Intracranial hemorrhage in adult patients with hematological malignancies

In adult patients with hematological malignancies, infection is the most common complication. Intracranial hemorrhage (ICH) is the second most common complication, and is associated with high morbidity and mortality [1‐4]. Several comprehensive reviews have highlighted the following risk factors for ICH in cancer patients: hypertension, vessel wall abnormality, invasion or compression of vessels from a tumor in or adjacent to the brain, low platelet count or platelet dysfunction, coagulation factor deficiency, disseminated intravascular coagulation (DIC), sepsis, and hyperleukocytosis [1, 5‐8]. Hematological malignancies comprise a diverse group of neoplasms, and may directly or indirectly lead to neurological complications and ICH [9, 10]. In recent decades, prophylactic platelet transfusions to maintain the platelet count at a safe threshold have decreased the risk of hemorrhagic complication [11, 12]. However, ICH is still a frequent complication in patients with hematological malignancies, and many questions remain unanswered with regard to the clinical management of ICH in patients with hematological malignancies.

Patients with lymphoid malignancy more frequently experience central nervous system (CNS) involvement than do patients with myeloid leukemia [13, 14]. ICH could be the initial presentation in patients with hematological malignancies [15, 16]. The relationship of ICH and CNS involvement is still underinvestigated. Evidence on the clinical manifestations in ICH among the various hematological malignancies is relatively limited. To clarify the clinical manifestations and prognosis of ICH among patients with hematological malignancies, we retrospectively reviewed the medical records of patients admitted to the National Taiwan University Hospital between 2001 and 2010, and analyzed the data.

The cause of ICH is very important and holds implications for further therapy. Since no patient received autopsy after ICH, the definite cause of ICH in patients with hematological malignancies is inconclusive. Among the 72 patients with ICH, 46 (64%) patients had thrombocytopenia (platelets less than 20,000 cells/μl), 34 (47%) had sepsis, and 15 (21%) had prolongation of prothrombin time. Consequently, thrombocytopenia, sepsis and prolongation of prothrombin time are the major predisposing factors for ICH.

The definite causes of ICH could be further investigated by autopsy study. Occurrence of ICH in patients with acute leukemia has been reported [3, 4]. Case reports of ICH included patients with primary CNS lymphoma [23‐25], intravascular lymphoma [26, 27], and myeloma [28, 29]. However, comparisons of the clinical characteristics and outcome in patients with various hematological malignancies were limited. The current study reveals that patients with AML had a higher incidence of ICH than patients with other hematological malignancies (6.3% vs 1.1%; P = 0.001).

The incidence of ICH is less common in patients with lymphoma and myeloma, among those with intracranial involvement. ICH occurred more frequently in patients with CNS involved lymphoid malignancy relative to those with CNS involved acute leukemia. The pathogenesis of ICH among patients with various hematological malignancies may be different. Leukemias are circulating precursors of lymphoblastic or myeloid neoplasm that involve the bone marrow and peripheral blood. Leukemias often exert an indirect effect on the nervous system, causing thrombocytopenia, coagulation factor deficiency, sepsis, therapy-related complications, and vessel wall abnormalities [9]. In contrast, for most lymphoma and myeloma patients, the tumor cells do not invade tissues and vessels. As Glass [9] proposed, the tumor cells may exert direct effects as solid tissue tumors on cerebral tissue and blood vessels, resulting in vascular occlusion and end-organ ischemia, which in turn, potentially cause thrombosis and hemorrhagic transformation. In the current study, we considered that ICH might partly contribute to the direct invasion or intravascular involvement of tumor cells in patients with lymphoma and myeloma, and the definite mechanism of lymphoma and myeloma associated ICH should be further investigated.

Patients with CNS lymphoma or myeloma involvement should be aware of the increased risk of ICH [23‐27]. L-Asparaginase is one of the combined chemotherapy agents frequently used to treat acute lymphoblastic leukemia; it may decrease the plasma antithrombin and fibrinogen levels, potentially inducing bleeding [30]. Hyperviscosity syndrome and direct tumor invasion also have been reported, which could lead to fatal ICH in patients with multiple myelomas [28, 29]. L-asparaginase and myeloma associated hyperviscosity syndrome implicate bleeding tendency, however, both factors did not disclose the clinical significance of outcome in ICH patients with hematological malignancies in the current study

The types and locations of ICH events in patients with hematological malignancies are also rarely reported [2, 5, 31]. A rapid onset of focal neurological deficit with clinical signs of increased intracranial pressure is strongly suggestive of a diagnosis of ICH, but cranial imaging is required to differentiate it from ischemic stroke [32, 33]. In this study, neuroimaging not only disclosed the types and locations of ICH, but could also predict the outcome of patients with ICH. A neuroimaging study should be performed rapidly after symptoms or signs of neurological deficit in patients with hematological malignancies.

We found most (78%) ICH events in patients with hematological malignancies tended to be IPH, which was congruent with prior reports [5, 34]. Subdural hemorrhage is common among older members of the general population [35]. Among our study patients with hematological malignancies, older patients had more SDH than younger patients (P = 0.002). Symptoms of SDH have a slower onset than those of ICH, because the lower pressure in veins causes them to bleed more slowly than arteries [35]. Given that SDH is associated with a relatively good prognosis in patients with hematological malignancies, clinical awareness of neurological symptoms and signs in older patients, and the rapid use of neuroimaging, could improve diagnostic accuracy and thus the outcome of ICH. Although SAH represents only 5% of all strokes, it is responsible for 25% of all fatalities related to stroke in the general population [36].

In the current study, SAH affected only 21% patients with hematological malignancies but the mortality rate in the SAH group was 90%. Advances have been made in surgical intervention for SAH [36], but none of the SAH patients in the current study received surgery. Surgical intervention showed a trend of improved 30-day outcome (P = 0.085) in the current study. Further research or surgical intervention is needed to improve the prognosis for SAH patients with hematological malignancies. Hemorrhage extending into the ventricles is associated with obstructive hydrocephalus and a relatively poor prognosis in ICH of general population [29, 37]. Most patients with hematological malignancies who developed ICH had a poor prognosis. IVH is not an independent poor prognostic factor in patients with hematological malignancies.

Multivariate analysis using Cox's proportional hazard test revealed that ICH in patients with hematological malignancies was associated with three independent factors. These were prolonged prothrombin duration (P = 0.008; OR 10.5; 95% CI 1.3 to 85.5), subarachnoid hemorrhage (P = 0.021; OR 10.9; 95% CI 1.3 to 89.9), and multifocal cerebral hemorrhage (P = 0.026; OR 4.7; 95% CI 1.6 to 14.0). Several studies have demonstrated that prolongation of prothrombin duration is related to fatal ICH outcome in patients with hematological malignancies [2‐4]. The current study examined prolonged prothrombin duration as one of the independent prognostic factors for ICH in patients with hematological malignancies. Leukemic cells may express fibrinolysis and other proteolysis enzymes, which has been implicated in the pathogenesis of bleeding in some patients [38‐40]. Chemotherapy-related endothelial injury and reduction of coagulation factors also could play a role in the pathogenesis [38, 39]. Coagulopathy in patients with hematological malignancies could play an important role in the pathogenesis of ICH. Prolongation of prothrombin time could be ignored during the period of chemotherapy of patients with hematological malignancies; we suggest regular follow-up of prothrombin time and prompt correction in patients with hematological malignancies. This could potentially decrease the mortality of ICH .

A total of 11 patients underwent craniotomy and hematoma evacuation. Surgical intervention showed a trend of improved 30-day outcome (P = 0.085) in ICH patients with hematological malignancies. Five of the seven survivors had long-term survival (more than 1 year) with minimal neurological sequelae. Although few patients underwent surgical intervention, we would advocate aggressive surgical treatment such as craniotomy and hematoma evacuation for those patients with non-refractory hematological malignancies. Recently, activated factor VII has been used successfully in patients with ICH [40‐42]. A subsequent phase III clinical trial revealed that hemostatic therapy with rFVIIa reduced the growth of hematomas, but did not improve patient survival or functional outcome after intracerebral hemorrhage [43]. Further clinical trials should be conducted in ICH patients with hematological malignancies.

There were some limitations to this study. First, we tried to investigate all the adult patients with hematological malignancies. However, this study is a retrospective cohort in a single university hospital between 2001 and 2010. Given the secular changes in the rapidly evolving field of hematology, patients may have received different chemotherapy protocols and supportive management. Second, thrombocytopenia (64%), sepsis (47%) and prolongation of prothrombin time (21%) were the most common risk factors of ICH. However, there was no patient autopsied for the definite cause of ICH. Furthermore, a prospective multicenter clinical study should be conducted to define the incidence of ICH in this population. We limited the definition of cases to patients with positive neuroimaging study to prevent confounding factors. Consequently, a few patients with refractory leukemia and lymphoma who did not consent to neuroimaging studies were excluded from this study.

ICH is more common in patients with AML than in patients with other types of hematological malignancy. ICH occurred in patients with lymphoma when there was CNS neoplastic involvement. Prognosis did not differ according to type of hematological malignancy. Prolonged prothrombin duration, SAH, and multiple-site hemorrhage were all independent prognostic factors of ICH in patients with hematological malignancies. Neuroimaging studies of the location and type of ICH could assist with outcome prediction for patients with hematological malignancies.