Thrombin Generation in Two Families with Myh-9-Related Platelet Disorder

Abstract MYH-9 related platelet disorders are inherited macrothrombocytopenias. Before the genetic cause was identified, four overlapping syndromes (May-Hegglin, Epstein, Fechtnerand Sebastian syndrome) described the additional clinical manifestations in MYH-9 disorders including renal failure, hearing loss, pre senile cataract and inclusion bodies in leucocytes that are present in different combinations. The MYH-9-gene codes for the cytoplasmic contractile protein non muscular myosin heavy chain IIA, present in several tissues, which explains the additional symptoms. The bleeding tendency is usually mild to moderate but rarely, thrombotic complications are also seen (1). We report on the thrombin generation potential (ETP) in MYH9 patients with and without arterial thrombosis. In the first family (family A) 4 members were evaluated: a 51 year old woman (platelet count 36), her 24 year old daughter (platelet count 46), and the brother of the woman (57 years; platelet count 39) and his 30 year old son (platelet count 44). All four were affected by MYH-9 disorder with macrothrombocytopenia and inclusion bodies in the leucocytes and a 5521G>A mutation, causing Glu1841Lys. 3 of them had a moderate bleeding tendency [ISTH /SSC bleeding scores 9, 13, 4 where <4 is normal) (3)] and in the 51 year old women and her brother, renal insufficiency and hearing loss were already present. Both patients had an arterial thrombosis (myocardial infarction and pons infarction respectively) before 50 year of age. Both showed hyperlipidemia and hyperhomocysteinemia. In the second family (Family B) macrothrombocytopenia and small to medium size inclusion bodies in the leucocytes were found in the mother (38 years; platelet count 36) and the daughter (age15 years, platelet count 46) caused by a c. 4679 T>G mutation resulting in p.Val1560Gly. Their bleeding tendency was mild (bleeding scores 4 and 3 respectively). Thrombelastography (ROTEM) was normal in all five individuals. ETP was seen to be below the normal range in family B. However, in family A, the two members affected by thrombosis had a normal ETP (Fig 1), indicating that other factors compensated for the low platelet count and clinically even led to a breakthrough of arterial thrombosis despite the low platelet count. We suggest that other centers also assess the ETP in their MYH-9 patients according tour protocol to gather data on the potential association of the ETP with the phenotype. References Althaus K, Greinacher A: MYH-9 Related Platelet Disorders: Strategies for Management and Diagnosis. Transfus Med Hemother. 2010 October; 37(5): 260–267. Girolami A , Vettore S, Bonamigo E, Fabris F: Thrombotic events in MYH9 gene-related autosomal macrothrombocytopenias (old May–Hegglin, Sebastian, Fechtner and Epstein syndromes) J Thromb Thrombolysis. 2011 Nov;32(4):474-73. Rodeghiero F, Tosetto A, Abshire T et al.; ISTH/SSC Joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessmenttool: a standardizedquestionnaire and a proposal for a newbleedingscore for inherited bleeding disorders. J Thromb Haemost 2010; 8: 2063–5. Figure 1. Endogenous thrombin potential in two families with MYH-9 related disease Figure 1. Endogenous thrombin potential in two families with MYH-9 related disease Thrombin generation was performed on frozen platelet rich plasma on 5 members from two different families (family A and B) with MYH-9 related disease. Two members in the first family (A:1 and A:2) had a previous arterial thrombosis (pons infarction and myocardial infarction, respectively, marked with a star). Disclosures No relevant conflicts of interest to declare.

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A 64-year-old man suffering from ST-elevation myocardial infarction and severe thrombocytopenia: Procedures in the case of a patient not fitting the guidelines

SAGE Open Medical Case Reports ◽

10.1177/2050313x19840520 ◽

2019 ◽

Vol 7 ◽

pp. 2050313X1984052

Author(s):

Dawid Ilnicki ◽

Rafał Wyderka ◽

Przemysław Nowicki ◽

Alicja Sołtowska ◽

Jakub Adamowicz ◽

...

Keyword(s):

Myocardial Infarction ◽

Platelet Count ◽

Coronary Angiography ◽

Antiplatelet Therapy ◽

St Elevation Myocardial Infarction ◽

Severe Thrombocytopenia ◽

Therapeutic Decisions ◽

Increased Risk ◽

Low Platelet Count ◽

St Elevation

The objective of this case report is to present how the chronic condition significantly complicates life-saving procedures and influences further treatment decisions. A 64-year-old man suffering from arterial hypertension and immune thrombocytopenic purpura presented to the Emergency Department with anterior ST-elevation myocardial infarction. An immediate coronary angiography was performed where critical stenosis of the proximal left anterior descending was found. It was followed by primary percutaneous intervention with bare metal stent. In first laboratory results, extremely low platelet count was found (13 × 109/L). Consulting haematologist advised the use of single antiplatelet therapy and from the second day of hospitalisation only clopidogrel was prescribed. On the sixth day of hospital stay, patient presented acute chest pain with ST elevation in anterior leads. Emergency coronary angiography confirmed acute stent thrombosis and aspiration thrombectomy was performed. It was therefore agreed to continue dual antiplatelet therapy for 4 weeks. As there are no clinical trials where patients with low platelet count are included, all therapeutic decisions must be made based on clinician’s experience and experts’ consensus. Both the risk of haemorrhagic complications and increased risk of thrombosis must be taken into consideration when deciding on patient’s treatment.

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Familial Thrombocytopenia With Morphological Changes In Megakaryocytes: A Possible New Inherited Purpura

10.1055/s-0038-1653275 ◽

1981 ◽

Author(s):

F Frassoni ◽

F Piovella ◽

C Castagnola ◽

P Almasio ◽

M M Ricetti ◽

...

Keyword(s):

Electron Microscopy ◽

Bone Marrow ◽

Platelet Count ◽

Factor Viii ◽

Bleeding Time ◽

Great Increase ◽

Morphological Changes ◽

Bleeding Tendency ◽

Peripheral Area ◽

Low Platelet Count

Results of an investigation concerning a familial thrombocytopenia with morphological abnormalities of bone marrow megakaryocytes and moderate bleeding tendency are presented. The laboratory and clinical data of a young woman and her mother are described. Both patients presented orolonged bleeding time which correlated with a low platelet count and which was not asso ciated with morphological or functional platelet impairment or plasmatic factors defects. Examination of bone marrow aspirates of both proposita revealed the presence of unusual features.Smears revealed a great increase of megakaryo cyte count and most of them had the appearance of micromegakaryocytes. The nature of these celi was confirmed by immunofluorescence for factor VIII-related antigen and fibronectin. Electron microscopy performed on megakaryocytes showed the presence of a wide peripheral area of amornhous substance, while platelet ultrastructure did not show any abnormality.

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Routine Measurement of Endogenous Thrombin Potential (ETP) To Assess Hemostatic Function in Patients with Liver Cirrhosis.

Blood ◽

10.1182/blood.v108.11.4014.4014 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4014-4014

Author(s):

Alain P. Gadisseur ◽

Jeoffrey Schouten ◽

Sven Franque ◽

Marc Van der Planken ◽

Peter Michielsen ◽

...

Keyword(s):

Liver Cirrhosis ◽

Thrombin Generation ◽

Pearson Correlation ◽

Area Under The Curve ◽

Classification Systems ◽

Bleeding Tendency ◽

Endogenous Thrombin Potential ◽

Automated Assay ◽

The Mean

Abstract The maintenance of hemostasis through the production of most of the coagulation proteins is a basic liver function. In patients with cirrhosis of the liver the decrease in these proteins is one of the contributory factors to an increased bleeding tendency. Normally the hemostatic capacity of the liver is measured through routine clotting tests as the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT). In the Child classification for liver cirrhosis the coagulation as expressed by the PT is one of the determinants. Recently a test has become available which will make it possible to routinely measure the endogenous thrombin generation potential (ETP) which may be a better alternative. In this test according to the method first described by Hemker (1993) thrombin generation is continuously measured by use of a chromogenic substrate. Results are calculated as area under the curve and as a percentage of normal. We analysed 110 patients with liver cirrhosis classified according to the Child classification, 79 patients with stage A, 19 stage B and 12 stage C, without known pre-existing coagulation abnormalities like inherited bleeding disorders, or anticoagulant drugs. In these patients ETP, APTT, PT/INR, FV, FVII and FXI were measured. We used a fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany). The results for the mean PT were 81% (CI95 77 - 85) for Child A patients, 53% (CI95 44 - 63) for Child B, and 41% (CI95 33 - 50) for Child C. For the mean INR the results were 1.11 (CI95 1.08 - 1.14) for Child A patients, 1.65 (CI95 1.22 - 2.08) for Child B, and 1.82 (CI95 1.34 - 2.31) for Child C. The results for the mean normalized ETP were 0.87 (CI95 0.84 - 0.90) for Child A patients, 0.78 (CI95 0.68 - 0.88) for Child B, and 0.58 (CI95 0.51 - 0.64) for Child C (p<0.001). While the normalized ETP correlated well with both PT and INR for Child B (P<0.05) and C (p<0.01), there were significant differences within the child A patients where no significant correlation could be identified (Pearson correlation 0.203, R2=0.04, p=0.075. We conclude that the fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany) is a potentially interesting test to measure the coagulation abilities in patients with liver cirrhosis which in the future may supersede the PT/INR in classification systems for hepatic disease.

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LOW PLATELET COUNT AND FATAL MYOCARDIAL INFARCTION: A POPULATION BASED ANALYSIS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(15)60218-2 ◽

2015 ◽

Vol 65 (10) ◽

pp. A218

Author(s):

Venkat Vuddanda ◽

Abhishek Goyal ◽

Marjan Mujib ◽

Sahil Khera ◽

Dhaval Kolte ◽

...

Keyword(s):

Myocardial Infarction ◽

Platelet Count ◽

Population Based ◽

Low Platelet Count ◽

Fatal Myocardial Infarction

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Thrombosis in Patients with Immune Thrombocytopenia ,Review of Literature

Blood ◽

10.1182/blood-2020-136513 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Maimoonah Rasheed ◽

Ashraf Tawfiq Soliman ◽

Mohamed A Yassin

Keyword(s):

Platelet Count ◽

Venous Thrombosis ◽

Immune Thrombocytopenia ◽

Thrombotic Event ◽

Bleeding Tendency ◽

Accelerated Atherosclerosis ◽

Immune Mediated ◽

Increased Risk ◽

Low Platelet Count ◽

Active Disease

Introduction ITP is characterized by low platelet count due to immune mediated destruction and bleeding tendency. However, during last few decades thromboembolic events have been reported in patients with ITP. This review is done to study the reported cases of thromboembolic phenomenon in patient with ITP in an attempt to assess the patient characteristics and to understand the underlying mechanism. Methods We searched google Scholar, PubMed about cases with ITP and thrombosis the summary is presented in the following table (Table 1). Results Around 30 reported cases of ITP with thrombotic events were identified and a total of 36 events were recognized in last 10 years. The ages ranged from 3 years to 81 years with a mean of 51 years. Most of the patients were young and middle aged (18-65 years of age), meanwhile around 9 patients were elderly (age > 65 years). Only 3 cases were observed in pediatric age. Almost equal incidence in both genders was recognized. Half of the patient had chronic ITP while in the rest it was diagnosed less than a year. 20 out of 36 (55.6%) events happened at platelet count less than 100*10^9. While 16 events were reported with platelet count higher than this or unknown. Majority of the patients (around 64%) developed arterial events while fewer developed venous thrombosis. For treatment, most of the patients (44%) were not receiving any particular treatment for ITP at the time of thrombotic event. While 6 events (17%) happened while being treated with IVIG and 10 events (28%') happened while on TPO-RA. Only 3 patients were treated with corticosteroids prior to the event. In patients treated with TPO-RAs arterial and venous events were almost similar (57% vs 43% respectively) while majority of the events happened at lower than normal platelet count (7/10 events). Almost half of the patients had one or more underlying risk factor predisposing to atherosclerosis and thrombosis. Most of the patients were treated appropriately for the events with either antiplatelet agents or anticoagulation while simultaneously treatment for ITP was given. Corticosteroids were most frequently used for ITP during the episode followed by IVIG (52% and 28% of total treated patients respectively). Only 1 patient was treated with TPO-RA after the event for low platelet counts while others received other treatments (Rituximab, Danazol and splenectomy). Discussion Thrombosis is a complex process involving arteries and veins. Accelerated atherosclerosis and plaque rupture is the underlying event for arterial thrombosis. While in venous thrombosis immobility and procoagulant states are the main factors. Immune thrombocytopenia is characterized by immune mediated destruction and impaired production of platelets predisposing to bleeding mostly. However, it is a unique pathological process that is linked to both bleeding and thrombosis. Multiple factors predispose patients to thrombosis in ITP. The patients with chronic and active disease are particularly at risk of paradoxical thrombosis due to accelerated atherosclerosis as in other autoimmune conditions, predisposing to arterial thrombotic events. Active disease is also characterized by increased turnover of platelets in bone marrow and higher levels of circulating platelets microparticles (PMPs) which promote thrombin formation and promote venous thrombosis. The patients treated with IVIG and TPO-RA are at higher risk as compared to other forms of treatment. IVIG is used in acute states as it prevents the destruction of platelets but simultaneously promotes thrombosis by increasing blood viscosity and thrombin production. TPO-RAs are agents which mimic the action of thrombopoietin on megakaryocytes promoting their growth and differentiation and increasing platelet production. Increasing platelet count above the normal target might contribute to thrombosis however megakaryocyte activation itself leads to increased risk of thrombosis, despite low platelet count. In patients with ITP and thrombotic events, judicious use of antiplatelet therapy and anticoagulation is indicated along with simultaneous therapy directed at improving platelet count. Conclusion Patient with active ITP are predisposed to thrombosis in addition to bleeding. A treating physician needs to be vigilant to diagnose early the events and then to institute proper use of antiplatelets and anticoagulation along with therapy directed at ITP. Figure Disclosures No relevant conflicts of interest to declare.

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The presence of idiopathic thrombocytopenic purpura correlates with lower rate of acute ST-elevation myocardial infarction

Future Cardiology ◽

10.2217/fca-2020-0183 ◽

2021 ◽

Author(s):

Mitchell Davis ◽

Mohammad Reza Movahed ◽

Mehrtash Hashemzadeh ◽

Mehrnoosh Hashemzadeh

Keyword(s):

Myocardial Infarction ◽

Platelet Count ◽

Protective Effect ◽

Idiopathic Thrombocytopenic Purpura ◽

Tobacco Use ◽

Nationwide Inpatient Sample ◽

Thrombocytopenic Purpura ◽

Gender And Age ◽

Low Platelet Count ◽

St Elevation

Background: Platelets are important in the pathogenesis of myocardial infarction (MI). We hypothesize that patients with acquired thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) may have lower MI rate. Materials & method: The Nationwide Inpatient Sample was used for this study. We analyzed the correlation between ST-elevation MI (STEMI) and ITP utilizing ICD-9 codes. Results: STEMI rate was lower in patients with ITP. We found that, in 2002, STEMI occurred in 0.64% of patients with ITP versus 0.89 (p < 0.007) and for 2011 0.30 versus 0.48 (p < 0.005). After adjusting for tobacco use, diabetes, hypertension, hyperlipidemia, gender and age, STEMI rate remained lower in ITP patients. Conclusion: ITP appears to be associated with lower STEMI rate suggesting low platelet count may exert protective effect from STEMI.

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Eltrombopag for the Treatment of the Inherited Thrombocytopenia Deriving From MYH9 Mutations

Blood ◽

10.1182/blood.v116.21.2533.2533 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2533-2533

Author(s):

Alessandro Pecci ◽

Catherine Klersy ◽

Paolo Gresele ◽

Anna Savoia ◽

Tiziana Fierro ◽

...

Keyword(s):

Platelet Count ◽

Bleeding Tendency ◽

Bleeding Diathesis ◽

Normal Range ◽

Minor Response ◽

Platelet Counts ◽

Related Disease ◽

Major Response ◽

Inherited Thrombocytopenia ◽

A Minor

Abstract Abstract 2533 MYH9-Related Disease (MYH9-RD) is one of the less rare forms of inherited thrombocytopenia. It derives from mutations of the gene MYH9 for the heavy chain of nonmuscle myosin IIA and is characterized by congenital macrothrombocytopenia variably associated with young-adult onset of hearing loss, cataract, and a severe proteinuric nephropathy. Only platelet transfusions are available for increasing platelet counts in this condition, but they expose to the risks of acute reactions, transmission of infectious diseases, and refractoriness to subsequent platelet transfusions. Moreover, this treatment suffers from scarceness of blood donors. Novel thrombopoiesis-stimulating agents have been developed and 2 of them, eltrombopag and romiplostin, have been approved for increasing platelet count in a few forms of acquired thrombocytopenia. Since it has been recently shown that megakaryocytes of patients with MYH9-RD respond in vitro to TPO stimulation, we reasoned that TPO-mimetics could be effective also in this condition and decided to test the effect of eltrombopag. Therefore, we performed a phase II, multicentre, open-label, dose escalation trial. Twelve adult patients with a platelet count lower than 50×10e9/L and a diagnosis of MYH9-RD confirmed by identification of the causative MYH9 mutations received orally eltrombopag 50 mg daily for 21 days (Revolade®, GSK). Patients with platelet counts lower than 100×10e9/L at day 21 increased eltrombopag to 75 mg daily for 21 additional days. Patients with platelet counts between 100 and 150×10e9/L at day 21 continued eltrombopag 50 mg daily for the following 21 days, while patients with more than 150×10e9 platelets/L stopped therapy. The primary endpoints were the achievement of a platelet count over 100×10e9/L or at least three times the baseline value (major response), or at least twice the baseline value but less than major response (minor response). Secondary end points included safety and tolerability, and the reduction of bleeding tendency. After 3 weeks at the eltrombopag dose of 50 mg daily, 3 patients achieved platelet counts of 150×10e9/L or more and stopped therapy. Two had a platelet counts between 100 and 150×10e9/L and continued treatment at the same dosage, while 7 had less than 100×10e9 platelets/L and received eltrombopag 75 mg daily for 3 weeks. A major response was obtained in 8 patients (67%), in 5 of them after 3 weeks of eltrombopag 50 mg daily, and in 3 cases after 3 additional weeks at the dose of 75 mg. Three patients (25%) achieved a minor response, 1 after 3 weeks at 50 mg daily, and 2 after 3 additional weeks at 75 mg. In one patient the treatment resulted in no response. Mean platelet count at the end of treatment was significantly higher than at baseline (105 versus 31×10e9 platelets/L, p=0.0022). In the 11 patients that achieved major or minor responses, mean platelet count was still higher than baseline 15 days after discontinuation of the drug, while it returned to levels near baseline 15 days later. Platelet size did not change either during treatment or after its cessation, and this indicates that the increases in platelet count were paralleled by corresponding increases in total platelet mass. The extent of platelet aggregation was within the normal range after all tested agonists in 5 of the 7 patients that achieved platelet counts higher than 100×10e9/L, while it was slightly reduced after ADP and collagen in 2 patients. Mean serum TPO level was higher than the normal range and this figure did not change neither during treatment with eltrombopag nor after its discontinuation. Ten of 12 patients had grade 1 or 2 bleeding symptoms, as measured by the WHO bleeding scale, at baseline, while 2 were asymptomatic. Upon treatment, bleeding diathesis quickly ameliorated and disappeared in 8 cases, while it remained unchanged in the only patient with no response to eltrombopag and in another one with a minor response. The benefit in terms of bleeding diathesis lasted well beyond treatment discontinuation. Treatment was well tolerated in all cases, with only two patients reporting mild and transient headache and one patient suffering from transient dry mouth at the beginning of treatment. In conclusion, 50–75 mg of eltrombopag per day increased platelet count and reduced bleeding tendency in most patients with MYH9-RD. Further research is required to ascertain whether TPO mimetics are effective also in other forms of inherited thrombocytopenia. Disclosures: Off Label Use: Eltrombopag for MYH9-related disease.

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Microparticle-Associated Thrombogenic Mechanism Might Compensate Bleeding Tendency in Patients with Myelodysplastic Syndromes.

Blood ◽

10.1182/blood.v120.21.2821.2821 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2821-2821

Author(s):

Nora V. Butta ◽

Monica Martin Salces ◽

Raquel de Paz ◽

Ihosvany Fernández Bello ◽

Mayte Álvarez Román ◽

...

Keyword(s):

Platelet Count ◽

Myelodysplastic Syndromes ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Time Lag ◽

Procoagulant Activity ◽

Bleeding Tendency ◽

Compensatory Mechanisms ◽

Increased Risk ◽

Spearman Test

Abstract Abstract 2821 Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders with clonal bone marrow anomalies characterized by ineffective hematopoiesis, morphologic and functional hematopoietic cells abnormalities, and an increased risk of transformation to acute myeloid leukemia. Previous work from our lab has shown that MDS patients had an impairment in platelet activation, more externalization of phosphatidylserine (PS) indicating an increased platelet apoptosis and, in some cases, thrombocytopenia. However, these patients do not bleed at the frequency that would be expected taking into account these facts. Objective: The aim of this work was to identify the existence of some compensatory mechanisms that could be counteracting the expected bleeding tendency in these patients. Since apoptosis is accompanied by membrane blebbing and production of PS-exposing procoagulant microparticles (MP) shed from the plasma membrane, we assessed the thrombogenic capacity of MP and evaluate their correlation with exposure of PS. We also studied the ability of plasma to generate thrombin after stimulus. Methods: Seventy-five patients with MDS, 36% female, mean age 77 years (range: 41 to 93 years) and sixty-eight healthy controls, 29% female, mean age 52 years (range 20 to 76 years) were included. Whole blood was collected in citrated tubes and centrifuged at 1,500 g for 15 min at 23°C to obtain platelet poor plasma (PPP). PPP was subjected to 2 additional centrifugations at room temperature (first: 15 min at 1,500 g and second: 2 min at 13,000 g) following SSC-ISTH recommendations to obtain platelet free plasma (PFP). MP procoagulant activity was determined in PFP with the ZYMUPHEN MP-Activity kit (HYPHEN BioMed, Neuville sur Oise, France). Plasma thrombin generation was measured using the Calibrated Automated Thrombogram (CAT) as described by Hemker at final concentration of 1pM tissue factor and 4 microM phospholipids. Four CAT parameters were recorded: endogenous thrombin potential (ETP, total amount of thrombin generated over time), lag time (time to the beginning of the explosive burst of thrombin generation), time to peak (TTP, time to reach the maximum thrombin concentration) and peak height (maximum thrombin concentration obtained). Apoptosis was determined by assessing the level of PS externalization by the binding of FITC-Annexin V to platelets by flow cytometry. Thrombocytopenia was defined as platelet count less than 50,000 platelets/microliter. Results: Platelet count in MDS patients varied from 4,000 to 478,000 platelets/microliter. We observed an increased MP-associated procoagulant activity in MDS patients with thrombocytopenia compared to controls (p<0.05). This would be related to the increased apoptosis observed in platelets from MDS patients with thrombocytopenia (Spearman test r = 0.655, p <0.01). CAT evaluation of plasma procoagulant activity did not show differences between patients and controls in any of the measured parameters. Conclusions: Our results showed an increased procoagulant activity associated to plasma MPs in MDS with thrombocytopenia that might contribute to the minor risk of bleeding observed in these patients. However, further studies are necessary to assess the clinical significance of this finding. Disclosures: No relevant conflicts of interest to declare.

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Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations

Blood ◽

10.1182/blood-2010-08-304725 ◽

2010 ◽

Vol 116 (26) ◽

pp. 5832-5837 ◽

Cited By ~ 88

Author(s):

Alessandro Pecci ◽

Paolo Gresele ◽

Catherine Klersy ◽

Anna Savoia ◽

Patrizia Noris ◽

...

Keyword(s):

Platelet Count ◽

Receptor Agonist ◽

Severe Thrombocytopenia ◽

Bleeding Tendency ◽

Platelet Counts ◽

Related Disease ◽

Increase Platelet Count ◽

Thrombopoietin Receptor ◽

Thrombopoietin Receptor Agonist ◽

Inherited Thrombocytopenia

Abstract Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 × 109/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 × 109/L stopped therapy, those with 100 to 150 platelets × 109/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets × 109/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 × 109/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42).

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Hypercoagulability as a Cause of Sudden Neurosensory Hearing Loss

Otolaryngology ◽

10.1177/019459987908700220 ◽

1979 ◽

Vol 87 (2) ◽

pp. 268-273 ◽

Cited By ~ 2

Author(s):

Joan T. Zajtchuk ◽

Maj William H. Falor ◽

Mai Miller F. Rhodes

Keyword(s):

Hearing Loss ◽

Platelet Count ◽

Generation Time ◽

Thrombin Generation ◽

Antithrombin Iii ◽

Coagulation Abnormalities ◽

Show Evidence ◽

Phase Platelet ◽

Antithrombin Iii Activity

Fourteen patients with a documented sudden neurosensory hearing loss and four patients with other diseases causing neurosensory hearing loss were studied. The standardized coagulation workup included hematocrit, activated partial thromboplastin generation time, thrombin generation, prothrombin time, phase platelet count, platelet adhesivity, protamine sulfate, serum antithrombin III activity, fibrinogen, and Factor VIII values. Only those patients having documented evidence of a neurosensory hearing loss occurring within hours or days were included in this study. Eight of the 14 patients with a documented sudden neurosensory hearing loss satisfied our laboratory criteria for a diagnosis of in vitro hypercoagulability. Three of these patients had abnormal thrombin generation values, 4 had abnormal serum antithrombin III values, and 1 had an elevated platelet count. Four other patients with other diseases causing neurosensory hearing loss did not show evidence of in vitro hypercoagulability. It would appear from this data that coagulation abnormalities play a role in the pathogenesis of sudden neurosensory hearing loss.

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