Intracranial Hemorrhage in Patients with Haematological Malignancy, a Nested Case-Control Study

Background

Intracranial hemorrhage (ICH) is one of the most serious side-effects of severe thrombocytopenia in hematology patients. ICH is rare, but can have devastating consequences (death/major morbidity). It is unknown why some patients bleed and others do not. This study's aims were to identify risk factors for ICH in patients with hematologic disorders, and identify the short-term outcomes for these patients at 30 days (major morbidity/mortality).

Methods

The InCiTe study is a UK-wide case-control study of ICH nested within a 4 year prospective surveillance study (ISRCTN05026912). Each ICH case was matched to one control. Cases were adult hematology patients (≥ 16 yrs) who had any type or severity of ICH and were receiving, about to receive or had just received myeloablative chemotherapy or hematopoietic stem cell transplant (HSCT). Only patients treated with curative intent were included. Control patients fulfilled the same inclusion criteria as cases (apart from ICH) and were treated at the same hospital immediately before the index case. Cases and controls were matched to type of treatment (chemotherapy or HSCT) so that potential transplant-related risk factors could be assessed. Hospitals across the UK participated in monthly e-mail reporting of any cases of ICH occurring during the preceding calendar month. Case and control forms were sent to any participating hospital reporting an eligible case.

Results

Monthly reporting occurred between June 2011 & June 2015. Over 90% of hospitals reported every month whether or not a case of ICH had occurred. 148 ICH cases were reported during the study from 84 recruiting hospitals. Median age of cases was 60 years (range 17 to 80), 50% were male, 61% (90/148) had acute myeloid leukemia, of whom 13 had acute promyelocytic leukemia. 91% (134/148) were being treated/about to be treated with chemotherapy, 8% (12/148) were undergoing an allogeneic HSCT, and 1% (2/148) an autologous HSCT. Only 18% (26/148) were in complete remission (CR) from their hematologic malignancy at time of ICH. Median platelet count at time of ICH was 17 x 10⁹/L (IQR 8 to 37). In the 4 days preceding ICH, cases had median 3 days with platelet count < 50 x 10⁹/L (IQR 1.75 to 4), 1.5 days with platelet count < 20 x 10⁹/L (IQR 0 to 3), and 0 days with platelet count < 10 x 10⁹/L (IQR 0 to 2).

140 cases and matched controls were used to assess ICH risk factors. Variables considered for inclusion within the model were: Hb, WCC, creatinine, CRP, albumin, platelet count, platelet refractoriness, sex, age, hematologic diagnosis, CR status, use of anticoagulants, height, weight, abnormal coagulation, liver impairment, hypertension, previous CNS abnormality, renal impairment, recent history of bleeding, smoking, diabetes, ischaemic heart disease, use of therapeutic antibiotics, and antifungals.

Independent risk factors for ICH identified from a multivariable conditional logistic regression analysis were: WCC (OR 1.2 per 1 x 10⁹/L rise in WCC; 95% CI 1.05 to 1.36; P < 0.0001); CRP (OR 1.01 per 1mg/L increase in CRP; 95% CI 1 to 1.01; P = 0.006), platelet refractoriness (OR 5.3; 95% CI 1.29 to 21.76; P = 0.01); female gender (OR 2.78; 95% CI 1.28 to 6.03; P = 0.006); and use of therapeutic antibiotics (OR 0.34; 95% CI 0.12 to 0.92; P = 0.03). Creatinine (OR 1.01 per 1µmol/L rise in creatinine; 95% CI 1 to 1.02; P = 0.06) was borderline significant.

Less than a third of patients who had an ICH survived the event with no long term sequelae. 75 cases (51%) died within 30 days, of these 87% (65/75) died due to their ICH. 28% (42/148) had a Glasgow Coma Scale < 9 at time of ICH, of these 81% (34/42) died. 73 cases survived, however, 40% (29/73) had a persistent neurological impairment at 30 days, and of these only 17% (5/29) were independent in all activities of daily living. 30 day survival was 49.3 % (95% CI 40.8 to 57.2) for cases and 93.5% (95% CI 84.7 to 97.3) for controls.

Discussion

Risk factors for ICH that were identified in this large case-control study relate to infection or sepsis: these include a high WCC (possibly also due to presence of leukemic cells in circulation), high CRP (inflammation increases the risk of bleeding), and platelet refractoriness; use of antibiotics decreases the risk. By comparison, platelet count and haemoglobin were not identified as important factors. Outcomes after ICH were poor. The role of further risk-adjusted strategies as a preventative strategy requires more research.

Funding

NHSBT