Abstract
Background
Hypokalemia is common in heart failure (HF) and is associated with increased mortality. Potassium supplements are commonly used to treat hypokalemia and maintain normokalemia. However, their long-term effects on outcomes in chronic HF are unknown. We used a public-use copy of the Digitalis Investigation Group (DIG) trial dataset to determine the associations of potassium supplement use with outcomes using a propensity-matched design.
Methods
Of the 7788 DIG participants with chronic HF, 2199 were using oral potassium supplements at baseline. We estimated propensity scores for potassium supplement use for each patient and used them to match 2131 pairs of patients receiving and not receiving potassium supplements. Matched Cox regression models were used to estimate associations of potassium supplement use with mortality and hospitalization during 40 months of median follow-up.
Results
All-cause mortality occurred in 818 (rate, 1327/10000 person-years) and 802 (rate, 1313/10000 person-years) patients respectively receiving and not receiving potassium supplements (hazard ratio {HR} when potassium supplement use was compared with nonuse, 1.05; 95% confidence interval {CI}, 0.94–1.18; P=0.390). All-cause hospitalizations occurred in 1516 (rate, 4777/10,000 person-years) and 1445 (rate, 4120/10,000 person-years) patients respectively receiving and not receiving potassium supplements (HR, 1.15; 95% CI, 1.05–1.26; P=0.004). HR (95% CI) for hospitalizations due to cardiovascular causes and worsening HF were respectively 1.19 (95% CI, 1.08–1.32; P=0.001) and 1.27 (1.12–1.43; P<0.0001).
Conclusion
The use of potassium supplements in chronic HF was not associated with mortality. However, their use was associated with increased hospitalization due to cardiovascular causes and progressive HF.
Keywords: Heart failure, potassium supplement, mortality, hospitalization, propensity score
1. Introduction
Hypokalemia is common in heart failure (HF) and is associated with poor outcomes [1]. Oral potassium supplements are often used to treat hypokalemia and maintain normokalemia in HF patients with low serum potassium levels. However, the long-term effects of potassium supplement use on outcomes in chronic HF are unknown. The objective of this study was to examine the associations of potassium supplement use with mortality and hospitalization in a propensity-matched cohort of ambulatory chronic HF patients.
2. Materials and methods
2.1. Study patients
The Digitalis Investigation Group (DIG) trial was a multi-center randomized clinical trial, the design and results of which have been reported previously [2, 3]. Briefly, 7788 ambulatory chronic HF patients (6800 had left ventricular ejection fraction ≤45%) in normal sinus rhythm receiving angiotensin-converting enzyme inhibitors and diuretics were randomized to receive digitalis and placebo. Overall, 2199 (28%) patients were receiving oral potassium supplements at baseline and 5589 (72%) patients were not receiving potassium supplements. Data on the use of potassium supplements were available from all 7788 participants.
2.2. Study design: propensity score matching
We focus our current analysis to a subset of 4262 patients, who were assembled through propensity score matching [4–7]. Because patients in the DIG trial were not randomized to receive potassium supplements, the probabilities of actually receiving potassium supplements varied according to the baseline characteristics of those patients. The propensity matching approach allows the assembly of a cohort who would be well-balanced in all measured baseline covariates. Importantly, this can be done without access to the outcomes data, thus maintaining a degree of blindness, which is a key feature of randomized clinical trials [4–7].
The propensity score for potassium supplement use for a patient is the conditional probability of receiving these drugs given that patient’s baseline characteristics [4–7]. We estimated propensity scores for the use of potassium supplements for each of the 7788 patients with a non-parsimonious multivariable logistic regression model using baseline characteristics presented in Figure 1, and checking for plausible interactions [1, 8–10]. We then matched patients who were receiving potassium supplements with those who were not receiving potassium supplements but had similar propensity to receive them [1, 8–10]. Using a greedy matching protocol, we were able to match 97% (2131 of 2199) of patients receiving potassium supplements, yielding a matched cohort of 4262 patients. We then estimated absolute standardized differences to assess pre-match imbalances and post-match balance in baseline covariates and presented those findings as a Love plot [1, 8–12]. An absolute standardized difference of 0% would suggest no residual bias, and those below 10% suggest negligible bias.
Fig. 1.
Love plots for absolute standardized differences in covariates between patients receiving and not receiving potassium supplements, before and after propensity score matching.
(ACE=angiotensin-converting enzyme; NYHA=New York Heart Association)
2.3. Study outcomes
The primary outcomes for the current analysis were all-cause mortality and all-cause hospitalization, and secondary outcomes included mortality and hospitalizations due to cardiovascular causes and HF. DIG participants were followed for a median of 38 months and vital status data were complete for 99% of the patients [13].
2.4. Statistical analysis
For descriptive analyses, we used Pearson Chi square and Wilcoxon rank-sum tests for the pre-match, and McNemar’s test and paired sample t-test for the post-match comparisons, as appropriate. For the pre-match comparison, of the 5589 patients not receiving potassium supplements, a random sample of 2131 patients were selected and were compared with 2131 matched patients receiving potassium supplements. This was done to have similar pre- and post-match sample sizes (n=4262), and to avoid overestimation of significant p values from a larger sample size (n=7788). We then used Kaplan-Meier plots and matched Cox regression analysis to estimate associations of potassium supplement use with total and cause-specific deaths and hospitalizations in the matched cohort [1, 8]. Formal sensitivity analyses were conducted to determine the effect of a potential hidden confounder on our study findings [14]. Subgroup analyses were conducted to determine the homogeneity of the association between potassium supplement use and mortality. All statistical tests were evaluated using two-tailed 95% confidence levels, using SPSS-15 for Windows [15].
3. Results
3.1. Patient characteristics
Patients (n=4262) had a mean (±SD) age of 64 (±11) years, 28% were women and 16% were nonwhites. There were significant pre-match imbalances in key baseline covariates including gender, race, comorbidity, disease severity and baseline serum potassium, all of which were balanced after matching (Table 1). Absolute standardized differences for all measured covariates were below 5% indicating negligible post-match bias (Figure 1).
Table 1.
Baseline patient characteristics
| Variables | Before matching* | After matching | ||||
|---|---|---|---|---|---|---|
| No potassium supplement use (N = 2131) |
Potassium supplement use (N = 2131) |
P values |
No potassium supplement use (n = 2131) |
Potassium supplement use (n = 2131) |
P values |
|
| Age,(yrs) | 63.6 (±11) | 64.2 (±11) | 0.086 | 64.2 (±11) | 64.2 (±11) | 0.858 |
| Female | 496 (23%) | 582 (27%) | 0.002 | 598 (28%) | 582 (27%) | 0.605 |
| Non-white | 269 (13%) | 350 (16%) | <0.0001 | 348 (16%) | 350 (16%) | 0.967 |
| Body mass index (kg/m2) | 27.3 (±5.3) | 27.6 (±5.7) | 0.088 | 27.5 (±5.6) | 27.6 (±5.7) | 0.567 |
| Duration of HF (mo) | 30 (±39) | 30 (±36) | 0.976 | 30 (±36) | 30 (±36) | 0.975 |
| Primary cause heart failure | ||||||
| Ischemic | 1503 (71%) | 1372 (64%) | <0.0001 | 1357 (64%) | 1372 (64%) | 0.646 |
| Hypertensive | 203 (10%) | 261 (12%) | 0.004 | 259 (12%) | 261 (12%) | 0.963 |
| Idiopathic | 281 (13%) | 338 (16%) | 0.013 | 346 (16%) | 338 (16%) | 0.771 |
| Others | 144 (7%) | 160 (8%) | 0.341 | 169 (8%) | 160 (8%) | 0.649 |
| Prior myocardial infarction |
1361 (64%) | 1254 (59%) | 0.001 | 1216 (57%) | 1254 (59%) | 0.237 |
| Current angina | 598 (28%) | 541 (25%) | 0.048 | 536 (25%) | 541 (25%) | 0.886 |
| Hypertension | 964 (45%) | 1102 (52%) | <0.0001 | 1108 (52%) | 1102 (52%) | 0.876 |
| Diabetes | 594 (28%) | 647 (30%) | 0.074 | 651 (31%) | 647 (30%) | 0.921 |
| Chronic kidney disease | 904 (42%) | 1053 (49%) | <0.0001 | 995 (47%) | 1053 (49%) | 0.082 |
| Medications | ||||||
| Digoxin (pretrial use) | 839 (39%) | 1068 (50%) | <0.0001 | 1078 (51%) | 1068 (50%) | 0.769 |
| Digoxin (trial use) | 1063 (50%) | 1054 (50%) | 0.783 | 1050 (49%) | 1054 (50%) | 0.927 |
| ACE inhibitors | 1999 (94%) | 2004 (94%) | 0.749 | 1991 (93%) | 2004 (94%) | 0.436 |
| Hydralazine & nitrates | 15 (1%) | 33 (2%) | 0.009 | 38 (2%) | 33 (2%) | 0.583 |
| Diuretics | 1512 (71%) | 2025 (95%) | <0.0001 | 2020 (95%) | 2025 (95%) | 0.332 |
| PS diuretics | 182 (9%) | 130 (6%) | 0.002 | 149 (7%) | 130 (6%) | 0.252 |
| Symptoms and signs of heart failure | ||||||
| Dyspnea at rest | 440 (21%) | 541 (25%) | <0.0001 | 543 (26%) | 541 (25%) | 0.972 |
| Dyspnea on exertion | 1572 (74%) | 1687 (79%) | <0.0001 | 1688 (79%) | 1687 (79%) | 1.000 |
| Jugular venous distension |
253 (12%) | 328 (15%) | 0.001 | 345 (16%) | 328 (15%) | 0.499 |
| Third heart sound | 456 (21%) | 563 (26%) | <0.0001 | 578 (27%) | 563 (26%) | 0.631 |
| Pulmonary râles | 312 (15%) | 382 (18%) | 0.004 | 398 (19%) | 382 (18%) | 0.551 |
| Lower extremity edema | 374 (18%) | 565 (27%) | <0.0001 | 558 (26%) | 565 (27%) | 0.815 |
| NYHA class III–IV | 608 (29%) | 780 (37%) | <0.0001 | 779 (37%) | 780 (37%) | 1.000 |
| Heart rate (beats per minute), |
78 (±13) | 80 (±13) | <0.0001 | 80 (±12) | 80 (±13) | 0.836 |
| Systolic BP (mmHg) | 128 (±21) | 127 (±21) | 0.034 | 127 (±21) | 127 (±21) | 0.416 |
| Diastolic BP (mmHg) | 76 (±11) | 75 (±11) | 0.033 | 75 (±12) | 75 (±11) | 0.694 |
| Chest radiograph findings | ||||||
| Pulmonary congestion | 281 (13%) | 354 (17%) | 0.002 | 357 (17%) | 354 (17%) | 0.934 |
| Cardiothoracic ratio >0.5 |
1191 (56%) | 1411 (66%) | <0.0001 | 1410 (66%) | 1411 (66%) | 1.000 |
| Serum potassium (mg/dL) | 4.4 (±0.5) | 4.3 (±0.5) | <0.0001 | 4.3 (±0.5) | 4.3 (±0.5) | 0.554 |
| Serum creatinine (mg/dL) | 1.3 (±0.4) | 1.3 (±0.4) | 0.002 | 1.3 (±0.4) | 1.3 (±0.4) | 0.696 |
| Ejection fraction (%) | 33 (±12) | 31 (±13) | <0.0001 | 30 (±12) | 31 (±13) | 0.370 |
ACE=angiotensin converting enzyme; BP=blood pressure; HF=heart failure.
Of the 5589 patients not receiving potassium supplements, a random sample of 2131 patients were selected and paired with 2131 matched patients receiving potassium supplements. This was done to have similar pre- and post-match sample sizes, and to avoid overestimation of significant p values from a larger sample size.
3.2. Potassium supplement use and mortality
During a median follow up of 40 months, 1620 (38%) patients died from all causes, 1290 (30%) due to cardiovascular causes and 607 (14%) due to progressive HF. All-cause mortality occurred in 818 (rate, 1327/10000 person-years) and 802 (rate, 1313/10000 person-years) patients receiving and not receiving potassium supplements respectively (hazard ratio {HR} when potassium supplement use was compared with its nonuse, 1.05; 95% confidence interval {CI}, 0.94–1.18; P=0.390; Figure 2a and Table 2). This association was homogeneous across a wide spectrum of HF patients (Figure 3). Associations between potassium supplement use and cause-specific mortalities are displayed in Table 2. In the pre-match cohort of 4262 patients, 1503 (35%) died from all causes. All-cause mortality occurred in 818 (38%) and 685 (32%) patients receiving and not receiving potassium supplements respectively (HR, 1.30; 95% CI, 1.17–1.43; P<0.0001).
Fig. 2.
Kaplan-Meier plots for all-cause mortality and all-cause hospitalization by the use of oral potassium supplements.
Table 2.
Mortality by potassium supplement use
| Outcomes | Rate / 10000 person-years follow up (total number of events / follow-up in years) |
Rate difference (per 10,000 person- years)* |
Hazard ratio (95% CI)† |
P value | ||
|---|---|---|---|---|---|---|
| No potassium supplement use (N = 2131) |
Potassium supplement use (N = 2131) |
|||||
| All-cause | 1313 (802 / 6109) |
1327 (818 / 5928) |
+ 67 | 1.05 (0.94–1.18) |
0.390 | |
| Cardiovascular | 1044 (638 / 6109) |
1100 (652 / 5928) |
+ 56 | 1.07 (0.95–1.22) |
0.275 | |
| Worsening heart failure‡ | 476 (291 / 6109) |
533 (316 / 5928) |
+ 57 | 1.18 (0.98–1.42) |
0.081 | |
| Other cardiac§ | 521 (318 / 6109) |
516 (306 / 5928) |
− 5 | 0.98 (0.82–1.17) |
0.784 | |
| Other vascular¶ | 47 (29 / 6109) |
51 (30 / 5928) |
+4 | 1.15 (0.63–2.09) |
0.648 | |
| Non-cardiac, non-vascular | 196 (120 / 6109) |
214 (127 / 5928) |
+ 18 | 1.08 (0.81–1.43) |
0.611 | |
| Unknown | 72 (44 / 6109) |
66 (39 / 5928) |
− 6 | 0.69 (0.42–1.16) |
0.161 | |
Absolute rate differences were calculated by subtracting the rates of death in the potassium-supplement group from the rates of death in the no potassium-supplement group (before values were rounded).
Hazard ratios and confidence intervals (CI) were estimated from matched Cox proportional-hazards models.
This category includes patients who died from worsening heart failure, even if the final event was an arrhythmia.
This category includes deaths presumed to result from arrhythmia without evidence of worsening heart failure and deaths due to atherosclerotic coronary disease, bradyarrhythmias, low-output states, and cardiac surgery.
This category includes deaths due to stroke, embolism, peripheral vascular disease, vascular surgery, and carotid endarterectomy.
Fig. 3.
Hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality associated with potassium supplement use in subgroups of patients with chronic heart failure. (ACE=angiotensin-converting enzyme)
3.3. Potassium supplement use and hospitalization
Overall, hospitalizations due to all causes, cardiovascular causes, and worsening HF occurred respectively in 2961 (69%), 2362 (55%) and 1483 (35%) patients. All-cause hospitalizations occurred in 1516 (rate, 4777/10000 person-years) and 1445 (rate, 4120/10000 person-years) patients receiving and not receiving potassium supplements respectively (HR for potassium supplement use, 1.15; 95% CI, 1.05–1.26; P=0.004; Figure 2b and Table 3). Results of our sensitivity analysis suggest that in the absence of hidden bias, a sign-score test for matched data with censoring provides strong evidence (two-tailed p=0.003) that the use of potassium supplement was associated with an increased risk of all-cause hospitalization. A hidden covariate that would increase the odds of potassium supplement use by only 4.9% may potentially explain away this association [14]. Associations between potassium supplement use and cause-specific hospitalizations are displayed in Table 3.
Table 3.
Hospitalization by potassium supplement use
| Cause for hospitalization* | Rate / 10000 person-years follow up (total number of events / follow-up in years) |
Rate difference ( / 10,000 person- years)† |
Matched hazard ratio (95% CI)‡ |
P value | |
|---|---|---|---|---|---|
| No potassium Supplement use (N = 2131) |
Potassium supplement use (N = 2131) |
||||
| All-cause | 4120 (1445 / 3507) |
4777 (1516 / 3173) |
+ 657 | 1.15 (1.05–1.26) |
0.004 |
| Cardiovascular | 2690 (1127 / 4189) |
3284 (1235 / 3761) |
+ 594 | 1.19 (1.08–1.32) |
0.001 |
| Worsening heart failure | 1318 (676 / 5129) |
1717 (807 / 4701) |
+ 399 | 1.27 (1.12–1.43) |
<0.0001 |
| Ventricular arrhythmia, cardiac arrest |
147 (88 / 5990) |
132 (77 / 5812) |
− 15 | 1.07 (0.75–1.53) |
0.715 |
| SV arrhythmias§ | 170 (101 / 5931) |
195 (112 / 5745) |
+ 25 | 1.06 (0.78–1.44) |
0.697 |
| AV block, bradyarrhythmia | 15 (9 / 6098) |
19 (11 / 5906) |
+ 4 | 1.14 (0.41–3.15) |
0.796 |
| Suspected digoxin toxicity |
58 (35 / 6052) |
53 (31 / 5887) |
− 5 | 0.92 (0.53–1.61) |
0.923 |
| Myocardial infarction | 215 (128 / 5947) |
191 (111 / 5807) |
− 24 | 0.93 (0.69–1.24) |
0.603 |
| Unstable angina | 417 (236 / 5661) |
483 (262 / 5429) |
+ 66 | 1.16 (0.95–1.41) |
0.157 |
| Stroke | 155 (93 / 5985) |
215 (124 / 5755) |
+ 60 | 1.26 (0.93–1.71) |
0.140 |
| Coronary revascularization¶ | 65 (39 / 6034) |
70 (41 / 5846) |
+ 5 | 1.07 (0.64–1.79) |
0.793 |
| Cardiac transplantation | 18 (11 / 6093) |
31 (18 / 5896) |
+ 13 | 2.60 (0.93–7.29) |
0.069 |
| Other cardiovascular** | 468 (265 / 5665) |
521 (283 / 5427) |
+ 53 | 1.09 (0.90–1.32) |
0.400 |
| Respiratory infection | 290 (170 / 5860) |
320 (181 / 5665) |
+ 30 | 1.18 (0.92–1.51) |
0.189 |
| Other non-cardiovascular | 1509 (743 / 4924) |
1547 (730 / 4720) |
+ 38 | 1.05 (0.93–1.19) |
0.414 |
| Unspecified | 20 (12 / 6095) |
27 (16 / 5910) |
+ 7 | 1.83 (0.68–4.96) |
0.232 |
| Number of hospitalizations | 9714 (986 / 1015) |
11893 (1093 / 919) |
+ 2179 | ||
Data shown include the first hospitalization of each patient due to each cause.
Absolute differences were calculated by subtracting the percentage of patients hospitalized in the potassium supplement group from the percentage of patients hospitalized in the no potassium supplement group (before values were rounded).
Hazard ratios and confidence intervals (CI) were estimated from a Cox proportional-hazards models that used the first hospitalization of each patient for each reason.
Supraventricular (SV) arrhythmias include Atrioventricular (AV) block and bradyarrhythmias
This category includes coronary-artery bypass grafting and percutaneous transluminal coronary angioplasty
This category includes embolism, venous thrombosis, peripheral vascular disease, hypertension, other vascular surgery, cardiac catheterization, other types of catheterization, pacemaker implantation, installation of automatic implantable cardiac defibrillator, electrophysiologic testing, transplant-related evaluation, nonspecific chest pain, atherosclerotic heart disease, hypotension, orthostatic hypotension, and valve operation
4. Discussion
Findings from the current analysis demonstrate that oral potassium supplement use was not associated with all-cause mortality in chronic HF, but was associated with increased all-cause hospitalization, which was mostly driven by cardiovascular and HF hospitalizations. Considering that the use of potassium supplements is a marker of hypokalemia, the lack of an independent association between potassium supplement use and all-cause mortality suggest that potassium supplements may have eliminated the increased mortality associated with hypokalemia [1]. However, the association between potassium supplement use and increased cardiovascular hospitalization, which was primarily driven by an increase in HF hospitalization, is somewhat puzzling. Even though the underlying mechanism for this latter association remains unclear, data from animal studies suggest a possible association between plasma potassium and salt appetite [16, 17]. To the best of our knowledge this is first report of an association between potassium supplement use and outcomes in a propensity-matched cohort of chronic HF patients in which those receiving and not receiving potassium supplements were well-balanced in all measured baseline covariates.
Hypokalemia is associated with increased mortality without increase in hospitalization suggesting that most hypokalemia-associated deaths may be sudden and caused by fatal arrhythmias [1]. We find a reversal of these associations in those using oral potassium supplements: no association with mortality and an association with increased hospitalization. Potassium supplement use is only indicated to treat and prevent hypokalemia and thus may be considered a marker of hypokalemia. Yet, our findings suggest that hypokalemia-associated mortality was eliminated in those receiving potassium supplements [1]. This is likely mediated via the correction of hypokalemia. It is unknown whether potassium supplements have intrinsic survival benefit in HF. In patients with hypertension, potassium-sparing diuretics, but not potassium supplements, have been shown to reduce the risk of cardiac arrest [18–20]. Findings from the current analysis suggest that in patients with chronic HF potassium supplements may eliminate hypokalemia-associated deaths. However, potassium supplements do not correct other electrolyte imbalances such as hypomagnesemia, and may not also efficiently replenish tissue potassium [21]. Aldosterone antagonists, such as spironolactone, on the other hand, may replenish body potassium, and also prevent disease progression and mortality in HF [22–25].
Our findings suggest that potassium supplements neutralize the excess deaths associated with hypokalemia, and support their use to correct hypokalemia. However, our findings also suggest that potassium supplements may not provide any additional mortality reduction. Therefore, once hypokalemia has been corrected, aldosterone antagonists may be preferable over chronic potassium supplements for the maintenance of normokalemia [23, 24, 26]. When aldosterone antagonists are used, potassium supplements are often not needed and may even be deleterious [27]. This is also suggested by our subgroup analyses in which the subgroup of patients receiving potassium-sparing diuretics were the only subgroup in which the use of potassium supplements was associated with a trend toward increased mortality (Figure 3). For patients who fail to maintain normokalemia despite the use of aldosterone antagonists in appropriate doses, potassium supplements may be used judiciously to maintain serum potassium between 4 and 5 mEq/L [1, 28]. HF patients, who are elderly, have diabetes or renal insufficiency, or are receiving inhibitors of the renin-angiotensin system or beta-blockers, or non-steroidal anti-inflammatory drugs, are at increased risk of hyperkalemia [29, 30]. Aldosterone antagonists and potassium supplements should be used with caution along with close monitoring of serum potassium levels in these patients.
A rather unexpected finding of our study was increased hospitalizations associated with the use of potassium supplements. While we do not have a clear mechanistic insight into this association, data from animal studies suggest that potassium supplements may increase salt appetite [16, 17]. This notion is also supported by the fact that hyperkalemia-associated hospitalizations were mostly due to cardiovascular causes and worsening HF. We had no data on diuretic dosages and it is possible that use of potassium supplements was a marker of disease severity and use of higher doses of diuretics. Symptomatic HF patients receiving higher doses of diuretics are more likely to develop hypokalemia and receive potassium supplements. However, our matched patients were well balanced in all measured baseline characteristics that also included markers of symptoms and disease severity. Finally, the association between potassium supplement use and hospitalization was relatively sensitive to a potential unmeasured covariate. However, sensitivity analysis cannot determine if such a hidden confounder exists. For a covariate to become a confounder it should be a strong predictor of hospitalization and not be strongly correlated with any of the measured covariates in our study.
Our study has several limitations. Patients in our study were predominantly white, male, relatively young, and in normal sinus rhythm, from the pre-beta-blocker era of HF therapy, which may limit generalizability. Thus, the results of this study should be interpreted with caution, and need to be replicated in contemporary propensity-matched HF populations, and preferably in prospective randomized clinical trials.
In conclusion, the use of potassium supplements was not associated with mortality but was associated with increased hospitalization in chronic HF patients. Once hypokalemia has been corrected with potassium supplements, aldosterone antagonists may be preferable for the maintenance of normokalemia in those with recurrent hypokalemia requiring chronic oral potassium supplement use.
Acknowledgement
The Digitalis Investigation Group (DIG) study was conducted and supported by the NHLBI in collaboration with the DIG Investigators. This Manuscript was prepared using a limited access dataset obtained by the NHLBI and does not necessarily reflect the opinions or views of the DIG Study or the NHLBI.
Funding/Support: Dr. Ahmed is supported by the National Institutes of Health through grants from the National Heart, Lung, and Blood Institute (5-R01-HL085561-02 and P50-HL077100), and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama.
Footnotes
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