryocyte, T cell-mediated platelet destruction and impaired megakaryocytic function. Symptoms can manifest as petechiae, purpura, mucosal bleeding and rarely fatal intracranial hemorrhage, as well as reduced quality of life. A wide range of bleeding manifestations exists and it is impossible to tell who will bleed, when and where. The goal of treatment is to prevent severe/life-threatening bleeding. Treatment modalities target various aspects of ITP pathophysiology such as the inhibition of autoantibody production (decreased autoimmune process), modulation of T cell activity (with prolongation of platelets survival), and stimulation of platelet production. The American Society of Hematology and the International Society of Thrombosis and Hemostasis published guidelines on the treatment of ITP patients, where first line treatment focuses on inhibition of autoantibody production and platelet degradation, second-line treatments include immunosuppressive drugs and splenectomy, and third-line treatments aim to stimulate platelet production by megakaryocytes. New available strategies might change the order of treatment lines. As in other situations, treatment should be tailored according to the patient's age, life style, comorbidities and compliance.

[MANAGEMENT OF ANTICOAGULANT AND ANTIPLATELET THERAPY IN PATIENTS UNDERGOING PLANNED ENDOSCOPIC PROCEDURES].

INTRODUCTION: Antithrombotic and antiplatelet therapy is widely used for primary and secondary prevention of venous and arterial diseases. Hemorrhage is a frequent complication in patients taking these drugs, especially during and post invasive procedures. There are several oral anticoagulants and antiplatelet drugs that differ from each other in the mechanism of action and metabolism, the need for drug monitoring, antidote, and the peri-procedural management of the drug. The risk of bleeding in gastrointestinal endoscopic procedures can be high (≥ 1.5%), depending on the procedure. Patients taking antithrombotic and antiplatelet therapy should undergo evaluation before endoscopic procedure in order to stratify their risk for bleeding during the procedure on the one hand, and the risk of thromboembolism- if the drug is interrupted, on the other hand. This review provides general recommendations and approaches for patients undergoing elective gastrointestinal endoscopic procedures while receiving antithrombotic or antiplatelet drugs.

Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab.

BACKGROUND: Anti-complement factor H (CFH) antibodies is an extremely rare cause of atypical hemolytic uremic syndrome (aHUS) in adults, with less than 10 cases reported thus far. Although infectious diarrhea is a common inciting trigger for aHUS episode, there are no reports of an association with inflammatory bowel disease. Eculizumab is an emerging treatment for aHUS. Eculizumab has not been reported thus far to be given for aHUS due to anti-CFH antibodies. We report here for the first time on an adult patient with ulcerative colitis (UC) who developed aHUS due to anti-CFH antibodies, presented with decreased serum levels of both C3 and C4. She had an excellent response to treatment with eculizumab. CASE PRESENTATION: A 27-year-old Caucasian woman, who suffered from steroid-dependent UC, was admitted with microangiopathic hemolytic anemia and acute kidney injury with nephrotic syndrome. ADAMTS 13 was normal and comprehensive workout for secondary causes of HUS was negative. Both serum complement level of C3 and C4 were low. Kidney biopsy was compatible with the diagnosis of HUS with negative immunofluorescence. Because of only partial response to plasma exchange and high dose steroids, eculizumab was commenced. After two weeks signs of microangiopathy subsided, and kidney function began to recover. Few months after the diagnosis, a complement components investigation revealed antibodies against CFH at high titer of 2000 arbitrary units. Today her creatinine is stable with no proteinuria and no signs of HUS.

Acquired thrombasthenia due to inhibitory effect of glycoprotein IIbIIIa autoantibodies.

BACKGROUND: A 75 year old patient presenting with mucocutaneous bleeding was diagnosed with acquired thrombasthenia. The diagnosis was based on lack of platelet aggregation with adenosine diphosphate (ADP), arachidonic acid and collagen, and normal aggregation induced by ristocetin. OBJECTIVE: To study the mechanism of platelet function inhibition in a patient with acquired thrombasthenia. METHODS: Aggregation assays of platelets from the patient and healthy controls were performed. In addition, anti-glycoprotein (GP) IIbIIIa antibodies bindingto normal in the presence or absence of the patient's serum was by flow cytometry. RESULTS: Aggregation of normal platelets in the presence of patient's plasma was inhibited four- and 2.5-fold in the presence of ADP and arachidonic acid respectively, while collagen-induced aggregation was completely abolished. Ristocetin-induced aggregation was normal. The patient's serum inhibited binding of commercial anti-glycoprotein IIbIIIa antibodies to normal platelets twofold by flow cytometry. Treatment with anti-CD20 monoclonal antibody (rituximab) normalized the patient's platelet aggregation. CONCLUSIONS: These results suggest that the patient developed inhibitory anti-GPIIbIIIa autoantibodies that caused acquired thrombasthenia.

Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (TTP) is an uncommon disease in adults, characterized by fever, neurological manifestations, microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and the presence of antibodies against the enzyme ADAMTS13. Treatment with plasmapheresis has increased the survival from 10% to more than 90%. Still, there is a subset of patients with resistant TTP who fail to respond to plasmapheresis or remain dependent on this procedure. There is mounting evidence that rituximab may play an important role in remission induction of resistant/relapsing TTP, but the extent of the remission is unknown. We present here four patients with chronic-relapsing TTP who responded favorably to rituximab. All four patients achieved prolonged remission of 23 to 82 months after the treatment. One patient relapsed 6 years afterthe initial treatment with rituximab and re-entered remission following retreatment.

Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine.

BACKGROUND: In December 2020 the Israeli Health Ministry began a mass vaccination campaign with the BNT162b2 vaccine. This was an important step in overcoming the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic. Autoimmune phenomenon have been described after receiving vaccinations. PATIENTS/METHODS: Here we describe a case series of patients who developed acquired Thrombotic Thrombocytopenic Purpura, a rare autoimmune disease, within several days of receiving the BNT162b2 vaccine. CONCLUSIONS: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity should be evaluated in patients with history of aTTP before and after any vaccination, especially the SARS-CoV-2 vaccination, and immunosuppression treatment should be considered before vaccination in cases of low ADAMTS13 activity. Patients should be closely monitored after the vaccine for clinical situation and laboratory data. Post vaccination thrombocytopenia assessment should include immune thrombocytopenic purpura, vaccine-induced immune thrombotic thrombocytopenia and acquired thrombotic thrombocytopenic purpura.

Prolonged activated partial thromboplastin time with no clear explanation.

: Evaluation of bleeding risk before operation includes history of bleeding, complete blood count and basic coagulation tests, prothrombin time and activated partial thromboplatin time (aPTT). In this article, we present a patient with colon cancer who presented with asymptomatic prolonged aPTT of 72-100 s, while past a PTT values were within normal limits. aPTT was corrected in vitro by mixing with normal plasma. Further laboratory workup excluded coagulation factors deficiencies or an acquired inhibitor to coagulation factors. The patient underwent uncomplicated laparoscopic anterior resection of a recto-sigmoid carcinoma after receiving fresh frozen plasma and correction of aPTT. Further investigation revealed a rare disorder of an acquired prekallikrein deficiency. We describe the patient's clinical presentation, laboratory workup and review the literature of contact phase proteins deficiency.

Antiphospholipid syndrome characteristics and adverse pregnancy outcomes after 20 weeks of pregnancy.

OBJECTIVE: To assess outcomes after 20 weeks of pregnancy according to autoantibody profile and clinical presentation of maternal antiphospholipid syndrome (APS). METHODS: The present retrospective cohort analysis included women diagnosed with APS at a tertiary medical center in Israel between January 1, 2012, and December 31, 2016. Anticardiolipin antibodies, anti-ß2-glycoprotein antibodies, and lupus anticoagulant were assessed. Participants were stratified by type of APS (obstetric vs thrombotic), antibody profile, and antibody titer (low vs high). Primary composite outcomes were rated as severe (stillbirth, fetal growth restriction at <34 weeks, severe pre-eclampsia, or delivery at <32 weeks) and mild (stillbirth, any fetal growth restriction, any pre-eclampsia, or delivery at <34 weeks). RESULTS: A total of 99 women were included in the analysis. The primary composite outcomes were similar regardless of stratification. Lupus anticoagulant positivity was associated with delivery before 37 weeks. When compared with low antibody titer, high antibody titer was associated delivery at or before 32 weeks (P=0.045) and 34 weeks (P=0.029). CONCLUSION: High antibody titer might be associated with an increased risk of severe prematurity among pregnant women with APS.

Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria.

We reported previously that jasmonates can kill human cancer cells. Many chemotherapeutic drugs induce mitochondrial membrane permeability transition, membrane depolarization, osmotic swelling, and release of cytochrome c, involving the opening of the permeability transition pore complex (PTPC). Because jasmonates exert their cytotoxic effects independent of transcription, translation, and p53 expression, we hypothesized that these compounds may act directly on mitochondria. Mitochondrial membrane depolarization was determined by flow cytometry, and cytochrome c release by Western blotting. Mitochondria were isolated by mechanical lysis and differential centrifugation. Cytotoxicity was measured by a tetrazolium-based assay, and mitochondrial swelling by spectrophotometry. Jasmonates induced membrane depolarization and cytochrome c release in intact human cancer cell lines. Jasmonates induced swelling in mitochondria isolated from Hep 3B hepatoma cells, but not in mitochondria isolated from 3T3 nontransformed cells or from normal lymphocytes, in a PTPC-mediated manner. Methyl jasmonate induced the release of cytochrome c from mitochondria isolated from cancer cell lines in a PTPC-mediated manner, but not from mitochondria isolated from normal lymphocytes. A correlation was found between cytotoxicity of methyl jasmonate and the percentage of leukemic cells in the blood of patients with chronic lymphocytic leukemia (CLL). Jasmonates induced membrane depolarization in CLL cells, and swelling and release of cytochrome c in mitochondria isolated from these cells. In conclusion, jasmonates act directly on mitochondria derived from cancer cells in a PTPC-mediated manner, and could therefore bypass premitochondrial apoptotic blocks. Jasmonates are promising candidates for the treatment of CLL and other types of cancer.

Fertility status among women treated for aggressive non-Hodgkin's lymphoma.

In young women treated for intermediate-high-grade non-Hodgkin's lymphoma with CHOP (cyclophosphamide, adriamycin, oncovine and prednisone), there is insufficient data concerning gonadotoxicity or the need for fertility-preserving measures. The aim of the present study was to evaluate the fertility status in the first complete remission of women who were treated for aggressive non-Hodgkin's lymphoma. A cohort of 36 women with aggressive non-Hodgkin's lymphoma in first remission, who were treated in five university-affiliated hospitals in Israel, was evaluated. All women were aged younger than 40 years at diagnosis and received frontline protocols, including cyclophosphamide and adriamycin, mostly CHOP. Menstrual cycle characteristics, as well as pregnancies before the diagnosis, during treatment and in first complete remission, were evaluated. The patients' mean age at the diagnosis was 28 +/- 7 years (range 17 - 40 years). All patients were treated with chemotherapy, although 10 patients received additional radiotherapy. Follow-up time at first complete remission was 84 +/- 48 months. Before diagnosis, all patients had menstrual cycles, which were regular in 31 (86%). Three patients received gonadtropin-releasing hormone analogs, whereas nine received contraceptive pills together with cytotoxic treatment. During treatment, 18 patients (50%) had amenorrhea, six (17%) had irregular menstrual cycles, and 12 (33%) continued their regular cycles. All but two women resumed menses in the first complete remission, and these were regular in 22 (61%) patients. In 63% of patients, the menstrual cycle recovered within 3 months of the discontinuation of chemotherapy. Eighteen patients (50%) became pregnant during the first complete remission. There was no significant difference between those patients who received fertility-preserving measures versus the remainder concerning regular menstrual cycles recovery or pregnancies. The two patients who developed amenorrhea were 40 years old at the time of diagnosis. In conclusion, the rate of gonadal dysfunction is very low among young, CHOP treated, non-Hodgkin's lymphoma female patients. Fertility-preserving techniques are not needed for women aged younger than 40 years and should probably be reserved for those who are at high risk for gonadal toxicity.

Screening for thrombophilia.

Thrombophilia screening may be useful in patients at high risk of VTE because it may improve clinical outcome. Family screening allows primary prophylaxis for high-risk situations and counseling of women considering hormonal therapy and pregnancy. Until we find useful and inexpensive screening tools, it is not recommended to test every patient or her/his relatives. Each index case should be carefully evaluated by an expert physician who should tailor the laboratory testing and treatment modalities.

The Seventh American College of Chest Physicians Guidelines for the antenatal and peripartum management of thrombophilia: A tutorial.

The latest guidelines for the prevention of venous thromboembolism were published by the American College of Chest Physicians in September 2004. This set of updated guidelines represents a discussion of treatments of venous thrombosis, thromboprophylaxis, and revision of those published in 2001. These guidelines propose some "official" recommendations for health-care providers for women during the peripartum period. The purpose of this article is to settle some ambiguity and to present these recommendations in a clinical format.

Serum CA 125 as a prognostic factor in non-Hodgkin's lymphoma.

Cancer antigen 125 (CA 125) is a glycoprotein expressed in normal tissues originally derived from coelomic epithelia such as peritoneum, pleura, pericardium, fallopian tubes and endometrium. Serum CA 125 levels are elevated in various benign and malignant conditions that involve stimulation of these tissues. Although elevated levels have been reported in patients with non-Hodgkin's lymphoma (NHL), its role as a prognostic factor remained uncertain. In this study, serum CA 125 levels were measured prospectively in 108 consecutive patients with NHL: at diagnosis in 106, in remission in 39 and at relapse in 7. Levels were elevated in 43% at diagnosis. This finding was associated with advanced disease stage, bulky tumors, bone marrow involvement, extranodal disease (in stages III and IV), occurrence of B symptoms, pleural or peritoneal effusions, high serum LDH levels, high serum beta2 microglobulin (beta2-M) levels, elevated International Prognostic Score, poor performance status and partial or no response to treatment. No difference in CA 125 level was found between the indolent and aggressive lymphomas. Serum CA 125 levels at diagnosis had strong association with event-free and overall survival (p = 0.01 and 0.003, respectively), with the patients with increased levels having worse survival. Patients with high CA 125 levels at diagnosis who achieved remission showed a significant decrease in CA 125 levels in remission. In conclusion, CA 125 is not only a reliable marker for staging and assessing tumor activity in NHL, elevated levels are also predictive of decreased survival.

Removal of retrievable vena cava filters in routine practice: a multicenter study.

UNLABELLED: Vena cava filters (VCFs) are used to prevent pulmonary embolism when anticoagulation is contraindicated or in the event of progression of thrombosis despite adequate anticoagulation. Retrievable VCFs provide a potential advantage over permanent VCFs, but the appropriateness of their use and the frequency with which they are removed is not well established. OBJECTIVES: Document the indications for insertion of retrievable VCFs, filter removal in hospital practice. METHODS: Observational study conducted in three academic medical centers. Consecutive patients undergoing retrievable VCF insertion were identified. Clinical data was extracted from the patients' charts and follow up data were obtained from treating physicians after discharge. RESULTS: 300 patients were studied. The indication for filter insertion was acute bleeding (46.1%) or surgery (24.2%) in patients with acute thrombosis, prevention of venous thromboembolism in trauma (13.3%), potential bleeding in patients with deep vein thrombosis (9.1%) thromboembolism while on adequate anticoagulation (5.7%) and other (1.3%). 21 (7%) filters were removed. An unsuccessful attempt at retrieval was undertaken in a further 9 (3%) patients. CONCLUSIONS: The use of retrievable VCFs was appropriate, with the possible exception of their prophylactic use in major trauma. The majority of VCFs were not removed, for reasons that are not apparent.

Oral contraception and thrombophilia.

PURPOSE OF REVIEW: To describe current knowledge related to the association between oral contraception and the thrombophilias. RECENT FINDINGS: The use of oral contraception increases the risk of venous thromboembolism as well as arterial thrombosis. Third-generation pills seem to increase the risk of venous thromboembolism compared with second-generation pills. This effect seems to be reversed or absent for the risk of arterial thrombosis. The effect of oral contraception on the risk of venous thromboembolism is more pronounced during the first year of use. All these risks are further increased in patients with an inborn or acquired tendency for coagulation (thrombophilia). SUMMARY: Prospective users of oral contraception are potential candidates for screening/testing, because a positive screen may substantially decrease the risk of a thrombotic event. At present, the available testing methods are not cost effective, and the absolute risk is not defined for each thrombophilia. Until these shortcomings are solved, it is not recommended to test every woman who wishes to use oral contraception. Nevertheless, before starting on oral contraception, each patient should be carefully screened by a physician who should identify an increased risk of thrombophilia and tailor the laboratory testing.