0
Original Research |

Hemodynamics and Epoprostenol Use Are Associated With Thrombocytopenia in Pulmonary Arterial Hypertension FREE TO VIEW

Kelly M. Chin, MD*; Richard N. Channick, MD, FCCP; James A. de Lemos, MD; Nick H. Kim, MD; Fernando Torres, MD; Lewis J. Rubin, MD, FCCP
Author and Funding Information

*From the Department of Internal Medicine (Drs. Chin, de Lemos, and Torres), University of Texas Southwestern Medical Center, Dallas, TX; and Department of Internal Medicine (Drs. Channick, Kim, and Rubin), University of California, San Diego, CA.

Correspondence to: Kelly M. Chin, MD, University of Texas Southwestern Pulmonary Hypertension Program, 5909 Harry Hines Blvd, Dallas, TX 75235-9254; e-mail: kelly.chin@utsouthwestern.edu

*No significant difference in platelet counts was seen based on PAH etiology.

*Etiology, use of endothelin receptor antagonists, and use of sildenafil were not associated with thrombocytopenia (data not shown). ORs are for a 1-unit change.

*Data are presented as mean ± SD. Svo2 was higher among epoprostenol-treated patients, while other hemodynamic results were similar between the two groups.

*Based on the multivariable model, platelet count can be estimated as platelet count = 295,000 – (1.22 × epoprostenol dose) – (6 × mean right atrial pressure). Given the R2 of the model, these variables account for a statistically significant but numerically modest portion of the overall variability in platelet counts.

This work was performed at University of Texas Southwestern and University of California, San Diego.

Drs. Chin, Channick, Kim, Rubin, and Torres have received consulting fees and/or honoraria from Gilead, distributor of Flolan (epoprostenol). Dr. de Lemos had no disclosures.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


This work was performed at University of Texas Southwestern and University of California, San Diego.

This work was performed at University of Texas Southwestern and University of California, San Diego.

Drs. Chin, Channick, Kim, Rubin, and Torres have received consulting fees and/or honoraria from Gilead, distributor of Flolan (epoprostenol). Dr. de Lemos had no disclosures.

Drs. Chin, Channick, Kim, Rubin, and Torres have received consulting fees and/or honoraria from Gilead, distributor of Flolan (epoprostenol). Dr. de Lemos had no disclosures.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(1):130-136. doi:10.1378/chest.08-1323
Text Size: A A A
Published online

Background:  Thrombocytopenia develops in some patients with advanced pulmonary arterial hypertension (PAH) while receiving IV epoprostenol therapy. In this study, we evaluate whether epoprostenol use, other PAH medication use, hemodynamics, or PAH etiology are associated with thrombocytopenia in PAH.

Methods:  Platelet counts were evaluated in 47 PAH patients receiving IV epoprostenol, and in 44 patients with an inadequate response to initial therapy with oral agents in a cross-sectional study. Associations between thrombocytopenia (platelet count < 150,000/mL) and epoprostenol use, hemodynamics, PAH etiology, and use of other PAH medications were evaluated in univariable and multivariable analyses.

Results:  PAH subtypes included idiopathic (69%), fenfluramine (18%), connective tissue disease (10%), and congenital heart disease (2%)-associated PAH. Thrombocytopenia was observed in 34% of patients treated with epoprostenol, compared with 15% of patients receiving oral therapy (odds ratio [OR], 2.9; p < 0.05), and the association between epoprostenol and thrombocytopenia remained significant after adjustment for differences in hemodynamics (OR, 5.0; p < 0.05). Right atrial pressure (OR, 1.12 per mm Hg; p < 0.05) and mixed venous oxygen saturation (Svo2) [OR, 0.92 per percentage; p < 0.05] were also associated with thrombocytopenia in univariable analyses; after logistic regression analysis, both the use of epoprostenol and Svo2 were independently associated with thrombocytopenia. In a separate analysis including only patients with current or prior epoprostenol use, epoprostenol dose and right atrial pressure were inversely associated with platelet count.

Conclusion:  Epoprostenol use and severity of hemodynamic abnormalities are associated with thrombocytopenia in PAH, and these effects appear to be independent and additive.

Figures in this Article

Continuous IV epoprostenol is used in the treatment of pulmonary arterial hypertension (PAH), leading to improvement in hemodynamics, functional class, and survival.1 In addition to vasodilatory and antiproliferative actions, epoprostenol inhibits platelet aggregation and renders platelets less responsive to their natural agonists.24 The clinical effects of platelet inhibition are generally modest, and in fact most patients receive and tolerate concomitant therapy with warfarin without difficulty.

For unclear reasons, thrombocytopenia develops in some PAH patients while receiving epoprostenol. Criteria for a probable or definite case of drug-induced thrombocytopenia require withdrawal of the suspected medication5; and because prostacyclins are rarely discontinued, in most cases there is uncertainty as to whether the prostacyclin is causing or contributing to the thrombocytopenia.

In order to further investigate this association, we performed a cross-sectional study in which platelet counts were measured among patients with severe PAH treated with either oral agents or with IV epoprostenol. We also report four cases in which severe thrombocytopenia developed associated with epoprostenol use, including one patient who had normalization of platelet count when epoprostenol was discontinued for 2 months.

This study included current and former epoprostenol-treated PAH patients seen over a 12-month period as well as a comparison group of PAH patients receiving oral therapy. Patients were required to have undergone right-heart catheterization while receiving treatment and have a platelet count within 1 month of catheterization. In order to minimize potential bias related to the severity of PAH, oral therapy patients were included only if they had had an “inadequate response” to their current treatment, defined as postcatheterization plans to add an oral, IV, or inhaled medication. Decisions for add-on therapy were left to the treating physician and were based on overall clinical picture, including hemodynamics. Accepted oral therapies included bosentan, ambrisentan, and sildenafil. Patients were excluded if they were receiving any other prostacyclin (iloprost or treprostinil) at the time of right-heart catheterization, or if HIV or liver disease were the cause of PAH. Patients with other forms of pulmonary hypertension (chronic thromboembolic disease, lung disease, left-heart disease) were also excluded.

The primary outcome of the study was prevalent thrombocytopenia, defined as platelet count < 150,000/mL. Odds ratios (ORs) for thrombocytopenia were calculated for the following variables: PAH etiology, hemodynamic indexes (right atrial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, and mixed venous oxygen saturation [Svo2]) and medication use (epoprostenol, endothelin receptor antagonists, sildenafil). A logistic regression model including these variables was also developed. Six patients who previously received epoprostenol were excluded from this portion of the analysis.

A second multivariable analysis was performed in order to determine whether there was an association between epoprostenol dose and platelet count. In this multiple linear regression model, absolute platelet count was the dependent variable and epoprostenol dose as well as the above variables were evaluated as independent variables; for this model, current and prior epoprostenol-treated patients were included. For both models, variables were entered into the model if the p value was < 0.1 and removed for p > 0.2 using a forward stepwise process. Statistical software (NCSS; Kaysville, UT) was used for the analysis. Institutional Review Board approval was obtained from the University of California, San Diego, and Institutional Review Board-exempt review was approved at University of Texas Southwestern.

A total of 93 patients with PAH were studied, including 47 patients currently receiving epoprostenol, 6 patients who had previously received epoprostenol, and 40 patients receiving oral therapy with plans to add on an oral, inhaled, or IV agent. Patients had idiopathic PAH (69%), and PAH associated with fenfluramine use (18%), connective tissue disease (10%), or congenital heart disease (2%). Frequency of PAH subgroups was similar among patients receiving epoprostenol compared with those receiving oral medications, including the frequency of patients with connective tissues diseases (10% of the oral therapy group and 10.6% of the epoprostenol group, Table 1), and platelet count and rate of thrombocytopenia did not differ by etiology.

Table Graphic Jump Location
Table 1 Platelet Count by Underlying Etiology*

*No significant difference in platelet counts was seen based on PAH etiology.

Overall, 22 of 87 patients (25%) had thrombocytopenia, defined as a platelet count < 150,000/mL. Patients with thrombocytopenia had a lower average Svo2 (60% vs 65%, p < 0.01) and a higher right atrial pressure (14 mm Hg vs 10 mm Hg, p < 0.01) than patients without thrombocytopenia. When stratified by right atrial pressure, 14% of patients with a normal right atrial pressure (≤ 10 mm Hg), 32% of patients with a high right atrial pressure (11 to 14 mm Hg), and 42% of patients with a very high right atrial pressure (≥ 15 mm Hg) had thrombocytopenia (p = 0.03).

Patients receiving epoprostenol were more likely to have thrombocytopenia than patients receiving oral therapy (OR, 2.9; confidence interval [CI], 1.01 to 8.42; p = 0.047), and this association remained significant after adjustment for hemodynamics (OR, 5.0; CI, 1.4 to 17.5; p < 0.01). Hemodynamic markers of PAH severity (right atrial pressure, Svo2) were also associated with thrombocytopenia in univariable analyses (Table 2).

Table Graphic Jump Location
Table 2 Associations Between Epoprostenol, Hemodynamic Variables, and Thrombocytopenia (Platelet Count < 150,000/mL)*

*Etiology, use of endothelin receptor antagonists, and use of sildenafil were not associated with thrombocytopenia (data not shown). ORs are for a 1-unit change.

After stepwise logistic regression analysis, epoprostenol use (OR, 5.2; p < 0.01) and Svo2 (OR, 0.89 per percentage increase; p < 0.01) were found to be associated with thrombocytopenia, while PAH etiology, use of other PAH medication (endothelin receptor antagonist or sildenafil), and other hemodynamic variables were not associated. The effects of Svo2 and epoprostenol use were independent and additive, with patients who were receiving epoprostenol and had an Svo2 below the mean of 64% having a > 12-fold–increased risk of thrombocytopenia than patients without either risk factor (OR, 12.6; 95% CI, 1.4 to 116; p < 0.05). Hemodynamic results for patients receiving epoprostenol were not worse than results for patients receiving oral therapy, with a slightly higher mean Svo2 in the epoprostenol-treated group and similar results for all other hemodynamic comparisons (Table 3).

Table Graphic Jump Location
Table 3 Comparison of Hemodynamic Variables Between Patients Receiving Oral Therapy and Epoprostenol*

*Data are presented as mean ± SD. Svo2 was higher among epoprostenol-treated patients, while other hemodynamic results were similar between the two groups.

In a separate analysis among patients currently or previously receiving epoprostenol, epoprostenol dose along with several hemodynamic variables correlated inversely with platelet count (Table 4, Fig 1). After stepwise multiple regression analysis, right atrial pressure and epoprostenol dose were both inversely associated with platelet count while other variables were eliminated from the model. Similar to the analyses for prevalent thrombocytopenia above, the effects of the hemodynamic abnormalities and epoprostenol on platelet count were independent and additive. No statistical interaction was present, as highlighted graphically in Figure 1, in which epoprostenol dose remained inversely associated with platelet count after stratification by right atrial pressure.

Table Graphic Jump Location
Table 4 Univariable and Multivariable Associations Between Clinical Variables and Platelet Count*

*Based on the multivariable model, platelet count can be estimated as platelet count = 295,000 – (1.22 × epoprostenol dose) – (6 × mean right atrial pressure). Given the R2 of the model, these variables account for a statistically significant but numerically modest portion of the overall variability in platelet counts.

Figure Jump LinkFigure 1 Platelet counts; stratified correlations between right atrial pressure (RAP), epoprostenol (EPO) dose and platelet count. Right atrial pressure (r = − 0.44, p < 0.001; top, A) and epoprostenol dose (r = − 0.33, p = 0.02; bottom, B) were inversely associated with platelet count. Stratification shows that both right atrial pressure and epoprostenol dose appear to have generally independent effects on platelet level. Statistical tests for interaction were negativeGrahic Jump Location

Patients receiving higher doses of epoprostenol had slightly lower pulmonary vascular resistance than patients receiving lower doses (correlation between epoprostenol dose and pulmonary vascular resistance, r = − 0.27, p < 0.05); correlations between epoprostenol dose and other hemodynamic variables were not significant.

Case Reports

Patients included in the study were required to have undergone cardiac catheterization during the study period. However, in several patients thrombocytopenia became severe enough that catheterization was either not performed at all or was delayed until platelets improved modestly. Four of these patients are described below in order to more completely demonstrate the range of thrombocytopenia seen during the study period. All four patients were evaluated by a hematology consultant with no other cause of thrombocytopenia identified, although most did not undergo bone marrow biopsy. Patients one through three remained on epoprostenol throughout the study period; patient four discontinued epoprostenol for 2 months with normalization of platelet count during this time period.

Patient 1:

A 49-year-old man with idiopathic PAH had a platelet count of 315,000/mL at the time epoprostenol was initiated. Over 6 weeks, his platelet count fell to 136,000/mL, and then over the next 2 years platelets slowly continued to fall reaching a plateau of 20,000 to 50,000/mL, with occasional values < 10,000/mL. Epoprostenol dose was 34 ng/kg/min.

Patient 2:

A 53-year-old woman with idiopathic vs methamphetamine-associated PAH had a platelet count of 204,000/mL at the time epoprostenol was initiated. Over 4 years, her platelet count fell slowly to the 20,000/mL range. Epoprostenol dose was 75 ng/kg/min.

Patient 3:

A 22-year-old woman with Down syndrome and a history of PAH associated with a ventricular septal defect had a platelet count of 167,000/mL at the time of epoprostenol initiation. Three months later, her platelet count fell to 8,000/mL. She had a history of possible idiopathic thrombocytopenic purpura, but with this episode she had only a modest response to steroids plus IV Ig. Epoprostenol dose was 25 ng/kg/min.

Patient 4:

A 62-year-old woman with scleroderma, moderate interstitial lung disease, and mild thrombocytopenia (platelet count, 70,000 to 100,000/mL) attributed to use of cyclophosphamide received a diagnosis of PAH and was begun on bosentan (day 30) and IV treprostinil (day 134). Treprostinil was changed to epoprostenol (day 633) due to continued severe PAH, and platelet counts fell over 1 week to 45,000/mL and then over 6 months fell to < 20,000/mL (Fig 2). A bone marrow biopsy showed an unremarkable normocytic marrow, and she was treated for possible idiopathic thrombocytopenic purpura with IV solumedrol and then IV Ig. No change in platelet count was seen until the patient, for other reasons, chose to discontinue epoprostenol. Platelet count peaked at 227,000/mL after 2 months off epoprostenol, only to fall again after epoprostenol was restarted. Latest epoprostenol dose was 25 ng/kg/min.

Figure Jump LinkFigure 2 Platelets counts over 2.5 years. Thrombocytopenia preceded initiation of treprostinil on day 134 and persisted over the next 2 years. After transition to epoprostenol (epo) on day 633 (top, A), thrombocytopenia worsened. Epoprostenol was off days 860 to 929 with improvement in thrombocytopenia (bottom, B) but fell again once epoprostenol was restarted. IVIG = IV IgGrahic Jump Location

The results of this study suggest that abnormal right-heart hemodynamics and use of epoprostenol are associated with thrombocytopenia in patients with severe PAH, and that higher doses of epoprostenol are associated with lower platelet counts than lower doses of epoprostenol. The effects of hemodynamic abnormalities and epoprostenol were independent and additive, with the highest rates of thrombocytopenia seen among patients with both severe hemodynamic abnormalities and use of epoprostenol.

Most patients had only mild thrombocytopenia with no obvious clinical consequences, but some patients, including all four of the patients in the case reports, had significant morbidity related to thrombocytopenia. Adverse events included severe hemorrhage following central line placement, nasal bleeding requiring hospital admission, a subdural hematoma after a fall, and several other events requiring transfusions. Thrombocytopenia was also a factor in two of these four patients being declined as candidates for lung transplantation.

There are several potential mechanisms through which hemodynamic abnormalities could lead to thrombocytopenia. First, elevated right atrial pressure might lead to hepatic congestion and secondary hypersplenism, as has been described in left-heart failure.6 Although the four patients described in the case series did not have splenomegaly on abdominal ultrasound, correlation between spleen size and thrombocytopenia due to hypersplenism can be poor.7 Second, platelet consumption/destruction could occur within the vascular irregularities in the lungs,813 similar to other vascular diseases.14 Finally, platelet survival could be reduced in some patients through autoimmune mediated destruction, despite the lack of an association in this study with overt connective tissue disease.

However, even after adjusting for hemodynamics, epoprostenol use remained associated with thrombocytopenia, and higher epoprostenol dose correlated inversely with platelet counts. This was not due to differences in PAH etiology between the two groups, and was not because patients on epoprostenol had more severe hemodynamic abnormalities. It is possible that the use of epoprostenol and higher epoprostenol doses were markers of PAH severity not captured by standard hemodynamic measurements, but this seems less likely given the strong predictive power of hemodynamics on symptoms and survival in PAH. Additionally, in the one patient in whom epoprostenol was discontinued, platelet counts improved after discontinuation of epoprostenol despite worsening hemodynamics, and then fell after re-initiation at a lower dose despite improvement in hemodynamics, suggesting that epoprostenol caused the thrombocytopenia.

Thrombocytopenia associated with epoprostenol treatment has been described previously in case reports and case series, including PAH associated with portal hypertension and splenomegaly,15 and PAH associated with lupus.16,17 One abstract18 also described new onset thrombocytopenia in 28 of 43 epoprostenol-treated PAH patients. No association between platelet count or epoprostenol dose was reported, but thrombocytopenia did resolve in two patients who discontinued epoprostenol.

Most drug-induced thrombocytopenia relates to the formation of autoantibodies that recognize platelet surface glycoproteins in combination with the medication. This is usually seen in only a small percentage of exposed patients, and a dose-response relationship is not typical. Bone marrow toxicity is another potential cause of drug-induced thrombocytopenia, but isolated thrombocytopenia is uncommon. Further complicating this issue is that epoprostenol is prostacyclin, a naturally occurring prostaglandin that should not be immunogenic.

A direct epoprostenol effect on platelets is also considered, but epoprostenol should actually prolong platelet survival through inhibition of platelet activation. Epoprostenol reduces platelet activation in vitro and in vivo,19,20 prolongs platelet survival during extracorporeal perfusion,21 and has been used therapeutically to prolong platelet survival in patients with peripheral vascular disease.22,23

A more specific bone marrow effect on megakaryocytes is also a consideration: the epoprostenol (prostacyclin) receptor is present in megakaryocytes,24,25 and one study26 using a megakaryocyte leukemic cell line derived from human erythroblastic leukemia cells found that epoprostenol suppressed megakaryocytopoiesis. However, direct medication effects on megakaryocytopoiesis have rarely been reported, and additional studies using other megakaryocyte lines or preferably nontransformed megakaryocytes will be necessary.

This study did not investigate platelet counts or rates of thrombocytopenia in PAH patients treated with other prostacyclin analogs such as treprostinil, beraprost, or iloprost. A prior study27 of 31 patients transitioned from epoprostenol to treprostinil did describe an increase in platelet counts from 195,000 to 242,000/mL (p < 0.01) after 12 weeks of treprostinil treatment, but uncertainty about dosing equivalency between treprostinil and epoprostenol28 makes interpretation of the increase in platelet counts difficult.

Potential problems in our study include possible differences among patients that might not have been controlled for in the multivariable analyses. This includes duration of treatment, use of other medications, and other comorbidities. In some of the case study patients, thrombocytopenia developed only after years of epoprostenol treatment; it is unclear whether this related to the cumulative effects of the medication, progression of the pulmonary vasculopathy, or other factors, and future studies should attempt to evaluate these factors.

In summary, this study found that 34% of epoprostenol-treated patients had thrombocytopenia at the time of their most recent catheterization and that both epoprostenol use and more severe hemodynamic abnormalities were associated with thrombocytopenia. While these results suggest that epoprostenol use may be causing thrombocytopenia, additional study will be required. An unexpected finding was that 15% of patients receiving oral therapies also had thrombocytopenia; this correlated modestly with severity of pulmonary hypertension. Treatment options for thrombocytopenia in PAH are limited due to our incomplete understanding of the pathophysiology, and discontinuation of epoprostenol is rarely recommended.

CI

confidence interval

OR

odds ratio

PAH

pulmonary arterial hypertension

Svo2

mixed venous oxygen saturation

Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol with conventional therapy in primary pulmonary hypertension. N Engl J Med. 1996;334:296-301. [PubMed] [CrossRef]
 
Alheid U, Reichwehr I, Fortermann U. Human endothelial cells inhibit platelet aggregation by stimulating cAMP and cGMP. Eur J Pharmacol. 1989;164:103-110. [PubMed] [CrossRef]
 
Dickinson NT, Jang EK, Haslam RJ. Activation of cGMP stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelets aggregation. Biochem J. 1997;323:371-377. [PubMed]
 
Beghetti M, Reber G, de MP, et al. Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation. Eur Respir J. 2002;19:518-524. [PubMed] [CrossRef]
 
Rizvi MA, Kojouri K, George JN. Drug-induced thrombocytopenia: an updated systematic review. Ann Intern Med. 2001;134:346. [PubMed]
 
Heck J, Keitel K, Wusthoff D, et al. Frequency and pathogenesis of thrombocytopenia in cardiac failure [in German]. Dtsch Med Wochenschr. 1976;101:1381-1384. [PubMed] [CrossRef]
 
Shah SH, Hayes PC, Allan PL, et al. Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis. Am J Gastroenterol. 1996;91:2580-2583. [PubMed]
 
Robbins IM, Kawut SM, Yung D, et al. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;27:578-584. [PubMed] [CrossRef]
 
Lopes AA, Maeda NY, Ebaid M, et al. Effect of intentional hemodilution on platelet survival in secondary pulmonary hypertension. Chest. 1989;95:1207-1210. [PubMed] [CrossRef]
 
Jubelirer SJ. Primary pulmonary hypertension: its association with microangiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med. 1991;151:1221-1223. [PubMed] [CrossRef]
 
Rostagno C, Prisco D, Boddi M. Evidence for local platelet activation in pulmonary vessels in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. Eur Respir J. 1991;4:147-151. [PubMed]
 
Steele P, Ellis JH Jr, Weily HS, et al. Platelet survival time in patients with hypoxemia and pulmonary hypertension. Circulation. 1977;55:660-661. [PubMed] [CrossRef]
 
Peters AM, Rozkovec A, Bell RN, et al. Platelet kinetics in congenital heart disease. Cardiovasc Res. 1982;16:391-397. [PubMed] [CrossRef]
 
Zahavi J, Zahavi M. Enhanced platelet release reaction, shortened platelet survival time and increased platelet aggregation and plasma thromboxane B2 in chronic obstructive arterial disease. Thromb Haemost. 1985;18:105-109
 
Findlay JY, Plevak DJ, Krowka MJ, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transpl Surg. 1999;5:362-365. [PubMed] [CrossRef]
 
Robbins IM, Gaine SP, Schilz R, et al. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;117:14-18. [PubMed] [CrossRef]
 
Horn EM, Barst RJ, Poon M. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;118:1229-1230. [PubMed] [CrossRef]
 
Hargett CW, Ahearn GS, Krichman AM, et al. Thrombocytopenia associated with chronic intravenous epoprostenol therapy [abstract]. Chest. 2004;126:760S
 
Friedman R, Mears JG, Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation. 1997;96:2782-2784. [PubMed] [CrossRef]
 
Sakamaki F, Kyotani S, Nagaya N, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation. 2000;102:2720-2725. [PubMed] [CrossRef]
 
Skogby M, Adrian K, Friberg L, et al. The effect of epoprostenol on platelet activation and consumption during experimental extracorporeal perfusion. Artif Organs. 1999;23:984-987. [PubMed] [CrossRef]
 
Sinzinger H, Horsch AK, Silberbauer K. The behaviour of various platelet function tests during long-term prostacyclin infusion in patients with peripheral vascular disease. Thromb Haemost. 1983;50:885-887. [PubMed]
 
Fonseca V, Mikhailidis DP, Boag F, et al. Thrombocytopenia and lupus-like anticoagulant in a patient with peripheral vascular disease: response to infusion of prostacyclin. Angiology. 1985;36:258-263. [PubMed] [CrossRef]
 
Sasaki Y, Takahashi T, Tanaka I, et al. Expression of prostacyclin receptor in human megakaryocytes. Blood. 1997;99:1039-1046
 
Vittet D, Duperray C, Chevillard C. Cyclic-AMP inhibits cell growth and negatively interacts with platelet membrane glycoprotein expression on the Dami human megakaryoblastic cell line. J Cell Physiol. 1995;163:645-655. [PubMed] [CrossRef]
 
Shen HW, Chen YL, Chern CY, et al. The effect of prostacyclin agonists on the differentiation of phorbol ester treated human erythroleukemia cells. Prostaglandins Other Lipid Mediat. 2007;83:231-236. [PubMed] [CrossRef]
 
Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005;172:1586-1589. [PubMed] [CrossRef]
 
Shapiro S, Hill NS. Transition from IV to subcutaneous prostacyclin: premature withdrawal? Chest. 2007;132:741-743. [PubMed] [CrossRef]
 

Figures

Figure Jump LinkFigure 1 Platelet counts; stratified correlations between right atrial pressure (RAP), epoprostenol (EPO) dose and platelet count. Right atrial pressure (r = − 0.44, p < 0.001; top, A) and epoprostenol dose (r = − 0.33, p = 0.02; bottom, B) were inversely associated with platelet count. Stratification shows that both right atrial pressure and epoprostenol dose appear to have generally independent effects on platelet level. Statistical tests for interaction were negativeGrahic Jump Location
Figure Jump LinkFigure 2 Platelets counts over 2.5 years. Thrombocytopenia preceded initiation of treprostinil on day 134 and persisted over the next 2 years. After transition to epoprostenol (epo) on day 633 (top, A), thrombocytopenia worsened. Epoprostenol was off days 860 to 929 with improvement in thrombocytopenia (bottom, B) but fell again once epoprostenol was restarted. IVIG = IV IgGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Platelet Count by Underlying Etiology*

*No significant difference in platelet counts was seen based on PAH etiology.

Table Graphic Jump Location
Table 2 Associations Between Epoprostenol, Hemodynamic Variables, and Thrombocytopenia (Platelet Count < 150,000/mL)*

*Etiology, use of endothelin receptor antagonists, and use of sildenafil were not associated with thrombocytopenia (data not shown). ORs are for a 1-unit change.

Table Graphic Jump Location
Table 3 Comparison of Hemodynamic Variables Between Patients Receiving Oral Therapy and Epoprostenol*

*Data are presented as mean ± SD. Svo2 was higher among epoprostenol-treated patients, while other hemodynamic results were similar between the two groups.

Table Graphic Jump Location
Table 4 Univariable and Multivariable Associations Between Clinical Variables and Platelet Count*

*Based on the multivariable model, platelet count can be estimated as platelet count = 295,000 – (1.22 × epoprostenol dose) – (6 × mean right atrial pressure). Given the R2 of the model, these variables account for a statistically significant but numerically modest portion of the overall variability in platelet counts.

References

Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol with conventional therapy in primary pulmonary hypertension. N Engl J Med. 1996;334:296-301. [PubMed] [CrossRef]
 
Alheid U, Reichwehr I, Fortermann U. Human endothelial cells inhibit platelet aggregation by stimulating cAMP and cGMP. Eur J Pharmacol. 1989;164:103-110. [PubMed] [CrossRef]
 
Dickinson NT, Jang EK, Haslam RJ. Activation of cGMP stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelets aggregation. Biochem J. 1997;323:371-377. [PubMed]
 
Beghetti M, Reber G, de MP, et al. Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation. Eur Respir J. 2002;19:518-524. [PubMed] [CrossRef]
 
Rizvi MA, Kojouri K, George JN. Drug-induced thrombocytopenia: an updated systematic review. Ann Intern Med. 2001;134:346. [PubMed]
 
Heck J, Keitel K, Wusthoff D, et al. Frequency and pathogenesis of thrombocytopenia in cardiac failure [in German]. Dtsch Med Wochenschr. 1976;101:1381-1384. [PubMed] [CrossRef]
 
Shah SH, Hayes PC, Allan PL, et al. Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis. Am J Gastroenterol. 1996;91:2580-2583. [PubMed]
 
Robbins IM, Kawut SM, Yung D, et al. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;27:578-584. [PubMed] [CrossRef]
 
Lopes AA, Maeda NY, Ebaid M, et al. Effect of intentional hemodilution on platelet survival in secondary pulmonary hypertension. Chest. 1989;95:1207-1210. [PubMed] [CrossRef]
 
Jubelirer SJ. Primary pulmonary hypertension: its association with microangiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med. 1991;151:1221-1223. [PubMed] [CrossRef]
 
Rostagno C, Prisco D, Boddi M. Evidence for local platelet activation in pulmonary vessels in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. Eur Respir J. 1991;4:147-151. [PubMed]
 
Steele P, Ellis JH Jr, Weily HS, et al. Platelet survival time in patients with hypoxemia and pulmonary hypertension. Circulation. 1977;55:660-661. [PubMed] [CrossRef]
 
Peters AM, Rozkovec A, Bell RN, et al. Platelet kinetics in congenital heart disease. Cardiovasc Res. 1982;16:391-397. [PubMed] [CrossRef]
 
Zahavi J, Zahavi M. Enhanced platelet release reaction, shortened platelet survival time and increased platelet aggregation and plasma thromboxane B2 in chronic obstructive arterial disease. Thromb Haemost. 1985;18:105-109
 
Findlay JY, Plevak DJ, Krowka MJ, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transpl Surg. 1999;5:362-365. [PubMed] [CrossRef]
 
Robbins IM, Gaine SP, Schilz R, et al. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;117:14-18. [PubMed] [CrossRef]
 
Horn EM, Barst RJ, Poon M. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;118:1229-1230. [PubMed] [CrossRef]
 
Hargett CW, Ahearn GS, Krichman AM, et al. Thrombocytopenia associated with chronic intravenous epoprostenol therapy [abstract]. Chest. 2004;126:760S
 
Friedman R, Mears JG, Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation. 1997;96:2782-2784. [PubMed] [CrossRef]
 
Sakamaki F, Kyotani S, Nagaya N, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation. 2000;102:2720-2725. [PubMed] [CrossRef]
 
Skogby M, Adrian K, Friberg L, et al. The effect of epoprostenol on platelet activation and consumption during experimental extracorporeal perfusion. Artif Organs. 1999;23:984-987. [PubMed] [CrossRef]
 
Sinzinger H, Horsch AK, Silberbauer K. The behaviour of various platelet function tests during long-term prostacyclin infusion in patients with peripheral vascular disease. Thromb Haemost. 1983;50:885-887. [PubMed]
 
Fonseca V, Mikhailidis DP, Boag F, et al. Thrombocytopenia and lupus-like anticoagulant in a patient with peripheral vascular disease: response to infusion of prostacyclin. Angiology. 1985;36:258-263. [PubMed] [CrossRef]
 
Sasaki Y, Takahashi T, Tanaka I, et al. Expression of prostacyclin receptor in human megakaryocytes. Blood. 1997;99:1039-1046
 
Vittet D, Duperray C, Chevillard C. Cyclic-AMP inhibits cell growth and negatively interacts with platelet membrane glycoprotein expression on the Dami human megakaryoblastic cell line. J Cell Physiol. 1995;163:645-655. [PubMed] [CrossRef]
 
Shen HW, Chen YL, Chern CY, et al. The effect of prostacyclin agonists on the differentiation of phorbol ester treated human erythroleukemia cells. Prostaglandins Other Lipid Mediat. 2007;83:231-236. [PubMed] [CrossRef]
 
Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005;172:1586-1589. [PubMed] [CrossRef]
 
Shapiro S, Hill NS. Transition from IV to subcutaneous prostacyclin: premature withdrawal? Chest. 2007;132:741-743. [PubMed] [CrossRef]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
Medical Therapy For Pulmonary Arterial Hypertension*: ACCP Evidence-Based Clinical Practice Guidelines
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543