Low Serum Calcium Tied to Extent of Bleeding in ICH

Pauline Anderson

September 15, 2016

Researchers are reporting an association between low serum calcium levels and the extent of bleeding in patients with intracerebral hemorrhage (ICH), and they believe that impaired coagulation explains the association.

"We may have discovered a new therapeutic target for ICH," said lead author, Andrea Morotti, MD, stroke research fellow, Massachusetts General Hospital, Boston.

"The main message of our paper is to raise the hypothesis that calcium plays a role in ICH pathophysiology, but of course, we need confirmation in further studies as this was a single-center retrospective study."

There is currently no acute treatment to prevent or improve outcome for patients with ICH, which has a mortality of 40% to 50%, said Dr Morotti.

Their findings were published online September 6 in JAMA Neurology.

The new study included 2103 patients with ICH, mean age 72.7 years, who had serum calcium measured at hospital admission. Of these, 1874 had normal serum calcium levels and 229 had hypocalcemia, defined as a total serum calcium level less than 8.4 mg/dL.

In study participants, the median baseline ICH volume was 18 mL, and the median time from symptom onset to baseline non–contrast-enhanced computed tomography (NCCT) was 4 hours.

Compared with normocalcemic patients, those with hypocalcemia had a higher median baseline hematoma volume (37 mL vs 16 mL; P < .001), were younger (68.9 vs 73.1 years; P < .001), and less frequently received antiplatelet medications (42.8% vs 49.7%; P = .049).

The mortality rate at 30 days was significantly higher among hypocalcemic patients (59.8% vs 44.2%; P < .001).

Ionized Calcium

Ionized calcium levels were available for about 25% of the study group and correlated well with total serum calcium levels. The ionized calcium level was inversely correlated with the international normalized ratio and the activated partial thromboplastin time.

"These are not very accurate measures of coagulation, but there is an association, and we think that low calcium mediates this association," said Dr Morotti.

Ionized calcium is more accurate than total calcium in measuring the biologically active component of calcium, added Dr Morotti. "So future studies should confirm our results using ionized calcium."

Dr Morotti noted that the level of calcium did not have to be very low to affect bleeding. "Patients with a borderline low calcium, but not super low, had increased bleeding."

The researchers also looked at hematoma expansion, defined as an increase of more than 30% or 6 mL from baseline ICH volume, in the 66.2% of the patients who had a follow-up NCCT scan. A higher serum calcium level was significantly associated with a reduced risk for ICH expansion in multivariable logistic regression (odds ratio, 0.72; 95% confidence interval, 0.54 - 0.97; P = .03).

The relationship between low serum calcium and bleeding in patients with ICH has been suggested in previous papers, but these were "very small cohorts," said Dr Morotti. "We kind of confirmed this association in a cohort of more than 2000 patients."

A possible mechanism explaining the association is through blood pressure. Lower calcium levels can lead to vasoconstriction and elevated blood pressure, which could cause increased bleeding and increase the risk for hematoma expansion.

However, results of this study don't seem to bear this out.

"We didn't see a difference in ICH location; typically deep bleeding is associated with hypertension, but we didn't find this positive association," explained Dr Morotti. "And acute blood pressure values did not differ between hypercalcemic and normocalcemic patients."

Calcium Hypothesis

On the other hand, he said, the current findings indirectly support the hypothesis that a low serum calcium level contributes to a larger ICH volume and an increased risk for hematoma expansion through impaired coagulation.

And this makes sense from a pathophysiologic point of view, said Dr Morotti. "Calcium is a cofactor involved in basically all the steps of coagulation."

While calcium is "a very cheap and widely available biomarker," it's too early to start modifying calcium levels of patients with ICH arriving in the emergency department, said Dr Morotti.

"There is not enough evidence to recommend such a big change in clinical practice."

In an accompanying editorial Mark J. Alberts, MD, Department of Neurology and Neurotherapeutics, and Ravi Sarode, MD, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, point out that although calcium is an integral part of various steps of the coagulation cascade and platelet activation, it has never been directly attributed to a bleeding or thrombotic disorder.

"It is assumed that there is never a significant deficiency of calcium, either acute or chronic, that might lead to impaired hemostasis."

The editorial writers urged caution in interpreting the new data because the association is found with just a one-time hypocalcemia value.

"It would be useful to inquire into any mild bleeding tendencies that these patients might have had in the past and to see whether they might have been related to chronic hypocalcemia."

They also suggested that alternative hypotheses should be considered. It's possible, they said, that patients taking certain antihypertensive medications, for example, diuretics, might have lower calcium levels, or that they have a deficiency in vitamin D, which may reduce serum calcium levels.

Although the causal and mechanistic links between low calcium and bleeding in ICH are "abstruse," the new study "provides important insights" and the findings "are welcome and needed," the editorialists write.

"We can easily and rapidly increase serum calcium levels if this simple intervention might reduce the risk of hematoma expansion."

But Dr Alberts and Dr Sarode say they doubt it will be that simple. "It almost never is when dealing with strokes."

The study was supported by grants from the National Institute of Neurological Disorders and Stroke. Dr Morotti has disclosed no relevant financial relationships. Dr Alberts reports having been a consultant and speaker for Chiesi and Genentech.

JAMA Neurol. Published online September 6, 2016. Abstract, Editorial

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