Ischemic Stroke as First Manifestation of Essential Thrombocythemia
Report of Six Cases
Background Ischemic stroke as a presenting sign of essential thrombocythemia has been infrequently reported. We describe six patients in whom cerebrovascular disease was the first manifestation of this myeloproliferative disease. A positive endogenous megakaryocyte and/or erythroid colony growth from blood was a diagnostic criterion of essential thrombocythemia in patients with platelets counts lower than 600×109/L.
Case Descriptions These six patients represented 0.54% of all patients with first stroke, 42.8% of all hematologic disorders associated with stroke, and 12.5% of all patients with essential thrombocythemia diagnosed from 1986 to 1992 at our institution. Eleven acute cerebrovascular accidents (6 transient ischemic attacks, 5 definitive cerebral infarcts) were registered. Mean time from ischemic stroke to diagnosis of essential thrombocythemia was 4.5 months (range, 1 to 12 months). The mean platelet count was 597×109/L (range, 414 to 760×109/L). Four patients had platelets counts lower than 600×109/L. All patients had circulating erythroid progenitors, megakaryocytic progenitors, or both.
Conclusions Ischemic stroke as a presenting manifestation of essential thrombocythemia is probably underrecognized. The diagnosis of thrombocythemia should not be excluded on the basis of platelet counts lower than 600×109/L. The availability of in vitro culture of hematopoietic progenitors from peripheral blood makes it possible to diagnose early and atypical cases.
Hematologic disorders are unusual causes of acute cerebrovascular accidents.1 In young adults the prevalence of acute cerebrovascular accidents attributed to hematologic disorders varies between 0% and 7%.2 3 Essential thrombocythemia is a myeloproliferative disorder that may cause cerebral ischemia, particularly in the course of the disease and in the presence of platelet counts greater than 1000×109/L.4 5 However, ischemic stroke as a presenting sign of essential thrombocythemia with platelet counts lower than 1000×109/L has been rarely reported.6
We describe six patients in whom essential thrombocythemia was recognized during investigation of an ischemic stroke. They accounted for 0.54% of all patients with their first stroke who had been consecutively hospitalized during a 7-year period.
Subjects and Methods
The medical records of 1099 patients with first-ever acute cerebrovascular accident admitted consecutively to the Service of Neurology of our institution between January 1986 and December 1992 were searched for the diagnosis of any hematologic disorder, in particular essential thrombocythemia.
The clinical condition of patients in whom essential thrombocythemia was recognized during investigation of an ischemic stroke was assessed at least by a neurologist and a hematologist. Demographic characteristics and salient features of clinical history, physical examination, and neurological examination were recorded. Diagnostic evaluation included laboratory tests (complete hematologic screening, routine biochemical profile, urinalysis), serology for syphilis (VDRL), chest roentgenography, abdominal ultrasonography, 12-lead electrocardiography, brain CT scan and MRI, two-dimensional echocardiography, arterial digital subtraction angiography and/or Doppler ultrasonography of the supra-aortic trunks, bone marrow aspiration and cytogenetic analysis, bone marrow biopsy, and in vitro culture of hematopoietic progenitors from peripheral blood.
The diagnosis of essential thrombocythemia was made according to Polycythemia Vera Study Group criteria7 and included a platelet count persistently greater than 600×109/L, hemoglobin 13 g/100 mL per deciliter or lower or normal red cell mass (men, <36 mL/kg; women, <32 mL/kg), stainable iron in marrow or failure of iron trial (<1 g/100 mL per deciliter rise in hemoglobin after 1 month of iron therapy), no Philadelphia chromosome, absence of prominent bone marrow fibrosis, and no known cause for reactive thrombocytosis. When all of the Polycythemia Vera Study group criteria were met except for a platelet count greater than 600×109/L, a positive endogenous megakaryocyte and/or erythroid colony growth from blood was required to establish a definitive diagnosis of essential thrombocythemia.8
Peripheral blood samples were collected in heparinized tubes (20 mL), and mononuclear cells were isolated by centrifugation in Ficoll-Hypaque gradient (density, 1.077). Erythroid progenitors were cultured as described by Iscove et al.9 Briefly, 2×105 mononuclear cells were added to a culture medium of methyl cellulose containing (per milliliter) 30% fetal calf serum, 10% bovine serum albumin, 2.5% normal human serum, 4×10−3 mol/L thioglycerol, and 1 IU of erythropoietin. Plates were incubated at 37°C in 5% CO2 air at 100% humidity for 14 days. The spontaneous growth of burst-forming units, erythroid (BFU-E) was studied with the use of the same culture medium without the addition of erythropoietin. BFU-E were defined as multiple clusters of 50 or more cells each and recognized by distinctive orange-red staining. Cells were then removed and stained with May-Grünwald-Giemsa. Megakaryocytic progenitors were cultured in accordance with the method of Messner et al.10 Briefly, 2×105 mononuclear cells were added to a medium containing methyl cellulose, 30% normal human plasma, and 5% phytohemagglutinin-stimulated leukocyte conditioning medium. Spontaneous megakaryocyte growth was assessed with the use of the same culture medium without phytohemagglutinin-stimulated leukocyte conditioning medium. After 14 days of incubation, colony-forming units, megakaryocyte (CFUMEG) were defined as aggregates of at least five cells with translucent cytoplasm and a distinct cell border of high refractivity. Cells were removed and stained with May-Grünwald-Giemsa. The nature of the cells was checked by positive labeling with a monoclonal antibody directed against the glycoprotein IIb/IIIa complex.
During a 7-year period, from January 1986 to December 1992, 1099 patients were admitted to our hospital because of first stroke, and we found 6 (0.54%) (2 men and 4 women, aged 32 to 79 years [mean, 62.5 years]) in whom cerebrovascular disease was the first manifestation of essential thrombocythemia. Other possible mechanisms of ischemic infarction (thrombotic, cardioembolic, or hemodynamic) were excluded on the basis of negative or normal results of routine laboratory tests, VDRL, two-dimensional echocardiography, and arterial digital subtraction angiography and/or Doppler ultrasonography of the supra-aortic trunks. This group represented 12.5% (6/48) of the total number of patients with essential thrombocythemia diagnosed during the study period and accounted for 42.8% (6/14) of all hematologic disorders associated with ischemic stroke identified from 1986 to 1992. The remaining disorders consisted of polycythemia vera (2), smoker’s polycythemia (1), thrombotic thrombocytopenic purpura (1), familial protein C deficiency (1), IgA myeloma (1), acute leukemia (1), and Waldenström’s macroglobulinemia (1).
Clinical data of the patients are summarized in the Table⇓. Risk factors for cerebrovascular disease included hypertension in 2 patients, cigarette smoking in 2, hypercholesterolemia in 1, and history of atrial fibrillation in 1. A total of 11 acute cerebrovascular accidents (6 transient ischemic attacks [TIAs], 5 definitive cerebral infarcts) were registered. Three patients had experienced episodes of TIAs in the same vascular territory before first stroke occurrence. Cerebral infarct was seen on CT scan and/or MRI in 4 patients. The carotid territory was involved in 3 patients (cortical in 1, subcortical in 1, and both cortical and subcortical in 1) and the vertebrobasilar in 1 patient. The vascular territory was undetermined in 2 patients. Speech disturbances were present in 4 patients (dysarthria in 3, aphasia in 1), pure motor hemiparesis in 2, motor plus sensory involvement in 1, visual field sparing in 1, and transient pure sensory stroke in 1.
The mean platelet count was 597×109/L (range, 414 to 760×109/L) (Table⇑). The mean time from ischemic stroke to diagnosis of essential thrombocythemia was 4.5 months (range, 1 to 12 months). All patients had circulating erythroid progenitors (4), megakaryocytic progenitors (5), or both (3) (Table⇑).
Patients were given hydroxyurea (15 mg/kg daily) and acetylsalicylic acid (500 mg daily). During a subsequent mean period of observation of 56.6 months (range, 32 to 77 months), 3 patients have remained symptom free, 1 patient exhibited mild brachiocrural hemiparesis, and 1 patient had moderate disability due to spastic right hemiparesis. One patient had recurrence of focal cerebral ischemia and died at 32 months.
Hematologic disorders were identified as the definitive cause of cerebrovascular disease in 1.27% of patients, which is slightly higher than that reported in general stroke registries (between 0% and 0.8%).1 2 11 12 13 Ischemic stroke attributed to essential thrombocythemia was found in 0.5% of cases, which is similar to a figure of 0.4% reported in the Lausanne Stroke Registry (0.4% of cases).12
Our 12.5% rate of ischemic stroke as inaugurating symptom of essential thrombocythemia may be explained by a high index of suspicion based on a protocolized workup established at our institution that includes in vitro culture of hematopoietic progenitors in persistent borderline thrombocytosis (≤600×109/L). In 4 patients in our series with platelet counts lower than 600×109/L, the detection of spontaneous growth of erythroid and megakaryocytic progenitors allowed us to establish an early diagnosis of the myeloproliferative disorder. As far as we are aware, the use of these assays to confirm the diagnosis of essential thrombocythemia in patients with ischemic stroke has not been previously reported. Spontaneous growth of erythroid and megakaryocytic progenitors, a phenomenon not detected in reactive thrombocytosis and healthy subjects,8 14 has been considered strong evidence for a myeloproliferative disorder. Moreover, the presence of spontaneous colony growth is associated with an increased risk of thromboembolic complications regardless of the platelet count.15
Of a total of 11 acute cerebrovascular accidents, there were 6 cases of TIAs and 5 definitive cerebral infarcts. This high incidence of TIA is consistent with microcirculatory disturbances found in essential thrombocythemia.
There are no clear guidelines of management of patients with ischemic stroke due to essential thrombocythemia. Control of thrombocytosis with chemotherapeutic agents in combination with antiplatelet drugs has been the recommended therapeutic approach.4 16 Although the risk-benefit ratio of hydroxyurea remains disputed, this nonalkylating agent has been proposed as the treatment of choice for patients with essential thrombocythemia and high risk of thrombosis, defined as age greater than 60 years and a previous thrombotic event.17 In a recent prospective randomized trial, the occurrence of thrombosis was significantly higher in patients assigned to the arm of no myelosuppresive therapy compared with those treated with hydroxyurea.18 With regard to the use of antiplatelet drugs, in the special situation of symptomatic patients with arterial vascular disease, venous thrombosis, or embolic complications, the use of aspirin (in conjunction with treatment to lower the platelet count) is clearly indicated.19 Although it is known that ischemic and thrombotic manifestations of essential thrombocythemia are platelet-mediated and sensitive to antiplatelet drug therapy, at very high platelet counts aspirin is associated with a bleeding risk that may be attributed to aggravation of platelet dysfunction of the myeloproliferative disorder. For this reason, the need to reduce platelet count to at least below 1000×109/L seems mandatory. However, the relative benefits and risks of aspirin use in the long-term prevention of thrombotic events remain to be assessed in prospective clinical trials.
We conclude that ischemic stroke as a presenting manifestation of essential thrombocythemia is probably underrecognized. Physicians should be aware that essential thrombocythemia cannot be definitively excluded on the basis of platelet counts below 600×109/L. The availability of in vitro culture of hematopoietic progenitors from such an eminently accessible source as peripheral blood makes it possible to diagnose early and atypical cases.
This study was supported in part by grant 93/0224 from the Fondo de Investigaciones Sanitarias. We thank Marta Pulido, MD, for editing the manuscript and translating into English.
Reprint requests to Dr Adrià Arboix, Servicio de Neurología, Hospitals de Barcelona de L’Aliança, Sant Antoni M. Claret 135, E-08025 Barcelona, Spain.
- Received February 2, 1995.
- Revision received May 16, 1995.
- Accepted May 18, 1995.
- Copyright © 1995 by American Heart Association
Hart RG, Kanter MC. Hematologic disorders and ischemic stroke. Stroke. 1990;21:1111-1121.
Sandercock PAG, Warlow CP, Jones LN, Starkey IR. Predisposing factors for cerebral infarction: the Oxfordshire Community Stroke Project. Br Med J. 1989;298:75-80.
Ross Russell RW, Wade JPH. Haematological causes of cerebrovascular disease. In: Toole JF, ed. Handbook of Clinical Neurology: Vascular Diseases. Amsterdam, Netherlands: Elsevier Science Publishers BV; 1989:463-481.
Jabaily J, Iland HJ, Laszlo J, Massey EW, Faguet GB, Brière J, Landaw SA, Pisciotta AV. Neurologic manifestations of essential thrombocythemia. Ann Intern Med. 1983;99:513-518.
Bernard PG. Cerebrovascular symptoms in primary thrombocytosis. Stroke. 1978;9:110. Abstract.
Iscove NN, Sieber F, Winterhalter H. Erythroid colony formation in cultures of mouse and human bone marrow: analysis of the requirement for erythropoietin by gel filtration and affinity chromatography on agarose-concanavalin A. Am J Cell Physiol. 1974;83:309-320.
Messner HA, Jamal N, Izaguirre C. The growth of large megakaryocyte colonies from human bone marrow. J Cell Physiol. 1982;1(suppl) 45-51.
Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke. 1988;19:1083-1092.
Cortelazzo S, Viero P, Finazzi G, D’Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol. 1990;8:556-562.
Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood. 1984;64:1-12.