(Stroke. 1996;27:1002-1005.)
© 1996 American Heart Association, Inc.
Articles |
Carotid Artery Thrombus Associated With Severe Iron-Deficiency Anemia and Thrombocytosis
From the Department of Neurology, Washington University School of Medicine, St Louis, Mo.
Correspondence to Dr Paul T. Akins, Department of Neurology, Washington University School of Medicine, Box 8111, 660 S Euclid Ave, St Louis, MO 63110.
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Abstract |
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Background Thrombus within the carotid artery usually occurs in vessels with severe atherosclerotic disease and may embolize to cause transient ischemic attacks and cerebral infarctions. The risk factors for carotid artery thrombus formation in the absence of atherosclerosis are not well characterized. A case series is presented that suggests an association of carotid artery thrombus with severe iron-deficiency anemia and thrombocytosis.
Case Descriptions We describe three women with severe iron-deficiency anemia and thrombocytosis secondary to menorrhagia who developed carotid artery thrombi. Thrombi were detected radiographically. The patients were treated with anticoagulation and antiplatelet therapy. In two patients, follow-up neuroimaging 10 to 14 days later demonstrated resolution of the thrombus and no identifiable vascular disease.
Conclusions Severe iron-deficiency anemia with thrombocytosis may be a risk factor for carotid artery thrombus formation. Medical management with anticoagulation and antiplatelet therapy is a reasonable approach for these patients while the thrombus resolves.
Key Words: anemia • anemia, hypochromic • carotid artery thrombosis • cerebral embolism and thrombosis
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Introduction |
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Although artery-artery emboli from carotid artery disease are a common cause of stroke, angiographic identification of thrombus in the carotid artery is uncommon. For example, Buchan et al1 reported its detection in 29 of approximately 2000 angiograms for ischemic cerebrovascular disease. The majority of carotid thrombi form over atherosclerotic lesions that are frequently stenotic or ulcerated.1 2 3 4 In these cases, thrombus formation is an intermediate step leading to carotid occlusion or thromboemboli or both.
In a small number of cases, carotid artery thrombi have been detected in patients without identifiable carotid disease. The causes for thrombus formation in these patients are unclear and probably multifactorial. Hypercoagulable states from cancer or oral contraceptives2 3 were present in some cases. Thrombi have also been detected in patients using stimulant drugs such as cocaine.3 5 While iron-deficiency anemia has been associated with papilledema,6 idiopathic intracranial hypertension,7 venous sinus thrombosis,8 9 10 and ischemic stroke,11 12 13 14 we suggest a possible relationship of severe iron-deficiency anemia and thrombocytosis with carotid artery thrombus on the basis of the following case reports and a review of the literature.
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Case Reports |
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Patient 1
A 44-year-old right-handed woman presented with transient tingling lasting several minutes in the distal left upper and lower extremities, occurring twice on the day of admission and once 3 days earlier. She had a craving for ice. Her past medical history was remarkable for anemia and menorrhagia. She was taking no medications, including no oral contraceptives. Family history was negative for neurological or hematologic diseases.
She was afebrile, and blood pressure was 120/64 mm Hg. The general physical and funduscopic examinations revealed nothing abnormal. The patient's stool was hemoccult-negative. Her initial neurological examination was normal. The patient developed left-sided neglect and a left hemiparesis on rising from the stretcher for orthostatic blood pressure measurements, although her blood pressure did not fall. These deficits resolved over 1 hour.
The patient was admitted to the neurology service. Her noncontrast head
CT was normal. Laboratory analysis was remarkable for a
microcytic hypochromic anemia and thrombocytosis (see below). The
patient was treated with blood transfusion, oxygen, and aspirin. A
second episode of left-sided neglect and left hemiparesis occurred
after the patient had a bowel movement on the first day of
hospitalization. Cerebral arteriography demonstrated a thrombus in the
bulb of the right internal carotid artery (Fig 1
left).
The patient was treated with intravenous heparin and
aspirin. She had no recurrent symptoms. After 10 days, repeated
arteriography (Fig 1 right) demonstrated resolution of the thrombus. No
underlying vascular lesion was identified.
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The white blood cell count was 5500/mm3 with a normal differential, hemoglobin 6.6 g/dL, hematocrit 22.6%, mean corpuscular volume 56.6 (80 to 97.6 fL), and platelets 666 000/mm3. The peripheral smear showed marked red blood cell hypochromia and microcytosis with slight poikilocytosis. Serum iron was <10 µg/dL, ferritin <10 µg/L, total iron binding capacity 399 µg/dL, and transferrin saturation <3%. Results of additional tests were all normal, including hemoglobin electrophoresis, paroxysmal nocturnal hemoglobinuria marker, protein S and C, antithrombin III, erythrocyte sedimentation rate, antinuclear antibody, rapid plasma reagin, anticardiolipin antibody, thyroid stimulating hormone, chemistry panel, urinalysis, prothrombin time, and partial thromboplastin time. Electrocardiogram and chest x-ray were normal. Transesophageal echocardiogram was normal except for a small patent foramen ovale with Valsalva maneuver only, and lower-extremity venous Doppler studies were negative.
The patient received intravenous iron replacement and oral anticoagulation with warfarin to achieve an international normalized ratio of 2 to 3. She was discharged home. One month later, her hemoglobin was 10.9 g/dL, and platelets were 218 000/mm3. After 1 year, her anticoagulation was discontinued, aspirin treatment was begun, and a hysterectomy was performed. She has had no recurrent symptoms and returned to full activities during a 2-year follow-up period.
Patient 2
A 20-year-old right-handed woman with a history of common
migraine presented with headache and left hand weakness. Three
days before, she noted sudden onset of left arm weakness. One day
before, the patient developed persistent, rhythmic jerking of her left
arm that was independent of her posture. She denied involvement of her
face, torso, or leg. She complained of 3 days of steady bifrontal
headaches without associated photophobia. Her past medical
history was remarkable for menorrhagia. Her brother had had a single
stroke at the age of 6 months of unclear etiology. She was taking no
medications, including no oral contraceptive medications.
General physical and funduscopic examinations revealed nothing abnormal. The patient's stool was hemoccult-negative, and there were no orthostatic changes in vital signs. Neurological evaluation revealed mild hemineglect, mild left facial weakness, and a left hemiparesis with decreased tone. The jerking stopped after the administration of intravenous phenytoin. Distal strength in the left arm and leg was 0/5, and proximal strength was 3/5. Primary sensory modalities were preserved, but graphesthesia and stereognosis were diminished on the left. Deep tendon reflexes were increased on the left, and the left plantar response was extensor.
She was admitted to the neurology service. Laboratory analysis showed the following significant values: hemoglobin 6.3 g/dL, hematocrit 21.5%, mean corpuscular volume 54.5 fL, and platelets 544 000/mm3. The peripheral smear contained microcytic hypochromic red blood cells with anisocytosis. Serum iron was <10 µg/dL, total iron binding capacity 355 µg/dL, transferrin saturation 3%, and ferritin <10 µg/mL. Results for hemoglobin electrophoresis, paroxysmal nocturnal hemoglobinuria marker, erythrocyte sedimentation rate, anticardiolipin antibody, antinuclear antibody, lupus anticoagulant, protein S and C, antithrombin III, syphilis serologies, and prothrombin and partial prothrombin times were all normal.
MRI of the head showed an acute right parietal infarct. Cerebral
angiography revealed a right internal carotid artery thrombus (Fig 2
left). Transesophageal echocardiogram
showed a small patent foramen ovale with spontaneous
left-to-right shunt. Lower extremity Doppler studies and
ventilation/perfusion scanning were normal.
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The patient was treated with blood transfusion, intravenous
heparin, aspirin, and oral iron supplementation. After 5 days, she
developed thrombocytopenia. The heparin was discontinued, and she was
treated with prednisone and intravenous immunoglobulin for
heparin-induced thrombocytopenia. A three-dimensional
time-of-flight MR angiogram (Fig 2
right) revealed resolution
of the thrombus. At the time of discharge, she had mild residual left
upper-extremity clumsiness.
Patient 3
A 39-year-old right-handed woman presented to the
hospital with acute onset of right arm and leg weakness. Her past
medical history was remarkable for iron-deficiency anemia secondary
to menorrhagia. She was taking iron supplements only. She did not use
tobacco or illicit drugs. Family history was negative for stroke or
hypercoagulable states.
Her pulse was 104 beats per minute, and blood pressure was 139/82 mm Hg without orthostatic changes. The general physical and funduscopic examinations were normal. Stool hemoccult test was negative. Pelvic examination demonstrated a large, prolapsed, pedunculated uterine myoma. The neurological examination was notable for mild inattentiveness, intact naming and repetition, a right hemiparesis with 0/5 strength in the right arm and 4/5 strength in the right leg, increased deep tendon reflexes on the right, and an extensor plantar response on the right.
The initial head CT without contrast was normal. A bilateral carotid
angiogram demonstrated a thrombus in the left common carotid artery
(Fig 3) and absent filling of the anterior division of
the left middle cerebral artery. A transthoracic
echocardiogram was normal.
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Laboratory analysis showed the following significant values: hemoglobin 7.1 g/dL, hematocrit 24.2%, mean corpuscular volume 62.9 fL, and platelets 652 000/mm3. Serum iron was 20 µg/dL, total iron binding capacity 404 µg/dL, transferrin saturation 5%, and ferritin <10 µg/L. Serum glucose level was 273 mg/dL, and cholesterol level was 262 mg/dL. Hemoglobin electrophoresis, erythrocyte sedimentation rate, anticardiolipin antibody, antinuclear antibody, paroxysmal nocturnal hemoglobinuria marker, protein S and C, antithrombin III, syphilis serologies, and prothrombin and partial prothrombin times were all normal.
The patient was treated with blood transfusion, iron supplementation, warfarin, insulin, and leuprolide acetate to reduce bleeding from the uterine leiomyoma for 3 months. She then underwent myectomy, and was continued on aspirin therapy. Follow-up carotid Doppler studies were normal.
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Discussion |
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TopAbstractIntroductionCase ReportsDiscussionReferences |
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Iron-deficiency anemia has been associated with cerebrovascular disease under three conditions. First, it may be found in patients with venous sinus thrombosis8 9 10 and has also been reported with central retinal vein thrombosis.15 16 Thrombocytosis17 occurs in iron-deficiency anemia and may contribute to venous thrombosis. It was reported in some but not all cases of iron-deficiency anemia associated with venous sinus thrombosis.
Second, severe anemia may cause reversible focal deficits on an anemic hypoxic basis,18 19 20 sometimes in the setting of associated severe atherosclerotic disease.19 In these reported cases, the anemia was chronic and not associated with hypotension. The focal deficits may represent unmasking of minor or silent central nervous system lesions. Alternatively, the condition of focal neurological deficits in the setting of severe anemia may fall under the more general category of reversible focal neurological deficits seen with metabolic disorders such as hypoglycemic, hepatic, and uremic encephalopathy in the absence of demonstrable structural lesions.
Third, iron-deficiency anemia has been associated with cerebral infarctions, presumably on an arterial basis.6 11 12 13 14 In two of these reports,13 14 cerebral angiography was normal. The three cases we present suggest an association of iron-deficiency anemia with thrombocytosis and carotid artery thrombus. Despite an extensive search, we were unable to find other causes for hypercoagulability in these three cases. Follow-up vascular studies failed to detect underlying vascular abnormalities such as atherosclerotic plaques or dissections. While atherosclerosis is commonly encountered in the common carotid artery and the internal carotid bulb, this location is unusual for carotid dissections. In two cases, patent foramina ovale were detected, but emboli would be expected to travel distally and not lodge in the common carotid artery or the carotid bulb.
The presence of iron-deficiency anemia and thrombocytosis in patients with carotid artery thrombi has been reported previously. Caplan et al3 reported a young woman with severe iron- and folate-deficiency anemia with a nonadherent carotid thrombus attached to a fatty streak. Yarnell et al2 described a patient with menorrhagia, hypochromic microcytic anemia, thrombocytosis of 608 000/mm3, and a stroke, whose angiogram revealed a large intraluminal mass in the carotid bifurcation. After treatment with anticoagulation, repeated angiography 5 weeks later was normal except for a shallow smooth indentation at the site of the former thrombus. Seibert and Swanson21 reported a woman with a history of bleeding duodenal ulcers and thrombocytosis of 850 000/mm3 with an internal carotid artery ball thrombus and no associated atherosclerosis. The authors did not comment on associated iron-deficiency anemia, but the history and thrombocytosis are suggestive of this diagnosis.
Why may iron-deficiency anemia and thrombocytosis be associated with thrombus formation in the carotid arteries without identifiable vascular disease? Thrombus formation requires platelet activation and aggregation onto an endothelial surface with subsequent fibrin deposition. A straightforward hypothesis is that the thrombocytosis leads to thrombus formation. Although there is a clear correlation between low platelet counts and hemorrhage, the correlation between high platelet counts and thrombosis is poor. For example, in patients with essential thrombocythemia, the magnitude of platelet count elevations does not predict the patients at high risk for thrombotic events.22 23 Abnormal platelet activation and function are probably more important than absolute platelet count.
Can the anemia and thrombocytosis act synergistically to promote thrombus formation? Wales and Martin24 and Gareeboo25 observed that arterial bruits were common in patients with severe anemia and resolved with the correction of the anemia. The bruits are a physical sign of turbulent flow. Turbulence develops when the critical Reynolds number is exceeded. This value can be calculated by the following equation: Reynolds number=rVd/n, where r is the radius of tube, V is velocity of flow, d is fluid density, and n is fluid viscosity. In anemia, the Reynolds number is elevated because of increases in flow velocity (V) and decreases in blood viscosity (n). The degree of anemia observed in these patients would be expected to double cerebral blood flow to maintain cerebral oxygen delivery.26 27 The turbulent flow may damage endothelium and lead to platelet aggregation. This effect would be most prominent at vessel bifurcations such as the carotid bulb.
Knowledge regarding optimal management of patients with carotid thrombus is limited. The retrospective case series by Buchan et al1 suggested that early endarterectomy and thrombectomy carried a high risk of perioperative stroke (4 of 11 patients). Medical therapy and follow-up neuroimaging constitute a reasonable approach for these patients to avoid the risk for embolization from urgent carotid endarterectomy. In patients with associated iron-deficiency anemia and carotid artery thrombus, correction of the anemia with transfusions and iron replacement and a search for the cause should also be undertaken.
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Acknowledgments |
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We are grateful for the valuable input from Dennis W. Choi, MD, PhD, Joel S. Perlmutter, MD, and William J. Powers, MD, regarding the clinical management of these patients and manuscript preparation.
Received December 26, 1995; revision received February 6, 1996; accepted February 6, 1996.
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