Iron Repletion Increases Platelet Aggregation and Reduces Platelet Count in Iron Deficient Premenopausal Women

Abstract Background: Iron deficiency, heavy menstrual bleeding, and anemia are interrelated conditions with high prevalence in women's health. Together, they impact an estimated 310 million premenopausal women worldwide. Iron deficiency has been associated with development of anemia as well as thrombocytosis. However, the effects of iron deficiency on platelet function remain unknown. Objective: We set out to investigate the impact of IV iron repletion on platelet function, platelet count, and other blood cell indices in iron deficient premenopausal women. Methods: We conducted a prospective single-center study of iron deficient premenopausal women who underwent iron repletion with a single dose of 1000 mg of low molecular weight iron. Pre-infusion and post-infusion blood samples were obtained for laboratory analysis. Standard of care monitoring of iron indices and complete blood counts were also included in the analysis. Pre-infusion rates of anemia and thrombocytosis were calculated using minimum hemoglobin and peak platelet count in the 6 months preceding iron infusion. Platelet function was quantified by Fluorescence-Activated Cell Sorting (FACS) quantification of platelet activation marker antibodies for GPIIb/IIIa (PAC1) and P-selectin (CD62P) after exposure to multiple platelet agonists. Platelet aggregation was assessed by flow of anticoagulated whole blood at a shear rate of 300 s -1 for 5 minutes through chambers coated with type I collagen, imaged with differential interference contrast optics, and quantitatively represented through computation of percent total surface coverage. Pre-infusion and post-infusion cell indices and aggregation data were compared by paired samples t-test. All statistical analyses were performed in GraphPad Prism (Version 8.0.0). Results: Thirteen patients were included in the analysis. Heavy menstrual bleeding was the suspected cause of iron deficiency in 83% of patients. Thrombocytosis was present in 15% of patients at pre-infusion and no patients at post-infusion. Average ferritin was 14 µg/L at pre-infusion and 126 µg/L at post-infusion. The peak platelet count within 6 months pre-infusion was 309 K/mm 3 (±89) vs. 274 (±64) K/mm 3 at post-infusion (p<0.05). The average change to 6-month pre-infusion peak and post-infusion platelet count was -35.2 K/mm 3 (95%CI: -66.2, -5.23). The mean 6-month minimum hemoglobin was 11.9 (±1.9) g/dL vs. 13.3 (±1.1) g/dL at post-infusion (p<0.005). Acquisition of FACS platelet reactivity data are ongoing, with preliminary results for the first 7 consecutively enrolled study patients displayed in Figure 1. Platelet aggregation measured at pre-infusion showed 14% surface coverage, with a significant increase to 29% at post-infusion (p < 0.05). None of the 13 women experienced a thrombotic event during the study period. Conclusion: Correction of iron deficiency results in decreased platelet count and improves platelet aggregation over collagen. Iron repletion may also improve platelet reactivity in response to physiologic agonists. These findings may suggest that iron deficiency impairs hemostasis and that correction of low iron may be even more critical for women with heavy menstrual bleeding. Figure 1 Figure 1. Disclosures Shatzel: Aronora Inc,: Consultancy.

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The Effect of Dimethyl Sulfoxide on In Vitro Platelet Function

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648027 ◽

1976 ◽

Vol 36 (01) ◽

pp. 221-229 ◽

Cited By ~ 16

Author(s):

Charles A. Schiffer ◽

Caroline L. Whitaker ◽

Morton Schmukler ◽

Joseph Aisner ◽

Steven L. Hilbert

Keyword(s):

Platelet Count ◽

Platelet Aggregation ◽

Dimethyl Sulfoxide ◽

Platelet Function ◽

Platelet Volume ◽

Short Term ◽

Platelet Factor ◽

Short Term Exposure ◽

Structural Abnormalities

SummaryAlthough dimethyl sulfoxide (DMSO) has been used extensively as a cryopreservative for platelets there are few studies dealing with the effect of DMSO on platelet function. Using techniques similar to those employed in platelet cryopreservation platelets were incubated with final concentrations of 2-10% DMSO at 25° C. After exposure to 5 and 10% DMSO platelets remained discoid and electron micrographs revealed no structural abnormalities. There was no significant change in platelet count. In terms of injury to platelet membranes, there was no increased availability of platelet factor-3 or leakage of nucleotides, 5 hydroxytryptamine (5HT) or glycosidases with final DMSO concentrations of 2.5, 5 and 10% DMSO. Thrombin stimulated nucleotide and 5HT release was reduced by 10% DMSO. Impairment of thrombin induced glycosidase release was noted at lower DMSO concentrations and was dose related. Similarly, aggregation to ADP was progressively impaired at DMSO concentrations from 1-5% and was dose related. After the platelets exposed to DMSO were washed, however, aggregation and release returned to control values. Platelet aggregation by epinephrine was also inhibited by DMSO and this could not be corrected by washing the platelets. DMSO-plasma solutions are hypertonic but only minimal increases in platelet volume (at 10% DMSO) could be detected. Shrinkage of platelets was seen with hypertonic solutions of sodium chloride or sucrose suggesting that the rapid transmembrane passage of DMSO prevented significant shifts of water. These studies demonstrate that there are minimal irreversible alterations in in vitro platelet function after short-term exposure to DMSO.

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Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660138 ◽

1985 ◽

Vol 54 (04) ◽

pp. 808-812 ◽

Cited By ~ 7

Author(s):

Ulf Berglund ◽

Henning von Schenck ◽

Lars Wallentin

Keyword(s):

Platelet Aggregation ◽

Angina Pectoris ◽

Platelet Function ◽

Plasma Levels ◽

Platelet Reactivity ◽

Inhibitory Effect ◽

Controlled Study ◽

Double Blind ◽

Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

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Disturbance Of Platelet Function In The Nephrotic Syndrome

10.1055/s-0038-1653301 ◽

1981 ◽

Author(s):

E Walter ◽

D Deppermann ◽

K Andrassy ◽

E Weber

Keyword(s):

Nephrotic Syndrome ◽

Platelet Count ◽

Platelet Aggregation ◽

Kidney Function ◽

Platelet Function ◽

Platelet Adhesiveness ◽

Spontaneous Aggregation ◽

Spontaneous Platelet Aggregation ◽

Platelet Functions

Thromboembolic phenomena often (30 %) complicate the nephrotic syndrome. It was therefor investigated, wether disturbed platelet functions play a role in this disease.28 normals, 34 patients with nephrotic syndrome and 18 of them with impaired kidney function were tested. In 20 patients the measurements were repeated after administration of aspirin plus dipyridamo1e.Patients with nephrotic syndrome showed in comparison to normals the following changes: 1. increased platelet count (p < 0.01), 2. enhanced platelet adhesiveness (Wright-test: p < 0.001), 3. increased spontaneous aggregation (PAT I: p < 0.001; PAT III: p < 0.01), 4. enhanced PF 4-activity (heparin neutralisation: p < 0.001), 5. elevated β TG-levels only in impaired kidney function. There was no difference in the reaction of platelets against ADP as well as collagen. The changes in platelet function correlated with the severity of the nephrotic syndrome (proteinurea, hypalbuminaemia, hyperlipo- proteinaemia). After aspirin plus dipyridamole administration spontaneous platelet aggregation and adhesiveness were normalized.There is a disturbance of platelet function in patients with nephrotic syndrome, which can be reversed with antiaggregating agents.

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Iron Deficiency Anemia in Adolescents Who Present with Heavy Menstrual Bleeding

Journal of Pediatric and Adolescent Gynecology ◽

10.1016/j.jpag.2016.10.010 ◽

2017 ◽

Vol 30 (2) ◽

pp. 247-250 ◽

Cited By ~ 30

Author(s):

Amanda G. Cooke ◽

Timothy L. McCavit ◽

George R. Buchanan ◽

Jacquelyn M. Powers

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Deficiency Anemia

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Influence of Hepatocellular Carcinoma on Platelet Aggregation in Cirrhosis

Cancers ◽

10.3390/cancers13051150 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1150

Author(s):

Alberto Zanetto ◽

Marco Senzolo ◽

Elena Campello ◽

Cristiana Bulato ◽

Sabrina Gavasso ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Platelet Count ◽

Platelet Aggregation ◽

Platelet Function ◽

Adenosine Diphosphate ◽

Compensated Cirrhosis ◽

Impedance Aggregometry ◽

Child Class ◽

Von Willebrand ◽

Willebrand Factor

Hyper-functional platelets are being proposed as a potential therapeutic target in multiple cancers. Whether this can be considered in patients with cirrhosis and hepatocellular carcinoma (HCC) is unknown as their platelet function has not yet been investigated. We evaluated platelet function in cirrhosis patients with HCC. Patients with cirrhosis with and without HCC were prospectively recruited. Platelet aggregation, a marker of platelet function, was assessed by impedance aggregometry with adenosine diphosphate (ADP), arachidonic acid (ASPI), and thrombin (TRAP) stimulation. Plasmatic levels of Von Willebrand factor antigen (VWF) were also determined. One-hundred patients were recruited (50 cirrhotics with and 50 without HCC). Cirrhosis severity by Child class and platelet count were comparable between cirrhotics with and without HCC. Cirrhotics with HCC had higher ADP- (45 vs. 28; p < 0.001), ASPI- (47 vs. 28; p < 0.001), and TRAP- (85 vs. 75; p = 0.01) induced platelet aggregation than cirrhotics without HCC, all indicative of platelet hyper-function. The relatively increased platelet aggregation in patients with HCC was confirmed after adjusting the analysis for platelet count/severity of thrombocytopenia. Levels of VWF were higher in patients with vs. without HCC (348 vs. 267; p = 0.006), particularly in compensated cirrhosis. In patients with cirrhosis, HCC is associated with increased platelet aggregation and higher VWF. The clinical implications of these findings deserve further investigation.

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Management of heavy menstrual bleeding on anticoagulation

Hematology ◽

10.1182/hematology.2020000138 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 533-537

Author(s):

Bethany Samuelson Bannow

Keyword(s):

Iron Deficiency ◽

Blood Loss ◽

Oral Anticoagulants ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

School Work ◽

Medical Interventions ◽

Recurrent Venous Thromboembolism ◽

Menstruating Women ◽

Hormone Therapies

Abstract Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.

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Population Screening for Von Willebrand's Disease in Adolescents with Heavy Menstrual Bleeding

Blood ◽

10.1182/blood.v120.21.477.477 ◽

2012 ◽

Vol 120 (21) ◽

pp. 477-477

Author(s):

Deena Khamees ◽

Jennifer Klima ◽

Sarah H. O'Brien

Keyword(s):

Iron Deficiency ◽

Electronic Medical Records ◽

Iron Deficiency Anemia ◽

Medical Records ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Treatment Center ◽

Deficiency Anemia ◽

Bleeding Disorders ◽

Study Population

Abstract Abstract 477 Background Heavy menstrual bleeding (HMB) is the most common presenting symptom in women with von Willebrand's disease (VWD), reported in 80–90% of patients. The American Congress of Obstetricians and Gynecologists recommends that VWD screening be performed in all adolescents presenting with severe menorrhagia; however, the frequency of VWD screening in clinical practice remains unknown. Combining administrative health claims data and electronic medical records from a large population of Ohio Medicaid-enrolled adolescents, our objectives were to determine the frequency of 1) VWD screening and 2) new patient evaluations at a hemophilia treatment center in adolescents with HMB. We also sought to determine what patient-level factors predicted VWD screening. Methods The data for this study were obtained from Partners for Kids, an accountable care organization providing health care for Medicaid patients in Central (Columbus, OH and surrounding counties) and Southeastern Ohio (rural counties). Our study population included females 10–17 years of age with two or more ICD-9-CM diagnoses of HMB (626.2, 626.3, 626.8) continuously enrolled in Partners for Kids for at least 6 months prior to and 12 months following first diagnosis of HMB. We defined severe HMB as HMB plus one of the following clinical features appearing in the 12 months following first diagnosis: 1) inpatient stay for HMB, 2) iron deficiency anemia (ICD-9 codes 280.0, 280.8, 280.9), or 3) evidence of blood transfusion (CPT code 36430). We extracted data from Partners for Kids regarding patient age, county of residence, inpatient and outpatient diagnoses and procedures, and laboratory testing. By linking patient name and date of birth to electronic medical records at Nationwide Children's Hospital (the pediatric hemophilia treatment center for Central and Southeastern Ohio), we determined which patients had a hematology visit since time of first HMB diagnosis. Results Our study included 673 patients, 16% of whom met study definition for severe HMB. VWD screening occurred in only 10% of the total study population, but was significantly higher (24%) in patients with severe HMB (p <0.001). Patients living in Central Ohio (location of the region's hemophilia treatment center) were more likely to be screened for VWD (OR 2.1, p <0.03) than patients in Southeastern Ohio. When compared to 15–17 year olds, the youngest patients (aged 10–11 years) were more likely to be screened for VWD (OR 3.6, 95% C.I.: 1.6–8.1, p =0.002), and 12–14 year olds were also more likely to be screened than the oldest patients (OR 2.7, 95% C.I.: 1.5–4.8, p =0.001). Fifty-one (7.6%) patients were seen by the regional hemophilia treatment center. Almost 10% of all patients had a diagnosis of iron deficiency anemia, although only 26% of patients were screened for this common complication of HMB. Though only 3% of the study population (11% of the severe HMB population) was diagnosed with a bleeding disorder within 1 year of diagnosis of HMB, over a third of these (36%) were VWD. The prevalence of platelet function defects was similar to VWD. Discussion Despite recommendations by the American Congress of Obstetricians and Gynecologists, VWD screening is performed in a minority of adolescents with HMB, even among those with the most severe disease. Given the low rates of screening, our population reported frequencies of inherited bleeding disorders in adolescents with HMB are likely under-estimates. The low rate of screening for iron deficiency anemia in adolescents with HMB is also of concern. Future studies are needed to identify and overcome barriers to laboratory screening for inherited bleeding disorders in young women with HMB. 1. Laboratory Evaluation and Final Diagnoses in Adolescents with Heavy Menstrual Bleeding Disclosures: O'Brien: GSK: Consultancy, topic not relevant to this paper Other.

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Novel 12-LOX Inhibitor ML355 Attenuates Platelet Reactivity and Impairs Thrombus Growth, Stability and Vessel Occlusion In Vivo

Blood ◽

10.1182/blood.v126.23.3442.3442 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3442-3442 ◽

Cited By ~ 1

Author(s):

Reheman Adili ◽

Theodore R Holman ◽

Michael Holinstat

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Platelet Adhesion ◽

Ex Vivo ◽

Platelet Reactivity ◽

Thrombus Formation ◽

Vessel Occlusion ◽

Growth Stability

Abstract Background: Adequate platelet reactivity is required for platelet adhesion and aggregation at the site of vascular injury to maintain hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi, the predominate underlying cause of myocardial infarction and stroke. While current anti-platelet treatments limit platelet function, they often result in an increased risk of bleeding. 12-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated by our lab and others to regulate PAR4 and GPVI-mediated platelet reactivity suggesting a role of 12-LOX in regulation of vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Aims: To determine how 12-LOX regulates thrombus formation in vivo and whether platelet 12-LOX is an effective target for anti-platelet therapeutics, wild-type (WT) or 12-LOX deficient (12-LOX-/-) mice were treated with or without the 12-LOX inhibitor, ML355, and were assessed for inhibitory effects on platelet activation in vitro, ex-vivo and in vivo. Methods: The effect of the novel 12-LOX inhibitor ML355 on human platelet function was assessed in vitro by platelet aggregometry, ex vivo by perfusion chamber. In vivo thrombus formation and vessel occlusion in small and large vessels were studied in 12-LOX-/-, WT mice and mice treated with ML355 using intravital microscopy using the FeCl3 injury models. Results: Using in vitro platelet aggregation assays, ML355 dose dependently inhibited thrombin, PAR1-AP, and PAR4-AP-induced aggregation in washed human platelets. Interestingly, the negative regulatory effects of ML355 inhibition of 12-LOX can be overcome by high concentration of thrombin. Additionally, ML355 was able to attenuate ADP-induced platelet aggregation both in platelet-rich-plasma and whole blood. In ex vivo flow chamber assays, platelet adhesion and thrombus formation on collagen-coated surfaces at high shear was attenuated in both mouse and human whole blood after incubation with ML355. Further, platelet aggregation and thrombus growth in 12-LOX-/- mice was impaired in FeCl3-induced mesenteric or carotid artery thrombosis models. Thrombi in 12-LOX-/- mice were unstable and frequently form emboli, which resulted in impaired vessel occlusion or reopening. Additionally, thrombus formation and vessel occlusion was impaired in ML355 treated WT mice. Conclusions: The highly selective 12-LOX inhibitor ML355 inhibits platelets aggregation induced by various platelet agonists and ML355 inhibition of platelet function is not agonist specific. Platelet function at high shear in ex vivo conditions in both mice and human was attenuated in the presence of ML355. Thrombus growth, stability, and vessel occlusion was impaired in mice deficient for 12-LOX. Finally, the highly selective 12-LOX inhibitor ML355 attenuates thrombus formation and prevents vessel occlusion in vivo. Our data strongly indicates 12- LOX is an important determinant of platelet reactivity and inhibition of platelet 12-LOX may represent a new target for anti-platelet therapeutics. Disclosures No relevant conflicts of interest to declare.

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Could body mass index be an indicator for endometrial biopsy in premenopausal women with heavy menstrual bleeding?

Archives of Gynecology and Obstetrics ◽

10.1007/s00404-016-4043-8 ◽

2016 ◽

Vol 294 (2) ◽

pp. 395-402 ◽

Cited By ~ 3

Author(s):

Hakan Guraslan ◽

Keziban Dogan ◽

Cihan Kaya ◽

Mehmet Baki Senturk ◽

Birgul Guraslan ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Premenopausal Women ◽

Endometrial Biopsy ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding

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Influence of aspirin or heparin on platelet function and postoperative blood loss after coronary artery bypass surgery

Perfusion ◽

10.1191/0267659106pf845oa ◽

2006 ◽

Vol 21 (1) ◽

pp. 61-66 ◽

Cited By ~ 7

Author(s):

Edmundas Sirvinskas ◽

Audrone Veikutiene ◽

Pranas Grybauskas ◽

Jurate Cimbolaityte ◽

Ausra Mongirdiene ◽

...

Keyword(s):

Platelet Count ◽

Coronary Artery ◽

Platelet Aggregation ◽

Blood Loss ◽

Platelet Function ◽

Artery Bypass ◽

Postoperative Blood Loss ◽

Group 3 ◽

Group 2 ◽

Group 1

The aim of the study was to assess the effect of aspirin or heparin pretreatment on platelet function and bleeding in the early postoperative period after coronary artery bypass grafting (CABG) surgery. Seventy-five male patients with coronary artery disease who underwent CABG with cardiopulmonary bypass (CPB) were studied. The patients were divided into three groups: Group 1 ( n = 25) included patients receiving aspirin pretreatment, Group 2 ( n = 22) received heparin pretreatment, and Group 3 ( n = 28) included patients who received no antiplatelet or anticoagulant pretreatment. Twenty-four hours after surgery, all patients were administered aspirin therapy that was continued throughout their hospitalization period. We assessed the following preoperative blood coagulation indices: activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen. We compared platelet count and platelet aggregation induced by adenosinediphosphate (ADP) before surgery, 1 h after surgery, 20 h after surgery and on the seventh postoperative day. We assessed drained blood loss within 20 postoperative hours. Preoperative blood coagulation indices did not differ among the groups. Platelet count was also similar. One hour after surgery, platelet count significantly decreased in all groups ( p <0.001), after 20 postoperative hours it did not undergo any marked changes, and on the seventh postoperative day, it significantly increased in all groups ( p <0.001). Before surgery, the lowest index of ADP-induced platelet aggregation was found in Group 1 ( p <0.05). One hour after surgery, platelet aggregation significantly decreased in all groups, most markedly in Group 3 ( p <0.001), yet after 20 h, its restitution tendency and a significant increase in all groups was noted. On the seventh day, a further increase in the statistical mean platelet aggregation value was noted in Groups 2 and 3. Comparison of platelet aggregation after 20 postoperative hours and on the seventh day after surgery revealed a significantly higher than 10% increase of the index in 32% of patients in Group 1 ( p <0.05), 27.3% of patients in Group 2 ( p <0.05) and in 35.7% of patients in Group 3 ( p <0.001). The lowest statistically significant value of postoperative blood loss was noted in Group 2 ( p <0.01). Our study has shown that aspirin or heparin pretreatment had no impact on the dynamics of platelet function in the early postoperative period after CABG. The lowest postoperative blood loss was noted in patients pretreated with heparin.

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