Severe Immune-mediated Thrombocytopenia Research Articles

COVID-19-A Trigger Factor for Severe Immune-Mediated Thrombocytopenia in Active Rheumatoid Arthritis.

Thrombocytopenia is defined as a platelet count below 150,000/mm3 for adults. There is still controversy about whether individuals with platelet counts of 100,000/mm3 to 150,000/mm3 should be classified as having genuine thrombocytopenia or borderline thrombocytopenia. Thrombocytopenia is considered mild when the platelet count is between 70,000 and 150,000/mm3 and severe if the count is less than 20,000/mm3. Thrombocytopenia in rheumatoid arthritis is a rare complication, with an incidence estimated between 3 and 10%. The main etiological aspects include drug-induced thrombocytopenia and immune thrombocytopenic purpura. The most common hematological abnormalities in SARS-CoV-2 infection are lymphopenia and thrombocytopenia. It has been observed that the severity of thrombocytopenia correlates with the severity of the infection, being a poor prognosis indicator and a risk factor for mortality. COVID-19 can stimulate the immune system to destroy platelets by increasing the production of autoantibodies and immune complexes. Autoimmunity induced by viral infections can be related to molecular mimicry, cryptic antigen expression and also spreading of the epitope. During the COVID-19 pandemic, it is of great importance to include the SARS-CoV-2 infection in differential diagnoses, due to the increased variability in forms of presentation of this pathology. In this review, our aim is to present one of the most recently discovered causes of thrombocytopenia, which is the SARS-CoV-2 infection and the therapeutic challenges it poses in association with an autoimmune disease such as rheumatoid arthritis.

A Case of Evanʼs Syndrome Triggered by Vedolizumab

Clinical trials have shown Vedolizumab to be a safe and highly effective therapy in treating inflammatory bowel disease. Its unique gut-specific mechanism of action has made it an attractive agent in recent years. However, Vedolizumab's side effect profile and long-term effects are not yet fully understood. We report a patient with ulcerative colitis (UC) presenting with epistaxis found to have a Vedolizumab-induced severe immune-mediated thrombocytopenia and hemolytic anemia, otherwise known as Evan's syndrome. Our patient is a 26 year-old man with a history of ulcerative pancolitis who presented with epistaxis and hematuria one week after his first Vedolizumab infusion. In terms of his UC history, he had been diagnosed with UC one year prior through colonoscopy and was initially managed with Mesalamine and Adalimumab with persistent symptoms of bloody diarrhea and abdominal pain. He was then switched to Vedolizumab and within five days, began experiencing severe epistaxis and scant hematuria. Physical exam was notable only for mild left lower quadrant tenderness. He was found to have a severe thrombocytopenia with a nadir of 7 K/μL. He had findings consistent with a hemolytic anemia with an indirect bilirubinemia, elevated LDH, and decreased haptoglobin. Direct Coomb's testing was positive and he was diagnosed with Evan's syndrome. He was treated with corticosteroids, intravenous immunoglobulin, and Rituximab. Both his UC symptoms and blood counts improved on treatment. He was eventually discharged on a Prednisone taper. All of his blood counts returned to normal four weeks after discharge. Evan's syndrome is a rare autoimmune disorder characterized by a Coomb's positive autoimmune hemolytic anemia and thrombocytopenia. It has been associated with several disorders and medications. However, to our knowledge, this is the first documented case of Vedolizumab-induced Evan's syndrome. This case highlights the potential for a paradoxical immunogenicity associated with the drug. Although there is excellent safety data on Vedolizumab, clinicians should be aware of this potentially rare but serious side effect. Rapid recognition and treatment of this uncommon disorder is essential. Ongoing post-market drug safety monitoring may help to fully understand all of the potential long and short term side effects of Vedolizumab.2099 Figure 1 No Caption available.

Varicella-associated immune thrombocytopenic purpura in a child with bleeding manifestations with review of literature

Chickenpox is a benign and self-limiting viral exanthematous infection, but sometimes it may be associated with complications. Mild thrombocytopenia occurs in 1-2% of children with varicella, but severe immune-mediated thrombocytopenia associated with bleeding is a rare complication. Various other mechanisms for thrombocytopenia have been implicated-decreased bone marrow production of platelets, disseminated intravascular coagulation, virally-induced platelet aggregation followed by phagocytosis or lysis, direct viral invasion of platelet precursors and viral-derived neuraminidase causing enzymatic desialylation of platelets followed by removal of abnormal platelets by reticuloendothelial system. We report a case of severe thrombocytopenia, possibly immune-mediated with bleeding in the form of petechiae and epistaxis in a child recovering from chickenpox, who is successfully treated with steroids. This may at least in part guide clinicians to recognize this rare but potentially dangerous complication of chickenpox.

A Rare Hematological Adverse Event Induced by Bevacizumab: Severe Thrombocytopenia

BackgroundBevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, is approved for the treatment of various malignancies, and its hematological toxicities are considered infrequent. MethodsA colorectal cancer patient receiving chemotherapy (5-fluorouracil and oxaliplatin) plus bevacizumab developed acute, severe thrombocytopenia. We postulated that this thrombocytopenia could be directly triggered by bevacizumab. ResultsA man with stage IV colorectal cancer and synchronous liver metastasis had received 10 cycles of FOLFOX plus bevacizumab (5 mg/kg) without significant hematological toxicity. Due to thrombocytopenia, oxaliplatin was withdrawn after cycle 11. On cycle 12, shortly after bevacizumab infusion and before 5-fluorouracil infusion, the patient developed fever, lower limbs purpura, grade 1 proctorrhagia, and epistaxis. Platelets had decreased from 105,000/mm3 to 3000/mm3 within 1 hour after bevacizumab infusion. Flow cytometry identified platelet-associated immunoglobulins. Despite 2 apheresis-derived platelet transfusions, oral corticotherapy, and gamma globulin infusions, thrombocytopenia persisted, but was finally successfully treated with a peptibody thrombopoietin mimetic, which was introduced 28 days after the last bevacizumab infusion. ConclusionsClinicians should keep in mind that bevacizumab can induce acute and potentially severe immune-mediated thrombocytopenia.

Treatment of Severe Immune‐Mediated Thrombocytopenia with Human IV Immunoglobulin in 5 Dogs

Background: Glucocorticoids with or without other immunotherapy are the initial treatment of choice for dogs with severe immune‐mediated thrombocytopenia (IMT). The majority of treated dogs will have improvements in platelet counts within 5 to 7 days of starting therapy, but complications from hemorrhage often occur before a response is seen. Human IV immunoglobulin (hIVIG) blocks Fc receptors on mononuclear phagocytic cells in dogs; it is used in people with idiopathic thrombocytopenic purpura.Hypothesis: The purpose of this study was to describe adverse effects and benefit of hIVIG in addition to conventional immunosuppressive therapy in dogs with severe IMT.Animals: Five client‐owned dogs with severe primary IMT.Methods: Case series. The hospital database was searched for dogs with primary IMT treated with hIVIG.Results: No adverse effects were noted during or after hIVIG infusion in any treated dog. Over a 6‐month follow‐up, all dogs were clinically normal when using conventional immunosuppressive therapy. Human IVIG was administered 3 days after initiation of immunosuppressive therapy in 4 dogs, and, after 2 days, in 1 dog. In all dogs, the mean platelet counts pre‐and 24 hours post‐hIVIG infusion (0.28–0.76 g/kg) were 2,500/μL and 50,600/μL (62,750/μL for the 4 responders), respectively. One dog failed to respond as promptly to hIVIG (0.34 g/kg), and the platelet count increased to 66,000/μL after 9 days of immunosuppressive therapy. The mean duration of hospitalization post‐hIVIG in all 5 dogs was 1.8 days (12 hours for responders), and the mean total length of hospitalization was 4.6 days (3.5 days for responders). Active hemorrhage resolved and no packed red blood cell transfusions were required after hIVIG infusion for responders.Conclusions and Clinical Importance: Human IVIG was well tolerated and appeared to be associated with rapid platelet count recovery and amelioration of clinical signs in most dogs with IMT.

Treatment of Severe Immune-Mediated Thrombocytopenia with Human IV Immunoglobulin in 5 Dogs

Glucocorticoids with or without other immunotherapy are the initial treatment of choice for dogs with severe immune-mediated thrombocytopenia (IMT). The majority of treated dogs will have improvements in platelet counts within 5 to 7 days of starting therapy, but complications from hemorrhage often occur before a response is seen. Human IV immunoglobulin (hIVIG) blocks Fc receptors on mononuclear phagocytic cells in dogs; it is used in people with idiopathic thrombocytopenic purpura. The purpose of this study was to describe adverse effects and benefit of hIVIG in addition to conventional immunosuppressive therapy in dogs with severe IMT. Five client-owned dogs with severe primary IMT. Case series. The hospital database was searched for dogs with primary IMT treated with hIVIG. No adverse effects were noted during or after hIVIG infusion in any treated dog. Over a 6-month follow-up, all dogs were clinically normal when using conventional immunosuppressive therapy. Human IVIG was administered 3 days after initiation of immunosuppressive therapy in 4 dogs, and, after 2 days, in 1 dog. In all dogs, the mean platelet counts pre- and 24 hours post-hIVIG infusion (0.28-0.76 g/kg) were 2,500/pL and 50,600/microL (62,750/microL for the 4 responders), respectively. One dog failed to respond as promptly to hIVIG (0.34 g/kg), and the platelet count increased to 66,000/microL after 9 days of immunosuppressive therapy. The mean duration of hospitalization post-hIVIG in all 5 dogs was 1.8 days (12 hours for responders), and the mean total length of hospitalization was 4.6 days (3.5 days for responders). Active hemorrhage resolved and no packed red blood cell transfusions were required after hIVIG infusion for responders. Human IVIG was well tolerated and appeared to be associated with rapid platelet count recovery and amelioration of clinical signs in most dogs with IMT.

Treatment of Immune-Mediated Thrombocytopenia Purpura with Concurrent IVIg and Platelet Transfusion: A Retrospective Review of 40 Patients.

Introduction: In January 2000, two patients with severe Immune-Mediated Thrombocytopenia (ITP) at our institution were successfully treated with prolonged infusions of IVIg and platelets. The dose of IVIg was 1 g/kg given by continuous infusion over 24 hours with concurrent platelets (1 pheresis unit every 8 hours). Based on these preliminary results, we evaluated this protocol in a larger series of 40 ITP patients.Methods: We performed an IRB-approved retrospective review of adult hospitalized patients with ITP treated with this regimen from January 2000 - December 2005. Patients with clinically significant thrombocytopenia and either active bleeding, need for anticoagulation, or requirement for a surgical procedure received the combined treatment. The subjects received IVIg and platelets as described above. Additional treatments, such as steroids, immunosupressives, or rituximab, as well as splenectomy were utilized at the discretion of the hematologist overseeing their care.Results: The average age of patients treated was 52 years. The majority of patients ranged from 20–80 years old, but 12.5% were older than 80 years. The average pretreatment platelet count was 10,000/μl, with an increase to 55,000/μl after 24 hours, and 69,000/μl after 48 hours. By 72 hours, the average platelet count had begun to decline, although the platelet count remained at an acceptable level (58,200/μl). After 24 hours, 62.7% of patients had a platelet count > 50,000/μl. Bleeding was controlled initially in all patients, and those requiring a procedure experienced no bleeding complications. Over half of the patients (52.5%) required additional treatments for recurrent or refractory ITP, and 32.5% of the patients underwent splenectomy. Six of the 21 patients requiring later retreatment (29%) received IVIg and platelets again in a similar fashion. The average retreatment platelet counts after 24 and 48 hours were 53,000/μl and 49,000/μl respectively, with clinical improvement in bleeding in all patients. No side effects of the combined treatment were noted. The response rates for the 3 IVIg products used were similar.Discussion: For ITP, IVIg and platelets are considered to be first line treatment for patients with very low platelet counts, active bleeding, or those requiring urgent procedures. There is limited literature on the optimal dose and schedule for administration of IVIg and platelets. Our approach for administration of IVIg and platelets concurrently was associated with minimal side effects, resolution of bleeding, ability to safely undergo procedures, and rapid restoration of adequate platelet counts. Additionally, elderly patients had equivalent benefit with no increased side effects, indicating that this regimen is appropriate and safe for patients of all age groups.

Anti‐HPA‐1a in a case of post‐transfusion purpura: binding to antigen‐negative platelets detected by adsorption/elution

Post-transfusion purpura (PTP) is a rare transfusion reaction almost exclusively observed in female patients. Affected patients develop severe immune-mediated thrombocytopenia in the course of a strong anamnestic alloimmune reaction against a platelet-specific antigen. The pathophysiology of thrombocytopenia has remained elusive. Immunological analysis in the HPA-1a-alloimmunized patient described in this report revealed an antibody with features considered typical of PTP: not only was anti-HPA-1a detectable in plasma, but it could also be eluted from the patients' (alloantigen negative) platelets, and anti-HPA-1a could be detected in eluates from both antigen positive and negative test platelets, which had been incubated in the patient's serum. This is in contrast to two sera with HPA-1a alloantibodies obtained from mothers of children with neonatal alloimmmune thrombocytopenia which were strictly HPA-1a specific. It is proposed that alloantibodies with HPA-1a-like specificity explain the patient's immune thrombocytopenia. The technique described in this report is proposed for further investigation, as it might be useful for discrimination of alloantibodes in PTP and alloantibodies of transfused thrombocytopenic patients.

Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs

To evaluate the effect of prednisone alone, compared with a combination of prednisone and vincristine, on platelet counts in bleeding dogs with severe primary immune-mediated thrombocytopenia (IMT). Prospective case study. 24 dogs with severe primary IMT PROCEDURE: All dogs received immunosuppressive doses of prednisone (1.5 to 2 mg/kg [0.7 to 0.9 mg/lb] of body weight, PO, q 12 h). In addition, 12 dogs received a single dose of vincristine (0.02 mg/kg [0.01 mg/lb], IV). Platelet count, transfusion requirement, and outcome were monitored. A response was defined as an increase in platelet count to > or = 40,000/microl. Dogs in the prednisone group that failed to respond received 1 dose of vincristine on day 7. Dogs that received prednisone and vincristine had a significantly faster increase in platelet count to > or = 40,000 platelets/microl than dogs that received prednisone alone (mean +/- SD, 4.9 +/- 1.1 vs 6.8 +/- 4.5 days, respectively). A similarly rapid response was observed in dogs that received vincristine on day 7 after treatment with prednisone alone failed. Furthermore, duration of hospitalization was reduced in the vincristine group, compared with the prednisone group (5.4 +/- 0.3 vs 7.3 +/- 0.5 days, respectively). No adverse effects attributable to vincristine were observed in any dog. Administration of combined vincristine and prednisone is associated with more rapid increase in platelet numbers and shortened duration of hospitalization in dogs with IMT, compared with use of prednisone alone. Early use of vincristine seems warranted in dogs with severe primary IMT.

GESTATIONAL THROMBOCYTOPENIA AND IMMUNE THROMBOCYTOPENIAS IN PREGNANCY

Appropriate management of thrombocytopenia in the pregnant patient is important for the well-being of both mother and fetus. The healthy-appearing mother with mild thrombocytopenia may have either gestational benign thrombocytopenia, which does not produce fetal thrombocytopenia, or immune-mediated thrombocytopenia, which can produce fetal thrombocytopenia. These two types of pregnancy-associated thrombocytopenias can be differentiated. Gestational benign thrombocytopenia is initially discovered during pregnancy, and in these patients a reliable test for antiplatelet antibody is usually negative. Conversely, patients with immune-mediated thrombocytopenia may have a history of thrombocytopenia before the pregnancy, and these patients usually have a detectable antiplatelet antibody. The pregnancy patient who presents with a normal platelet count and a history of neonatal alloimmune thrombocytopenia in a prior pregnancy or with a history of an infant of a close relative with NAT must be carefully monitored. Antiplatelet antibody assays performed on mother's and baby's blood will help determine if an antiplatelet antibody is present in maternal plasma, if the antibody reacts with the baby's platelets, and (with appropriate typing plasma) the antigenic specificity of the maternal and fetal platelets. In addition, antigenic typing of the father's platelets will help determine the risk of NAT in the current pregnancy. If a fetus is at risk for severe immune-mediated thrombocytopenia from either an autoantibody or an alloantibody, the fetal platelet count should be measured, if possible, from blood obtained by umbilical cord puncture. If the fetal platelet count is less than 50,000/microL or cannot be measured but is thought to have a high probability of being less than 50,000/microL, strong consideration should be given to a cesarean delivery.

The long-term use of zidovudine in patients with severe immune-mediated thrombocytopenia secondary to infection with HIV

Various treatments for HIV-related thrombocytopenia have been reported. Since etiologies of the thrombocytopenia may differ with regard to risk group treatment outcomes may also vary. We have recently studied the long-term use of zidovudine in individuals with sexually transmitted HIV infection and severe thrombocytopenia. Twenty-five men, median age 34 years (range, 23-51 years), were treated with zidovudine (1000 mg/day) for a median duration of 12 months (range, 2.5- less than 26 months). Nineteen patients (76%) had had episodes of symptomatic bleeding secondary to thrombocytopenia prior to study entry. All patients bleeding symptoms resolved with therapy. Six (24%) achieved a complete response, with normalization of platelet counts, while 11 patients (44%) achieved a partial response, giving an overall response rate of 68%. The median time to partial or complete normalization of platelet counts was 12 weeks (range, 4-62 weeks). Toxicities were minimal during the study period. Only one patient developed an AIDS-defining diagnosis while on therapy. We conclude that patients with sexually transmitted HIV infection and immune thrombocytopenia may need a prolonged period of therapy with zidovudine to achieve a platelet response. Other treatment modalities may be required for the 30% of patients who do not respond to zidovudine.