Peak Platelet Count Research Articles

A Randomized, Double-Blind, Placebo-Controlled Study With Pegylated Recombinant Human Megakaryocyte Growth and Development Factor (PEG-rHuMGDF) as an Adjunct to Chemotherapy for Adults With De Novo Acute Myeloid Leukemia

AbstractTo determine the safety, biologic, and clinical benefits of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF; Amgen, Thousand Oaks, CA) after myelosuppressive chemotherapy in acute myeloid leukemia (AML), 108 adult patients with de novo AML were randomized to receive either PEG-rHuMGDF (2.5 μg/kg/d or 5 μg/kg/d) for up to 21 doses (group A), a single dose of 2.5 μg/kg PEG-rHuMGDF, 7 daily doses of 2.5 μg/kg PEG-rHuMGDF (group B), or placebo. The greatest biologic activity was seen in group A with a median peak platelet count of 1,084 × 109/L, occurring at a median 9 days after the last dose of study drug, compared with 517 × 109/L and 390 × 109/L in group B and placebo group, respectively. Thrombocytosis (platelets >1,000 × 109/L) was seen at rates of 52%, 8%, and 9% in groups A, B, and placebo, respectively, but were not associated with any adverse event. There was no effect on median time to transfusion independent platelet recovery (≥20 × 109/L). The median time to neutrophil recovery (≥500/μL) and red blood cell transfusion requirements were similar in all groups, and there was no apparent stimulation of leukemia. PEG-rHuMGDF was biologically active and well tolerated. Further investigation of dose and scheduling is required, specifically earlier dosing before and during chemotherapy.

Exogenous control of cardiac gene therapy: Evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transfer of expression cassettes containing corticosteroid response element promoters

Objective: Because of the relative inaccessibility of the heart for repeated gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector. Incorporation into the vector of a regulatable promoter that is responsive to pharmacologic agents that are widely used and well tolerated in clinical practice represents such a control strategy. Methods: A replication-deficient adenovirus or an adeno-associated virus containing a chimeric promoter composed of 5 glucocorticoid response elements and the murine thrombopoietin complementary DNA (AdGRE. mTPO or AAVGRE. mTPO) was administered to the hearts of Sprague-Dawley rats. Platelet levels were evaluated as a reporter of transgene activity with or without dexamethasone. For comparison, rats received a control adenovirus vector, AdCMV. mTPO or AdCMV.Null, and the control adeno-associated virus vector AAVCMV. luc, which encodes for the firefly luciferase (luc) gene. Results: Platelet elevation in the AdGRE. mTPO group peaked 4 days after dexamethasone administration, with a return to baseline 1 week after the initial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGRE. mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respect to baseline without diminution with subsequent dexamethasone administrations out to 169 days. In contrast, the AdCMV.Null and AAVCMV. luc groups demonstrated no increase in platelet counts and the AdCMV. mTPO group demonstrated a slow rise to a single peak platelet count independent of dexamethasone administration. Conclusion: It may be possible to control on demand the expression of a gene transferred to the heart. This strategy should be useful in cardiac gene therapy. (J Thorac Cardiovasc Surg 1999;118:26-35)

Postoperative Thrombocytosis after Coronary Artery Bypass Grafting: A Potential Danger even after Hospital Discharge

Objective: Thrombocytosis (platelet counts >400 × 10³/mm³) following coronary artery bypass grafting has been described to occur frequently (20–30%) and to be associated with thrombotic complications postoperatively. The purpose of the present study is to establish when the peak value of platelet count occurs, and how high it is, as well as to determine the duration of thrombocytosis. Methods: Thirty consecutive patients undergoing elective coronary artery bypass grafting, who subsequently developed postoperative thrombocytosis (group 1) were considered for the study. Another 30 patients with platelet counts within normal limits postoperatively served as controls (group 2). Platelet count was monitored on a weekly basis during 5 weeks postoperatively. Patient characteristics, operation data and cardiopulmonary bypass data in group 1 did not differ from group 2 patients, except for a higher incidence of hyperlipidemia, i.e., 97% (29/30 patients) in group 1 compared to 40% (12/30) in group 2 (p < 0.001). Results: Neither deaths nor nonfatal myocardial infarctions occurred during the study period. Postoperative thrombocytosis was diagnosed on 6.1 ± 1.5 days postoperatively, and peak platelet count reached 14 ± 4.0 days postoperatively (6–21 days). The highest platelet count observed was 905,000/mm³. Platelet counts returned to normal values within 5 weeks. Three late vein graft occlusions occurred in all groups, and thus coinciding with the maximum platelet count observed. Conclusions: Postoperative thrombocytosis is a potentially dangerous complication, with an increased risk for vein graft occlusion. Postoperative thrombocytosis, when it occurs, is diagnosed around the 6th postoperative day, reaches its peak 2 weeks postoperatively and may last as long as 5 weeks. Close surveillance of patients with postoperative thrombocytosis is emphasized.

Partial splenic embolization in five children with hypersplenism: effects of reduced-volume embolization on efficacy and morbidity.

To evaluate the effects of reducing the volume of spleen infarcted during partial splenic embolization (PSE) for treatment of hypersplenism in children. Five children with hypersplenism underwent embolization of 30%-40% of the splenic volume. The results were compared with those of a previous study of 70%-80% PSE performed in 17 children. The hospital stay after the procedure was reduced from 16.0 days +/- 8.0 to 6.6 days +/- 5.6. The febrile period decreased from 15.0 days +/- 8.1 to 5.0 days +/- 6.6. The peak white blood cell count was 8,300/mm3 +/- 4,600 (8.3 x 10(9)/L +/- 4.6) versus 19,400/mm3 +/- 7,800 (19.4 x 10(9)/L +/- 7.8) in the earlier study. The peak platelet count was 153,000/mm3 +/- 65,000 (153 x 10(9)/L +/- 65) versus 636,000/mm3 +/- 406,000 (636 x 10(9)/L +/- 406). The platelet count after a mean follow-up of 14 months was 70,000/mm3 +/- 7,000 (70 x 10(9)/L +/- 7) versus 230,000/mm3 +/- 62,000 (230 x 10(9)/L +/- 62) after a mean follow-up of 45 months. The frequency of variceal hemorrhage decreased from 3.5 to 0.5 episodes per year. The frequency of epistaxis decreased from 30 to 15 episodes per month. Reduced-volume embolization decreased morbidity. All patients maintained a platelet count above baseline, and no patient required repeat embolization.

Transient Low T Cell Response to Streptococcal Pyrogenic Exotoxin-C in Patients with Kawasaki Disease

Superantigens (SAs) are known to induce transient anergy followed by T cell activation. Recent reports have suggested that SAs are involved in the pathogenesis of Kawasaki disease (KD). In the present study, we investigated the peripheral T cell response to SAs by measuring proliferation and IL-2 production to determine whether the T cell anergy is induced by SAs in patients with KD. T cells were obtained from 45 Japanese patients with KD in different stages of the disease and were stimulated by streptococcal pyrogenic exotoxin (SPE)-A, SPE-C, and toxic shock syndrome toxin-1 (TSST-1). T cells from patients with KD in the acute or convalescent stage up to 2 mo showed significantly lower proliferation and IL-2 production than did T cells from healthy control subjects stimulated by SPE-C, but not SPE-A or TSST-1. The T cell response to SPE-C normalized within 1 y. The low T cell response to SPE-C in the acute stage correlated with a peak platelet count and the C-reactive protein-positive period. These findings suggest that the transient low T cell response to SPE-C in patients with KD may have been related to SA-induced anergy or disappearance of SPE-C-responding cells from the circulation. The present results suggested that SPE-C may be involved in the pathogenesis of KD.

Effects of Mpl ligands on platelet production and function in nonhuman primates.

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates dose-dependentbyinducing megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human TPO, nonpegylated or pegylated recombinant human megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover), platelet TPO receptor density, and marrow megakaryocyte volume, ploidy, number and mass. Mpl ligand therapy sustains normal peripheral platelet concentrations following myelosuppressive chemotherapy in baboons and corrects peripheral platelet counts in HIV-infected chimpanzees with severe thrombocytopenia. Whereas Mpl ligands do not directly induce platelet aggregation in vitro, they enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo following treatment with Mpl ligands. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the direct effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.

Oral high‐dose methylprednisolone and intravenous immunoglobulin treatments in adult chronic idiopathic thrombocytopenic purpura

Ten adult patient of chronic idiopathic thrombocytopenic purpura (CITP) used oral prednisone and were treated with seven doses of oral high-dose methylprednisolone (30 mg/kg). Nine of ten patients responded after HDMP treatment (plt > 150 × 109/L). Two patients having 8 and 10 years of history achieved long-term remission after first HDMP treatment. One unresponsive and one responsive patients did not accept IVIG treatment as second therapy and lost the follow-up. The remaining six patients received IVIG (0.5 mg/kg for 5 days) as second therapy after 3 months. Platelet count increased above 150 × 109/L in 4 patients and between 60–80 × 109/L in 2 patients. The peak platelet counts of both therapy users were higher under HDMP than IVIG therapy (252 ± 110.4 vs 174.2 ± 83.7 × 109/L), but the difference was not significant. Responses were transient and returned to pretreatment values at 14–30 days, excluding long-term remission of 2 (2/10) patients after HDMP treatment. No side effect was observed. Thus, oral HDMP appears a good initial therapy for continuous remission in a small ratio of patients and a good security for emergency situations and prior to surgery in adult CITP patients. Am. J. Hematol. 56:191–192, 1997. © 1997 Wiley-Liss, Inc.

Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocyte colony formation and platelet production. It is likely to be useful in the management of severe thrombocytopenia. To determine its clinical activity and safety, we gave it to patients with advanced cancer before chemotherapy. Patients were randomly assigned to receive either PEG-rHuMGDF or placebo in a three to one ratio. PEG-rHuMGDF was given at a dose of 0.03, 0.1, 0.3, or 1.0 microgram/kg body weight. The study drug or placebo were administered daily by subcutaneous injection for up to 10 days or until a target platelet count was reached. 17 patients, median age 59 years, received either PEG-rHuMGDF (13 patients) or placebo (four patients). PEG-rHuMGDF produced a dose-dependent increase in platelet counts. Patients given placebo. 0.03, and 0.1 microgram/kg of PEG-rHuMGDF had median increases in platelet counts of 16%, 12%, and 39%. Those receiving 0.3 and 1.0 microgram/kg of PEG-rHuMGDF had an increase in blood platelets of between 51% and 584%. Platelets rose from day 6 of PEG-rHuMGDF administration and continued to rise after stopping the drug. The platelet count peaked between days 12 and 18 and remained above 450 x 10(9)/L for up to 21 days. There were no alterations in white-blood-cell count or haematocrit, and low toxicity. Platelets taken from patients during PEG-rHuMGDF administration and at the time of peak platelet count were morphologically and functionally normal. The potency with which PEG-rHuMGDF stimulates platelet production and its low toxicity indicate that this is likely to be a useful agent for the management of thrombocytopenia.

Recovery of respiratory function in survivors with paraquat intoxication.

The purpose of this study was to investigate chest radiograms and respiratory function changes, including pulmonary function tests and alveolar-arterial oxygen difference, in survivors with paraquat intoxication. Chest radiograms and pulmonary function tests for 21 paraquat-poisoned patients were performed 10 d after paraquat intoxication; 3 mo later, the tests were repeated in 16 patients who survived. Forced vital capacity, forced expiratory volume in 1 s, diffusing capacity of the lung, and alveolar-arterial oxygen difference were compromised after paraquat intoxication. Forced expiratory volume in 1 s and forced vital capacity correlated significantly with initial platelet counts (r = .453 and .443, respectively) 10 d after intoxication. The alveolar-arterial oxygen difference also correlated significantly with peak serum total bilirubin concentrations (r = .443) and initial platelet counts (r = .469). The follow-up data for respiratory functions forced expiratory volume in 1 s; 74.33 +/- 27.1% versus 97.89 +/- 16.39%; forced vital capacity: 71.44 +/- 26.03% versus 93.22 +/- 13.92%; diffusing capacity of lung: 60.11 +/- 27.61% versus 81.67 +/- 24.56%; alveolar-arterial oxygen difference: 37.95 +/- 24.32 mm Hg versus 7.75 +/- 9.94 mm Hg) and chest radiograms of survivors with moderate to severe paraquat poisoning showed significant improvements 3 mo after intoxication. The results demonstrated that paraquat-induced respiratory function impairments could recover significantly, at least partially, with time. In addition, pulmonary structure damage improved, as shown in the follow-up chest radiographs.

Effects of vincristine and prednisone on platelet numbers and function in clinically normal dogs

SUMMARY Effects of a single iv administered therapeutic dose of vincristine sulfate on platelet numbers and function were evaluated in 16 clinically normal dogs over the 2 weeks after drug administration. Results were statistically compared with those of a previous control study in which the same 16 dogs were administered saline solution (iv), instead of vincristine. Of the 16 dogs, 8 were orally administered daily immunosuppressive doses of prednisone concurrently throughout the saline-control and vincristine study periods. Platelet numbers and mean platelet volume were measured, using an automated hematology analyzer. Platelet function was evaluated by turbidimetric measurement of platelet aggregation in response to collagen, platelet-activating factor, and adenosine diphosphate (adp), and by clot retraction (diluted whole-blood method) and buccal mucosa bleeding time. Vincristine had a significant (P &lt; 0.05) effect on circulating platelet numbers. Vincristine induced a transient mild decrease in platelet numbers, followed by a moderate increase in numbers, with peak platelet count observed 8 days after drug administration. Mean platelet volume was not significantly affected by administration of vincristine. Vincristine had no significant effects on platelet aggregation in response to collagen, low or high doses of platelet-activating factor, and a high dose of adp. The maximal degree of platelet aggregation attained in response to a low dose of adp was not significantly affected by prior administration of vincristine. The maximal rate of platelet aggregation induced by a low dose of adp after vincristine administration, however, was significantly (P &lt; 0.05) lower than the rate of aggregation induced by a similar dose of adp in the previous control study. Vincristine had no significant effects on clot retraction and bleeding time. Prednisone did not significantly affect platelet numbers and function, and did not modify vincristine's effects on the same variables.

Intravenous gammaglobulin has no advantages over oral corticosteroids as primary therapy for adults with immune thrombocytopenia: A prospective randomized clinical trial

Symptomatic immune thrombocytopenia in adults is potentially lethal, and, when conventionally treated with oral corticosteroid agents, approximately two thirds of patients will have some response in platelet count, but this is seldom durable. Since cytotoxic drugs are of limited benefit at this stage, splenectomy becomes necessary in 70% of patients. Intravenous gammaglobulin has been advocated as an alternative to prednisone as the primary form of treatment. A prospective, randomized comparison was carried out between oral prednisone (1 mg/kg/day; group 1; n = 17), high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5; group 2; n = 13), or a combination of both agents given on the same schedule (group 3; n = 13). The groups were well matched clinically and hematologically. No mortality occurred after initiating therapy, but one patient experienced a cerebrovascular accident. Response, defined as a platelet count greater than 50 × 10 9/L, was achieved in 82%, 54%, and 92% of patients in groups 1, 2, and 3, respectively, but was only significant between groups 2 and 3 (P = 0.0365). The median times to peak platelet counts were 8.5 days (range 7 to 21 days), 7 (range 5 to 10 days), and 7 (range 3 to 23 days), respectively. Although there was a trend in favor of the steroid-administered groups, relapse was not significantly different, which occurred at a median of 184, 32, and 76 days, respectively, nor was the average time to splenectomy different at 339, 59, and 98 days, respectively. At a minimum of 2 years of follow-up, 5 of 17 in group 1, 2 of 13 in group 2, and 1 of 13 in group 3 had achieved platelet counts of greater than 100 × 10 9/L and, therefore, did not require splenectomy. In contrast, where this indication was present for failure to respond, 8 of 12 (67%) in group 1, 4 of 8 (50%) in group 2, and 9 of 12 (75%) in group 3 remain in complete remission. Significantly more patients in group 2 than group 3 experienced a relapse (P = 0.0365). It is concluded that in previously untreated adults with symptomatic immune thrombocytopenia, gammaglobulin offers no advantage over conventional corticosteroid administration as the primary form of therapy. Additionally, more intense immunosuppression, resulting from the use of both agents combined, is no better than single agent corticosteroid agents and appears to be an unnecessary and unwarranted expense.

Partial splenic embolization in patients with liver cirrhosis and hepatocellular carcinoma: Effects on portal hemodynamics

Partial splenic embolization (PSE) was performed on patients with liver cirrhosis to control hypersplenism and gastroesophageal varices. In this study, we evaluated the effects of PSE on the portal hemodynamics and hepatic function of 17 cirrhotic patients with hepatocellular carcinoma. The mean splenic volume and the peak platelet count increased significantly and the splenic vein pressure decreased significantly after PSE. However, the portal blood flow did not change. Changes in the 15-min retention rate of indocyanine green and the arterial ketone body ratio were not significant, but the redox tolerance index increased from 0.24 ± 0.28 × 10−2 to 0.59 ± 0.35 × 10−2. These results suggest that PSE may reduce perioperative risks in cirrhotic patients with hepatocellular carcinoma who are candidates for hepatic resection.

Effect of recombinant human erythropoietin on platelet production in dialysis patients.

Two hundred forty-four anemic hemodialysis patients were randomized into recombinant erythropoietin and placebo-treated groups during a 12-wk double-blind phase, followed by a 24-wk open-label period. Mean platelet count rose from the baseline value of 242 x 10(9)/L to 264 x 10(9)/L on day 5 of epoetin therapy (P < 0.001, paired t test). Mean platelet count peaked at 290 x 10(9)/L on day 40 and remained at a significantly elevated level below the peak thereafter. The peak platelet count did not exceed the normal range in a majority of cases. Platelet count was unaffected by placebo. Patients without an erythropoietic response during the first few weeks of therapy exhibited a rise in platelet count comparable to that in patients with a satisfactory erythropoiesis. Patients with low initial serum ferritin concentrations had baseline platelet counts comparable to those with normal or high ferritin values and showed a similar rise in platelet count during therapy. As a group, patients with baseline platelet counts above 400 x 10(9)/L showed no rise in platelet count, whereas those with normal or reduced platelet counts showed a marked thrombopoietic response to epoetin. Erythropoietin therapy did not significantly alter the incidence of blood access thrombosis when compared with placebo treatment.

Thrombocytosis in patients with tumors producing colony-stimulating factor

We investigated the cause of thrombocytosis in 14 patients with tumors producing colony-stimulating factor (CSF). Of the 14 patients, 10 had tumors producing granulocyte-CSF (G-CSF) and 4 had tumors producing granulocyte-macrophage--CSF (GM-CSF). Thrombocytosis of greater than 400 x 10(9)/L was noted in 8 of 10 patients with G-CSF-producing tumors and all 4 patients with GM-CSF-producing tumors. Median peak platelet counts were, respectively, 511 x 10(9)/L (range, 384 to 694 x 10(9)/L) and 579 x 10(9)/L (range, 526 to 910 x 10(9)/L) in patients with tumors producing G-CSF and GM-CSF. In most patients, thrombocytosis declined towards the terminal stage. High interleukin-1 (IL-1) and IL-6 levels were found in addition to CSFs in the plasma or culture supernatants of tumor cells obtained from most patients. In patients with GM-CSF- producing tumors, these specimens had megakaryocyte-CSF (Meg-CSF) activity, which was abolished by anti-GM-CSF antibody. These specimens also had megakaryocyte potentiating (Meg-Pot) activity attributable to both GM-CSF and IL-6. In patients with G-CSF-producing tumors, only Meg- Pot activity due to IL-6 was detected. These results indicate that the thrombocytosis in GM-CSF-producing tumors was caused by both the Meg- CSF activity of GM-CSF and the Meg-Pot activity of IL-6 plus GM-CSF, while that in G-CSF-producing tumors was due to the Meg-Pot activity of IL-6.

Thrombocytosis in Patients With Tumors Producing Colony-Stimulating Factor

AbstractWe investigated the cause of thrombocytosis in 14 patients with tumors producing colony-stimulating factor (CSF). Of the 14 patients, 10 had tumors producing granulocyte-CSF (G-CSF) and 4 had tumors producing granulocyte-macrophage–CSF (GM-CSF). Thrombocytosis of greater than 400 × 109/L was noted in 8 of 10 patients with G-CSF–producing tumors and all 4 patients with GM-CSF–producing tumors. Median peak platelet counts were, respectively, 511 × 109/L (range, 384 to 694 × 109/L) and 579 × 109/L (range, 526 to 910 × 109/L) in patients with tumors producing G-CSF and GM-CSF. In most patients, thrombocytosis declined towards the terminal stage. High interleukin-1 (IL-1) and IL-6 levels were found in addition to CSFs in the plasma or culture supernatants of tumor cells obtained from most patients. In patients with GM-CSF–producing tumors, these specimens had megakaryocyte-CSF (Meg-CSF) activity, which was abolished by anti–GM-CSF antibody. These specimens also had megakaryocyte potentiating (Meg-Pot) activity attributable to both GM-CSF and IL-6. In patients with G-CSF–producing tumors, only Meg-Pot activity due to IL-6 was detected. These results indicate that the thrombocytosis in GM-CSF– producing tumors was caused by both the Meg-CSF activity of GM-CSF and the Meg-Pot activity of IL-6 plus GM-CSF, while that in G-CSF–producing tumors was due to the Meg-Pot activity of IL-6.

Serum interleukin-6 in Kawasaki disease.

Kawasaki disease (KD) is an acute febrile illness of infancy and early childhood. In spite of extensive studies, the cause of KD is not known. Interleukin 6 (IL-6) has manyfold biological functions involved in the immune or inflammatory responses of the host to various stimuli. Here the author investigated whether IL-6 might be responsible for manifestations of KD, such as immunoglobulin hypersecretion, lymphocyte activation and systemic vasculitis. Serum IL-6 levels in KD were determined by ELISA. Usually sera from healthy children contained only negligible levels of IL-6. Serum IL-6 was markedly elevated in all patients with acute KD, which gradually decreased during the course of the disease. Serum IL-6 correlated with serum concentration of C-reactive protein and with serum soluble interleukin-2 receptor level, but did not show any correlation with peak platelet count during subacute phase of the disease. Increased serum IL-6 level did not show any relation to development of coronary aneurysms and dilatation. Further studies will be needed to examine the source and the pathogenetic roles of increased serum IL-6 in KD.

The recovery of circulating progenitor cells after chemotherapy in AML and ALL and its relation to the rate of bone marrow regeneration after aplasia.

Peripheral blood levels of BFU-e, CFU-GM and CFU-mix were studied serially in nine patients with acute leukaemia in remission during the period of recovery that followed induction or consolidation chemotherapy. Following 23 courses of treatment in the nine patients, the values for all three classes of progenitor were found to be higher in ALL than in AML (mean peak CFU-GM levels 5.8 x 10(3)/ml and 0.8 x 10(3)/ml respectively) and the highest levels were observed in patients recovering the most rapidly from bone marrow aplasia. Peak levels of these progenitors correlated best with the rate and extent of platelet recovery and all patients achieving blood levels of greater than 1.0 x 10(3) CFU-GM/ml had recovered greater than 100 x 10(9)/l platelets by 20 d and had peak platelet counts of greater than 400 x 10(9)/l within 40 d following chemotherapy. The peak values for circulating progenitors fell markedly after repeated courses of treatment in three of the five AML patients studied and this is likely to limit useful harvesting of such cells during later consolidation courses in this disease.

Isolated thrombocytopenia in patients infected with HIV: Treatment with intravenous gammaglobulin

Isolated thrombocytopenia occurs frequently in patients infected with HIV. Studies of mechanisms of thrombocytopenia and clinical response to therapy suggest that the thrombocytopenia is often antibody mediated (ITP). The best approach to treatment of these patients is uncertain in that the routine modalities (steroids, splenectomy, vinca alkaloids) that are used to increase the platelet count in patients with classic ITP are known to be immunosuppressive. We report here the results of intravenous gammaglobulin (IVGG) treatment of 22 patients with HIV-related acute and chronic ITP who had severe thrombocytopenia and bleeding symptoms. Only one patient had an opportunistic infection at the time of treatment. Eight patients were homosexual, eight had hemophilia, three were i.v. drug abusers, two children had congenital acquisition of HIV, and one was the wife of an HIV + i.v. drug abuser. The average pretreatment platelet count was 22,000/microliter (hemophiliacs were treated at higher platelet counts than were the other patients), and the mean peak platelet count measured on days 5 to 8 was 182,000/microliter. Nineteen of 22 patients had peak platelet counts greater than 50,000/microliter following IVGG and 17/22 had peak counts greater than 100,000/microliter. After the initial infusions, all but three refractory patients could maintain adequate platelet counts with IVGG alone infused no more often than once every 2 weeks. The outcomes for the 22 patients after multiple maintenance IVGG infusions were remission, 5; stable without therapy, 1; maintenance, 13; and refractory, 3. The eight hemophiliacs with ITP responded better than did the eight homosexual ITP patients; their mean peak platelet count was 227,000/microliter versus 142,000/microliter in the homosexuals. In summary, patients with HIV-related ITP without opportunistic infections responded well to IVGG, with peak platelet counts comparable to those of ITP patients not infected with HIV. IVGG may be a useful therapy of ITP in HIV+ patients, since it appears to be less immunosuppressive than are conventional therapies, and none of the 22 HIV+ patients developed an opportunistic infection while receiving IVGG alone.

Cryoprecipitates in Kawasaki syndrome: association with coronary artery aneurysms.

Cryoprecipitates are postulated to play a role in the pathogenesis of several vasculitis illnesses and infectious diseases. To investigate the presence of cryoprecipitates in Kawasaki syndrome, we studied sera from 25 children with acute Kawasaki syndrome. None of the subjects was treated with intravenous gamma-globulin. Cryoprecipitates were detectable in sera of 11 of 25 (44%) children studied. The mean (+/- SE protein concentration of the cryoprecipitates was 88.0 (+/- 20.2) micrograms/ml serum. Cryoprecipitates consisted primarily of IgG and IgM; no complement components were detected but highly sensitive methods were not used. The presence of cryoprecipitates in the serum of children with acute Kawasaki syndrome was associated with the subsequent development of coronary artery aneurysms detected by echocardiogram (P less than 0.05). There was no association between detectable cryoprecipitates and either peak platelet count or erythrocyte sedimentation rate. In one patient, measurement of cryoprecipitates in serial samples showed a reduction in concentrations that paralleled subsidence of disease activity. We speculate that cryoprecipitates may be a marker for increased risk of coronary aneurysm formation and may play a role in the pathogenesis of the cardiac disease in Kawasaki syndrome.

Combined plasma exchange and intravenous gammaglobulin in the treatment of patients with refractory immune thrombocytopenic purpura.

Plasma exchange (PE) and intravenous gammaglobulin (IVGG) are potentially effective therapies in immune thrombocytopenic purpura (ITP). In this study, eight patients refractory to IVGG and to prednisone were treated with a protocol of combined PE and IVGG therapy using a single PE on each of 3 consecutive days, followed by 2 consecutive days of IVGG at 1 g per kg. Four of the eight patients responded to the combined therapy with a mean peak platelet count of 132,000 per microliter (range, 74,000 to 225,000/microliter). Responses lasted approximately 2 weeks. These four patients were among the five who had initially responded to IVGG before becoming refractory; none of the three patients without an initial response to IVGG responded to the combined therapy. Age, duration of disease, and splenectomy status did not appear to be related to response to the combined therapy. Two patients began maintenance treatment (1 PE followed by 1 g/kg IVGG on the same day), but both became unresponsive after three treatments. PE combined with IVGG may be a useful treatment for some patients with refractory ITP who have uncontrollable bleeding or require major surgery. The development of resistance to IVGG effect may be mediated by an increase in the level of antiplatelet antibodies. PE, by lowering antiplatelet antibody levels, may then allow IVGG infusion to be effective again in elevating the platelet count.