Heparin-Associated Thrombocytopenia: Case Report and Prospective Study

Summary: Heparin-associated thrombocytopenia: Case report and prospective study. A. S. Gallus, K. T. Goodall, W. Beswick and C. N. Chesterman, Aust. N.Z. J. Med ., 1980, 10 , pp. 25–31.
After observing a patient with heparin-induced thrombocytopenia we prospectively recorded the incidence of thrombocytopenia associated with heparin treatment by measuring the platelet count every second day in 166 patients given therapeutic heparin for various thrombo-embolic disorders, and 51 patients given low-dose heparin prophylaxis. A platelet count below 100×10^g/litre developed in nine patients (5.4%) during or soon after full-dose heparin therapy, and in one patient given low-dose heparin. Careful clinical review suggested that heparin was either the most likely cause or a contributing cause of thrombocytopenia in 51166 patients (3.0%) receiving therapeutic heparin and none of the patients who received prophylactic heparin. Associated laboratory studies suggest that heparin-initiated platelet aggregation in vivo is a useful marker for heparin-induced thrombocytopenia.     

Characteristics of type I Gaucher disease associated with persistent thrombocytopenia after treatment with imiglucerase for 4-5 years

The characteristics of Gaucher disease (GD) associated with persistent thrombocytopenia despite imiglucerase enzyme therapy in type 1 GD (GD1) were investigated by retrospective analysis of International Collaborative Gaucher Group (ICGG) Registry data. The study involved 1016 GD1 patients with an intact spleen for whom date of diagnosis, therapy initiation, and platelet counts were known, and who received continuous imiglucerase therapy for 4 to 5 years. These patients were stratified by last platelet count: ≥ 120 × 10(9) /l (n = 772); ≥ 100 to <120 × 10(9) /l (n = 94); ≥ 80 to <100 × 10(9) /l (n = 80); and <80 × 10(9) /l (n = 70; 20 with <60 × 10(9) /l) and characterized by initial and cumulative average imiglucerase dose, body mass index, platelet count, anaemia, hepatomegaly, splenomegaly, and skeletal assessments at baseline and after 4-5 years of therapy. Statistically significant associations were found between persistent thrombocytopenia and baseline platelet count (<80 × 10(9) /l), splenomegaly, and anaemia (all P < 0·0001). After 4-5 years, statistically significant associations were found with splenomegaly (P < 0·0001), anaemia (P < 0·0001), white blood cell count (P = 0·049), hepatomegaly (P = 0·004) and bone pain (P = 0·035). Exponential platelet decay in relation to splenomegaly suggests that platelets increase only when spleen volume decreases substantially.     

Factors influencing platelet recovery after autologous transplantation of G-CSF-mobilized peripheral blood stem/progenitor cells following myeloablative therapy in 50 heavily pretreated lymphoma patients

Delayed platelet recovery following autologous PBPCs transplantation after myeloablative therapy remains an unresolved problem in lymphoma patients heavily pretreated with several chemotherapy cycles and/or radiotherapy. In the present study of 50 lymphoma patients, the factors influencing platelet recovery after myeloablative therapy followed by autologous PBPCs transplantation were analysed retrospectively. The median age was 42 years (range, 15-58). Fourteen patients had HD and 36 had NHL (13 high-grade and 23 low-grade); most (80%) had stage III or IV. Twenty-two patients had received radiotherapy to various extents before mobilization. The mean number of previous chemotherapy cycles was seven (range 3-24) of different regimens (range 1-4). A median of three leukapheresis procedures (range 1-5) was performed after G-CSF mobilization. Single leukapheresis was sufficient in only one patient. A significant correlation was found between the BFU-E content of autografts and platelet recovery after transplantation. Neither the patient's age and sex nor the stage and grade of lymphoma had any effect on platelet recovery after transplantation. Neither the type of myeloablative therapy used or the dose of G-CSF administered after transplantation had any effect on platelet recovery after transplantation. The type of previous chemotherapy cycles was a major adverse factor affecting the progenitor cell yield in the autografts. Lymphoma patients previously treated with ASHAP and/or Dexa-BEAM cycles had less progenitor cell yield. The chemotherapeutic agents used in previous cycles also had a clear adverse effect on the progenitor cell yield in the autografts. Lymphoma patients previously treated with cycles including cytarabine and/or cisplatin showed significantly less progenitor cell yield and slower platelet recovery after transplantation. All seven patients with delayed platelet recovery had received cytarabine and/or cisplatin in several previous ASHAP and/or Dexa-BEAM cycles. All seven patients had a BFU-E count of less than 1 x 10(5)/kg yield in the autografts.     

Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing antiviral therapy

BACKGROUND: Erythropoietin (EPO) not only stimulates erythropoiesis but also thrombopoiesis. As pegylated-interferon-alpha(PEG-IFN-alpha)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-alpha induced thrombocytopenia. Further, we hypothesize that EPO increases platelet reactivity and protease activated receptor 1 (PAR-1) expression during combination antiviral therapy. METHODS: Forty patients with chronic hepatitis C received either 10,000 IU EPO 3 x/week or placebo in a randomized, placebo-controlled, double-blinded fashion for 4 wk and combination antiviral therapy with PEG-IFN-2a and ribavirin. RESULTS: EPO alleviated the decrease in hemoglobin during combination antiviral therapy with ribavirin (10%vs 20%, p < 0.0001). Platelet counts decreased stronger in EPO than in placebo group on day 28 (p= 0.007). EPO induced a 40% increase in PAR-1 (p < 0.0001), which was accompanied by 100% increase in platelet reactivity (p < 0.0001). PFA-100 platelet plug formation time and PEG-IFN-alpha-induced vWF-increase were not different between study groups. CONCLUSIONS: Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-alpha induced thrombocytopenia after the first 4 wk of combination therapy. EPO caused PAR-1 receptor upregulation on platelets, which promoted an increase in platelet reactivity without affecting PFA-100 platelet plug formation time. EPO is not a useful option for short-term support of platelet production during antiviral therapy.     

Angioimmunoblastic T cell lymphoma (AITL) with autoimmune thrombocytopenia

We present a case of angioimmunoblastic T cell lymphoma (AITL) with autoimmune thrombocytopenia. A 85-year-old man was admitted to our hospital with thrombocytopenia, generalized lymphadenopathy, pleural effusion, and splenomegaly in June 2000. Blood chemistry revealed hemoglobin and platelet counts of 8.8 g/dL and 26 x 10(9)/L, respectively. The level of platelet-associate-IgG was 2568.9 ng/10(7) cells. The direct Coombs test was positive. The level of serum IL-6 was 10.2 pg/ml. Megakaryocytes in the bone marrow increased. Lymph node biopsy showed diffuse proliferation of atypical lymphoid cells with a clear cytoplasm accompanied by plasma cells and small vessels. He was diagnosed as having AITL with autoimmune thrombocytopenia and hemolytic anemia. He received repeated platelet transfusion, and a limited effect of prednisolone therapy on his platelet count was observed. Combination chemotherapy lessened the extent of the lymphadenopathy and slightly elongated the interval of platelet transfusion. We next performed splenic irradiation and a slight increase in the platelet count was observed. He died of pneumonia in August 2000. Autoimmune thrombocytopenia associated with AITL is rare and the therapy containing prednisolone and chemotherapy is reported to be partly effective. Our case showed a minor response of autoimmune thrombocytopenia to splenic irradiation. Therapeutic intervention for hypersplenism should be considered if thrombocytopenia is not improved by chemotherapy alone.     

Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer

BACKGROUND: Thrombocytopenia is a significant problem in the treatment of cancer. OBJECTIVE: To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia. DESIGN: Phase I/II clinical cohort study. SETTING: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS: 29 patients with gynecologic cancer. INTERVENTION: Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy. MEASUREMENTS: Peripheral blood counts and platelet transfusions. RESULTS: Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 microg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44x10(9) cells/L and 20x10(9) cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count <20x10(9) cells/L, 1 and 4 [P = 0.002]; days with a platelet count <50x10(9) cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013). CONCLUSIONS: Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.     

Prospective, randomized trial of sequential interleukin-3 and granulocyte- or granulocyte-macrophage colony-stimulating factor after standard-dose chemotherapy in cancer patients.

BACKGROUND AND OBJECTIVE: Several in vitro and animal studies have shown that IL-3 primes hematopoietic stem cells to become more sensitive to later acting growth factors. We wanted to compare the toxicity and the synergistic stimulatory effect of interleukin-3 (IL-3) followed by granulocyte colony-stimulating factor (G-CFS) or granulocyte-macrophage colony-stimulating factor (GM-CSF) on white blood cell (WBC) and platelet counts, after standard-dose chemotherapy (CT) in patients with solid tumors. DESIGN AND METHODS: Fifty consecutive cancer patients with thrombocytopenia and/or leukopenia registered during a previous course of CT were randomized to receive, after the following course, IL-3 (10 microg/kg/day, s.c., day 1-5) followed by G- or GM-CSF (5 microg/kg/day, day 6-8). RESULTS: The nadir of WBC in the cycles supported with the combination of IL-3 and G-CSF was significantly higher than that observed in the CT cycles not supported by growth factors (p < 0. 005). Furthermore, severe leukopenia was abrogated in all the cycles supported with IL-3+G-CSF, while in the cycles without cytokines, this event was registered in 62.5% of the cases (p < 0.0005). Finally, the recovery of WBC was achieved a mean of 4 days earlier in the cycles supported with IL-3+G-CSF. As for thrombocytoprotection, no significant differences were evidenced, but severe thrombocytopenia was abrogated in all the cycles supported by IL-3+G-CSF (p < 0.05). Furthermore, platelet recovery after CT was achieved on average 3.5 days earlier in the IL-3+G-CSF group than in the previous cycles. The nadir of WBC count in the cycles supported by the combination of IL-3 and GM-CSF was significantly higher than that observed in the CT cycles not supported by growth factors (p < 0.005). Furthermore, severe leukopenia was abrogated in 40% of the cycles supported by IL-3+GM-CSF, while in the cycles without cytokines, this event was registered in 80% of the cases (p < 0.005). Finally, the recovery of WBC was achieved a mean of 3.5 days earlier in the cycles supported by IL-3+GM-CSF. As far as thrombocytoprotection is concerned, there were no significant differences in the nadir between the cycles supported by the association IL-3+GM-CSF and the cycles not supported by cytokines. However, severe thrombocytopenia was registered in 20% of the cycles not supported by growth factors but in only 10% of the cycles supported by IL-3+GM-CSF (p < 0.05). Furthermore, platelet recovery after CT was achieved on average 3 days earlier in the IL-3+GM-CSF group. The combination of IL-3 and G-CSF would appear to be more effective than the combination of IL-3 and GM-CSF in the control of both severe thrombocytopenia and leukopenia. Indeed, severe leukopenia was abrogated in all the cycles in arm A, but only in 40% of the cycles in arm B (p < 0.0005). Furthermore, considering a platelet count below 49     

Stable Response after Administration of Stem Cell Factor Combined with Granulocyte Colony-Stimulating Factor in Aplastic Anemia

We report successful treatment with 25 microg/kg of recombinant methionyl human stem cell factor (SCF) combined with 400 microg/m2 of recombinant human granulocyte colony-stimulating factor (G-CSF) in 2 patients with aplastic anemia refractory to immunosuppressive therapy. In one patient, hemoglobin levels increased from 6.4 g/dL to 11.3 g/dL after 36 weeks of SCF/G-CSF treatment. Thereafter, the platelet count (24.0 x 10(9)/L) began to improve without the therapy, and as of week 272, the platelet count was 125.0 x 10(9)/L with a leukocyte count of 8.4 x 10(9)/L and a hemoglobin level of 12.9 g/dL. In the other patient, more than 3 years of SCF/G-CSF treatment ameliorated hemoglobin levels and platelet counts from 5.8 g/dL to 15.9 g/dL and 8.0 x 10(9)/L to 50.0 x 10(9)/L, respectively. After cessation of SCF/G-CSF treatment, the positive response was sustained, and the platelet count improved further to 71.0 x 10(9)/L as of week 242. These observations suggest the clinical benefit of SCF/G-CSF administration to patients with refractory aplastic anemia.     

Neonatal autoimmune thrombocytopenia: role of high-dose intravenous immunoglobulin G therapy

Summary High-dose intravenous immunoglobulin G (IVIgG) therapy results in a rapid reversal of thrombocytopenia in over 80% of children with acute immune thrombocytopenic purpura (ITP). Comparable results were observed in eleven infants with an analogous condition, neonatal autoimmune thrombocytopenia (NATP), who received IVIgG (2 g/kg body weight) administered alone (n=6) or in combination with steroids (n=5). The median platelet count pre-IVIgG therapy was 25×10⁹/l (range 5 to 74×10⁹/l). The overall response rate to IVIgG therapy, administered alone or in combination with steroids was 75% (12 of 16 treatment episodes). A good response to therapy was defined as an increase in the platelet count to 50×10⁹/l and at least twice the pre-treatment value at 48 h after completion of the IVIgG infusion. The rapid and generally excellent response to IVIgG therapy in infants with NATP suggests that this treatment approach should be considered as first-line therapy for severely thrombocytopenic infants with this self-limiting but potentially serious disorder.Presented at the International Workshop on ITP, August 26 and 27, 1988, Lucerne, Switzerland     

Adefovir dipivoxil-associated thrombocytopenia in a patient with chronic hepatitis B

A 56-year-old male patient received adefovir dipivoxil (10 mg/day) for chronic hepatitis B resistant to lamivudine. On the fifth week of treatment, the platelet count dropped to 26 x 10(3) mm(-3); anti-platelet antibodies were detectable in serum. The drug was discontinued and the platelet count improved spontaneously. A re-challenge with adefovir caused a new episode of thrombocytopenia, again after a five-week treatment period. To date, thrombocytopenia has not been described after adefovir therapy for chronic hepatitis B and seems to be a rare event.     

Combination therapy for radiation-induced bone marrow aplasia in nonhuman primates using synthokine SC-55494 and recombinant human granulocyte colony-stimulating factor

Combination cytokine therapy continues to be evaluated in an effort to stimulate multilineage hematopoietic reconstitution after bone marrow myelosuppression. This study evaluated the efficacy of combination therapy with the synthetic interleukin-3 receptor agonist, Synthokine- SC55494, and recombinant methionyl human granulocyte colony-stimulating factor (rhG-CSF) on platelet and neutrophil recovery in nonhuman primates exposed to total body 700 cGy 60Co gamma radiation. After irradiation on day (d) 0, cohorts of animals subcutaneously received single-agent protocols of either human serum albumin (HSA; every day [QD], 15 micrograms/kg/d, n = 10), Synthokine (twice daily [BID], 100, micrograms/kg/d, n = 15), rhG-CSF (QD, 10 micrograms/kg/d, n = 5), or a combination of Synthokine and rhG-CSF (BID, 100 and 10 micrograms/kg/d, respectively, n = 5) for 23 days beginning on d1. Complete blood counts were monitored for 60 days postirradiation and the durations of neutropenia (absolute neutrophil count < 500/microL) and thrombocytopenia (platelet count < 20,000/microL) were assessed. Animals were provided clinical support in the form of antibiotics, fresh irradiated whole blood, and fluids. All cytokine protocols significantly (P < .05) reduced the duration thrombocytopenia versus the HSA-treated animals. Only the combination protocol of Synthokine + rhG-CSF and rhG-CSF alone significantly shortened the period neutropenia (P < .05). The combined Synthokine/rhG-CSF protocol significantly improved platelet nadir versus Synthokine alone and HSA controls and neutrophil nadir versus rhG-CSF alone and HSA controls. All cytokine protocols decreased the time to recovery to preirradiation neutrophil and platelet values. The Synthokine/rhG-CSF protocol also reduced the transfusion requirements per treatment group to 0 among 5 animals as compared with 2 among 5 animals for Synthokine alone, 8 among 5 animals for rhG-CSF, and 17 among 10 animals for HSA. These data showed that the combination of Synthokine, SC-55494, and rhG-CSF further decreased the cytopenic periods and nadirs for both platelets and neutrophils relative to Synthokine and rhG-CSF monotherapy and suggest that this combination therapy would be effective against both neutropenia and thrombocytopenia consequent to drug- or radiation- induced myelosuppression.     

Autologous transplantation of Ph-negative peripheral blood stem cells for treatment of chronic myelogenous leukemia

A 21-year-old man, diagnosed in March 1997 as having chronic myelogenous leukemia (CML), received hydroxyurea followed by daily interferon (IFN) until December 1998, when the additional chromosome abnormality of +8 appeared. As no suitable matched donor was available, the patient received mobilization therapy consisting of mini-ICE (idarubicin, cytarabine, etoposide) followed by G-CSF subcutaneously. During hematopoietic recovery, a total of 12 x 10(6)/kg CD34-positive cells were harvested. Cytogenetic analysis of peripheral blood stem cell (PBSC) products using FISH revealed 1% BCR/ABL fusion signals. In March 1999, he received conditioning therapy consisting of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by infusion of 5 x 10(6)/kg CD34-positive cells. A neutrophil count of 500/microliter and a platelet count of 5 x 10(4)/microliter were attained by days 20 and 38, respectively. Bone marrow aspirates showed 2.6% BCR/ABL fusion signals on day 35 after autologous PBSC transplantation, and the patient remained in chronic phase until the sixth month, when a cytogenetic relapse (Ph, +8:4/20) occurred. These observations suggest that Ph-negative progenitor cells can be harvested using a mini-ICE regimen followed by G-CSF, and that autologous PBSC transplantation is feasible in patients with CML resistant to IFN.     

Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine.

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.     

A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation

Anemia is a universal finding in patients undergoing autologous bone marrow transplantation (BMT). Effective therapies to increase the number of autologous red blood cells could result in a lower morbidity and mortality associated with red blood cell transfusions. We examined whether the addition of erythropoietin (Epo) to intensive therapy supported by progenitor cell transplantation and granulocyte colony- stimulating factor (G-CSF) would result in a lower requirement for red blood cell transfusions. Thirty-five patients with lymphoma were randomized to receive Epo versus placebo. Epo (600 U/kg three times per week) or placebo was begun 3 weeks before administration of high-dose therapy. Epo was held during the week of the preparatory regimen, and restarted on the day after BMT. All patients also received G-CSF following BMT. No significant differences were noted between the two groups in terms of patient characteristics at pretreatment or post-BMT evaluation. There were no differences in the total number of red blood cell units transfused (median Epo: 8 v placebo: 6, P = .22) nor the number of platelet transfusions given (median Epo: 12 v placebo 5, P = .14). Engraftment of granulocytes (absolute neutrophil count > or = 500/microL) occurred in a median of 12 days (range, 9 to 33) for the patients receiving Epo and G-CSF, compared with a median of 10 days (range, 8 to 22) for those receiving placebo and G-CSF (P = .70). Likewise, there were no differences in the time to platelet count > or = 20,000/microL without further transfusions with a median of 22 days (range, 15 to 150+) for those receiving Epo and G-CSF compared with a median of 20 days (range, 11 to 54) for those patients receiving placebo and G-CSF (P = .28). The combination of G-CSF and Epo as administered in this study appears to be safe but does not result in an improvement in the total number of red blood cell transfusions or total number of single donor platelet units transfused.     

Dapsone for thrombocytopenic purpura related to human immunodeficiency virus infection

PURPOSE: The purpose of this study was to determine the effect of dapsone on platelet count in patients with human immunodeficiency virus (HIV)-related autoimmune thrombocytopenia. PATIENTS AND METHODS: Eleven patients with HIV-related thrombocytopenia received dapsone (50 to 125 mg/day) for 2 to 43 months. Patients with the acquired immunodeficiency syndrome were not enrolled. RESULTS: Of the 11 patients, six developed platelet counts above 50 X 10(9)/L and did not require any other specific therapy. No significant side effects were observed. CONCLUSION: We conclude that dapsone may be effective in some patients with HIV-related thrombocytopenia.     

Synergistic effects of thrombopoietin and granulocyte colony- stimulating factor on neutrophil recovery in myelosuppressed mice

Severe suppression of the hematopoietic system is a major factor in limiting chemotherapy dose escalation. To determine whether a combination of human recombinant granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO) would alter recovery of platelets, red blood cells (RBCs), or neutrophils after myeloablative therapy, myelosuppressed mice were treated with sc injections of TPO (90 micrograms/kg), G-CSF (250 micrograms/kg). TPO plus G-CSF or vehicle and complete blood counts were measured. Marrow and spleen cells were obtained at various times and assayed for erythroid, myeloid, and megakaryocytic progenitors. The prolonged neutropenia in vehicle controls (14 days) was significantly shortened in mice treated with G- CSF or TPO for 14 days. The combination of TPO plus G-CSF further reduced the duration of neutropenia. TPO and TPO plus G-CSF treatments also significantly shortened thrombocytopenia compared to vehicle. Recovery of RBCs was also enhanced in mice treated with either G-CSF or TPO, or the combination. Furthermore, treatment with G-CSF and/or TPO hastened myeloid, erythroid, and megakaryocyte progenitor recovery compared to vehicle controls. These results show that the combination of TPO plus G-CSF acts synergistically to accelerate neutrophil recovery in myelosuppressed mice and does not compromise the platelet or RBC response to TPO therapy.     

Delayed-onset heparin-induced thrombocytopenia and thrombosis

BACKGROUND: Heparin-induced thrombocytopenia is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize complexes of platelet factor 4 and heparin. OBJECTIVE: To describe a syndrome termed delayed-onset heparin-induced thrombocytopenia, in which thrombocytopenia and thrombotic events begin 5 or more days after withdrawal of heparin. DESIGN: Case series. SETTING: Secondary and tertiary care hospitals. PATIENTS: 12 patients who presented with serologically confirmed, delayed-onset heparin-induced thrombocytopenia, including 6 outpatients presenting after hospital discharge. MEASUREMENTS: The platelet serotonin-release assay was used to measure IgG-induced heparin-dependent and heparin-independent platelet activation; an enzyme immunoassay that detects IgG against platelet factor 4-heparin complexes was also used. RESULTS: Patients with delayed-onset heparin-induced thrombocytopenia presented with thrombocytopenia and associated thrombosis a mean of 9.2 days (range, 5 to 19 days) after stopping heparin therapy. Nine patients received additional heparin, with further decrease in platelet counts. Compared with controls, patients with delayed-onset heparin-induced thrombocytopenia had higher titers of IgG antibodies to platelet factor 4-heparin and greater IgG-induced heparin-dependent and heparin-independent platelet activation. CONCLUSIONS: Delayed-onset heparin-induced thrombocytopenia should be suspected when patients present with thrombocytopenia and thrombosis up to 3 weeks after exposure to heparin. This syndrome could be caused by high titers of platelet-activating IgG induced by heparin.     

Heparin-induced thrombocytopenia: A prospective study

Thrombocytopenia is a well-described complication of heparin therapy. Few studies describe the incidence of thrombocytopenia when low-dose heparin (10,000–15,000 units/day) is used for prophylaxis of deep venous thrombosis. In our study, ten of 66 courses (15%) of heparin prophylaxis in coronary care unit patients were accompanied by a mild thrombocytopenia with platelet counts below 150 ± 10³/mm³. In all cases the platelet count returned to normal despite continued heparin therapy. Patients who became thrombocytopenic had significantly lower initial platelet counts. No cases of severe thrombocytopenia were seen (platelet count below 100 ± 10³/mm³). No patient developed thrombosis, bleeding or elevated fibrin split products. Mild thrombocytopenia occuring after 2–5 days of low-dose heparin is common, but clinically insignificant.     

Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia

Recombinant leukocyte A interferon is a highly purified single molecular species of alpha-interferon prepared by recombinant DNA methods. In 1982, a phase II trial to evaluate the efficacy of recombinant leukocyte A interferon for patients with previously treated chronic lymphocytic leukemia was begun, and 19 patients were entered in this study. Patients received one of two dose schedules depending on their pretreatment platelet counts. Those with platelet counts greater than 100,000/mm3 received 50 X 10(6) units/m2 intramuscularly three times weekly, with dose reductions to 25 X 10(6) units/m2 and 5 X 10(6) units/m2 for unacceptable toxicity. Those with platelet counts less than 100,000/mm3 received 5 X 10(6) units/m2 intramuscularly three times weekly. Toxicity was dose-dependent and included fever, chills, fatigue, anorexia, myalgias, headache, leukopenia, and thrombocytopenia. Response was evaluable in all but one of the patients entered in this study. Two of the 12 patients treated with 50 X 10(6) units/m2 had a partial response, three had no response, and seven had progressive disease. Of the six patients starting at 5 X 10(6) units/m2 in whom response was evaluable, two had no response and four had progressive disease. Five patients with progressive disease (three at 50 X 10(6) units/m2 and two at 5 X 10(6) units/m2) had an acceleration of disease while receiving recombinant leukocyte A interferon. It is concluded that the dose and schedule of recombinant leukocyte A interferon therapy tested in this study are not effective in previously treated patients with advanced chronic lymphocytic leukemia.     

Life-threatening severe immune thrombocytopenia during alpha-interferon therapy for chronic hepatitis C

Although mild thrombocytopenia is a common adverse effect of interferon therapy, severe life-threatening thrombocytopenia is extremely rare. Here, we report a case of chronic hepatitis C patient that developed severe thrombocytopenia during alpha-interferon therapy, possibly due to an autoimmune mechanism. A 24-year-old female presented chronic hepatitis C in May, 1998. Based on the clinicopathological findings including a liver biopsy, administration of alpha-interferon was begun. In the fourth week of therapy, she experienced mild dyspnea and general fatigue. Complete blood count demonstrated thrombocytopenia (48,000/microL). Despite the immediate withdrawal of interferon, her platelet count further decreased to 1,100/microL. Bone marrow aspirate and elevated platelet-associated IgG antibodies were suggestive of immune thrombocytopenia. She was treated with intravenous and oral administration of steroids. Her platelet count returned to normal level 5 days later. Response to steroid treatment was consistent with the diagnosis of alpha-interferon-induced immune thrombocytopenia in this patient.