Significance of intravenous immunoglobulins to the neonate born of a mother with idiopathic thrombopenic purpura

High dose gammaglobulin therapy for pregnant women with idiopathic thrombocytopenic purpura may be suitable for both mother and foetus during pregnancy. A newborn with severe thrombocytopenia secondary to maternal illness, was treated successfully by intravenous gammaglobulin, without toxicity. In such a case, we believe the platelet count is not the only criterion for starting immunoglobulin therapy.     

Danazol in chronic idiopathic thrombocytopenic purpura resistant to corticosteroids

16 patients (11 women and 5 men) with chronic idiopathic thrombocytopenic purpura (ITP) were treated for 3-6 months with Danazol in a daily dose of 300 mg. In 6 women and 1 man an increase in blood platelet count was observed and in all but 2 patients clinical symptoms of haemorrhagic diathesis disappeared. The platelet factor 3 availability and circulating immune complexes level determined before and after 2 months therapy disclosed normalization of both tests in the majority of patients. This amelioration in immunological tests in several, but not in all patients, coincided with platelet count increase. Side-effects were negligible. The authors conclude that Danazol may be of valuable in the management of chronic refractory to corticosteroids ITP patients and that its possible mechanism of action may be an interaction with the immunologic pathways of blood platelet destruction.     

High-dose intravenous therapy with immune globulin before delivery for idiopathic thrombocytopenic purpura.

A 15-year-old girl with a 9-year history of idiopathic thrombocytopenic purpura resistant to high-dose steroid therapy and to splenectomy was admitted to hospital at 35 weeks'' gestation with a platelet count of 10 X 10(9)/L. The bleeding time was normal, and measures of platelet aggregation were nearly so. Treatment with high intravenous doses of polyvalent immune globulin led to a rise in the platelet count to more than 110 X 10(9)/L within 5 days. An elective cesarean section was performed through the lower uterine segment with good hemostasis. After delivery the platelet count fell to its former level, but no postpartum bleeding occurred. There was a brief episode of thrombocytopenia in the infant, with some petechiae but no other hemorrhagic manifestations. No untoward effects of the immune globulin infusion were observed in either mother or daughter.     

High dose intravenous immunoglobulin repertoire versus anti-D. Disproportions in quantity and quality.

Here we consider certain therapeutic effects that intravenous administration of pooled high dose immunoglobulin and anti-D IgG share. Despite million-fold difference in doses such an effect occurs at least in idiopathic thrombocytopenic purpura (ITP). We postulate that spontaneous bleeding events may remit even when platelet numbers show refractoriness. We also mention the possible sparing of anti-D antibody-coated red blood cell (RBC) destruction and, finally, an acceleration of fibrotic involution. Fc receptors (FcRs) play a central role; beyond the well-established interactions with the immunoglobulin Fc fragment, FcRs are supposed to display special cognitive properties that enable them to pick out the therapeutic molecules from the recipient's IgG pool. Such subtle selection suggests some disarray in the host. On the other hand it may explain why the often-encouraging outcome of IVIG therapy remains unpredictable.     

Megakaryocytes and thrombocytopoiesis in idiopathic thrombocytopenic purpura

In idiopathic thrombocytopenic purpura (ITP) patients with histological signs of stronger auto-antibody synthesis (spleen follicle hyperplasia) more frequently revealed megakaryocyte changes due to antibodies and less frequently thrombocyte production compensatory increased than ITP patients with signs of weaker auto-antibody synthesis (spleen follicle normoplasia). The observation suggest that insufficient and frequently lacking compensatory increase of thrombocyte production in ITP is caused by an autoallergic disturbance of megakaryocyte maturation.     

Thrombocytopenia after autologous bone marrow transplantation in in acute lymphatic leukemia]

There is reported about the treatment of refractory thrombocytopenia in a 9 years old boy following the autologous bone marrow transplantation for acute lymphoblastic leukaemia. The megakaryocytes were found diminished in the bone marrow smears. Controls of the thrombocyte count and the kinetics with radioactively labeled platelets of a donor spoke in favour of immunothrombocytopenia. Threatening bleeding complications challenged the use of all treatment possibilities. The irradiation of the spleen was without any success. After the splenectomy the thrombocyte count increased slowly, but after a remarkable lag phase, however. A diminished reproduction capacity of the bone marrow graft for special cell sorts has to be taken into account in such cases. The usual cytodynamics after splenectomy cannot be expected at all.     

Long-term prognosis of the results of splenectomy in idiopathic thrombocytopenic purpura

The value of selected clinical and histological parameters for the prognosis of long-term results of splenectomies was investigated retrospectively in 50 patients with idiopathic thrombocytopenic purpura 4-14 years after surgery. Two parameters showed an association to the results of splenectomy, viz. spleen follicle size as well as site of thrombocytopenia degradation. Non-responders to splenectomy (n = 7) only turned up in spleen follicle hyperplasia, never in follicle normoplasia, however (p less than 0.01), four times more frequently in mainly extralienal thrombocyte degradation, also in predominantly lienal ones (p greater than 0.05).     

Fatal outcome of acute thrombocytopenic purpura associated with a viral infection in an 11-year-old child

A case of fatal intracranial hemorrhage is reported in an eleven year old girl with acute idiopathic thrombocytopenic purpura following a viral infection. The patient was randomized to the IgG-arm of the ITP therapy study. Immunoglobulin administration was not followed by a raise of the thrombocyte count. Neither the IgG therapy nor intensive therapeutic measurements were able to prevent the fatal course of cerebral hemorrhage in this case. Pathological and immunological findings indicate that our patient suffered from a fulminant ITP which must be considered as a part of a still active viral disease.     

Idiopathic thrombocytopenic purpura in pregnancy and neonatal period

In pregnancy and neonatal period both mother and child are endangered by bleeding complications due to maternal idiopathic thrombocytopenic purpura. Obstetrical and perinatal management therefore must aim at increasing maternal and fetal platelet count. In our paper six patients in nine pregnancies are reported. Two of them (five pregnancies) were treated with corticosteroids, four of the patients were successfully treated with i.v. immunoglobulins (IgG). Longterm steroid application and splenectomy during pregnancy may be hazardous for mother and fetus. IgG i.v. administration in contrast offers a new and safe way to control maternal and fetal platelet counts during pregnancy, delivery and the neonatal period.     

Intravenous immunoglobulin (i.v. IgG) for previously treated acute or for chronic idiopathic thrombocytopenic purpura (ITP) in childhood: a prospective multicenter study

In a prospective multicenter study 42 thrombocytopenic (less than 30 X 10(9) platelets/l) children with chronic idiopathic thrombocytopenic purpura (ITP) or with acute ITP, dependent on or refractory to corticosteroids, were given 0.4 g i.v. IgG/kg body weight/day on 5 consecutive days and thereafter once a week if the platelet count fell to less than 20 X 10(9)/l or if the patient bled. After the initial 5 days of i.v. IgG the platelets rose within a mean of 7-8 days to greater than 30 X 10(9)/l in all and to greater than 150 X 10(9)/l in 33 of 42 patients (79%). After a mean observation time of 26.6 months 26 of 42 patients (62%) showed a satisfactory long-term effect, i.e. no need for treatment for at least 6 months without bleeding and with no platelet counts below 20 X 10(9)/l. No difference in response rate was found between children with chronic and those with previously treated acute ITP. These results indicate that i.v. IgG could be used to control emergency situations, e.g. to stop bleeding or to prepare a patient for surgery. I.v. IgG also represents a good alternative to treatment modalities, such as splenectomy and/or the administration of cytostatic immunosuppressants with potentially serious side effects. In addition to the expected transient rise in serum IgG levels, i.v. IgG induced a more prolonged elevation of serum IgM. Platelet associated IgG, elevated before therapy, was correlated with the clinical long-term outcome.     

Slow infusions of vinblastine in the treatment of adult idiopathic thrombocytopenic purpura: a report on 43 cases

Forty-three adult patients with idiopathic thrombocytopenic purpura (ITP) were treated by slow intravenous infusions of vinblastine. Nineteen had ITP of recent onset (i.e. of less than 6 months duration) and had contraindication to steroids (3 patients), refractoriness to steroids (6 patients) or to steroids and high dose intravenous immunoglobulins (IVIg, 10 patients). Of the 19 patients, 10 achieved complete response (CR), 2 achieved partial response (PR), 2 had minor response (MR) and the remaining 5 patients had no response (NR). Six of the complete responders remained in CR after 12 to 48 months, whereas all other responders relapsed within 3 months, in spite of maintenance therapy. Twenty-four patients had chronic ITP (i.e. of 6 months duration or more) and had showed no or only transient response to steroids and/or splenectomy, and in many of them, to other therapeutic approaches. Four achieved CR, 4 PR, 6 MR and 10 NR. All but 3 responses were shorter than 3 months, in spite of maintenance therapy. Most responses to slow infusions of vinblastine began after the first infusion. Main side effects included leukopenia in 9 patients (but with absolute neutropenia in only one) and peripheral neuropathy in 2 patients. Interval from diagnosis was the only prognostic factor of response to treatment. We conclude that slow infusions of vinblastine may be a useful approach in ITP of recent onset, when contraindication or refractoriness to steroids and/or IVIg exists. In our experience, this treatment has limited benefit in chronic ITP. In addition, it remains to be demonstrated that slow infusions of vinca alkaloids have any superiority over intravenous bolus injections of the same drugs.     

A patient with Graves' disease who developed hypothyroidism associated with thyroid stimulation blocking immunoglobulin during anti-thyroid drug therapy

A girl, 12 years of age, developed Graves' disease compounded with rheumatic fever and idiopathic thrombocytopenic purpura. Thrombocytopenia improved under short-term treatment with steroids and her mitral valvular insufficiency, due to the rheumatic fever, disappeared 4 years later. Initially, she had been treated with propylthiouracil (PTU) for 28 months. She suffered a relapse 9 months after stopping PTU and so she was given further PTU therapy. However, hypothyroidism developed 11 months after the initiation of therapy and continued, though further PTU treatment was discontinued. She now receives 1-thyroxine and maintains a euthyroid state. At the onset of the patient's hyperthyroidism, the TSH-binding inhibitor immunoglobulin (TBII) and the thyroid stimulating antibodies (TSAb) were found to be positive. During the remission period, only the thyroid stimulation blocking immunoglobulin (TSBI) was weakly positive. At relapse, only TBII was mildly positive. When hypothyroidism developed, both TBII and TSBI were positive, and TSAb was negative in all testings of her diluted IgGs. The patient's TBII and thyroid dysfunction were unaffected by high-dose intravenous gammaglobulin therapy or by treatment with prednisolone 0.5 mg/kg/day for 2 weeks. In conclusion, the emergence of TSBI during or after anti-thyroid drug therapy might possibly lead to hypothyroidism in patients with Graves' disease.     

特发性血小板减少性紫癜与巨细胞病毒、EB病毒感染相关性

目的：探讨小儿特发性血小板减少性紫癜（ITP）与巨细胞病毒、EB病毒感染的关系。方法：实验组：48例确诊断为ITP患儿,对照组：44例同期呼吸道感染患儿,应用酶联免疫吸附法（ELISA）对两组小儿外周血进行巨细胞病毒IgM抗体（HCMV-IgM）、EB病毒感染IgM抗体（EB-IgM）检测。结果：48例ITP患儿中HCMV-IgM抗体阳性者20例,阳性率为41.67%,明显高于对照组,两组之间差异有显著性（P〈0.01）;EBV-IgM抗体阳性者14例,阳性率为29.17%,明显高于正常对照组,两组之间差异有显著性（P〈0.05）。结论：1、巨细胞病毒感染是引起特发性血小板减少性紫癜的重要原因之一,且通过临床观察巨细胞病毒感染引起的ITP患儿病情重,病程长,治疗时间长,转为慢性ITP的可能性大;2、EB病毒感染可能是引起特发性血小板减少性紫癜的原因之一,并且EB病毒感染引起的特发性血小板减少性紫癜病情也偏重。     

Hemophilia and thrombocytopenia in a patient with impaired cellular immunity. A case report

ITP in hemophiliacs may produce severe bleeding complications. We here report on an eight-year-old boy suffering from severe hemophilia A, who developed ITP and an acquired impaired immune function similar to AIDS. Steroid therapy reverted the thrombocyte count to normal, however it had to be discontinued because of a severe Cushing syndrome. The thrombocytopenia also responded to IgG-therapy and the patient is treated with a long term schedule according to Imbach. It is of interest that the impaired T-helper/T-suppressor cell ratio (0.45) improved to a value of 1.0 after initiation of this therapeutic regimen. We conclude from our observation that i.v. immunoglobulin therapy is of particular value for the treatment of ITP in patients with impaired cellular immunity.     

血浆置换及血小板输注治疗特发性血小板减少性紫癜疗效观察

摘要 目的：探究血浆置换及血小板输注治疗特发性血小板减少性紫癜疗效。方法：选择2016年2月至2019年1月于我院接受治疗的60例特发性血小板减少性紫癜患者为研究对象,按照其选择治疗方式的差异将其分为血小板输注组（20例）及血浆置换（Plasma exchange,PE）组（40例）,对比两组患者治疗有效率、治疗前后血细胞计数变化情况以及治疗中各类不良反应发生情况。结果：血小板输注组患者治疗显效数10例,有效数6例,总有效率80.00 %,PE组患者治疗显效数27例,有效数12例,治疗总有效率97.50 %,PE组治疗总有效率高于血小板输注组（P<0.05）。与治疗前比较,PE组患者的PLT、RBC计数和Hb水平出现了明显的升高,WBC计数出现明显的下降（P<0.05）,血小板输注组PLT、RBC计数和Hb水平也出现明显升高,WBC计数水平出现下降（P<0.05）,但组间比较显示治疗后PE组患者上述指标均优于血小板输注组（P<0.05）。血小板输注组患者不良反应总发生人数为4人,不良反应总发生率为20.00 %,PE组总不良反应发生人数3人,不良反应总发生率为7.50 %,PE组不良反应总发生率明显低于血小板输注组（P<0.05）。结论：血血浆置换及血小板输注治疗均对特发性血小板减少性紫癜具有较好的治疗效果,能够显著改善患者血细胞计数异常情况,但血浆置换治疗安全性更高。     

Clinical effect and some pathogenic mechanisms of high dose monomeric IgG therapy in childhood chronic idiopathic thrombocytopenic purpura

8 children with chronic idiopathic thrombocytopenic purpura received a high dose therapy with monomeric IgG. Before and after the treatment immunological investigations were carried out. All the children showed a positive clinical response, in 5 children there was an increase of thrombocytes to 111-340 X 10(9)/l. A clinico-haematological effect could be shown in those children with an increased percentage of marrow megakaryocytes with IgG fixed on the membrane before treatment. There was no haematological effect neither in cases with fixed IgG and IgA nor IgM and IgA combined, as well as in the case when there was no fixed IgG on the membrane. A steady clinical effect was provided if the number of bone marrow megakaryocytes with fixed IgG reached the norm. The suppression of the synthesis of antithrombocytic antibodies of the same immunoglobulin class can be regarded as a specific mechanism of high IgG doses.     

Determination of antiplatelet antibodies on the surface of platelets by direct radioimmune method in patients with different types of immune thrombocytopenia

Direct radioimmune assay (RIA) have been developed for detection of antibodies associated wild platelet membrane. Platelets from 12 patients with idiopathic thrombocytopenic purpura (ITP) and 27 patients with chronic lymphocytic leukemia (CLL) (platelet count (100,000 in 1 microliters) have been tested. Antibodies on platelets surface have been detected in all 12 patients with ITP and in 21 patients with CLL. In 6 CLL patients the number of immunoglobulins associated with platelets surface does not increase control level. It is possible, that in some CLL patients development of thrombocytopenia is mediated not only by platelet associated antibodies but by other mechanisms, one of which can be linked with the depression of megakaryocytes growth in bone marrow. Direct RIA for measurement of antibodies on platelet surface detect antiplatelet antibodies with higher frequency than indirect enzyme-linked-immunosorbent-assay (ELISA), developed earlier for assessment of antiplatelet antibodies in serum. Increase of platelet count in CLL patients after steroid and cytostatic treatment correlated with the decrease of platelet surface associated antibodies.     

Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure, mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case

Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (>5 μg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case.     

Transient deficiency of peripheral blood accessory cells in supporting T cell mitogenesis in patients suffering from chronic idiopathic thrombocytopenic purpura after intravenous gammaglobulin treatment

Mitogenic response of blood lymphocytes to phytohemagglutinin (PHA) and to OKT3 monoclonal antibodies was investigated in 7 patients suffering from chronic idiopathic thrombocytopenic purpura (ITP) before, during and after high-dose intravenous (i.v.) immunogammaglobulin (IgG) infusion. The platelet count rose above the pre-treatment values during infusion therapy in all patients but one. Five out of seven patients presented elevated platelet-associated IgG (PA-IgG) levels at the time of the first infusion; four of these showed an increase in platelet count and a transient reduction or normalization of PA-IgG after IgG infusion. Five out of seven patients showed an impairment of T lymphocyte mitogenic response to PHA and OKT3 before therapy. All patients responded to IgG therapy with a transient deficiency of FcR mediated monocytes (Mo) in supporting T cell mitogenesis induced by both mitogens during and after IgG infusion. This reduced cooperative capability of Mo disappeared at various times after the end of therapy (range 3-12 days). The transient alteration of Mo function, possibly due to a modification in the surface number or in the affinity of Fc-receptors, can explain in part, the increase in platelet count during and after IgSRK infusion.     

Red cell sequestration during high dose intravenous immunoglobulin in idiopathic thrombocytopenic purpura

The cellular interactions involved in the platelet response after immunoglobulin infusion in acute and chronic idiopathic thrombocytopenic purpura (ITP) are unknown. There have been a number of theories including the competitive inhibition of platelet-binding to macrophages by the preferential sequestration of immunoglobulin coated red cells. We report a study to examine this hypothesis. Adult acute and chronic patients were given infusions of immunoglobulin at a rate of 0.4 g/kg body weight, daily for 5 days. Serum haptoglobin, lactate dehydrogenase and the absolute reticulocyte counts were monitored and no significant change in any value was seen during the period of study. A red cell survival was performed on four of the patients and no increase in the rate of red cell clearance occurred during the infusion period. We conclude from this that in these patients no significant degree of haemolysis was provoked by the infusion although this does not preclude this as a mechanism of action in some individuals.