Low Platelet Count Treatment

Conquer Low Platelets

Alternative And Natural Therapies For Itp (idiopathic Thrombocytopenia Purpura). Live Free From Itp. Complete Program To Increase Platelets. This Is What You Will Learn With this Guide: The Two Herbs That can help bring up your platelets. The Two Vitamins needed to keep those platelets from dropping. What foods may cause your platelets to drop. How science has confirmed the benefits of these herbs in their use with low platelets. Why your doctor may not know about these natural alternatives and how you can assist him in helping you. Different tests that naturopathic doctors do to determine your real state of health that may reverse the course of your body drastically. Understand some of the reasons why people develop low platelets. Discover how your digestive tract may be the culprit to your low platelet level problems. How you can prevent the most drastic step a splenectomy. How you can restore your health so that you dont need any more dangerous drugs. Get your life back and stop ending up in the hospital all the time. Learn why your immune system is attacking your platelets and how to calm it down. Learn what over the counter medications to stay away from if you have low platelets Continue reading...

Conquer Low Platelets Overview

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Thrombocytopenia

Hematologic malignancies frequently present with symptoms due to absolute and or functional thrombocytopenia. Currently, platelet transfusion remains the only proven method leading to rapid rise in platelet counts. The exact role and optimal dosing of the only approved platelet-lineage specific agent, IL-11, either in the prevention of the need for platelet transfusion or as a facilitator of platelet recovery, is unclear.89 Advanced clinical studies of thrombopoietin-like agents in patients with autoimmune thrombocytope-nia are in progress .

Novel Treatment Approaches

Investigators from Shanghai52 53 have recently reported results in 61 newly diagnosed APL patients who received induction therapy with combined ATRA (25 mg m2 day) plus arsenic trioxide (0.16 mg kg day). All patients subsequently received three courses of consolidation chemotherapy, and five cycles of maintenance with sequential ATRA, arsenic, and 6-MP and MTX. Among the 61 patients, 58 (95.1 ) entered CR at a median of 26 days and, with a follow up of 20-39 months, all of them were relapse free.52 Similar results, at least for induction, have been reported by Wang et al.,54 with a CR rate in 80 newly diagnosed patients treated with low-dose ATRA plus arsenic of 92.5 there were two early deaths (2.5 ), and four cases of resistant leukemia, but no data were presented on long-term outcomes. Estey et al.34 have treated 44 newly diagnosed APL patients with ATRA (45 mg m2 day) plus arsenic trioxide (0.15 mg kg day) added at day 10 (with addition of one dose of gemtuzumab ozogamicin if the...

Biological Activity and Side Effects

Many of the synthetic compounds developed from the original natural product lead were also extremely potent and showed broad-spectrum activity in human tumor colony-forming assays (88), and both adozelesin (22) and carzelesin (23) proceeded to clinical trial. However, adozelsin had only marginal efficacy in a phase II trial of untreated metastatic breast carcinoma (89). Similarly, carzelesin showed no activity in a phase II trial in patients with a variety of advanced solid tumors (90). A phase I trial of KW 2189 (24) established the maximum tolerated dose at 0.04 mg m2 d when given daily for 5 days, with leukopenia, neutropenia, and thrombocytopenia as dose-limiting toxicities (91). A phase II pilot study in metastatic renal cell carcinoma showed a good safety profile but no activity (92).

Causes Of Cancers In

Munzert et al. 17 described a patient with SLE who developed B-cell type NHL and M expansion of CD5+ B cells in his blood. CD5+ B cells are the equivalent of Lyb-1 B cells in mice which are associated with autoimmunity and lymphoma 80 , In humans, CD5+ B cells are associated with CLL, a disease characterized by a high rate of autoimmune features including autoimmune hemolytic anemia and thrombocytopenia. A link between CD5+ cell and RA was reported, however, their role in SLE is unclear 80-81 ,

Definition Of Remission

The importance in achieving a consensus on the definition of remission is to allow comparison of results from an assortment of studies and different institutions to provide the basis on which to make decisions about the care of patients. Consensus, as such, is required, but its achievement is compounded by the quality of the bone marrow specimen and the experience of the pathologist evaluating it. A morphologic complete remission (CR) is defined as having a neutrophil count > 1.0 X 109 L, platelet count > 100 X 109 L, normal bone marrow cellularity with trilineage hematopoiesis, with < 5 blasts and resolution of all extramedullary disease. 1Note that hemoglobin concentration or hematocrit are not included when evaluating remission status, but the patient has to be transfusion independent. Partial remission (PR) is not used for studies in which the objective is cure, but is used for phase I and II studies, conducted in patients with refractory or relapsed disease. In such cases,...

Contraindications and Side Effects It

Is contraindicated in cases of hypersensitivity or idiosyncratic responses to the drug or where there are preexisting blood dyscrasias. The drug can cause a serious cumulative bone marrow suppression, notably thrombocytopenia and leukopenia (121,122), that can contribute to the development of overwhelming infectious disease. This requires reducing dosages. Irreversible renal failure as a consequence of hemolytic uremic syndrome is also possible (121). Occasionally adult respiratory distress syndrome has also been seen. When extravasation is seen during administration, cellulitis, ulceration, and sloughing of tissue may be the consequence (123,124). The drug is known to be tumorigenic in rodents. Its safety in pregnancy is unclear and teratogenicity is seen in rodent studies. Other side effects include fever, anorexia, nausea, vomiting, headache, blurred vision, confusion, drowsiness, syncope, fatigue, edema, thrombophlebitis, hematemesis, diarrhea, and pain. It is not clear that all...

Management Of Myelosuppression

Probably the most common adverse event with imatinib is myelosuppres-sion. Grade 3 or higher neutropenia (i.e., neutrophils < 1 X 109 L) occurs in up to 35-45 of patients, and thrombocytopenia in 20-25 .26'28'32'51'52 Severe anemia is less common, occurring in 5-10 of the patients. All of these are more common in patients who have failed prior therapies (e.g., IFN-a), and are dose-related, occurring more frequently among patients treated with higher doses. Patients who develop grade 3 or higher neutropenia or thrombocy-topenia may have a lower probability of achieving a cytogenetic response. The adverse prognosis is particularly noticeable among patients whose myelosup-pression lasts longer than 2 weeks.5153 This has been attributed to a decreased dose intensity, as the current recommendation is to interrupt therapy in patients who develop this degree of myelosuppres-sion and reduce the doses for those who take more than 2 weeks to recover.54 To...

Imatinib Meslate In Accelerated And Blastphase

Blood or marrow, or a platelet count less than 100 X 103 L unrelated to anticancer therapy. Patients were treated with 400 or 600 mg of imatinib daily. Overall, 69 of the patients achieved a sustained hematologic response, 34 complete, and the rest either achieved a blast percentage in the marrow under 5 with incomplete peripheral blood recovery (marrow response) or a return to a second chronic phase (no criteria for accelerated disease as defined above). The rate of complete cytogenetic response was 17 , and the 1-year progression-free and overall survival was 59 and 74 , respectively. Patients treated with 600 mg compared to 400 mg realized greater benefit with a higher overall cytogenetic responses (28 vs 16 ) and better progression-free and overall 1-year survival rates (67 and 78 vs 44 and 65 ), with no significant increases in toxicity.

Cytarabinebased Combination Regimens

The largest series incorporating AML-type chemotherapy in patients with myeloid blast phase (blast count > 30 ) involved 162 patients treated at MD Anderson Cancer Center over an 11-year period from 1986 to 1997.23 Ninety patients received intensive combination chemotherapy, largely high-dose cytarabine-based. Overall, 28 of the patients responded to treatment, with CHR in 8 of the patients, and an additional 7 achieving all criteria for CHR, but with incomplete platelet count recovery. In addition, 11 of the patients achieved a return to chronic phase, and 2 of the patients were termed a partial response. The duration of response was approximately 4 months, which corresponded with survival as well. In a series of patients treated at the Karolinska Hospital in Sweden,24 47 of 83 patients with accelerated or myeloid blast-phase disease, treated with an anthracycline cytarabine-based regimen, achieved a return to chronic phase, the definition of which was less stringent than the MD...

Cml Treated With Hydroxyurea Or Busulfan

A large study of patients treated mostly with hydrox-yurea was the basis for the first widely recognized prognostic scoring system. Sokal et al. performed a multiple regression analysis of 625 chronic-phase patients aged 5-45 years and identified age, spleen size, hematocrit, platelet count, and the percentage of circulating blast cells as significant prognostic factors.14 The Sokal scoring system devised by this analysis classifies

Inhibitors Of The Downstream Pathways Ras signaling

Facilitates binding of this protein to cellular membranes, allowing them to function as intermediates in the process(es) of signal transduction. In the Ras pathway, prenylation is catalyzed by farnesyl protein transferase the farnesyl transferase inhibitors (FTIs) interfere with this step by inhibiting this enzyme. Given the central role that the ras oncogene plays in controlling cellular metabolism, multiple FTI compounds are currently being developed and tested across a wide range of hematologic malignancies. A phase I II study of tipifarnib, an FTI, in patients with a spectrum of myeloproliferative disorders reported preliminary results in 23 patients.34 Tipifarnib was administered at a dose of 300 mg p.o. b.i.d. for 21 days every 4 weeks. Clinical WBC responses normalization of WBC, complete remission (CR) or > 50 WBC count reduction, partial remission were seen in 5 of 21 (24 ) evaluable patients. No cytogenetic responses were seen in six evaluable patients. Grade 2 anemia and...

Clinical Presentation

The clinical presentation of CLL patients is diverse, with variability in presenting symptoms, physical examination findings, and laboratory test results. As noted above, patients often present without any symptoms, and the diagnosis is made on the basis of an elevated absolute lymphocyte count found on routine complete blood count (CBC). Less commonly, patients present with nontender lymphadenopathy, and are noted to have an elevated blood lymphocyte count on further evaluation. Some patients present with concomitant illnesses such as infection or chronic rhinitis, or less commonly, autoimmune phenomena such as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia purpura (ITP).

Criteria For Diagnosis

Nation is most helpful in evaluating response to treatment and is required to confirm complete remission. A bone marrow aspirate and biopsy are also useful in evaluating patients with thrombocytopenia to differentiate between an autoimmune process and lack of platelet production due to CLL marrow infiltration.

Role Of Other Diseaserelated Complications

CLL patients are known to be at an increased risk of developing autoimmune hematologic complications. The most frequent among these is Coombs positivity with or without resulting autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Pure red cell aplasia (PRCA) is a relatively rare complication, while immune neutropenia is extremely rare in CLL. When AIHA, ITP, or PRCA occur even in a patient who has not received any prior cytotoxic therapy, we consider these complications indications for instituting therapy.

Polyclonal Bcell Lymphoproliferative Disorder

An entity called polyclonal hairy B-cell lymphoprolifer-ative disorder (HBLD) has been described in Japan.7273 All of the patients were females, had splenomegaly and minimal or no lymphadenopathy persistent lympho-cytosis was noted in all the patients, some having anemia and thrombocytopenia. Abnormal lymphocytes present in the peripheral blood and bone marrow had round nuclei and abundant pale cytoplasm with long microvilli and prominent membranous ruffles. They expressed CD5- CD10- CD11c+ CD19+ CD20+ CD23 - by flow cytometry studies. Although these findings were similar to those of HCL, the surface marker of the kappa and lambda chains was unbiased and studies of immunoglobulin gene rearrangements and expressions showed a polyclonal proliferation of B cells.73

Indications For Treatment

Hairy cell leukemia is an indolent lymphoproliferative disorder, which, prior to the advent of successful systemic therapy, had a median survival of 53 months. Approximately 10 of the patients diagnosed with this disorder never require therapy. This population is characterized by older age, smaller spleen size, and minimal circulating hairy cells.1 The following criteria, though not validated, are commonly accepted as appropriate indications for therapy neutropenia characterized by an absolute neutrophil count (ANC) < 1 X 109 L, anemia with a hemoglobin < 10 g dL, or thrombocytopenia < (50-100) X109 L, recurrent serious infections, or symptomatic splenomegaly. Much less commonly, bulky or painful lymphadenopathy, constitutional symptoms including fevers, chills, sweats, or weight loss, vasculitis, bone involvement, or leukocytosis with a high proportion of circulating hairy cells (white cell count > 20 X 109 L) are also indications for treatment. Bone marrow involvement, no...

Responses To Lmb2 In Hcl Patients

All four patients with HCL, who had failed at least cladribine and interferon, had major responses.69 Patient 30 see Figure 33.2(a) prior to treatment had pancytopenia, with a pretransfusion hemoglobin as low as 8.5 g dL, a platelet count of 47,000 mm3, an absolute neutrophil count (ANC) of 360 mm3, and an enlarged spleen and precarinal lymph nodes. The pan-cytopenia resolved with elimination of the tumor cells. The hairy cell count of 478 L decreased > 90 from just one dose of LMB-2, as assessed on day 3. By day 8, the HCL count had decreased by > 99 , and was cleared following cycle 2. Flow cytometry is able to quantify HCL cells making up < 0.01 of the lymphocytes. The CR in patient 30 was associated with resolution of baseline splenomegaly and precarinal adenopa-thy, and transfusion independence. Recovery of normal counts is shown in Figure 33.2(a), with the platelet count first to recover, improving from a pre-treatment baseline of 53,000-133,000 L by day 22.

Specific Considerations Prior to Performance of Renal Biopsy

Before percutaneous renal biopsy, patients need to understand that the procedure is a diagnostic study and not a treatment. A platelet count and prothrombin (PT) and partial prothrombin times (PPT) should be obtained. Antiplatelet drugs such as aspirin or other nonsteroidal anti-inflammatory drugs should

Comprehensive Treatment Strategy For

Neutropenia thrombocytopenia Patients with mild to moderate, uncomplicated neutropenia and or thrombocytopenia can often be observed however, such patients should be evaluated on an individual basis. Patients with life-threatening neutropenia or throm-bocytopenia warrant active treatment and not simply supportive care (such as platelet transfusions and antibiotics), even though some such patients may be assigned to a low-risk IPSS subcategory. 5-Azacytidine can induce trilineage responses and along with decitabine (an investigational agent in phase III testing) can induce rapid and impressive improvements in peripheral blood counts. Patients with severe cytopenias (even without an increase in bone marrow (BM) blasts) should be considered for allo-geneic stem cell transplantation before they have life-threatening infectious or bleeding complications. Whether patients with cytopenias and no increase in BM blasts will have superior outcomes with reduced intensity stem cell...

Subchronic Toxicities

Occasionally, in the rodent but not the monkey, single-cell hepatolyte neurons is observed and this has been related to immunostimulation (265). Also, on occasion, in the monkey transient thrombocytopenia is observed, perhaps associated with complement activation (for review, see Ref. 169). Other toxicities noted in animals are mild and occur infrequently at therapeutic doses. For example, occasional increases in liver function enyzmes are noted, but these occur at high doses and are not associated with histopathological changes (169). 6.8.4.4 Platelet Effects. When phosphorothioate oligodeoxynucleotides have been administered by continuous i.v. infusion in patients with malignant diseases, transient thrombocytoplastin has been observed in a few patients (285). These effects were more frequent during the first course of therapy, were not obviously dose-related, and were not associated with bone marrow effects (253, 289). Most of the time, platelet counts...

Tubulointerstitial nephritides

Rifampicin-induced tubulointerstitial nephritis is interesting because, at least in some cases, a target might be identified 50 . There is often an association between renal failure and hematological abnormalities (hemolytic anemia and thrombopenia). Patients develop rifampicin-dependent IgG and IgM antibodies against the I antigen of red blood cells, which caused red blood cell lysis through interaction with the antigen on the erythrocyte surface. These antibodies, or a cell-mediated response against this antigen, could play a role in tubulointerstitial nephritis since the I antigen is also expressed on tubular epithelial cells.

Xenobioticinduced immune disregulation

Some drugs such as hydralazine or procainamide may induce lupus like diseases with antinuclear antibodies and proteinuria. D-penicillamine not only causes glomerulopathies, but also myasthenia, poly-myositis or lupus, suggesting that this compound provokes immune disregulation. Gold salts also are capable of inducing various immunopathological disorders such as pneumonitis, anemia, thrombocytopenia and hepatitis.

Scoring systems without karyotype analyses

Table 43.3 shows the main prognostic scoring systems proposed for MDS that do not include cytoge-netic factors. The Bournemouth score was the first proposed scoring system. Patients were assigned to one of three risk groups based on the number of cytopenias present and the proportion of blasts in the BM.53 The main criticism of this system is the emphasis on blood cytopenias in relation to the proportion of blasts in the BM.7 The scoring system proposed by the Spanish group uses the proportion of BM blasts, platelet count, and age.7 This system is easy to use and has been demonstrated to predict survival in

Histone Deacetylase Inhibitors

Butyrate is an acetylating agent that has been used to induce expression of fetal hemoglobin in sickle cell anemia and thalassemia, but proved unsuccessful for the treatment of AML in phase II trials.11 Sodium phenylbu-tyrate (PB), a derivative thought to be deliverable in oral form, has been shown to induce histone acetylation, p21 expression, G1 cell-cycle arrest, and apoptosis in vitro.12 In a trial conducted by Gore et al.,13 PB was given for 7 28 or 21 28 days to MDS and AML patients, with improvement in thrombocytopenia and neutrope-nia seen in a small number of patients. A dose-limiting toxicity of reversible encephalopathy was due to accumulation of phenylacetate. Currently, oral forms of PB are being investigated. Valproic acid, an oral antiepilep-tic agent, SAHA (suberoylanilide hydroxamic acid), and FK 228 (with FDA approval for cutaneous T-cell lymphoma) are newer HDAC inhibitors currently undergoing clinical trials.

Growth Kinetics of CLL in the Blood

Using flow cytometry, high numbers of circulating lymphocytes in S phase had a shorter therapy-free and total survival compared with those with fewer S-phase cells (65). Also, Orfao et al. (66) showed that a high absolute count of circulating S-phase leukocytes was associated with a higher incidence of hepatosplenomegaly, anemia, and thrombocytopenia, a higher number of lymphocytes in blood and bone marrow, advanced clinical stages, lower serum IgG and IgM, and poorer survival. Moreover, the fraction of circulating Ki-67-labeled cells in CLL correlated with the proportion of prolymphocytes and was higher in resistant CLL than in indolent cases (67). Even high proliferative in vitro responses to B-cell mitogens were significantly associated with poor survival, whereas unstimulated thymidine uptake did not predict outcome (62). Studies of lymphocyte doubling time (LDT) confirmed the above data. LDT is defined as the period needed for the peripheral lymphocyte count to double the...

Immunomodulation Antithymocyte globulincyclosporine

In a trial by Molldrem et al., unselected MDS patients with RA and refractory anemia with excess blasts (RAEB) were given rabbit ATG 40 mg kg day for 4 days, with an overall response rate of 44 .59 Higher responses of 64 were seen in patients with RA, 81 of whom maintained transfusion independence for a median of 36 months. This included 48 of those with severe thrombocytopenia and 55 of those with severe neutropenia. A follow-up with a total of 61 patients was reported in 2002, with an overall response of 34 .60

Autoimmune Conditions In Malignant Diseases

Autoimmune Thrombocytopenia 13-19 An autoimmune thrombocytopenia similar to idiopathic thrombocytopenic purpura (ITP) has been reported in neoplastic diseases. In different series a ma lignant disease was found in 4 19 of patients with thrombocytopenia and purpura 13 . In most cases, paraneoplastic autoimmune thrombocytopenia was associated with lymphoproliferative diseases, especially Hodgkin's disease, however, it was also described in epithelial cancers 18-19 , Corticosteroid treatment of paraneoplasitc autoimmune thrombocytopenic is less effective than in ITP, but splenectomy may induce long remissions 14 , As in the case of paraneoplastic autoimmune hemolytic anemia, several mechanisms have been proposed to explain the development of thrombocytopenia in malignancies and these include cross-reaction between a tumor-associated and thrombocyte antigens, or adhesion of immune complexes to the thrombocyte membrane 18 ,

Making The Diagnosis

The platelet count of reactive thrombocytosis accompanying inflammation, bleeding, cancer, or infection is rarely elevated to the degree seen in ET. A Serum, fer-retin level is helpful in excluding iron deficiency (bleeding as a cause of thrombocytosis). Thrombosis never occurs in secondary thrombocytosis. All patients considered to have ET should have cytogenetic or molecular studies performed to exclude CML, a disease that can present in a patient with an increased platelet count and only a modest elevation of the WBC. For patients with borderline or moderately elevated RBC values, a Cr51 RBC mass study is mandatory to exclude PV. JAK2

Antithrombotic therapy

In patients with PV who continue to have thrombotic or vascular symptoms, despite aspirin and good control of the hematocrit and platelet count with phlebotomy and myelosuppression, clopidogrel 75 mg daily or ticlopi-dine 250 mg orally twice daily should be considered.14

Laboratory Findings

Laboratory findings include platelet count in the range of 450,000-1,000,000 mm3, leukocytosis, basophilia, and the presence of megathrombocytes in the peripheral smear. Marrow cellularity is increased in 90 of the patients, with bizarre megakaryocytes with nuclear pleomorphisms and clustering of megakaryocytes. Enlargement of megakaryocytes with multilobulated nuclei, and their tendency to cluster in small groups along sinuses, is the hallmark of ET.21 The bone marrow may also appear normal. Bleeding times are prolonged in 10-20 of the patients. Platelet aggregation studies are frequently abnormal, most often demonstrating impaired aggregation in response to epinephrine, ADP, and collagen, but not to arachidonic acid and ristocetin.22 Laboratory features of acquired von Willebrand syndrome (simulating type II vW factor deficiency) are associated with a platelet count > 1000 X 109 L. An enhanced throm-botic risk in ET patients has been associated with a reduction in the...

Leukemic Transformation Of

Clinically heralded by organomegaly, worsening constitutional symptoms, anemia, thrombocytopenia, and leukocytosis. At the diagnosis of MMM, these patients had frequently presented with typical disease-related features, but about half had an increase in circulating myeloblasts. All episodes of LT were acute myeloid leukemia, with all French-American-British subtypes represented except M3. Additionally, 91 of patients displayed an abnormal karyotype. LT from MMM was usually fatal, with 89 patients (98 ) having expired of disease or therapy a median of 2.6 months (range 0-24.2) after LT. Supportive care alone or noninduction chemotherapy had similar outcomes in 48 patients and 19 patients, respectively (median survival < 3 months in both groups). Induction chemotherapy in 24 patients (26 ) had a 33 mortality with no complete remissions achieved median survival 3.4 months (range 0.9-24.3) . However, a subset of patients (n 10 41 ) reverted their marrow to a chronic phase of MMM after...

Diagnosis Symptoms and Clinical Signs

Mon symptoms and physical findings result from anemia, thrombocytopenia, and neutropenia, and include pallor and fatigue, anorexia, petechiae, purpura, bleeding, and infection. Occurrence of initial hyperleukocy-tosis (white blood cell count> 100,000 l) did not vary significantly in the different age groups. Initial involvement of the central nervous system (CNS) is seen less often in adolescents ( 10 ) and in children aged 213 years ( 8 ) than in infants ( 17 ) with AML (data not available for young adults, who rarely get diagnostic lumbar puncture). Infiltration of the skin, especially in monocytic leukemias, is also most frequent ( 20 ) in young children (< 2 years) and rarely seen in older children and adolescents. Likewise, leukemic infiltrations of the periosteum and bone occur more often in young children than in adolescents.

Diagnostic And Treatment Paradigms

For the remaining cases which fulfill the original criteria for HES,78 the WHO criteria,76 and other criteria,77 79 further screening should include complete bone marrow examination, including histologic examination, karyotype analysis, FIP1L1-PDGFRa by PCR or FISH, and documentation of disease and eosinophil clonality by FISH or molecular methods. Abnormal T-lymphocyte subsets may be identified immunophenotypically as immature T cells (CD3+, CD4 , and CD8) or aberrant T cells (CD3 and CD4+),80'81 with or without rearrangement of T-cell receptor genes.80-83 The usefulness of determining interleukin 5 (IL-5) and other cytokines plasma concentrations is unknown. Association of eosinophilia with systemic mastocytosis84,85 supports the determination of plasma tryptase concentrations. Assessment of splenomegaly, hepatomegaly, abnormal marrow function (e.g., anemia, thrombocytopenia, marrow fibrosis, and dysplasia), and elevated plasma concentrations of tryptase helps define...

Splenic Marginal Zone Lymphoma

The constituent cells of SMZL bear only passing resemblance to splenic marginal zone cells and do not share their immunophenotype.31 Patients typically present with splenomegaly often accompanied by anemia and thrombocytopenia. Peripheral blood involvement is often, but not always, present and in some of these cases the circulating neoplastic lymphocytes have a villous appearance. These cases were previously termed splenic lymphoma with villous lymphocytes.32 The use of this somewhat imprecise term will not only fail to include those cases without circulating villous lymphocytes but, more importantly, tends to include other cases of B-cell lymphoma with peripheral blood spillover since the cells of various lymphomas may sometimes adopt a villous appearance, either real or artifactual, in the peripheral blood. This is an important consideration since SMZL tends to respond favorably to splenectomy alone in contrast to its poor response to chemotherapy.33

Radioimmunotherapy RIT

Y-90 ibritumomab tiuexetan Y-90 ibritumomab tiuxe-tan has a murine rituximab conjugated to the iso-tope.80 The Y-90 ibritumomab tiuxetan regimen takes about 8 days to administer. On the first day, a dose of cold rituximab at 250 mg m2 is administered to bind nontumor CD20 sites and to facilitate better biodistribution. Because Y-90 is a beta emitter, it cannot be used for imaging thus, indium-111 -labeled ibritu-momab is substituted for biodistribution studies performed at days 2-3, and if needed, 6-7 to ensure appropriate localization of the isotope. On days 7-8, another low dose of cold antibody is delivered followed by 0.4 mCi kg of Y-90 ibritumomab tiuxetan (not to exceed 32 mCi) for patients with platelet counts of at least 150,000 mm3. The dose is reduced to 0.3 mCi in patients with a platelet count of 100-149,000 mm3.81

Clinical Staging and Immune Cytopenias

Patients with anemia and or thrombocytopenia of immune origin, rather than secondary to marrow infiltration by CLL B-lymphocytes, were not considered a separate prognostic group in any of the staging systems. It has been suggested by some investigators that CLL patients who have anemia and or thrombocytopenia of immune origin seem to have a better clinical outcome, compared with those who have anemia and or thrombocytopenia owing to bone marrow infiltration (23,24). Data from a large number of patients would be required to reach a definitive conclusion. Some investigators have suggested classifying these patients as stage C or Rai stage III or IV, immune (25).

Treatment Of Relapsed And Refractory Dlbcl

Famide, and also because they are excellent stem cell mobilizing regimens.7273 Overall response rates are over 60 , although the complete response rate is only 24 .73 The major advantage to improving salvage regimens is to demonstrate chemosensitivity, since this is arguably the most crucial characteristic-determining outcome following autologous stem cell transplantation in aggressive lymphomas. Of the ifosfamide-based salvage regimens for aggressive lymphomas, extensive data have been published on the ICE (ifosfamide, car-boplatin, etoposide) regimen developed at the Memorial Sloan Kettering Cancer Center (MSKCC).73-78 In an initial publication, investigators at MSKCC treated 163 consecutive transplant-eligible patients with relapsed or refractory aggressive NHL with 3 cycles of the ICE regimen. The overall response rate was 66 , allowing 89 of patients to proceed to a planned autologous stem cell transplant. There was minimal nonhematologic toxicity, although a third of patients...

Evaluation and management

If platelet function is felt to be the problem, one should first obtain a platelet count. If this is low, infusion of 10 units of platelet concentrate should be given. If, however, the platelet count is normal, but one suspects platelet function disorder (e.g. from preop aspirin use), then platelet concentrate should also be given. It is difficult, if not impossible, to obtain platelet function tests on an urgent basis. Disseminated intravascular coagulopathy may occur under various conditions such as sepsis. When this condition is suspected, serum fibrinogen level will be low. The fibrin degradation products will be high, the protamine sulphate test will be positive and the patient's platelet count will be low. The therapy is the IV infusion of heparin to stop the ongoing intravascular coagulation process. However, in the postoperative cardiac patient, this procedure may not be safe.

Clinical Features Of Hivassociated Castlemans Disease

In general, MCD presents in the fourth or fifth decade of life but occurs earlier in people who are HIV positive. Patients often present with generalized malaise, night sweats, rigors, fever, anorexia, and weight loss. On examination, they have multiple lymphadenopa-thy, hepatosplenomegaly, ascites, edema, and effusions both pulmonary and pericardial. Laboratory investigations may reveal thrombocytopenia, anemia, hypoalbuminemia, and hypergammaglobulinemia. The systemic symptoms are attributed to IL-6 and can be severe enough to cause pancytopenia, organ failure, particularly respiratory and renal, as well as shock, requiring admission into intensive care units. HIV-infected patients with MCD have a greater preponderance for pulmonary complications. MCD is more likely to lead to neuropathic complications than does locally confined Castleman's disease. Patients can develop polyneuropathies, leptomeningeal and CNS infiltration, as well as myasthenia gravis.114 The polyneuropathy is a...

Treatment Of Hivassociated Castlemans Disease

Splenectomy, in addition to establishing the histologic diagnosis, may have a therapeutic benefit as a debulking procedure, as some of the hematologic sequelae such as thrombocytopenia and anemia may in part be due to splenomegaly. Following splenectomy, there is often resolution of the constitutive symptoms but this may be short lived, and some form of maintenance therapy is needed to prevent relapse.115

Irinotecan hydrochloride

Irinotecan hydrochloride (CPT-11), a camptothecin derivative, is a prodrug that is converted to the active compound SN-38, which in turn inhibits topoisomerase I. CPT-11 was evaluated in a phase II study involving 13 patients (3 acute and 10 lymphoma) with relapsed or refractory ATL.111 Median age was 63 years (range 44-78 years). The OR rate was 38.5 (CR 7.7 PR 30.8 ) with a median response duration of 31 days. All responders had lymphoma subtype. Grade 3 or 4 toxicities included leukopenia (66.7 ), thrombocytopenia (41.7 ), anemia (33.3 ), and diarrhea (46.2 ). One treatment-related death occurred.

Clinical Approach

Venous stasis is present due to the uterus compressing the vena cava. Usually, the platelet count is slightly lower in the pregnant state. The lower limit of normal is 150,000 mm3 in the nonpregnant patient and 120,000 mm3 in the pregnant woman. 37.2 A. Heparin is a large, charged glycoprotein that does not cross the placenta very well. Osteoporosis and thrombocytopenia are long-term complications.

Hematological Paraneoplastic Syndrome

Thrombocytopenia Thrombocytopenia resulting from a paraneoplastic phenomenon is uncommon. Although autoimmune thrombocytopenia has been reported in CLL and B-cell lymphomas, it can hardly be differentiated from that caused by hypersplenism or direct bone-marrow replacement. Functional disorders Abnormal platelet aggregation studies have been reported in primary dermatological malignancies, as well as in some solid tumors. In most cases these defects are minor, but they can sometimes aggravate a pre-existing thrombocytopenia.

Purine Analog Based Combination Chemotherapy

Two small phase I studies of the combination of fludarabine and chlorambucil were conducted by Elias et al. (63) and Weiss et al. (64). Both demonstrated clinical activity, but the treatment was limited by significant myelosuppression, especially thrombocytopenia. Another study reported on continuous-infusion cisplatin (although not a classical alkylating agent, this drug also produces DNA crosslinks) and fludarabine plus cytarabine in 26 patients. Patients had received extensive prior treatment for CLL, and most of them were refractory to fludarabine. Responses were seen in 19 of the patients, myelosuppression was reported in more than half of the patients treated, and a high incidence of infectious complications was noted (65). The same three-agent regimen is under investigation in chemotherapy-naive patients. Wierda et al. (79) reported results in 135 patients the overall response rate was 95 , complete responses were seen in 63 , and molecular remissions were demonstrated in 31 of...

Toxicity and Adverse Effects

Linezolid was well tolerated in human volunteers after oral or i.v. administration of daily doses up to 625 mg b.i.d. (349, 350, 360, 361). The most common adverse effects were nausea (5.4 ), diarrhea (5.2 ), or oral cavity symptoms (tongue discoloration, 2.5 oral monilia, 2.2 ). Serious drug-related adverse events (e.g., elevated liver enzymes, atrial fibrillation, or worsening renal failure) occurred in < 1 of cases. In the linezolid compassionate-use trial of patients with significant, resistant Gram-positive infections, the overall adverse event rate was about 33 , of which approximately 6 were considered serious events (360). The most frequent adverse events reported were thrombocytopenia (2.6 ) and dermatological reaction (2.5 ) (361). Overall, at the end of therapy, linezolid was well tolerated by about 78 of patients (361).

Monoclonal Gammopathies

These paraproteins are also produced with other B-cell disorders which include multiple myeloma, and Waldenstrom's macroglobulinaemia mainly. To a lesser extent they may also be produced in patients with lymphoma, chronic lymphocytic leukaemia and hairy cell leukaemia. Usually haemolytic complications ensue but these complications are often multifactorial and not due to the paraproteinemia alone (e.g., thrombocytopenia, renal failure, clotting factor depletion, etc.). Splenectomy often improves platelet damage by this organ.

Radiolabeled Antibodies

90Y-ibritumomab tiuxetan was FDA approved in the United States at a dose of 0.4 mCi kg, with a dose reduction to 0.3 mCi kg in patients with low platelets (100,000-150,000 mL).22 Unlike 131I tositumomab, 90Y-ibritumomab tiuxetan does not require individualized dosimetry. Witzig et al. reported the superiority of 90Y-ibritumomab tiuxetan versus rituximab in 143 patients with CD20-positive relapsed or refractory low-grade, follicular, or transformed NHL who had received a median of two previous chemotherapies and half of whom were refractory to their last ther-apy.33 The response rates of 90Y-ibritumomab tiuxetan versus rituximab were 80 versus 56 , respectively (p 0.002), and complete responses were seen in 30 versus 14 (p 0.04), respectively. Overall response favored the follicular lymphoma subgroup with a response rate of 86 . The time to progression estimates were similar at 11.2 months in the 90Y-ibritumomab Combined safety data from 349 patients treated on this and four other...

Fractionation and Fragmentation of Heparin

The development of fractions (naturally depolymerized forms) and fragments (chemically or enzymatically depolymerized forms) of heparin added a new dimension in the prophylactic and therapeutic use of heparin. With these more defined materials, efforts were aimed at finding a safer antithrombotic agent that would effectively prevent venous thrombosis, yet would have a lower bleeding risk and a decreased incidence of heparin-induced thrombocytopenia (HIT).

Paraneoplastic syndromes

Classical HL is associated with the overexpression of a variety of cytokines and their receptors on Hodgkin's or Reed-Sternberg cells and in the surrounding inflammatory infiltrate. These cytokines, including interleukin 2 (IL-2), IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, transforming growth factor p (TGFp), and lympho-toxin A (LT-A), may be responsible for the systemic symptoms of HL and for the rare paraneoplastic syndromes associated with HL. Nephrotic syndrome, idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and cerebellar degeneration ataxia have all been reported in patients with HL.14-18 Typically, nephrotic syndrome or neurologic symptoms precede a diagnosis of HL or herald a relapse, although occasionally high-dose steroids used to treat many of these syndromes may contribute to a delay in diagnosis.14,16 Idiopathic thrombocytopenia has been described in patients preceding the diagnosis of HL, at the time of relapse, and in patients in clinical remis-

Radiolabeled Monoclonal Antibodies

Lym-1 has been conjugated to 131I in order to effect targeted delivery of this radioactive isotope to tumor cells of B-cell origin. Although 131I-Lym-1 has been tested primarily in patients with advanced NHL, the antibody has been given to several patients with B-CLL. Twenty-five patients with previously treated, advanced B-NHL and five patients with relapsed B-CLL were treated with fractionated, low-dose 131I-Lym-1, with a goal of 300 mCi per patient (122). Thirty percent of patients developed HAMAs, but only three patients had therapy interrupted as a result. Four of the five CLL patients responded (80 ). The same group also reported that patients who responded to 131I-Lym-1 therapy enjoyed improved survival (84 vs 22 wk) (123). Radiation dosimetry studies revealed a lower tumor radiation dose and a higher liver radiation exposure in CLL patients, compared with NHL patients, resulting in a lower therapeutic index for patients with CLL (124). Toxicity was acceptable, and the...

Preimplantation Orders

Although outpatient pacemaker implantation can be performed, the usual practice is to admit the patient to the hospital. This may be done on the day of the procedure if the patient's medical condition does not in itself mandate prior hospitalization. Routine pre-implant laboratory tests include a 12-lead ECG, a complete blood cell count (including platelet count), and measures of the prothrombin and activated partial thromboplastin times (aPTT), serum electrolytes, blood urea nitrogen (BUN), and creatinine. It may be valuable to have a recent posteroante-rior and lateral chest radiograph to compare to the post-procedure radiographs.

Haematological Leukemia

The second patient presented with extensive bruising, purpura and splinter haemorrhages. He was also found to have a right hemiplegia. Severe thrombocytopenia (8 x 109 1) was detected with positive LA, elevated IgG and IgM aCL and a false positive VDRL. A CT brain scan was compatible with a left parietal haemorrhagic infarction. Both the patients reported with renal carcinoma 47 had pulmonary embolism, while the second 48 only demonstrated a false positive VDRL as well as positive serology for SLE with thrombocytopenia. The tumour in this case was a hypernephroma.

Targeting Cd52 On Hcl Cells With Alemtuzumab

CD52 is a 12-amino-acid glycoprotein that is present on lymphocytes at up to 450,000 sites cell.48'49 It is also present on monocytes, macrophages, eosinophils, and the male reproductive tract.5051 Quigley et al. at the Scripps Clinic recently reported that in nine cases of classic HCL and one of HCLv, all patients expressed CD52 on 92-100 of the HCL cells.52 Fietz et al. reported recently that a patient with HCL and shortlived or poor responses to cladribine, interferon, splenectomy, and rituximab had hematologic benefit with alemtuzumab.53 The patient tolerated rituximab more poorly than alemtuzumab because of an allergic reaction to the former. With both mAbs, the patient had an improvement in thrombocytopenia, but failed to reverse blood transfusion dependence.

Immunosuppression And Chemotherapy

Inimunosuppressed patients have impaired host defenses as a result ol an underlying immunodeficiency or drug administration (primarily related to organ transplantation or cancer chemotherapy).Because chemotherapy is often cytotoxic to bone marrow, destruction of platelets and red and white blood cells results in thrombocytopenia, anemia, and leukopenia. Inimunosuppressed individuals are al greatly increased risk for Initec tion, and even minor periodontal infections can become life threatening if immune suppression is severe. Intraoral , bacterial, viral, and fungal infections may manifest. Patients receiving bone marrow transplantation require special attention because these patients receive very high-dose chemotherapy and are particular ) susceptible to dissemination of oral infections.

Drugsthat Prevent Fibrinolysis

Menorrhagia, whether primary or induced by an intrauterine contraceptive device. Tranexamic acid may also reduce bleeding after ocular trauma and in haemophiliacs after dental extraction where it is normally used in combination with desmopressin. The drug benefits some patients with hereditary angioedema presumably by preventing the plasmin-induced uncontrolled activation of the complement system which characterises that condition. Tranexamic acid may be of value in thrombocytopenia (idiopathic or following cytotoxic chemotherapy) to reduce the risk of haemorrhage by inhibiting natural fibrinolytic d stabilisation of small platelet plugs the requirement for platelet transfusion is thereby reduced. It may also be used for overdose with thrombolytic agents.

Laboratory Abnormalities In Hyperleukocytosis

Pseudohyperkalemia can be present in patients with a high white blood count secondary to breakdown of white cells in vitro with subsequent release of potas-sium.2 Other spurious laboratory data that can be seen in association with hyperleukocytosis include a falsely elevated platelet count (secondary to white cell fragments), pseudohypoxemia (secondary to oxygen consumption by leukocyte cells), falsely prolonged coagulation tests, and pseudohypoglycemia.421-24 Pseudohypoxemia and pseudohypoglycemia can be avoided by placing samples on ice and performing tests immediately.4,14

Platelet Interactions

Fondaparinux does not induce in vitro platelet aggregation or activation in the presence of heparin antibody obtained from patients clinically diagnosed with HIT (154,160-162). However, data from the clinical trials in orthopedic surgery reveal that platelet counts < 100,000 pi-1 do occur with fondaparinux treatment. In the fondaparinux groups 2.7 and 4.9 of patients vs 3.7 and 5.3 of patients treated with enoxaparin developed thrombocytopenia (147,148).

Lenalidomide Cc5013 Revlimid

Is very different than that of thalidomide, with thrombocytopenia and neutropenia predominating, and essentially no sedation, constipation, or neuropathy. The response rate among 34 patients with newly diagnosed MM treated with lenalidomide 25 mg daily for 21 out of every 28 days with pulse dexamethasone (40 mg day on days 1-4, 9-12, 17-20) was 91 (CR 6 ).122 ECOG has completed accrual to a large randomized study of lenalidomide with two different doses of dexamethasone, and the Southwest Oncology Group is currently conducting a 500-person randomized, double-blinded study comparing dexamethasone to dexamethasone plus lenalidomide (LD). The results of these two studies will establish whether LD could be an appropriate front-line regimen for patients with MM.

Treatment of Advanced CLL

On the basis of these results (observed in a previous interim analysis held in September 1996), it was decided to discontinue accrual in this group. As expected, median survival was better for stage B (81 mo) than for stage C patients (60 mo). Causes of death were related to CLL in 75 of cases, and overall survival did not differ among the three arms (67, 70, and 69 mo in the ChOP, CAP, and FDB groups, respectively). Incidences of infections (< 5 ) and autoimmune hemolytic anemia (< 2 ) during the six courses were similar in the randomized groups, whereas FDB, compared with ChOP and CAP, induced more frequent protracted thrombocytopenia (p 0.003) and less frequent nausea vomiting (p 0.003) and hair loss (p < 0.0001). For patients with stage B and C CLL, first-line FDB and ChOP regimens both provided similar overall survival and response rates at closing and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of...

Hydroxyurea hydroxycarbamide in sickle cell anaemia

Section is required to maintain a normal haematocrit or if the platelet count continues high (added risk of thrombosis). Anagrelide is an oral agent which inhibits platelet aggregation but at lower doses it lowers platelet counts in man due to a marked effect on megakaryocyte maturation. It is nonmutagenic and effectively controls thrombocytosis in PRV and essential thrombocythaemia (ET). Adverse effects are cardiovascular headache, forceful heartbeats, fluid retention and arrhythmias. H2-histamine receptor blockers alone or together. Hyperuricaemia, due to cell destruction, is prevented by allopurinol and iron and folate deficiency by replacement doses (due to the rapid response of the myeloproliferative erythron). Aspirin remains controversial. Low-dose aspirin (for antiplatelet action) may be used if the platelet count remains high or thrombosis occurs despite the above treatment but is best avoided in patients with a history of haemorrhage.

Circulating Blood Elements

The concentration of pluripotent hemopoietic progenitors in the circulation of the aged, despite that the baseline concentrations of these elements were the same in both groups, 27 and the risk of neutropenia, neutropenic infections and thrombocytopenia following cytotoxic chemotherapy increased after age 60 28-39. The fact that the prevalence and incidence of anemia of unknown causes increase with age may also be construed as evidence of progressive hemopoietic insufficiency 40-43. These observations support an age-related decline in hemopoietic reserve that may be of consequence in the presence of severe and prolonged hemopoietic stress. In condition of homeostasis, the hemopoietic activity appears adequate to preserve a normal peripheral blood count throughout a person's lifetime, in the majority of individuals 44-45. Even among the oldest old, it should not be assumed that anemia, neutropenia, thrombocytopenia or pancytopenias are a natural consequence of age.

Approach To Anemia In Pregnancy Definitions

In the pregnant woman with anemia, jaundice, and thrombocytopenia, the examiner must also consider other hemolytic processes, such as HELLP syndrome, which is a life-threatening condition best treated by delivery. In evaluating anemia, if other hematologic cell lines, such as the white blood cell count or platelet count, also are decreased, a bone marrow process, such as leukemia or tuberculosis infection of the marrow, should be considered. Bone marrow biopsy may be indicated in these circumstances. 31.4 A 36-year-old G2 PI at 24 weeks' gestation has fatigue of 4 weeks' duration. Her hemoglobin level is 8.0 g dL, leukocyte count 2.0 cells mm3, and platelet count 20.000 nim Which of the following is the most likely diagnosis

Clinical Trials of Fondaparinux

Fondaparinux (GlaxoSmithKline) has been evaluated in several clinical trials for the prevention of venous thromboembolism in patients undergoing major orthopedic surgery (148-151,175,176). Approval was obtained for use in hip fracture, hip replacement, and knee replacement surgeries (177). Dosing of fondaparinux is once daily at 2.5 mg s.c. to be started not before 6-8 h after surgery to avoid unwanted bleeding. Patients with low body weight and renal insufficiency require dose adjustment. Overall, there was no reduction in the bleeding risk compared to enoxaparin. Monitoring is not recommended. However, it is advised to closely monitor any thrombocytopenia under fondaparinux treatment. If the platelet count falls to < 100,000 jxl 1 fondaparinux should be discontinued, and it should be used with caution in patients with a history of HIT.

Proteasome Inhibitor Bortezomib

Seven patients (4 ) had a CR, and 12 (6 ) had a near-CR (NCR) (myeloma protein undetectable by electrophoresis but immunofixation positive). An additional 34 patients (18 ) achieved a PR, and 14 (7 ) others an MR.24 The median time to disease progression for bortezomib as a single agent was 7 months, compared with 3 months that was reported for the patients' previous therapy (P 0.01). In a landmark analysis, patients who achieved a CR or PR by the end of the second cycle survived significantly longer than those achieving other types of responses. Additional clinical benefits observed in these patients included increases in hemoglobin levels and platelet counts, resulting in a reduction in transfusion requirements. Moreover, levels of unaffected immunoglobu-lins improved. The factors that predicted poor response to bortezomib were older age (> 65 years) and > 50 plasma cells in the bone marrow. In this bortezomib trial, serum -microglobulin level, number or type of...

Blood And Bone Marrow Changes

Leukopenia and thrombocytopenia occur in 10-15 of patients at diagnosis. In some, thrombocytosis develops, presumably from the thrombopoietic effect of IL-6.1'2'21 This occurs more often in patients with osteosclerotic myeloma. Occasional plasma cells or plasmacytoid lymphocytes can be seen in the peripheral blood smear. A marked increase in plasma cells, 20 of leukocytes or > 2000 L, is seen in rare cases of primary plasma cell leukemia and more commonly in the terminal phase of myeloma.22

Lincoff AM Bittl JA Harrington RA et al for the Replace2 Investigators Reference

Fundamentally, heparin is not a particularly good anti-thrombin. Also, despite their efficacy, the high cost of GP IIb IIIa inhibitors and the risk of increased bleeding have limited their widespread use to approximately 50-60 of patients undergoing PCI. The REPLACE-2 trial established bivalirudin as an excellent replacement for heparin during PCI. In lower-risk patients, substitution of bivalirudin for GP IIb IIIa inhibitors would result in lower rates of bleeding along with cost savings without compromising efficacy. Notably, bivalirudin has not been proven in higher-risk patients, including acute coronary syndrome patients and ST-elevation MI. Nonetheless, bivalirudin is an obvious choice for a PCI patient with heparin-induced thrombocytopenia or who is at high risk for bleeding complications.

The Concept of Hypersplenism

The anemia of hypersplenism has two causes. There is an expansion of the total plasma volume as well as a pooling of red cells. In very large spleens, up to 40 of red cells may be sequestered there (141,142). The neutropenia of hypersplenism is usually only moderate and asymptomatic. It is caused by an increase in the marginated pool, some of which may be located within the spleen (143,144). On the other hand, the thrombocytopenia of hypersplenism is caused by splenic pooling (144,145). In massively enlarged spleens, up to 90 of platelets can be sequestered there. Nevertheless, the splenic transit time for platelets remains normal at about 10 min, and the splenic platelets remain part of the exchangeable pool (145).

Alloimmune Or Autoimmunelike Manifestations Following alloBMT

GVHD is a systemic disease caused by T cells in donor bone marrow attacking antigen-presenting cells and tissues of host origin, often causing acute morbidity and mortality during the first few weeks post-BMT. Chronic GVHD may develop several months after BMT. Therefore, GVHD is in fact a purely iatrogenic autoimmune-like disease that may affect almost every tissue, with skin, gastrointestinal tract and liver being the primary candidates. Indeed, chronic active hepatitis, vasculitis, autoimmune neuropathies and autoimmune thrombocytopenia, anemia and leukopenia are rather frequent complications. Chronic GVHD may also mimic lichen planus in the mucous membranes, ophthalmoxerostomia (Sjogren's sicca syndrome) and focal or systemic progressive sclerosis (scleroderma), chronic active hepatitis and SLE, to name just a few of the clinical syndromes that may result from acute and chronic GVHD. Interestingly, some of the symptoms are alloimmune (e.g., chronic active hepatitis) whereas others,...

Adverse reactions

The thionamide drugs are all liable to cause minor and major adverse effects. Minor are rash, urticaria, arthralgia, fever, anorexia, nausea, abnormalities of taste and smell. Major are agranulocytosis, thrombocytopenia, acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome, vasculitis.

Tyrosine Kinase Inhibitors

Two additional adverse effects, which occur with lower frequencies but have noteworthy clinical significance, are hepatic and hematological toxicity. Significant liver dysfunction occurs in fewer than 5 of patients and is managed with dose reductions or temporary interruptions in therapy.13 Therefore, liver function tests should be monitored routinely throughout the duration of imatinib therapy.14 Myelosuppression is the most common Grade 3 or 4 adverse event observed in patients being treated with imatinib.15 Marrow suppression may represent a beneficial therapeutic effect, but may also be due to toxicity to normal progenitor cells.14 Neutropenia and thrombocytopenia, the most common manifestations of the marrow suppression, are more common in patients with advanced disease. Colony stimulating factors (filgrastim) have been successfully employed to assist neutrophil recovery and facilitate more sustained administration of imatinib.15

Therapeutic Challenges

Adverse effects The major adverse effect associated with ibritumomab tiuxetan is myelosuppression, consisting mainly of neutropenia and thrombocytopenia.45 46 Because of this, several parameters must be met before patients can be treated with this agent. Qualifications for therapy include < 25 lymphoma involvement of bone marrow, platelet count > 100,000 cells mm3, and no history of hypocellular marrow or failed stem cell collection.28 The average time to neutrophil nadir is 62 days, while platelets typically nadir around day 53. Cells recover after approximately 22-35 days.43 Additional adverse effects include those seen with other anti-CD20 agents, such as fever, hypotension, chills, skin rash, and rarely nausea and vomiting.45 individuals because of fluctuating clearance rates of the compound.1 The major dose-limiting toxicity of 131I tositumomab is myelosuppression, similar to that seen with 90Y ibritumomab. Therefore, patients must have < 25 lymphoma involvement of bone...

Irradiation Of Blood Components

Pancytopenia (particularly leukope-nia and thrombocytopenia) develops late in the course (median 16 days).67 68 Infection or hemorrhage are the most common causes of death, occurring within 3 weeks of onset.67 68 Treatment is rarely effective, and the mortality rate is > 90 .67 68 In our institution, as in many others, patients with hematologic malignancies, as well as those who have undergone stem cell transplantation, routinely receive irradiated blood products from the time of initial diagnosis.

Hematologic Syndromes

Warm autoimmune hemolytic anemia (AIHA) and occasionally cold antibody-mediated hemolysis is seen most commonly in association with CLL,92 but 3-5 patients with NHL 93 and 1-2 with HD also develop this complication.94 Fludarabine associated hemolytic anemia is also observed in patients with CLL and occasionally in NHL. In a study of patients with NHL, AIHA was associated with female sex, poorer response rate to treatment, a higher incidence of monoclonal gam-mopathy, and inferior overall survival when compared to patients without AIHA.93 AIHA associated with lymphoma usually parallels the disease course and sometimes heralds the onset of relapsing disease. In contrast, autoimmune thrombocytopenia is seen more commonly with HD than with NHL. Unlike AIHA, when ITP recurs, it is seldom associated with a relapse. Treatment is the same as for de novo cases, and accompanies therapy for the underlying malignancy.

Combination with Cytotoxic Agents

An increasing number of phase II studies and a phase III study support incorporation of carboplatin as a standard agent in the management of patients eligible to receive first-line chemotherapy for MBC. The rationale for combining carboplatin with a taxane is based on their single-agent activities in MBC, their complementary mechanisms of action, and their activity in other malignancies. In addition to a possible synergistic interaction, in vitro data suggest that trastu-zumab may also reverse primary platinum resistance by modulating HER2 neu activity (18). In addition, when used in combination, paclitaxel appears to have a platelet-sparing action that reduces the thrombocytopenia seen with carboplatin alone (19).

Green Cross and Fluosol

The early clinical trials in Japan and the USA were at doses of 20-30 ml kg of emulsion. Subsequently, dosages of emulsion went up to 40 ml kg as a single dose and 56 ml kg in repeated doses (2, 3, 4 and 5.6 ml of PFC). Despite these very large dosages (for example, 40 ml kg provided 3 kg of emulsion and over 0.5 kg of PFC), patients showed only minor toxic symptoms. These symptoms were benign, reversible, and without meaningful functional impairment. In the various studies, from 10 to 30 per cent of patients experienced flulike symptoms beginning 4 hours after infusion and generally disappearing at about 24 hours. These were found to be due to the surfactant Pluronic-68 (Tremper et al., 1984), which causes C3 conversion and generation of C5a-related neutrophil-aggregating activity, transient neutropenia and thrombocytopenia. These adverse reactions were readily blocked by corticosteroids. In addition there was a temporary increase in the size of the liver and spleen, wherein the RES...

Monotherapy Of Farnesyl Transferase Inhibitors In Breast Cancer And Other Diseases

Table 1 summarizes the results of a phase I-II trial of tipifarnib monotherapy in patients with ER-positive metastatic breast cancer who have failed second-line endocrine therapy, or with ER-negative disease (37). Seventy-six patients received either 400 mg (N 6) or 300 mg (N 35) twice daily on a continuous schedule, or 300 mg BID using a 3-week on, 1-week off intermittent schedule (N 35). The clinical benefit rate (partial response or stable for at least 24 weeks) was comparable in the continuous (25 ) and intermittent schedules (23 ). There was no statistical association between response to tipifarnib and tumor characteristics, such as the status of ER, HER2, and mutation in three ras genes. Sites of response occurred in liver, lung, pleura, lymph nodes, breast, and skin nodules. There was significantly less toxicity associated with the intermittent compared with the continuous schedule, including neutropenia, anemia, thrombocytopenia, and neurotoxicity. Although there was high...

Initial Clinical Study Of nabPaclitaxel

Hematologic toxicity was dose dependent, but mild and not cumulative. The median absolute neutrophil count nadir (x109 L) ranged from 2.22 to 0.96. Febrile neutropenia was uncommon and no septic deaths were reported. The median platelet count nadir (x 109 L) ranged from 173 to 204. One patient received a platelet transfusion. The investigators concluded that hematologic toxicity was less than expected and that it did not substantially effect dose and treatment decisions during the trial.

Suberoylanilide Hydroxamic Acid Vorinostat

SAHA has been investigated in phase I clinical trials in hematological and non-hematological malignancies. The most common toxicities include fatigue, gastrointestinal symptoms, hyperglycemia, hypokalemia, anemia, and thrombocytopenia (29,30). Doses and schedules recommended for phase II studies include 300 mg po bid daily for 3 days a week, 400 mg po daily continuous, or 200 mg po bid daily continuous. The SAHA-related adverse events are generally rapidly reversible after study drug cessation. Inhibition of HDAC activity was achieved in peripheral blood mononuclear cells at the 200 mg dose level. At dose levels of 400 and 600 mg, the duration of HDAC inhibition lasted 10 or more hours. Tumor responses have been documented in patients with diffuse large B-cell lymphoma, laryngeal cancer, thyroid cancer, and mesothelioma. The FDA has recently approved SAHA (Zolinza, Mesck & Co., Inc.) for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with...

Acute and subacute toxicology

No animal died as a result of administration of MP4, and no changes were noted in body weight, food consumption or behavior for animals that received MP4. No electrocardiographic abnormalities were attributable to the product. Significant rises were noted in serum lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), even after correction for spectrophotometric interference by the hemoglobin itself. There were no histopathological findings in skeletal muscle. There were no treatment-related effects on coagulation parameters (PT, aPTT, platelet count), and changes in urinalysis were limited to the presence of very small amounts of detectable hemoglobin on Day 3.

Treatment of Autoimmunity in CLL

Autoimmune Thrombocytopenia There are no reported clinical trials of therapy in CLL-associated ITP, and it is wise to follow the Clinical Guidelines of the American Society of Hematology (131) for the treatment of ITP and treat the CLL independently as required. These recommend that asymptomatic thrombocytopenia should only be treated when the platelet count is less than 30 x 109 L. Hospitalization should be confined to patients with mucous membrane or other severe bleeding. Conventional-dose oral prednisolone is the treatment of choice for those who need any treatment, (those with severe bleeding or a platelet count less than 30 x 109 L). The severity of hemolysis or thrombocytopenia following fludarabine is often extreme, and it may be fatal. It is important not to stint on transfusions of red cells or platelets. Immunosuppression is a hazard in these patients, and further immunosuppressive treatment will intensify the risk of infection. When treatment with steroids fails,...

Antituberculosis Drugs

And itching with or without a rash, and thrombocytopenia. Rises in plasma bilirubin and hepatic enzymes may occur when treatment starts but are often transient and are not necessarily an indication for stopping the drug fatal hepatitis, however, has occurred. Hepatic function should be checked before starting treatment and at least for the first few months of therapy. Intermittent dosing, i.e. less than twice weekly, either as part of a regimen or through poor compliance, promotes certain effects that probably have an immunological basis, namely, an influenza-like syndrome (malaise, headache and fever, shortness of breath and wheezing), acute haemolytic anaemia and thrombocytopenia and acute renal failure sometimes with haemolysis. Red discolouration of urine, tears and sputum is a useful indication that the patient is taking the drug. Rifampicin also causes an orange discolouration of soft contact lenses.

Incidence And Clinical Presentation

Erythromelalgia (burning pain in the feet and hands accompanied by erythema, pallor, or cyanosis) is common in PV and is considered to be secondary to microvascular thrombotic complications (also seen in essential thrombocythemia, ET). It is more common when platelet counts are above 400,000 L.3 Laboratory abnormalities may include elevated hematocrit and red blood cell mass in almost all patients, platelet count > 400,000 L (in 60 ), and a white blood cell (WBC) count > 12,000 L (in 40 ). Bone marrow cellularity is increased in 90 of cases, and iron storage is absent in 95 .

Agnogenic Myeloid Metaplasia Ammmyelofibrosis With Myeloid Metaplasia

The hemoglobin ranges between 9 and 13 g dL. The WBC count is elevated in about half of the patients, normal in one third, and low in the remainder. Examination of the peripheral blood smear discloses a shift toward granulocytic immaturity, including a few myeloblasts and promyelocytes. Significant changes in the RBCs include variation in size and shape and teardrop-shaped forms (though teardrop forms are not specific for AMM). Large fragments and clumps of megakaryocytes and large platelets may be seen. Nucleated RBCs are noted in advanced cases. The platelet count may be increased, normal, or low, depending upon the stage of disease.

Moderate Efficacy Diuretics

Adverse effects in general are discussed below. Rashes (sometimes photosensitive), thrombocytopenia and agranulocytosis occur. Treatment with thiazide-type drugs causes an increase in total serum cholesterol, but on long-term usage even of high doses this is less than 5 . The questions about the appropriateness of use of these drugs for mild hypertension, of which ischaemic heart disease is a common complication, have been laid to rest by their proven success rates in randomised outcome comparisons.

Malignant BCells CD5CD19

The malignant B-CLL B-cell has been well characterized by surface immunophenotype. This latter feature gives us a potential clue as to its origin and functional capacity. In addition to the common B-cell antigens CD19, CD20, and CD21, these malignant cells have been demonstrated to express CD5 and variable amounts of surface-bound immunoglobulin (sIg). In normal hosts, CD5+ B-cells occur at the edge of germinal centers in the mantle zone of lymphoid follicles (14) and are found in cord blood. This latter marker on the malignant B-CLL clone may provide insight into the level of arrest in development of the monoclonal CLL B-cell. The faint expression of sIgs on the B-CLL B-cells is also common to normal B-cells at the edge of germinal centers. The sIgs in B-CLL are usually IgM and or IgD, and rarely IgG or IgA (15). The sIgs often have reactivity for multiple self-antigens (polyreactive autoantibodies) with low avidity and frequently behave like rheumatoid factor (9). Up to 25 of...

Established singleagent oral chemotherapy

In patients who have CMML with a significant myelo-proliferative component, high WBC count, or organomegaly, treatment with single-agent chemotherapy has been the standard of care. Oral agents such as busulfan, 6-mercaptopurine, hydroxyurea, and oral etoposide have been used empirically with some success, but a prospective randomized study conclusively determined the superiority of hydroxyurea over etopo-side in terms of overall survival in patients with mostly advanced proliferative disease (i.e., splenomegaly, mild thrombocytopenia, and increased bone marrow blasts) 24 months for hydroxyurea versus 9 months for etoposide.10 This is the only prospective randomized study to date that has compared two treatment regimens in patients with CMML. Although neither regimen induced complete remission (CR) or affected the natural history of the disease, the results supported the idea of using hydroxyurea plus supportive care as the standard-of-care arm in any future randomized trials. No...

Maternal Physiologic Changes With Pregnancy

Leukocytosis occurs during pregnancy, most likely due to increased levels of endogenous steroids. By the third trimester, white blood cell (WBC) may reach as high as 12,000 L and up to 20,000-30,000 L during labor.7 Platelet counts in the low normal range may be seen during gestation (gestational thrombocytopenia).6 Immune thrombocytopenic purpura occurs more often in young women any platelet count that acutely drops or is less than 50,000 L must be investigated.

Clinical Development Of Dasatinib In Chronic Myeloid Leukemia

84 patients (40 in CP, 11 in AP, 23 in myeloid BP, and 10 with Ph+ ALL) received dasatinib 15 to 240 mg daily (29). A CHR was achieved in 37 (93 ) patients in CP and a major cytogenetic response (MCyR) in 18 (45 ), including a CCyR in 14 (35 ). Major hematologic responses were observed in 31 (70 ) of 44 patients with AP, BP, or Ph+ ALL, and MCyR were achieved in 27 , 35 , and 80 of patients in AP, BP, and Ph+ ALL, respectively. Responses were maintained in 95 of patients with CP and in 82 of patients with AP after a median follow-up of more than 12 and 5 months, respectively. However, only one (10 ) patient with Ph+ ALL remained relapse-free after a median follow-up of four months (29). Overall, therapy with dasatinib therapy was well tolerated. The most frequently described toxicities were myelosuppression, gastrointestinal, and fluid retention syndromes. Grade 3-4 neutropenia or thrombocytopenia was observed in 45 and 35 of patients treated in CP and in 89 and 80 of those with AP,...

Risk Of Decompensation In Childs A Cirrhosis

Decompensation had markedly diminished survival, compared to those who remained compensated (Fig. 6). Multivariate analysis revealed that the major predictors of poor outcome were bilirubin > 17 mmol L, hepatic stigmata on physical examination, age > 54 yr, and platelet count < 130,000 x 106 L.

Second Era 19241973 Initial Clinical Investigations Into CLL 221 Major Contributors

In the first comprehensive report on CLL in 1924, Minot (Fig. 11) and Isaacs (23) compared their series of 92 CLL patients with 84 CLL patients reported by Ward. Figures 12 and 13 are extracted from their report. They showed that most cases of CLL occurred at 45-54 yr of age. The male female ratio was 3 1, symptoms were usually present 9 mo before the patient presented, and another 6 mo more was required to confirm the diagnosis. Minot and Isaacs (23) further report on 50 patients who received irradiation and 30 patients who did not and who served as controls. The source of irradiation was radium, administered over the lymph nodes and spleen. They noted that there was no difference in the duration of life span for the two groups 3.45 yr (40 mo). We have taken the liberty of using their data to draw Fig. 14. However, they did note that individual patients did benefit if the irradiation was given at 1 or more years prior to death. Although there seemed to...

Lymphoid Malignancies

Autoimmune traits have been identified in more than 8 of patients with B lymphoproliferative syndromes, compared with 2 of those with myeloproliferative states 29 . For example, autoimmune hemolytic anemia occurs in one-third of CLL patients at some time during the course of the disease, and a positive direct antiglobulin test has been claimed to be as frequent as 35 , depending on the stage of this leukemia 30 , Whereas antibodies to polymorphonuclear cells have only been found in a few cases of CLL, both immune thrombocytopenia in about 2 of the patients and a higher incidence of platelet-associed immunoglobulin

Clinical Trials

In the setting of a poor functional age, serious comor-bid medical conditions, and particularly patient preference, less intensive chemotherapy or aggressive supportive care may be more appropriate treatment options. Drugs such as hydroxyurea (generally given in doses of 500-3000 mg day, adjusted to the degree of leukocytosis and or treatment-related thrombocytopenia) and low-dose ara-C (at a dose of 10 mg m2) are well tolerated and will reduce leukocytosis for a period of time, though neither will impact survival.96 We use the phrase aggressive supportive care to emphasize that symptoms will be treated vigorously and to distinguish this modality from hospice. Blood and platelet transfusions should be administered to alleviate symptoms stemming from anemia and thrombocytopenia, and antibiotics initiated when appropriate. In addition, integrative therapies such as Reike, therapeutic touch, and herbal medicines may be used by the willing patient. These latter interventions often can be...

Prognostic Factors

Estudio y Tratamien to de las Hemopatias Malignas) and Italian (GIMEMA Gruppo Italiano Malattie Emato logiche dell' adulto) APL investigators defined low-, intermediate-, and high-risk subgroups of APL patients based on presenting white blood cell (WBC) and platelet counts (low risk WBC count < 10,000 L and platelet count > 40,000 L intermediate risk WBC count < 10,000 L and platelet count < 40,000 L high risk WBC count > 10,000 L).4 Based on the above analysis, as well as on data from numerous other groups, it is now well known and accepted that APL patients who present with WBC counts of more than 10,000 L have a high risk of treatment failure, due both to an increased incidence of deaths during induction and to a higher risk of relapse. Specific genetic findings, such as the bcr-3 PML breakpoint5 and internal tandem duplication (ITD) of the FLT3 gene,6-9 as well as microgranular morphology, are associated with high WBC count, but have not, in general, been found to have...

The Role Of Arac

While ara-C has historically been relegated to a minor role in the treatment of APL,57 more recent data suggest that certain patients, particularly those with high-risk APL, may derive considerable benefit from the addition of ara-C to their treatment. The German AML Cooperative Group,2425 which uses high-dose ara-C during induction, is one of the only groups to report essentially equivalent outcomes in patients with high and low WBC counts, suggesting that high-dose ara-C overcomes the negative prognostic impact of high WBC count. In the recently reported AIDA 2000 trial,26 intensification of consolidation therapy with ATRA and ara-C in high-risk patients led to a cumulative incidence of relapse of 2 , well below the 29 relapse rate seen in the earlier AIDA 0493 trial, and significantly below the 9 relapse rate noted in intermediate-risk patients consolidated with anthracyclines and ATRA alone. Finally, the European APL Group20 has reported preliminary results of a randomized trial...

Disease Presentation

Patients with acute lymphoblastic leukemia (ALL) present with signs and symptoms related to impaired hematopoiesis from progressively worsening bone marrow involvement. Anemia may result in fatigue, light-headedness, dyspnea, and pallor. Patients with thrombocytopenia may develop petechiae, purpura, and hemorrhage. Fevers and infections also commonly occur due to neutropenia. Approximately one-third of patients have been reported to have infections, hemorrhage, or constitutional symptoms at the time of diagnosis.1-3 Clinical characteristics for patients presenting with ALL are given in Table 12.1. Thrombocytopenia is also commonly observed at the time of diagnosis. Kantarjian et al. noted that 74

Host Factors

Hepatitis C via blood transfusion, had longer duration of disease, were heavy users of alcohol, and had co-infection with hepatitis B. HCC was only observed in patients with cirrhosis. Fourth, Gordon et al. studied 627 patients at one U.S. medical center, and confirmed the link of PTH to more aggressive disease. Logistic regression analysis revealed that the risk of liver failure was predicted primarily by acquisition of infection through transfusion (67). Those authors also found that serum albumin, prothrombin time, and platelet count predicted risk of future hepatic decompensation, and that the risk of developing HCC in cirrhotics was 1.2 yr. The finding that acquisition by transfusion predicted subsequent late clinical events suggests that the load of the initial viral inoculum may modify either the innate cytotoxicity of the virus or the immunological response of the host.

Morphologic Cr

Morphologic CR without complete recovery of platelet count is not considered a category of CR in AML patients.1 The same is true for ALL patients. Time to platelet recovery seems to predict outcome of patients with de novo ALL who have achieved CR.5 In one study, patients who did not achieve platelet recovery by day 48 had a significantly worse outcome than those who achieved platelet recovery by day 12. Therefore, in ALL, morphologic CR without platelet count recovery (> 100 X 109 L) should not be regarded as CR.

CD36 Deficiency

Of clinical importance, type I individuals may produce isoantibodies against CD36 following a transfusion or during pregnancy which can lead to refractoriness to blood group-matched platelet transfusions, post-transfusion purpura, or neonatal immune thrombocytopenia 66-71 . For this reason type I deficiency is sometimes referred to as the Naka-negative phenotype, where anti-Naka is a CD36 isoantibody formed following immunization with the wild-type protein. The identification of CD36 as the Naka isoantigen seen with type I deficiency suggests that CD36 is indeed absent from all cell types in these individuals.

Acute toxicity

The major acute toxicity of 2-CdA is myelosuppression. In their long-term follow-up study, investigators at Scripps Clinic noted a 16 incidence of Grade 3 and a 71 incidence of Grade 4 neutropenia in the first 135 consecutive treated patients.5 Ten percent had Grade 3 and 10 had Grade 4 thrombocytopenia. Grade 3 anemia occurred in 20 and Grade 4 in 2 . Forty-two percent developed neutropenic fever, though in only 13 , was an infection documented. Of these, the most common infecting organism was Staphylococcus, usually associated with the indwelling intravenous catheter. Although there were several oral herpetic infections and acute dermatomal herpes reactivations, no fungal infections were found. This high rate of neutropenia with culture negative neutropenic fever was also noted at similar rates in other single-institution series with 2-CdA. Despite the frequency of myelosuppression, additional acute toxicities were uncommon. There were no significant rates of nausea, vomiting,...

Splenectomy

Splenectomy was the treatment of choice for hairy cell leukemia before the introduction of effective cyto-toxic therapies. In the majority of cases, the peripheral blood counts responded favorably and patients survived for years after the operation, often without additional therapy. Splenectomy removes splenic sequestration of blood elements, thereby alleviating pancytopenia. However, in situations in which pancytopenia is secondary to bone marrow infiltration by hairy cells, splenectomy is less beneficial. CR, defined as hemoglobin greater than 11.0 g dL, granulocyte count greater than 1000 mm3, and a platelet count greater than 100,000 mm3 (Catovsky criteria), has been reported in 40-67 of patients (see Table 31.3). Improvement in at least one cytopenia is seen in up to 90 of patients. The most common hematologic parameter to improve postsplenectomy is the platelet count, often seen within days of the surgery. Patients who achieve a CR have improved survival compared to partial...

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