Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes

Abstract Thrombocytosis at presentation is uncommon in the myelodysplastic syndromes (MDS), and its influence on the clinical course of the disease and on prognosis is uncertain. To determine the clinical course and long-term outcomes of patients (pts) with thrombocytosis at initial diagnosis of MDS, we conducted a retrospective analysis of 503 pts diagnosed with MDS between Jan 1966 and July 2006 at the Minneapolis VA Medical Center. Original bone marrow and peripheral blood slides and reports were reviewed with a hematopathologist (H.M.) in all pts with high platelet counts (> 400 × 103/μL) and evidence of dysplasia. Clinico-pathological correlation was obtained by chart review. Patients with inadequate data, secondary causes of thrombocytosis, transient thrombocytosis, and those without evidence of dysplasia were excluded. Of 503 pts, 41 (8.2%) were found to have thrombocytosis at presentation. Their median age was 74 years. The spleen was enlarged (by imaging) in 6 pts. Peripheral blood counts (mean; range) at diagnosis were: hemoglobin (10.9 g/dL; 7.4 – 17.1), absolute neutrophils (7.9 × 103/μL; 0.8 – 30.7) and platelets (627 × 103/μL; 402 – 1231). The cases were re-classified according to the WHO classification of myeloid disorders as follows: chronic myelomonocytic leukemia-1 (CMML-1) = 17 (41%), refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) = 13 (32%) and others = 11 (27%; including 2 pts each with RA, MDS/myeloproliferative disorder-unclassified [MDS/MPD-U] and 5q- syndrome, and 1 pt each with RA with excess blasts [RAEB-1], therapy related MDS [tMDS], refractory cytopenia with multilineage dysplasia [RCMD], MDS-U and atypical chronic myeloid leukemia [Aty CML]). Bone marrow fibrosis was increased in 3 pts with CMML-1 and 1 with RARS-T, and was normal or only focally increased in all other pts. The IPSS risk category was Low in 15 pts, Int-1 in 3 pts and Int-2 in 2 pts. Cytogenetic data was not available in the other pts. Jak-2 mutation analysis was positive in 2 pts with RARS-T, negative in 1 pt each with RARS-T and MDS/MPD-U, and is pending in others. On follow-up, 2 pts with CMML-1 and 1 pt with Aty CML transformed to acute myeloid leukemia (AML) and both pts with 5q- syndrome transformed to CMML-2. Two pts with RARS-T progressed to RAEB-2 and 1 pt with CMML-1 progressed to CMML-2. One pt with CMML-1 developed marked myelofibrosis. Marked thrombocytosis required hydroxyurea treatment in 5 pts. One MDS-U pt received 5-azacytidine. Four of 41 (10%) pts experienced major bleeding events; 3 were receiving aspirin. Five pts required ongoing red cell transfusions. The median survival (MS) was 36 months in RARS-T, 60 months in CMML-1 and 27 months in others; the MS of all 41 pts was 48 months. Causes of death were AML in 3 pts, cytopenias due to MDS in 6 pts and unrelated/unknown in 21 pts. Eleven pts are currently alive. In conclusion, the majority of pts presenting with myelodysplasia and thrombocytosis fall in the MDS/MPD category of the new WHO classification (most commonly CMML or RARS-T), be older, and have low-risk features (IPSS Low or Int-1). The risks of spontaneous bleeding, transformation to AML, progression of disease or myelofibrosis are low, and the overall prognosis is relatively favorable. Platelet counts may reach levels requiring cytoreductive therapy. This study helps better understand the natural history and prognosis of this varied spectrum of MDS and overlap syndromes.

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The Burden of Clinically Significant Bleeding, Thrombocytopenia and Platelet Transfusions in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2019-125273 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 719-719

Author(s):

Kathleen Pao Lynn Cheok ◽

Rakchha Chhetri ◽

Li Yan A Wee ◽

Arabelle Salvi ◽

Simon McRae ◽

...

Keyword(s):

Risk Factors ◽

Antiplatelet Therapy ◽

Myelodysplastic Syndromes ◽

Cumulative Incidence ◽

Platelet Transfusion ◽

Severe Thrombocytopenia ◽

Bleeding Events ◽

Platelet Counts ◽

Immune Mediated ◽

Platelet Transfusions

Aim: Although 40-65% of myelodysplastic syndromes (MDS) patients are thrombocytopenic and require platelet transfusions, there is limited literature on the risk factors predictive of bleeding and the burden of immune mediated platelet refractoriness (PLT-R). Objectives: To evaluate the prevalence of thrombocytopenia, incidence of bleeding events, platelet transfusion dependency (PLT-TD) and immune-mediated platelet refractoriness (PLT-R) in MDS patients. Methods: A retrospective analysis of 754 MDS patients enrolled in the South Australian MDS (SA-MDS) registry was performed. Platelet counts <100, <50 and <20 (x109/L) were used to define mild, moderate and severe thrombocytopenia respectively. The severity of bleeding events was classified according to the International Society of Thrombosis and Haemostasis (ISTH) classification. PLT-TD was defined as transfusion of at least one unit of platelets each month for four consecutive months. All other patients were classified as transfusion independent (PLT-TI). Immune mediated PLT-R was defined if a patient had HLA-class I or HPA antibodies, poor platelet increments and required HLA-matched platelets. Medication history with regards to anticoagulation and/or antiplatelet therapy was also collected. Results: At diagnosis, 332 (45%) patients had thrombocytopenia and 106 (14%) patients had moderate to severe thrombocytopenia. During the study period, 249 bleeding events were recorded in 162 (21%) patients with a cumulative incidence of 33% (Fig 1A). Of the 249 bleeding events, 85 (34%) were major and 164 (66%) were clinically relevant minor bleeding. Notably, 16, 90 and 5 bleeding events were intracranial, gastrointestinal, intraocular respectively. While 41% (96/235) bleeding events occurred in the setting of moderate to severe thrombocytopenia, 21% and 38% (Fig 1B) of bleeding events occurred at platelet counts of >50-100 and >100x109/L respectively. Twenty-eight percent (69/249) bleeding events were associated with concomitant anticoagulation and/or antiplatelet therapy and importantly, platelets counts were >50x109/L and >100 x109/L in 57 (83%) and 46 (67%) at the time of bleeding events, respectively. During the disease course, 393 (52%) patients required at least one unit of platelet transfusion. 106 (14%) patients were PLT-TD and had significantly poor overall survival (OS) compared to PLT-TI (26 vs 42 months, p<0.0001). In total, 30/393 (7%) required HLA-matched platelet transfusions. 20/30 (66%) of PLT-R patients were female receiving disease modifying therapy (DMT). This was substantiated by cox regression analysis, demonstrating that females (HR=5.32, p=0.0006), older age (HR=0.97, p=0.028) and haemoglobin (Hb) at diagnosis (HR=1.03, p=0.009) were independent risk factors for PLT-R. Importantly, 20/76 (25%) female patients receiving platelets and DMT developed immune mediated PLT-R requiring HLA matched platelets. Conclusions: In our cohort of MDS patients, cumulative incidence of bleeding is 33% and 59% of the bleeding events occurred at platelet counts >50X109/L. For all bleeding events that occurred while on anticoagulation and/or antiplatelet therapy, 83% events occurred with platelet counts >50 x 109/L. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. We also showed that development of PLT-TD is associated with poor OS. Importantly, 1 in 4 female MDS patients receiving platelets and DMT required HLA-matched platelets. Platelet transfusions practices should be optimised for these high-risk groups. Disclosures No relevant conflicts of interest to declare.

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Associations Between Platelet Count and Survival and Disease Progression In Thrombocytopenic Patients with Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v116.21.2905.2905 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2905-2905

Author(s):

Mellissa Yong ◽

Carrie Kuehn ◽

Michael Kelsh ◽

Meghan Wagner ◽

Allen Yang ◽

...

Keyword(s):

Platelet Count ◽

Survival Time ◽

Disease Progression ◽

Median Survival ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Employment Equity ◽

Classification Schemes ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2905 Introduction: Myelodysplastic syndromes (MDS) are a group of malignant bone marrow stem cell disorders characterized by a predisposition for transformation to acute myelogeneous leukemia (AML). MDS disorders are heterogeneous in their morphology, cytogenetics, survival time, and ability to transform to AML. Although numerous classification schemes have been developed to provide a reproducible method for estimating patient survival and risk of leukemic evolution, research continues to identify factors that affect prognosis and survival time (e.g., treatment type, WHO FAB subgroups, karyotype, and transfusion status) and refine existing classification schemes. The goal of this analysis was to evaluate the effect of platelet counts on survival and disease progression to AML among thrombocytopenic (platelet count <100 × 109/L) MDS patients (n = 303) using the International MDS Risk Analysis Workshop (IMRAW) database. Methods: The IMRAW dataset includes demographic, clinical and prognostic information for patients treated in the United States, Europe, and Japan who were diagnosed with MDS between 1972 and 1994. Platelet count (× 109/L) was categorized as follows: 0 to <20, 20 to <30, 30 to <50, 50 to <70, 70 to <80, 80 to <90, 90 to <100, and ≥100. Survival was modeled using the Kaplan-Meier (K-M) estimator. One-, two-, and three-year survival rates and median, quartile, and restricted mean survival time were estimated using K-M methods. Time to evolution to AML was modeled using the Nelson-Aalen (N-A) cumulative hazard estimator with death prior to onset of AML as a competing risk event. One-, two-, and three-year cumulative rates of AML evolution were generated using N-A methods. Mean, median, and quartile values for time to AML evolution were also summarized. Cox proportional hazards modeling was used to estimate the hazard ratio (HR) for survival and evolution of MDS to AML. Results: Among thrombocytopenic MDS patients (n = 303), one-, two- and three-year survival were 58%, 44%, and 33%, respectively. Median survival was 19.6 months, with the lowest among those with a platelet count 0 to <20 × 109/L (10.9 months) and the highest among those with a platelet count 90 to <100 × 109/L (33.2 months). Patients with platelet counts (x 109/L) <70, 70 to <90, and ≥90 formed three distinct survival groups for approximately three years after MDS diagnosis (Figure 1). Across platelet categories, one-, two- and three-year survival ranged from 48.2% to 83.4%, 37.3% to 68.0%, and 30.5% to 39.9%, respectively (Table 1). Among non-thrombocytopenic MDS patients (platelet count ≥100 × 109/L), the one-, two- and three-year survival were 83.1%, 68.6%, and 59.1%, respectively, and the median survival was 47.3 months. Results of Cox models for thrombocytopenic MDS patients suggested an increased risk of death with platelet counts <90 × 109/L compared to platelet counts 90 to <100 × 109/L and no relationship was shown between strength of the HR and decreasing platelet count when adjusted for gender, age, year of diagnosis and institution (Table 1). Among thrombocytopenic MDS patients who developed AML (n = 73), median time to AML diagnosis from MDS diagnosis was 9.2 months. One-, two- and three-year evolution to AML rates were 21%, 30%, and 38%, respectively. Conclusions: Platelet count in thrombocytopenic MDS patients may be clinically relevant to survival and should be evaluated further. Platelet count does not appear to be associated with risk of evolution to AML. Evaluation of these relationships in a larger sample is warranted. Disclosures: Yong: Amgen Inc: Employment, Equity Ownership. Kuehn:Amgen Inc: Research Funding. Kelsh:Amgen Inc: Research Funding. Wagner:Amgen Inc: Research Funding. Yang:Amgen Inc: Employment, Equity Ownership. Franklin:Amgen Inc: Employment, Equity Ownership.

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A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia

Blood ◽

10.1182/blood.v85.11.3066.bloodjournal85113066 ◽

1995 ◽

Vol 85 (11) ◽

pp. 3066-3076 ◽

Cited By ~ 98

Author(s):

MS Gordon ◽

J Nemunaitis ◽

R Hoffman ◽

RL Paquette ◽

C Rosenfeld ◽

...

Keyword(s):

Phase I ◽

Myelodysplastic Syndromes ◽

Interleukin 6 ◽

Phase I Trial ◽

Acute Phase Proteins ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Hematopoietic Growth Factors ◽

Elevated Alkaline Phosphatase ◽

Platelet Counts

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.

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Burden of Cardiovascular Events and Bleeding Is High in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2020-143319 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Rakchha Chhetri ◽

Oisin Friel ◽

Monika M Kutyna ◽

Kathleen Pao Lynn Cheok ◽

Li Yan A Wee ◽

...

Keyword(s):

Risk Factors ◽

Antiplatelet Therapy ◽

Myelodysplastic Syndromes ◽

Anticoagulation Therapy ◽

Bleeding Complications ◽

Severe Thrombocytopenia ◽

Bleeding Events ◽

Platelet Counts ◽

Risk Of Bleeding ◽

Rbc Transfusion

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) patients are older and suffer with cardiovascular (CV) diseases. Management of these patients with antiplatelet and anticoagulation therapy is challenging as thrombocytopenia can increase the risk of bleeding. Aim: To assess burden and CV disease related mortality, review of anticoagulant /antiplatelet therapy and bleeding complications in MDS and oligoblastic AML patients. Methods: Electronic medical records of 910 MDS and oligoblastic AML patients enrolled in the South Australian MDS (SA-MDS) registry were reviewed. CV risk factors, CV and bleeding events requiring or occurring during hospitalisation, anticoagulation and/or antiplatelet therapy information were collected. Platelet counts of <100, <50 and <20 (x109/L) were defined as mild, moderate and severe thrombocytopenia respectively. Severity of bleeding events was classified using modified International Society of Thrombosis and Hemostasis (ISTH) classification. MDS patients require regular RBC transfusion, hence fall in hemoglobin ≥20 gm/L or ≥2 units of RBC transfusion were not used for defining major bleeding. Results: At the time of MDS diagnosis, 72% (658/910) and 42% (386/910) patients had ≥1 and ≥2 CV risk factors. Twenty-five percent patients required hospitalization for CV events prior to the MDS diagnosis and their median OS was significantly poor compared to patients who did not have CV events (Figure 1A). During median follow up of 28 months after MDS diagnosis, 27.5% (251/910) patients were admitted with or developed CV events during hospitalization. In a Cox-regression analysis age, absolute monocyte count, CV risk factors and prior CV events were independent predictors of CV events following MDS diagnosis (Figure 1B). The most frequent CV events were arrhythmia (137/399; 34%), congestive cardiac failure (129/399; 32%), and ischemic heart disease (94/399; 23%). Atrial fibrillation (AF) contributed towards 78% (108/137) of all arrhythmias. 39% of AF occurred in the setting of infections and 12% patients died during the same hospitalization or were palliated. 89% of AF patients had a CHADS2VASc2 score ≥2, however only 30% (20/65) and 24% (16/65) events with available information were treated with anticoagulation and antiplatelet therapy respectively. While 60% (39/65) AF events did not receive antiplatelet or anticoagulation therapies. Four AF patients developed ischemic stroke following MDS diagnosis and five patients had stroke before MDS diagnosis and were subsequently diagnosed with AF. Importantly, 36% (34/94) AF patients developed 45 bleeding events. The frequency of bleeding events was not significantly different between patients treated with anticoagulation/antiplatelet therapy versus who were not treated (13.8% vs. 13.6%). Although, cumulative incidence of bleeding and CV events was similar at 29% and 28% at five-years (Figure 1C-D), only some patients had both events. Of the 387 patients, 39% (n= 152) and 39% (n=153) patients required hospitalization only for CV or bleeding events, while only 21% (82/387) required hospitalization for both bleeding and CV events. Identifying these three groups early is crucial to optimize their outcome. Of the 387 bleeding events, 88 (24%) were major and 296 (76%) were clinically relevant minor bleeding. Notably, 127, 47 and 15 bleeding events were gastrointestinal, intracranial and intraocular respectively. While 50% bleeding events occurred in the setting of moderate to severe thrombocytopenia, 19% and 31% of bleeding events occurred at platelet counts of >50-100 and >100x109/L respectively (Figure 1E). Details of anticoagulation/antiplatelet therapy were available for 66% (161/243) of bleeding events. Importantly, 76% of bleeding events occurred without anticoagulation and antiplatelet therapy, while 10% and 13% bleeding occurred while on anticoagulation therapy and antiplatelet therapy respectively. Conclusions: Our analysis demonstrates a significant burden of CV and bleeding in MDS. Only 23% of all bleeding events occurred while on anticoagulation therapy and some patients with recurrent CV events did not require hospitalization for bleeding. However, large numbers of CV events are sub-optimally managed due to perceived excess risk of bleeding. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. Disclosures Hiwase: Novartis Australia: Research Funding.

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Quality of Life Burden Among Patients with Myelodysplastic Syndromes: Analysis of Survey Data

Blood ◽

10.1182/blood.v124.21.1303.1303 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1303-1303 ◽

Cited By ~ 1

Author(s):

Sandra E. Kurtin ◽

Eunice Chang ◽

Tanya GK Bentley

Keyword(s):

Quality Of Life ◽

Risk Score ◽

Myelodysplastic Syndromes ◽

Disease Risk ◽

Well Being ◽

Statistical Testing ◽

Platelet Counts ◽

Part Time ◽

Over Time

Abstract Background: Myelodysplastic syndromes (MDS) comprise a group of clonal myeloid malignancies primarily affecting the elderly and resulting in limited survival and poor quality of life. A previous survey of MDS patients demonstrated that lower hemoglobin (Hgb) levels and platelet counts are associated with worsening quality of life.1 We conducted a follow-up survey to: Examine the relationships between MDS patients’ quality of life and Hgb/platelet levels;Evaluate changes in these outcomes over time. Methods:The MDS Foundation recruited MDS patients between July 2013 and June 2014 to complete a one-time, web-based questionnaire. The survey included questions about patient demographics, disease risk (i.e., International Prognostic Scoring System [IPSS] score), and MDS characteristics. Quality of life was assessed using the standardized Functional Assessment of Cancer Therapy (FACT)-General (FACT-G; total score and Physical, Social/Family, Emotional, and Functional Well-Being subscales) and Thrombocytopenia scales, all of which were evaluated according to published scoring algorithms. Responses were analyzed using descriptive statistics, and statistical testing was conducted to compare FACT-G scores by categories of Hgb levels and platelet counts. Proportions and comparative results exclude missing data. Results: A total of 727 patients participated in the survey. More than half (58%; 331/570) of those who reported an MDS diagnosis date had been diagnosed for <3 years. Among patients who provided demographic data, patients were on average 68 years of age (n=502), 47% female (234/502), and 90% Caucasian/white (452/503). Over half of respondents (56%; 277/495) had completed 4+ years of college, and 20% (97/498) reported working full or part-time. Less than half (45%; 327/727) reported knowledge of their IPSS risk score; of these, 72% (237/327) were lower risk (IPSS “low” and “intermediate 1”) and 28% (90/327) were higher (IPSS “intermediate 2” and “high”). On a scale of 0 to 108, mean FACT-G total score was 73.1 among all respondents, 75.5 among those with lower IPSS risk, and 72.2 with higher risk. FACT-G total and subscale scores were generally higher among patients with Hgb≥9. Significant differences (p<0.01) by Hgb level existed in all subscales except Social/Family Well-Being (p=0.718), and by platelet count (p<0.02) for all except Social/Family (p=0.795) and Emotional Well-Being (p=0.141). Compared with respondents of the prior survey, current patients were: older (mean age: 68 vs. 63 years); more likely to be female (47% vs. 43%), Caucasian/white (90% vs. 83%), and completed 4+ years of college (56% vs. 40%); and less likely to be working full or part-time (20% vs. 33%). Fewer current than prior patients reported knowledge of their IPSS risk score (45% vs. 53%); of these, more current than prior patients were higher IPSS risk (28% vs. 21%). Results from both surveys indicated significant differences (p<0.01) by Hgb level in all FACT-G subscales except Social/Family Well-Being. Platelet counts significantly impacted the Functional and Thrombocytopenia but not Social/Family subscales in both surveys, and their impact on the Physical and Emotional subscales changed over time. Conclusions: The MDS patient population has changed somewhat but not dramatically in recent years. Their slightly older age and higher IPSS risk may in part explain why current patients are less likely than prior patients to be working, despite their higher education level. Hgb levels and platelet counts significantly impacted most aspects of MDS patients’ quality of life over both time periods. Until therapy options that minimize symptomatic cytopenias become available, more research is needed to identify better ways to improve the physical, functional, and emotional well being of symptomatic MDS patients. Focusing the attention of physicians, family members, and other MDS support structures on these aspects of patient care will benefit patients and their caregivers alike. References Kurtin S & Demakos E. Disease Burden and Treatment Impact associated with Myelodysplastic Syndromes: Initial Estimates. Leukemia Research, May 2011(S) – Proceedings of the 11th International Myelodysplastic Syndrome Symposia. Abstract 560. Disclosures Kurtin: Celgene, Millenium, Onyx, TEVA, Onconova, Incyte: Consultancy. Chang:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by MDS Foundation to conduct the analyses described in this abstract. Other. Bentley:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by MDS Foundation to conduct the analyses described in this abstract. Other.

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Ultrastructural investigations of MDL 19,660-induced effects on the canine platelet and megakaryocyte

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159412 ◽

1990 ◽

Vol 48 (3) ◽

pp. 374-375

Author(s):

D.E. Loudy ◽

J. Sprinkle-Cavallo ◽

J.T. Yarrington ◽

F.Y. Thompson ◽

J.P. Gibson

Keyword(s):

Antidepressant Drug ◽

Beagle Dogs ◽

Long Term Effects ◽

Short Term ◽

Platelet Counts ◽

Toxicological Studies ◽

Induced Aggregation ◽

Internal Architecture

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.

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