Key results for the association between white blood cell counts (WBC) and outcomes in acute ischemic stroke patients treated with IVT were: (i) Leukocytosis on admission independently predicted poor functional outcome and mortality. This association was even more pronounced in the subgroup of patients with combined leukocytosis and elevated CRP. (ii) Neither leukocytosis nor the combination of leukocytosis and elevated CRP was significantly associated with the occurrence of sICH. (iii) Leukopenia was not associated with any outcome.

Previous studies revealed an association between leukocytosis as well as elevated CRP on admission and more severe strokes and larger infarct volumes [6,7,8,9]. In line, patients with leukocytosis in the present study had higher baseline NIHSS than patients with normal WBC (median NIHSS 10 vs 8). This difference was even more pronounced in the subgroup of patients with combined leukocytosis and elevated CRP (median NIHSS 12 vs 8) suggesting that the extent of brain injury might — at least partly — be reflected by inflammatory parameters. Another explanation for the higher stroke severity in patients with elevated inflammatory parameters might be that those patients had significantly longer time intervals between stroke onset and administration than patients with normal WBC (median 166 min vs 140 min). Despite the fact, that our study was not designed to investigate potential causes of treatment delay, these associations stress the importance of investigating outcomes in this patient cohort. Yet, the effect of leukocytosis on outcomes and hemorrhagic complications in IVT-treated stroke patients in previous studies was controversial. One study, including 985 IVT-treated stroke patients, found an association between baseline leukocytosis and poor outcome [10], whereas in another study, including 846 IVT-treated stroke patients, baseline neutrophil count but not leukocytosis independently predicted poor outcome and mortality [11]. A third study found baseline WBC < 8.1 × 109/l to be associated with favorable outcome in IVT-treated stroke patients (n = 657) and suggested further investigation of WBC in larger prospective datasets [22]. Limitation of these studies is the relatively small number of patients with leukocytosis. In the present study, we found an independent association between leukocytosis and poor functional outcome and mortality, which remained stable over the long period of data collection (1995–2018). Interestingly, association with poor functional outcome and mortality was even stronger in patients with leukocytosis and elevated CRP. Additionally, the probability for poor functional outcome and mortality increased with rising WBC and CRP. However, every increase in WBC by 1 × 109/l increased the odds of poor functional outcome by 4% which is likely of minor clinical relevance. While we cannot evaluate the cause of the association between elevated inflammatory parameters and worse clinical outcome, it is likely that elevated inflammatory parameters contribute directly –e.g., via leucocyte clogging [23] — and indirectly — reflecting a co-existing disorder — to outcome after IVT.

Because patients with laboratory signs of systemic inflammation had higher NIHSS at onset and larger stroke volumes [6,7,8,9], it would have been likely that hemorrhagic complications after thrombolysis (sICH) occur more often in patients with laboratory signs of systemic inflammation than in those without. Accordingly, experimental research found that leukocytes contribute to vascular damage and disruption of the blood–brain barrier [24, 25]. Furthermore, one previous study revealed an independent association between baseline leukocytosis and occurrence of sICH [10] and another recent study investigating 510 ischemic stroke patients (196 treated with IVT) suggested an association of high WBC with parenchymal hemorrhage independent of infections [26]. However, in our study, after adjustment for potential confounders, neither leukocytosis nor the combination of leukocytosis and elevated CRP was independently associated with increased rate of sICH. Because increased baseline NIHSS, onset-to-treatment time and glucose levels on admission — all well-established risk factors of sICH — were more often present in patients with leukocytosis, we assume that the unadjusted association of leukocytosis with sICH is mostly due to these confounding parameters. Therefore, it seems unlikely that the association between elevated systemic inflammation parameters and poor outcome and mortality is caused by sICH.

Leukopenia — as defined by hematologic criteria — has not been investigated in IVT-treated stroke patients prior to this study. Numerous causes of leukopenia are likely to be associated with worse outcome (e.g., (viral) infections, (hematotoxic) drugs, autoimmune disorders, radiation, renal failure, malignancies, malnutrition) [27, 28]. Additionally, lymphopenia was shown to independently predict unfavorable outcome in intracerebral hemorrhage [29]. In our study, however, presence of leukopenia on admission was rare (1.0%) and did not change the odds for any outcome suggesting that leukopenia is rather a chance finding than a manifestation of an outcome modifying disorder in this patient cohort.

Strengths of our study are the large sample size (n = 10,813) which allowed adjusting for multiple confounding variables and thus clarifying the inconsistencies of previous studies. We also included a subgroup analysis with combined leukocytosis and elevated CRP which is a novelty and underlined the effect of systemic inflammation on clinical outcomes. Finally, we were able to assess outcomes in patients with leukopenia.

The present study has limitations apart from general limitations of register-based, retrospective studies: (i) causes of leukocytosis and elevated CRP were unclear and information on disorders that are likely associated with systemic inflammatory response (e.g., infections at admission, malignancies, rheumatologic disorders or certain medication) was not collected and it was not possible to determine whether leukocytosis was a trigger for stroke. However, as patients suffering from chronic infections or cancer are likely to have pre-existing disability, we were at least able to partly address this issue by adjusting for pre-stroke mRS. (ii) There is growing evidence on the strong linkage between ischemia and inflammation/ immunity [30, 31], and immunomodulation agents are evaluated for acute stroke therapy and stroke prevention [32, 33]. Yet, the observational design of our study does not allow conclusions on potential therapeutic measures modulating the inflammatory response. (iii) Leukocyte subclasses were not available. Thus, we were not able to examine the previously described association of neutrophils/ neutrophil-to-lymphocyte ratio with poor outcome, mortality and sICH [11] in our patient cohort. In addition, the association between leukopenia and outcomes was difficult to interpret as red blood cell and platelet counts were not available.