Abnormalities In Platelet Arachidonic Acid Metabolism In Chronic Idiopathic Thrombocytopenic Purpura

1981 ◽  
Author(s):  
M J Stuart ◽  
J G Kelton ◽  
J B Allen
Keyword(s):  
Arachidonic Acid ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Inverse Correlation ◽  
Arachidonic Acid Metabolism ◽  
Thromboxane B2 ◽  
Bleeding Tendency ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Platelet Thromboxane

Patients with chronic idiopathic thrombocytopenic purpura (CITP) have been described to have bleeding times (B.Ts) that were shorter than would be predicted by their platelet counts. This phenomenon was explained by the presence in CITP of a young platelet population with increased hemostatic competence (NEJM 287:155, ’72). In contradistinction, we have observed patients with CITP to have a bleeding tendency at platelet counts >75,000/cu mm. We therefore evaluated B.Ts and platelet arachidonic acid (AA) metabolism in 7 patients with CITP who demonstrated increased amounts of platelet associated IgG (PAIgG >3fg per platelet) and compared them to 20 healthy controls. 3/7 patients with CITP and platelet counts of >75,000/cu mm demonstrated marked prolongations in their B.Ts. (10’, 12’ and 14’, normal <7’). Marked abnormalities in the metabolism of AA through the cyclo-oxygenase (Thromboxane B2 and HHT) and lipoxygenase (HETE) pathways were also observed in patients with CITP. Platelets in CITP synthesized less amounts (p <0.005) of Thromboxane B2 (10.3 ± 3.1%) in comparison to controls (22.9 ± 1.8). Values for HHT were decreased (23.7 ± 4.9 vs 39.7 ± 1.9; p<0.005), while HETE production was increased (59.5 ± 7.8 vs 30.7 ± 1.8; p<0.001). No correlation was observed between PAIgG and platelet Thromboxane B2 formation. However, an inverse correlation (r=0.81, p<0.05 was observed between the B.T. and platelet Thromboxane B2 formation in patients with chronic ITP. We have demonstrated platelet dysfunction and impaired Thromboxane B2 formation in CITP. This association should be investigated in the individual patient, since the bleeding tendency in these patients is exacerbated by the superimposed impairment in platelet function.

scholarly journals Abnormal platelet function and arachidonate metabolism in chronic idiopathic thrombocytopenic purpura

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 326-329 ◽  
Author(s):  
MJ Stuart ◽  
JG Kelton ◽  
JB Allen
Keyword(s):  
Platelet Aggregation ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Platelet Function ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Arachidonate Metabolism

Abstract We observed several patients with chronic idiopathic thrombocytopenic purpura (ITP) whose bleeding times were more prolonged than would have been expected from their platelet counts. To investigate this further, we performed in vivo and in vitro platelet function studies, assessed arachidonate metabolism, and measured platelet-associated IgG (PAIGG) in seven patients with chronic ITP. The bleeding times of three of the patients were prolonged for greater than 7 min, and all of these patients had impaired platelet aggregation and abnormal platelet arachidonic acid metabolism as reflected by increased production of the lipoxygenase product HETE and a concomitant decrease in cyclooxygenase products, TXB2 and HHT (p less than 0.001). The abnormalities noted were not due to concomitant drug ingestion, since they were present on repeated evaluation. There was no relationship between the platelet count and the bleeding time; however, there was a significant inverse correlation between the bleeding time and TXB2 production in all patients evaluated (r = 0.81; p less than 0.05). There was no relationship between the level of platelet-associated IgG and any parameter of platelet aggregation or arachidonate metabolism. The abnormalities noted should be looked for in the individual patient with chronic ITP, since the bleeding tendency is exacerbated by the superimposed impairment of platelet function even at platelet counts of greater than 50,000/cu mm, levels generally regarded as “safe”.

scholarly journals Abnormal platelet function and arachidonate metabolism in chronic idiopathic thrombocytopenic purpura

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 326-329 ◽  
Author(s):  
MJ Stuart ◽  
JG Kelton ◽  
JB Allen
Keyword(s):  
Platelet Aggregation ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Platelet Function ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Arachidonate Metabolism

We observed several patients with chronic idiopathic thrombocytopenic purpura (ITP) whose bleeding times were more prolonged than would have been expected from their platelet counts. To investigate this further, we performed in vivo and in vitro platelet function studies, assessed arachidonate metabolism, and measured platelet-associated IgG (PAIGG) in seven patients with chronic ITP. The bleeding times of three of the patients were prolonged for greater than 7 min, and all of these patients had impaired platelet aggregation and abnormal platelet arachidonic acid metabolism as reflected by increased production of the lipoxygenase product HETE and a concomitant decrease in cyclooxygenase products, TXB2 and HHT (p less than 0.001). The abnormalities noted were not due to concomitant drug ingestion, since they were present on repeated evaluation. There was no relationship between the platelet count and the bleeding time; however, there was a significant inverse correlation between the bleeding time and TXB2 production in all patients evaluated (r = 0.81; p less than 0.05). There was no relationship between the level of platelet-associated IgG and any parameter of platelet aggregation or arachidonate metabolism. The abnormalities noted should be looked for in the individual patient with chronic ITP, since the bleeding tendency is exacerbated by the superimposed impairment of platelet function even at platelet counts of greater than 50,000/cu mm, levels generally regarded as “safe”.

Immature Platelet Fraction in Different Diagnosis of Thrombocytopenic States: An Approach to Distinguish Idiopathic Thrombocytopenic Purpura from Myelodysplastic Syndrome with Isolated Thrombocytopenia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1085-1085
Author(s):  
Koji Miyazaki ◽  
Miyako Taira ◽  
Tomiteru Togano ◽  
Manabu Ohsaka ◽  
Yuhko Suzuki ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Myelodysplastic Syndrome ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Inverse Correlation ◽  
Consensus Method ◽  
Thrombocytopenic Purpura ◽  
Distribution Width ◽  
Platelet Counts ◽  
Reticulated Platelets ◽  
Immature Platelet Fraction

Abstract It is sometimes confusing to distinguish idiopathic thrombocytopenic purpura (ITP) from thrombocytopenia due to dysmegakaryopoiesis, as seen in myelodysplastic syndrome (MDS) patients, especially MDS with isolated thrombocytopenia. In this study, we investigated the useful parameters for the different diagnosis of thrombocytopenia. The number of reticulated platelets reflects the rate of thrombopoiesis, and this clinical utility has been established in the laboratory diagnosis of thrombocytopenia due to increased peripheral platelet destruction, such as autoimmune thrombocytopenic purpura (AITP). However, the number of reticulated platelets has not been well investigated in the patients with myelodysplatsic syndrome (MDS), while some of them are misdiagnosed as ITP. The aim of this study is to evaluate the diagnostic utility of the measurements of reticulated platelets as well as other parameters of platelets, such as MPV (mean platelet volume), P-LCR (platelet larger cell ratio) and PDW (platelet distribution width). The reticulated platelets, expressed as the immature platelet fraction (IPF) were determined in 108 ITP and 57 MDS patients using the Sysmex XE-2100 blood cell counter with upgraded software (Sysmex, Kobe, Japan). This system enabled rapid, inexpensive, automated, stable measurements of reticulated platelets compared with the flow cytometry system, of which consensus method has not yet been identified to provide acceptable intra- and inter-laboratory results. The platelet counts in ITP and MDS patients were equivalent (ITP, 7.99 ± 0.40 × 104/μL; MDS, 8.05 ± 0.57× 104/μL). The IPF values in ITP patients (10.4 ± 0.61%) were significantly higher than those in MDS (5.82 ± 0.63%), and the inverse correlation between the IPF and the platelet counts was observed among the ITP patients, but not among the MDS. Both MPV and PDW in MDS (10.6 +/− 0.15 fL and 12.2+/−0.41 fL, respectively) were significantly higher than in ITP (7.7 +/− 0.38 fL and 9.4 +/− 0.48 fL, respectively), while P-LCR in MDS (28.7 +/− 1.2%) and ITP (23.6 +/− 1.3%) were not significantly different. Although MPV was correlated with IPF among either group, the correlation between IPF and either PDW or P-LCR was weak among MDS (IPF × PDW, r=0.673; IPF × P-LCR, r=0.660) compared with ITP (IPF × PDW, r=0.779; IPF × P-LCR, r=0.803). Next we precisely investigated the clinical features of the minor population of MDS with higher IPF. Most of these patients revealed the significantly higher values of PAIgG (Platelet-associated IgG) and/or poor response to the blood transfusion, suggesting the possibility of associated autoimmune mechanisms. The patients of MDS in overt leukemic stage also recorded higher IPF even if they had no or few blood transfusion. The IPF would be a useful parameter to distinguish ITP from MDS with isolated thrombocytopenia, which has been shown to have a favorable prognosis.

Bone Marrow Effects of High Dose Folic Acid Therapy in Chronic Idiopathic Thrombocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4016-4016
Author(s):  
Elizabeth Schulz ◽  
Rosangela Albuquerque Ribeiro Holanda ◽  
Francisco Dario Rocha Filho ◽  
Guilherme Alves de Lima Henn ◽  
Ricardo Alves Oliveira
Keyword(s):  
Bone Marrow ◽  
Folic Acid ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Peripheral Blood ◽  
High Dose ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Bone Marrow Biopsies ◽  
Platelet Counts ◽  
Marrow Cellularity

Abstract Chronic idiopathic thrombocytopenic purpura (CITP) is an autoimmune disorder characterized by the production of autoantibodies against specific platelet antigens and characterized by low platelet counts in peripheral blood over a period of at least 6 months. Corticosteroids have been generally used as first line therapy with serious side effects. Previously, we described the beneficial effect of high dose folic acid (HDFA), 5 to 20 mg PO daily), in the therapy of this disease. Presently, we report the treatment of two patients with severe thrombocytopenia with HDFA. A 46 year old splenectomized woman (P1) and a 32 year old non-splenectomized man (P2), who were moderately refractory to prednisone and prednisolone, had a previous history of undifferentiated connective tissue disease characterized by one episode of arthritis (P2 with a positive rheumatoid factor and morning stiffness). Both patients had normal serum folic acid and vitamin B12, and no signs of megaloblastic or dysplastic alterations were evidenced in bone marrow aspirates. Ham test was negative and CD55/CD59 values for both patients were equal to normal controls. Bone marrow biopsies were also performed prior to the treatment with folic acid (FA) to evidence a global decrease in bone marrow cellularity (30% in case 1 and 20% in case 2). Concomitant infections or other diseases were excluded. Prednisone was tapered slowly, and high dose folic acid administration was initiated at this time. P1 achieved complete remission (CR) in 5 months with slowly tapering of folic acid during one year, remaining with normal platelet counts after one more year with no treatment. P2 achieved sustained partial remission (PR) with platelet counts ranging 63 x 109L to 113 x109/L. Interestingly, sequential bone marrow biopsies performed 2 years after the beginning of HDFA therapy revealed a marrow cellularity of 50% and 35% for P1 and P2, respectively. We demonstrated that the successful CR and PR to HDFA are associated with a significant increase in the overall bone marrow cellularity in both cases (20% in P1 and 15% in P2). Apoptotic features in idiopathic thrombocytopenic purpura (ITP) were characterized by Houwerzijl et al who demonstrated apoptosis and para-apoptosis as ultrastructural alterations in bone marrow megacaryocytes, supportive of ineffective thrombopoiesis as an underlying phenomenon in this study. Buemi et al demonstrated that addition of folic acid to the medium of vascular smooth muscle cells in culture inhibited the percentage of apoptotic and necrotic cells through a decrease in homocysteine concentration. The exact mechanism through which high dose folic acid is able to increase platelets measured in peripheral blood of patients with ITP and induce sustained CR and PR is so far unknown and remains to be explained. However, the present response to HDFA suggest a qualitative and especially quantitative role for this drug in protecting and upgrading the hematopoietic bone marrow and, consequently, restoring the platelet production in these 2 patients.

Oral Eltrombopag Treatment Reduces the Need for Concomitant Medications in Patients with Chronic Idiopathic Thrombocytopenic Purpura.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3424-3424 ◽  
Author(s):  
Patrick F. Fogarty ◽  
James B Bussel ◽  
Gregory Cheng ◽  
Mansoor N Saleh ◽  
Balkis Meddeb ◽  
...  
Keyword(s):  
Idiopathic Thrombocytopenic Purpura ◽  
Phase Iii ◽  
Term Therapy ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Once Daily ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Rescue Treatment

Abstract INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, non-peptide thrombopoietin receptor agonist developed as a treatment for thrombocytopenia of various etiologies, including chronic idiopathic thrombocytopenic purpura (ITP). In 2 placebo-controlled studies totaling over 200 patients with chronic ITP, eltrombopag has demonstrated a significant increase in platelet counts and a reduction in clinically relevant bleeding after up to 6 weeks of treatment. EXTEND is an ongoing open-label, phase III extension study to assess the long-term safety and efficacy of oral eltrombopag. Although the primary objective of this study was to raise platelet counts to a safe level (≥50,000/μL), the ability of eltrombopag treatment to allow patients to reduce concomitant ITP medications and avoid the adverse events associated with those therapies was also of interest. METHODS: Adult patients with previously treated chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted to maintain platelet counts ≥50,000/μL and <400,000/μL, with doses between 75 mg once daily and 25 mg once daily or less often than once daily, if necessary. The effect of eltrombopag treatment on the ability of patients to reduce and/or discontinue baseline concomitant ITP medications was evaluated. RESULTS: As of the clinical cut-off date (January 7, 2008), 207 patients (median age, 50 years; 67% female) had received eltrombopag. At baseline, 69 (33%) patients reported the use of ITP medications; of these, 65 patients had at least 1 post-baseline visit by the clinical cut-off date and were evaluable for response status. Eighty percent (52/65) of these patients responded to eltrombopag with a platelet count of ≥50,000/μL during the study. Forty-eight percent (33/69) of patients attempted to reduce or discontinue their concomitant ITP medications during the study. Seventy percent (23/33) of these patients discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment as of the clinical cut-off date; of these, 65% (15/23) had maintained the discontinuation or reduction for at least 24 weeks as of the clinical cut-off date. Sixty-one percent (20/33) of patients discontinued at least 1 baseline ITP medication, and 55% (18/33) discontinued all baseline ITP medications, without subsequent rescue treatment. Discontinued or reduced medications included prednisone (n = 11); prednisolone (n = 8); danazol (n = 5); and azathioprine, dexamethasone, mycophenolic acid, and oxymetholone (n = 1 each). Only 12% (8/69) of patients increased the dose of concomitant ITP medication from baseline. CONCLUSION: In this study, long-term therapy with oral eltrombopag allowed 80% of patients with chronic ITP who were also receiving a concomitant ITP medication at baseline to maintain elevated platelet counts sufficient to permit a reduction in the use of concomitant ITP medications without the need for rescue therapy.

Acute kidney injury and nephrotic syndrome associated with eltrombopag therapy in chronic idiopathic thrombocytopenic purpura

2021 ◽  
Vol 14 (4) ◽  
pp. e241462
Author(s):  
Suchi Anindita Ghosh ◽  
Jean Patrick ◽  
Kyaw Zin Maw
Keyword(s):  
Acute Kidney Injury ◽  
Renal Failure ◽  
Nephrotic Syndrome ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Kidney Injury ◽  
High Dose ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Antibody Screen ◽  
Auto Antibody

A 77-year-old man was admitted with severe acute kidney injury and nephrotic syndrome. He was started on eltrombopag for chronic idiopathic thrombocytopenic purpura 6 weeks earlier. An ultrasound of the kidneys was normal and an auto-antibody screen was negative. The use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient’s development of acute renal failure and eltrombopag therapy. Literature review identified only one other case of nephrotic syndrome and acute kidney injury associated with eltrombopag therapy in which a kidney biopsy revealed focal segmental glomerulosclerosis. Due to the challenges faced during the prevailing SARS-CoV-2 pandemic and persistent low platelet counts a renal biopsy was not undertaken. On stopping eltrombopag, the patients renal function stabilised and he successfully went into remission following treatment with high dose corticosteroids and diuretics. This report of a serious case of reversible renal failure and nephrotic syndrome after treatment with eltrombopag may serve to inform clinicians about the possible severe renal adverse effects of eltrombopag before its commencement for future use.

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