Successful treatment of refractory thrombocytopenia with mycophenolate mofetil in a patient with systemic lupus erythematosus

While mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently seen in the context of active disease, severe thrombocytopenia causing significant bleeding is not that common. Corticosteroids are considered the first line therapy for severe thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy have been reported to be effective for patients who fail to respond to steroids or those who require moderate doses of steroids to maintain the platelet counts. Recent randomized controlled studies have shown that mycophenolate mofetil (MMF) is an efficacious and safe therapeutic agent in patients with proliferative forms of lupus nephritis. However, little information has been available regarding the role of MMF in the treatment of immune thrombocytopenia complicated with SLE. Hereby I describe a patient with SLE in whom thrombocytopenia was refractory to corticosteroids, intermittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gamma globulin, danazol, and splenectomy, and whose platelet counts eventually normalized during therapy with MMF. In this patient, thrombocytopenia is initially thought to be associated with active SLE involving major organ. However, after immunosuppressive agents were given, the refractory nature of thrombocytopenia seems to be an isolated phenomenon, independently of SLE activity.     

One-day intravenous therapy with high-dose gamma-globulin for idiopathic thrombocytopenic purpura

The effects of one-day intravenous therapy with gamma-globulin in a 25-year-old man with idiopathic thrombocytopenic purpura are reported. The patient showed resistance to prednisolone and had bleeding tendency. The thrombocytopenia improved after the intravenous administration of gamma-globulin at a dose of 1 g/kg. Splenectomy was carried out. The results suggested that the usual dose of gamma-globulin is not always necessary. The half-dose increased the platelet count.     

Devic's syndrome and SLE: challenges in diagnosis and therapeutic possibilities based on two overlapping cases

Neuromyelitis optica (NMO, Devic's disease), an uncommon demyelinating neuro-immunological disease, can be associated with autoimmune diseases. In SLE associated forms anti-aquaporin-4 antibody positivity can help differentiating between SLE nerve system manifestation and NMO. In the literature rituximab, or immunoablative dose cyclophosphamide (CYC) was effective for the therapy resistant forms. Authors present 2 SLE overlapping NMO cases, one of them with SLE associated interstitial lung disease (ILD). In both cases neurological manifestations anticipated other SLE symptoms. Patients previously were treated with high dose corticosteroid therapy, plasmapheresis, and one of them with azathioprine, and the other one with oral CYC (which could not prevent flares). 0.5 g/m2 body-surface monthly parenteral inductive CYC therapy was administered, in one patient followed by quarterly maintenance therapy. This patient completed her 18 month maintenance treatment and has been in neurological remission, but required steroid pulse and plasmapheresis for lung symptoms. The second patient had urogenital infection after the induction phase, followed by an exacerbation, requiring plasmapheresis and high dose parenteral corticosteroid treatment. After it he refused CYC therapy and has been taking azathioprine. He has no new symptoms, only residual ones. In our two patients conventional dose CYC therapy proved to be effective for NMO/SLE overlap, required only transient supportive therapy.     

Treatment of ANCA-Associated Vasculitis, Where to Go?

The introduction of (oral) cyclophosphamide (CYC) in the treatment of ANCA-associated vasculitides (AAV) has strongly improved prognosis but the side effects of long-term CYC treatment are serious. A number of recent randomized controlled studies have shown that the cumulative dose of CYC can be strongly reduced in the treatment of AAV or even reduced to zero. Maintenance treatment can be performed with azathioprine (AZA), or methotrexate (MTX) in case of intolerance, although the intensity and duration of maintenance treatment is still under discussion. More insight into the mechanisms involved in relapsing disease might allow individualized treatment. Induction of remission can be achieved in cases of mild disease expression with MTX but requires maintenance treatment to prevent relapses. Generalized disease can be treated with pulses of i.v. CYC or, possibly, with MMF. However, recent studies demonstrate the efficacy of RTX in inducing remission without the concomitant use of immunosuppressives. Corticosteroids are part of treatment in all regimens but the intensity and duration of steroid treatment is still being discussed. In life-threatening disease, the adjunctive efficacy of plasma exchange has been demonstrated and its usefulness in less severe disease is under investigation. Taken together, there are, indeed, alternatives for CYC in AAV.     

Immunosuppressive drugs have different effect on B lymphocyte subsets and IgM antibody production in immunized BALB/c mice

Infections are frequently associated with immunosuppressive therapy currently used to prevent organ rejection or treat autoimmune diseases. Such drugs suppress antibody production despite having different mechanisms of action. Antibodies are produced by a non-homogenous population of B lymphocyte subsets. B-1 cells produce natural antibodies and protect immediately after infection, while B2 cells produce antigen-specific IgM antibodies in a later response to infection. To understand how the immunosuppressive drugs affect antibody production by B cell populations, we immunized BALB/c mice with different antigens followed by administration of various immunosuppressive drugs. B-1a and B-1b lymphocytes from spleens of sacrificed animals were analyzed by flow cytometry, natural and antigen –specific IgG and IgM antibodies were determined by nephelometry and ELISA assays. Results showed that prednisone (PDN), cyclophosphamide (CYC), methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) decreased more than 60% of B-1a lymphocytes while cyclosporine (CsA) had little effect. Three drugs PDN, AZA and CYC suppressed the B-2 cells on day 30, while MTX affected this subpopulation early on day 5. Antigen-specific IgM antibodies were dramatically suppressed after 15 days of immunization in animals receiving PDN, CYC or AZA, while MMF, CsA and MTX showed little effect. Natural antibodies were equally decreased in all animals regardless of the specific drug used in treatment. These results will help to choose single or combinations of immunosuppressive drugs in the clinical setting.     

FDA licensure of NEUMEGA to prevent severe chemotherapy-induced thrombocytopenia

This paper discusses background information and the body of clinical data that has been accumulated to demonstrate the efficacy and safety of NEUMEGA (recombinant human interleukin 11) when used to prevent severe chemotherapy-induced thrombocytopenia and reduce the need for platelet transfusions in patients with nonmyeloid malignancies. NEUMEGA is recommended to be used at a dose of 50 microg/kg s.c. once daily starting the day after chemotherapy ends until a platelet count of 50,000 cells/microl is achieved after the expected nadir.     

Yersinia enterocolitica infection complicated by severe thrombocytopenia resistant to high-dose intravenous immunoglobulin

A young female patient developed severe thrombocytopenia 10 days after an infection with Yersinia enterocolitica, serotype 3. She was treated with high-dose intravenous immunoglobulin without effect, and later corticosteroids also failed to induce remission. After 10 days of profuse bleeding the platelet count rose slowly to normal. Her tissue type was HLA-B27. To our knowledge, thrombocytopenia complicating Yersinia infection has not been reported before.     

The Efficacy of Mycophenolate Mofetil in Remission Maintenance Therapy for Microscopic Polyangiitis and Granulomatosis with Polyangiitis

PurposeThe present study compared the efficacy of mycophenolate mofetil (MMF) with that of azathioprine (AZA) in Korean patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).Materials and MethodsThe medical records of 69 patients with MPA and GPA who received cyclophosphamide and subsequently received AZA or MMF for remission maintenance therapy were reviewed. All-cause mortality, relapse, end-stage renal disease (ESRD), cerebrovascular accident, and cardiovascular disease were evaluated as poor outcomes. Having a lower Birmingham Vasculitis Activity Score (BVAS) was defined as the lowest tertile of BVAS (BVAS ≤11 in this study).ResultsIn comparative analysis of the occurrence of poor outcomes among patients taking AZA only, MMF only, and MMF after AZA, patients taking MMF only exhibited a significantly lower cumulative ESRD-free survival rate than patients taking AZA only (p=0.028). In terms of ESRD occurrence between the groups based on BVAS at diagnosis, among patients with MPA and GPA with higher BVAS at diagnosis, patients taking MMF only exhibited a significantly lower cumulative ESRD-free survival rate than those taking AZA only (p=0.047). Among patients with MPA and GPA with the lowest tertile of BVAS at diagnosis, cumulative ESRD-free survival rates did not differ.ConclusionWith regard to ESRD occurrence, the efficacy of MMF in remission maintenance therapy was less effective than AZA in patients with MPA and GPA. However, among patients with lower BVAS, there was no difference in the occurrence of poor outcomes between patients taking MMF and those taking AZA.     

Association between mean platelet volume levels and inflammation in SLE patients presented with arthritis

Background

Systemic lupus erythematosus (SLE) may be characterized by periods of remissions and chronic or acute relapses. The complexity of clinical presentation of the SLE patients leads to incorrect evaluation of disease activity. Mean platelet volume (MPV) has been studied as a simple inflammatory marker in several diseases. There is no study in the literature about MPV levels in adult SLE patients with arthritis.

Objectives

We aimed to investigate the MPV levels in the SLE population with arthritis during and between activations.

Methods

The study consisted of 44 SLE patients with arthritis in activation period (Group 1), the same 44 SLE patients with arthritis in remission period (Group 2) and 44 healthy controls (Group 3). Erythrocyte sedimentation rate (ESR), creactive protein (CRP), white blood cell count, platelet count, and mean platelet volume (MPV) levels were retrospectively recorded from patient files.

Results

The mean ages of the SLE subjects were 42 ± 16 years, while the mean ages of controls was 41 ± 17 years. MPV was significantly lower in Group 1(7.66±0.89fL) than in Group 2 (8.61±1.06 fL) and Group 3(8.62±1.11fL) (p<0.0001). The differences between groups reached statistical significance.

Conclusions

We suggest that MPV levels decrease in patients with arthritis of SLE activation when compared to the same patients in remission and healthy controls.     

Examination and treatment for dilutional thrombocytopenia

Massive transfusion is defined as transfusion of more than total blood volume within 24 hours. There are several adverse effects associated with massive transfusion, and dilutional thrombocytopenia is known as one of the major adverse effects. Dilutional thrombocytopenia is caused by platelet loss out of the body and platelet dilution with replaced red cells and crystalloids. Volume of blood loss or replaced volume is a good indicator of dilutional thrombocytopenia, and previous reports suggest that severe thrombocytopenia doesn't occur before replaced volume surpasses over one hundred and fifty percent of total blood volume. Recently, an automated blood cell counter has spread and platelet count is available in a short time, even at night. To treat the patient with dilutional thrombocytopenia, platelet count is very helpful to decide when to start platelet transfusion. When platelet count decreases as low as 50,000/mm3, platelet transfusion should be considered. Nowadays, dilutional thrombocytopenia is less frequent complications of massive transfusion than before, because platelet transfusion tends to be performed before platelet count fall to the critical point. Thus, exceeded platelet transfusion might become another problem after massive transfusion.     

Neonatal alloimmune thrombocytopenia due to anti-HPA-2b (anti-Koa)

Most severe cases of neonatal alloimmune thrombocytopenia (NAIT) are due to anti-HPA-1a (anti-PlA1) antibodies. We report a case of NAIT due to anti-HPA-2b that resulted in in utero intracranial hemorrhage.A 33-year-old G2P1A0 Caucasian woman had a routine ultrasound at 34 weeks. The fetus appeared to have a left hemispheric hematoma. IVIG, 1g/kg, was started immediately and administered weekly until delivery. One day after receiving the first dose of IVIG, fetal platelet count was 18 x 10(9)/L, and Hb was 116 g/L. Eleven mL of matched platelets compatible by monoclonal antibody immobilization of platelet antigens (MAIPA) assay were transfused in utero, raising the platelet count to 62 x 10(9)/L. Repeat transfusions were done later that week and 1 week later, with pretransfusion counts of 19 x 10(9)/L and 16 x 10(9)/L, respectively. Delivery by C section was done at 35.5 weeks, after the third platelet transfusion. Platelet count at birth was 77 x 10(9)/L. Drainage of the hematoma was performed after transfusion. Testing with a solid phase ELISA revealed reactivity against GP1b/IX. MAIPA testing after platelet treatment with the protease inhibitor leupeptin demonstrated the presence of anti-HPA-2b. On PCR-SSP the mother was HPA-2a homozygous, the father was HPA-2a/2b. Antibodies against the HPA-2b antigen located on the GP1b/IX complex have been reported in rare cases of NAIT. Testing is complicated by proteolytic degradation of the antigen-bearing fragment. Compatible platelets are easily found since approximately 85 percent of donors are HPA-2a/2a.     

Eurolupus cyclophosphamide plus repeated pulses of methyl-prednisolone for the induction therapy of class III,IV and V lupus nephritis

ObjectiveTo study whether adding repeated 125 mg methyl-prednisolone pulses (MP) to Eurolupus fortnightly intravenous cyclophosphamide (CYC) improves remission of lupus nephritis (LN) compared with recommended schedules.MethodsObservational comparative study of patients with biopsy-confirmed class III, IV or V LN: 30 in the mycophenolate (MMF) group, 25 in the CYC group and 38 in the CYC-MP group. The main efficacy outcome was complete response at 12 months.ResultsPatients in the CYC-MP group received lower doses of prednisone within 6 months (mean 8.5 mg/d, vs. 15 mg/d in the MMF group vs. 24 mg/d in the CYC group, respectively). The complete response rates at 12 months were: CYC-MP 86%; CYC 56%; MMF 47% (p = 0.002) at Pr/Cr <0.5; CYC-MP 86%; CYC 65%; MMF 63% (p = 0.07) at Pr/Cr ≤0.7. The cumulative 12-month response rates for the CYC-MP, CYC and MMF groups were, respectively, 0.90, 0.58 and 0.63 (p = 0.004). In the adjusted Cox model, patients receiving CYC-MP were more likely to achieve complete response at Pr/Cr <0.5 than those in the MMF (HR vs. CYC-MP 0.33, 95%CI 0.16-0.65) and the CYC groups (HR vs. CYC-MP 0.47, 95%CI 0.21-1.04). Glucocorticoid-related toxicity was seen in 2.6% of the CYC-MP group, 24% of the CYC group and 20% of the MMF group (p = 0.029).ConclusionThe addition MP of 125 mg to each fortnightly dose of 500 mg of CYC improves response rates and reduces the need for oral glucocorticoids in patients with class III, IV and V LN.     

The experience of Flebogammadif® in primary immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is a common autoimmune disease characterized by autoantibody-induced platelet destruction, suboptimal megakaryocytic production of platelets and consequent bleeding. Numerous controlled trials have proved that the administration of high-dose intravenous immunoglobulins (IVIG) results in rapid increases in the platelet numbers. Therefore, they are indicated in emergency settings or in patients needing surgical procedures. Here, the efficacy and safety of Flebogammadif?, a new high-purity IVIG, was assessed by an open, multi-centre, non-controlled, prospective study in 20 adult patients diagnosed with ITP for at least 6 months before recruitment and with a platelet count ≤ 20,000/μl before treatment. Patients received 0·4 g/kg/body weight of Flebogammadif? for 5 consecutive days and were followed-up for 3 months. There were three efficacy end-points: proportion of patients who reached a platelet count ≥ 50 000/μl; time for the platelet count to reach that level; and duration of response. Safety parameters [adverse events (AE), laboratory determinations and vital signs] and viral markers were monitored regularly. A total of 14 patients achieved a platelet count of ≥ 50,000/μl. The median time to platelet response was ≤ 2·5 days and the median number of days in which the platelet count remained ≥ 50,000/μl was ≥ 7·0 days. A regression of haemorrhages was reported for 17 patients on day 14. Eight patients presented 20 AEs (mainly mild) related potentially to the study drug. Neither abnormalities in laboratory values nor in viral markers were registered during the follow-up period. In conclusion, Flebogammadif? was well tolerated and succeeded in providing a haemostatic platelet count in ITP patients.     

Obstetric prognosis of the gestational thrombocytopenia

To define clinical outcomes of marked gestational thrombocytopenia (GT) (<100,000/mm3) we identified twenty-nine infants born to 28 pregnancies at 26 women with GT among 8,364 deliveries during the years 1993- 1999. Cordocentesis was performed in 7 mothers with platelet counts less than 75,000/mm3. Cord blood platelet count was checked in all cases at delivery. The most significant decrease of platelet count in pregnancy with GT was less than 50,000/mm3 in 6 pregnancies (21.4%) and between 50,000 and 100,000/mm3 in 22 pregnancies (78.6%). In pregnancies with GT, 2 neonates (6.9%) had mild thrombocytopenia and 1 neonate (3.4%) moderate thrombocytopenia. Severe thrombocytopenia was not observed in any neonate born to mothers with GT. There were no cases of coagulation disturbance at delivery or in the postpartum period. Fourteen cases for which follow-up was carried out recovered platelet counts to more than 100,000/mm3 within one month postpartum. Two patients who became pregnant twice noticed recurrence of GT. In conclusion, GT is not associated with bleeding diathesis in the mother, resolves spontaneously during the postpartum period, and can recur in subsequent gestations, and the association of severe fetal/neonatal thrombocytopenia is very rare. No intervention is necessary during pregnancy or delivery, apart from a careful maternal and fetal surveillance if there is no obstetric indication.     

Low dose intravenous immunoglobulin for acute immune thrombocytopenic purpura in children

Acute immune thrombocytopenic purpura (ITP) is a self-limited autoimmune disorder to platelets. The disease responds well to intravenous immunoglobulin (IVIG) treatment. We studied the efficacy of low dose (1 g/kg) IVIG to treat acute ITP in children. Of 17 children with ITP and platelet counts < 20,000/microl, 13 (76%) had rapid platelet count recovery, reaching safe level (> 50,000/microl) within 4 days after 1 g/kg IVIG. Four children needed a second dose. In 5 of 15 patients, platelet counts recovered to normal without recurrence, while in 10 patients, platelet counts declined again 2-3 weeks after the initial treatment; 6 of whom (40%) needed re-treatment. All but one patient had complete recovery of the platelet count by 6 months. Adverse effects of low dose IVIG were minimal. We recommend that for childhood ITP, 1 g/kg IVIG should be tried initially. If inadequate response is seen (platelet count < 30,000/microl) by 48 hours, a second dose is needed.     

Warfarin-Induced Penile Necrosis in a Patient with Heparin-Induced Thrombocytopenia

A 56-yr-old man with lung adenocarcinoma presented with subsegmental pulmonary thrombosis. Platelet count on presentation was 531×10⁹/L. The patient was anticoagulated with subcutaneous low molecular weight heparin (LMWH). Next day, oral anticoagulation was initiated with 5 mg of warfarin once daily with LMWH and LMWH was discontinued at third hospital day. On the third day of oral anticoagulation therapy, he complained of left leg swelling and prolonged painful penile erection of 24 hr-duration. His platelet count reached a nadir 164×10⁹/L at that time, and the patient had a deficiency of protein C and S, with an activity level of 16% and 20% of normal value. Warfarin was stopped and he underwent penile aspiration. The next day, left leg edema and penile erection was disappeared, but penile and glans penis necrosis was started. This case illustrates that processes underlying heparin-induced thrombocytopenia (HIT) may also underlie warfarin-induced skin necrosis.     

射频消融治疗顽固性免疫性血小板减少症

目的探讨脾脏射频消融术治疗顽固性免疫性血小板减少症（ITP）的安全性和有效性。方法回顾分析我院开展的国际首例脾脏射频消融治疗ITP的疗效。结果 1例43岁女性食管癌患者,经反复外周血计数、血涂片和骨髓穿刺等检查证实合并原发性重症ITP,其血小板计数小于（5~10）×109/L,经规范抗幽门螺旋杆菌治疗、静滴人免疫球蛋白、甲基强的松龙、长春新碱和输注血小板等治疗无效。患者接受腹腔镜下脾脏射频消融术治疗,术后第22天血小板计数恢复正常,无围手术期并发症;随访超过8个月,患者呈完全应答。结论脾脏射频消融术治疗顽固性ITP安全、有效,值得扩大临床试验进一步验证其疗效。     

Mycophenolate mofetil for lupus nephritis: an update

Renal disease in systemic lupus erythematosus carries significant morbidity and mortality. Intensive immunosuppression to dampen kidney inflammation timely and maintenance therapy to prevent renal flares is necessary to reduce the long-term risk of renal failure. Mycophenolate mofetil (MMF) has emerged to be the first-line treatment of lupus nephritis for its better safety profile compared with cyclophosphamide. In controlled trials, MMF is non-inferior to cyclophosphamide for induction therapy but is superior to azathioprine as maintenance therapy. Although biologics have shown promise in refractory lupus nephritis, combining MMF with a number of novel biological agents does not enhance the therapeutic efficacy. Recently, low-dose combination of MMF and tacrolimus has been shown to be more efficacious than intravenous pulse cyclophosphamide in inducing remission of lupus nephritis in Chinese patients. Therapeutic monitoring of the serum mycophenolic acid level to enhance the efficacy of MMF in lupus nephritis is being explored.     

Recombinant human thrombopoietin clinical development

Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia. This can be associated with significant bleeding; currently, it is treated with supportive platelet transfusions. Frequent platelet transfusions can cause alloimmunization which requires HLA-matched donors and more frequent blood transfusions, and transmission of both viral and bacterial infections via platelet transfusions remains a concern. Furthermore, thrombocytopenia can mandate a decrease in the dose intensity of cytotoxic therapy by causing either delays or dose reductions in therapy administration. An intervention that reduces the risk or shortens the duration of severe thrombocytopenia would represent an important medical advance. Thrombopoietin (TPO), a naturally occurring, glycosylated polypeptide that was cloned by Genentech in 1994, is capable of inducing differentiation of stem cells into megakaryocytes and accelerating the maturation of megakaryocytes, thereby increasing the platelet count. Recombinant human TPO (rHuTPO) is currently undergoing testing in phase 1 and 2 studies in patients receiving myelosuppressive or myeloablative therapy. For the purposes of illustration, preliminary safety and activity data from one ongoing phase 1 myelosuppression trial (rHuTPO in women with advanced gynecologic malignancies receiving carboplatin) and one ongoing phase 1 myeloablation trial (rHuTPO for peripheral blood progenitor cell mobilization prior to myeloablative chemotherapy for high risk breast cancer) will be presented.     

Thrombopoietic activity of recombinant human interleukin-11 in nonhuman primates with ACNU-induced thrombocytopenia.

The effect of recombinant human interleukin-11 (rHuIL-11) on myelosuppressive nimustine (ACNU)-induced thrombocytopenia was assessed in nonhuman primates. A single intravenous (i.v.) injection of ACNU (15 mg/kg) was administered to cynomolgus monkeys on day 0. rHuIL-11 (100 microg/kg/day) or the vehicle was given subcutaneously (s.c.) from day 1 to day 21. In monkeys receiving ACNU, the circulating platelet count decreased to a low of 42 +/- 6 x 10(9)/L by day 21 but returned to pretreatment levels (375 +/- 48 x 10(9)/L) on day 30. Administration of rHuIL-11 prevented severe thrombocytopenia; the platelet count fell only to 138 +/- 23 x 10(9)/L on day 18, and platelet recovery was faster (458 +/- 91 x 10(9)/L by day 27) compared with that of the control animals. The size of bone marrow megakaryocytes from rHuIL-11-treated animals was larger than that of the controls, indicating that rHuIL-11 stimulated megakaryopoiesis in a myelosuppressive condition. Treatment with ACNU also caused leukopenia and moderate anemia. rHuIL-11 transiently and slightly decreased the white blood cell (WBC) and red blood cell (RBC) counts. Conversely, rHuIL-11 accelerated recovery of RBC count in the late administration period. These results support the assertion that rHuIL-11 may be an important therapeutic agent for reducing the severity and duration of thrombocytopenia following cancer chemotherapy.