Thrombocytopenia and Sepsis: A Life-Threatening Combination

Patients with thrombocytopenia who are admitted to the intensive care unit (ICU) with sepsis are at an increased risk of mortality, compared with patients admitted to the ICU with normal platelet levels, according to the results of a study recently published in Blood. This study builds on findings from pre-clinical animal trials that have suggested platelets influence the host response during sepsis.

Theodora A.M. Claushuis, MD, from the Center for Experimental and Molecular Medicine at the University of Amsterdam in the Netherlands, and colleagues conducted the prospective, observational study to clarify the relationship between thrombocytopenia at ICU admission and biologic and other clinical variables, outcome, and host response in patients with sepsis, as part of the MARS (Molecular Diagnosis and Risk Stratification of Sepsis) project.

“Our results provide insight into how platelets influence the immune response during sepsis in humans,” said Dr. Claushuis told ASH Clinical News.

The researchers evaluated this association by measuring 17 plasma biomarkers related to activation and dysregulation of pathways implicated in sepsis pathogenesis and by conducting whole-genome blood leukocyte expression profiling. The study included 931 adult patients who were consecutively admitted to two teaching hospitals in the Netherlands between January 2011 and July 2013. Patients were included in the study if they had an expected length of stay longer than 24 hours.

Patients were excluded from the study if they met any of the following criteria:

  • They had been transferred from other ICUs (except when transferred on the day of ICU admission).
  • They had been readmitted to the ICU at the same hospital or within 30 days after the first hospital admission.
  • They had a hematologic malignancy, liver cirrhosis, splenectomy, thrombocytosis (≥400×109/L), or unknown platelet counts in the first 24 hours after ICU admission.

Patients were classified according to their risk of infection on a four-point plausibility scale (none, possible, probable, or definite), with sepsis defined as the presence of infection within 24 hours of ICU admission and at least one other parameter described in the 2001 International Sepsis Definitions Conference.

Using the lowest platelet count within the first 24 hours of ICU admission, patients were also stratified into groups according to:

  • Very-low platelet counts: <50 x 109/L (n=61; 6.6%)
  • Intermediate-low platelet counts: 50-99 x 109/L (n=121; 13%)
  • Low platelet counts: 100-149 x 109/L (n=167; 17.9%)
  • Normal platelet counts: 150-399 x 109/L (n=580; 62.3%)

To account for baseline differences other than platelet counts (demographics, chronic comorbidity, concomitant drugs, medical admission type, and primary source of infection) the authors used propensity score matching. Results were also compared to normal values generated from plasma from 27 age- and gender-matched healthy volunteers.

“Platelet counts remained relatively stable across all groups in the first four to six days after ICU admission,” Dr. Claushuis and co-authors noted. “Thereafter, platelet counts [tended to] increase, although patients with very-low platelet counts remained thrombocytopenic for prolonged periods of time while in the ICU.”

Patients with very-low platelet counts were more likely to be younger than those with low or normal platelet counts, had fewer comorbidities, and were more often admitted for medical reasons. Among all platelet count groups, the primary source of infection was similar, though patients with normal platelet counts were more often admitted with pulmonary sepsis and less often with urinary sepsis. Patients with low or intermediate-low platelet counts were more severely ill at admission (as indicated by higher Acute Physiology and Chronic Health Evaluation IV and Sequential Organ Failure Assessment scores).

Patients in the very-low and intermediate-low platelet groups had a higher risk of mortality in the ICU, as well as a higher risk of mortality at day 30 and up to one year after ICU admission (TABLE), compared with patients with normal platelet counts (hazard ratios [HR] = 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively; p values not reported).

The TABLE reports full outcomes of sepsis stratified by platelet counts at admission to the ICU.

“[Evaluation of the genomic response of blood leukocytes showed that] thrombocytopenia was associated with a more disturbed host response, independent of disease severity,” Dr. Claushuis added. “Sepsis patients with thrombocytopenia had more impaired vascular integrity, increased cytokine levels, and had leukocytes with reduced (RNA) signaling in adhesion and diapedesis, compared with patients with normal platelet counts.”

The researchers also observed a distinct whole-blood leukocyte transcriptome pattern, revealing decreased leukocyte adhesion, diapedesis, and extravasation signaling.

“The association between increased mortality and thrombocytopenia is generally regarded as a reflection of disease severity,” Dr. Claushuis concluded. “Our study shows that apart from this, thrombocytopenic sepsis patients also have a different and more disturbed host response.”

The study results are limited in generalizability due to the location at two sites in the Netherlands. Additionally, though the researchers used propensity-matching to correct for baseline differences, they noted, “a bias may have remained after propensity matching due to unmeasured confounders.”


Reference

Claushuis TAM, van Vught LA, Scicluna BP, et al. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood. 2016 March 8. [Epub ahead of print]

TABLE. Outcomes of Sepsis Patients Stratified by Platelet Counts at ICU Admission
  Very low(<50×109/L) Intermediate-low(50-99×109/L) Low(100-149×109/L) Normal(150-399×109/L) p value
Patients, n 61(6.6%) 121(13%) 167(17.9%) 580(62.3%)
Median length of stay, in days [IQR]
   Length of
ICU stay
5[2-9] 3[2-8] 5[2-10] 5[2-10] 0.83
   Length of
hospital stay
20[8-33] 21[9-45] 24[11-49] 23[12-45] 0.21
ICU-acquired complications, n
   None 51
(83.6%)
105(86.8%) 133(79.6%) 476(82.1%) 0.43
   AKI 2(3.3%) 6(5%) 17(10.2%) 50(8.6%) 0.19
   ALI 2(3.3%) 2(1.7%) 8(4.8%) 29(5%) 0.40
Mortality, n
   ICU 29(47.5%) 40(33.1%) 27(16.2%) 82(14.1%) <0.001
   Hospital 34(55.7%) 56(46.3%) 46(27.5%) 156(26.9%) <0.001
   30 days 33(54.1%) 45(37.2%) 42(25.1%) 132(22.8%) <0.001
   60 days 34(55.7%) 54(44.6%) 48(28.7%) 160(27.6%) <0.001
   90 days 38(62.3%) 60(49.6%) 53(31.7%) 180(31%) <0.001
   1 year 43(70.5%) 68(56.2%) 71(42.5%) 244(42.1%) <0.001
ICU = intensive care unit; IQR = interquartile ratio; AKI = acute kidney injury; ALI = acute lung injury

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