Case Study
A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman Jansen N. Seheult, MB, BCh, BAO, MSc,1* Irina Chibisov, MD1,2 Laboratory Medicine 47:3:233-240 DOI: 10.1093/labmed/lmw023
ABSTRACT Herein, we present the case of a 22-year old obese Caucasian woman female with no acquired thrombophilic risk factors who was diagnosed with extensive cerebral sinus thrombosis. A detailed thrombophilia workup demonstrated persistently elevated plasminogen activator inhibitor 1 (PAI-1) activity levels, with an elevated PAI-1 antigen concentration and homozygosity for the PAI-1 4G allele (4G/4G genotype). The patient was treated with indefinite warfarin anticoagulation medication due to the unprovoked nature of her thrombotic event. Disturbances in the fibrinolytic system, in particular
PAI-1, have been related to an increased risk of arterial and venous thrombosis. In this article, we discuss the pathophysiology of hypofibrinolysis associated with elevated PAI-1 levels and the PAI-1 4G/5G polymorphism.
A 22-year old obese Caucasian woman with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 34.3 kg per m2 and no
significant past medical history arrived at the emergency department (ED) in early September 2014 seeking treatment for left-sided facial droop. She was diagnosed with Bell’s palsy and started on oral corticosteroid therapy. A routine laboratory workup for conditions such as Lyme disease testing yielded negative results. During the next 2 to 3 weeks, the patient developed left-sided ptosis, left lateral and upper gaze paralysis, progressive left-sided visual loss, and partial right-sided visual obscuration. She also reported pulsating tinnitus and bifrontal morning headaches. Her primary care physician referred her to the ED, where she underwent an extensive workup.
Abbreviations BMI, body mass index, ED, emergency department; CNS, central nervous system; DVT, deep venous thrombosis; MRI, magnetic resonance imaging; APTT, activated partial thromboplastin time; GPI, glycosylphosphatidylinositol; FLAER, fluorescent aerolysin; PAI, plasminogen activator inhibitor; JAK2, Janus kinase 2; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; FXIII:A, Factor XIII A; TAFI, thrombinactivatable fibrinolysis inhibitor; mRNA, messenger RNA; FVL, Factor V Leiden; CT, computed tomography; NA, nonapplicable; RBCs, red blood cells; WBCs, white blood cells; CSF, cerebrospinal fluid; PT, prothrombin time; INR, international normalized ratio; NA, nonapplicable; APTT, activated partial thromboplastin time; TT, thrombin time; dRVV, dilute Russell viper venom; TTI, tissue thromboplastin inhibition; Ig, immunoglobulin; SGU, standard IGM beta-2 glycoprotein unit; SMU, standard IgM beta-2 glycoprotein unit; SAU, standard IgA beta-2 glycoprotein unit; MPL, IgM phospholipid units; GPL, IgG phospholipid units; APC, activated protein C 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, and 2Institute for Transfusion Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, PA
*To whom correspondence should be addressed. [email protected]
Keywords: plasminogen activator inhibitor 1, hypofibrinolysis, cerebral sinus thrombosis, plasminogen inactivators, venous thrombosis, gene promoter regions
The patient reported no fever, chills, sweating, or other systemic symptoms. She had no history of recent travel and no previous pregnancies; she reported that she was not sexually active. She also reported that she was not taking oral contraceptive pills, any other estrogen containing contraceptive chemicals, or other medications. A careful history did not identify any other provoking factors for thrombosis. She has a family history of type II diabetes mellitus and provoked deep venous thrombosis (DVT) postoperatively in her maternal grandfather. The differential diagnosis featured a space-occupying lesion; infection,
C American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: [email protected] V
233
Case Study
Image 1 Axial magnetic resonance imaging (MRI) scan of our patient, a 22-year-old obese Caucasian woman. The image shows sections at the levels of the lateral ventricles and the cerebellum/optic nerves. On initial review, the images were reported as being unremarkable. Further review demonstrated the presence of sagittal sinus hyperintensity (short red arrow) with swirling effect and bulging of the optic nerves bilaterally (long red arrows).
including fungal disease; cerebral sinus thrombosis; paraneoplastic syndrome; central nervous system (CNS) autoimmune disease, and vasculitis.
Clinical and Laboratory Data A magnetic resonance imaging (MRI) scan with contrast was performed on the patient. The results were initially reported as being unremarkable (Image 1). A spinal tap demonstrated an elevated opening pressure of 31 cm H2O, but the results were otherwise unremarkable (Table 1). Due to the evidence of intracranial hypertension on lumbar puncture, the clinical team sought a second opinion on the results of the MRI that had been performed earlier. Further review demonstrated the presence of sagittal sinus hyperintensity with a swirling effect and bulging of the optic nerves bilaterally, which was indicative of cerebral venous sinus thrombosis. A computed tomography (CT) scan with contrast was ordered to evaluate the extent of thrombosis (Image 2). The CT scan revealed extensive left-sided subtotal dural venous sinus thrombosis, involving the superior sagittal sinus, straight sinus, and transverse sinus; partial empty sella; and buckling of the optic nerves bilaterally, all of which were suggestive of intracranial hypertension.
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Lab Medicine 2016;47:3;233–240
234
DOI: 10.1093/labmed/lmw023
Table 1. Results of Cerebrospinal Fluid Analysis of our Patient, a 22-Year-Old Obese Caucausian Woman Test
Result/Units
Reference Range/Units
Opening pressure Closing pressure CSF appearance RBC count WBC count CSF glucose CSF protein
31 cm H2O 25 cm H2O Clear 58 mL 0 mL 67 mg/dL 25 mg/dL
< 25 cm H2O < 15 cm H2O NA mL mL 40-75 mg/dL 15-45 mg/dL
NA, nonapplicable; RBC, red blood cells; WBC, white blood cells; CSF, cerebrospinal fluid.
A complete blood count revealed a microcytic, hypochromic anemia on admission, with a hemoglobin level of 6.3 g per dL; 2 units of packed red blood cells were transfused to correct the anemia. Further treatment included anticoagulation with warfarin, using a heparin bridge and intracranial thrombectomy due to the high clot burden. Four days later, bilateral optic nerve fenestration was performed to address the worsening visual acuity and a ventriculoperitoneal shunt was inserted for management of intracranial hypertension. A coagulation work-up was conducted in parallel to these treatment measures, to investigate for the underlying cause of
www.labmedicine.com
Case Study
defect in fibrinolysis. Repeat testing revealed a persistently elevated plasminogen activator inhibitor (PAI)–1 activity level with a corresponding elevation in PAI-1 antigen concentration (Table 3). The patient was also found to be homozygous for the PAI-1 4G/4G polymorphism. In addition, Janus kinase 2 (JAK2) mutation test results were negative, and repeat protein C activity levels were within the normal range.
Final Diagnosis
Image 2 Computed tomography (CT) scan of our patient, a 22-year-old obese Caucasian woman. The contrast shows extensive left subtotal dural venous sinus thrombosis involving the superior sagittal sinus, straight sinus, and transverse sinus (red arrows).
cerebral sinus thrombosis in the patient. The results of the initial investigations are shown in Table 2. The hypercoagulable work-up results were negative for lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoprotein-I antibodies on 2 separate occasions in September 2014 and early October 2014. On initial testing, the patient was noted to have elevated Factor VIII:C activity with a peak level of 5.54 U per mL; however, repeat testing in the steady state demonstrated normal levels (1.47 U per mL). The low activated partial thromboplastin time (APTT) results were likely secondary to the elevated Factor VIII:C as part of the acute-phase response. Protein C activity was mildly decreased at 64%; however, repeat testing while the patient had temporarily stopped taking warfarin demonstrated normal protein C activity (96%). The rest of the hypercoagulable work-up results were unremarkable. Flow cytometric tests performed for glycosylphosphatidylinositol (GPI)–linked antigens and fluorescent aerolysin (FLAER) on peripheral blood cells to rule out paroxysmal nocturnal hemoglobinuria (due to the combination of anemia and thrombosis) yielded negative results. Due to the age of the patient and her extensive clot burden, we performed further tests to investigate for an underlying
www.labmedicine.com
We diagnosed the patient with extensive cerebral venous sinus thrombosis secondary to hypofibrinolysis, due to her homozygous PAI-1 4G/4G polymorphism and elevated PAI-1 antigen activity levels.
Table 2. Results of Initial Laboratory Work-Up to Determine Presence or Absence of a Hypercoagulable State in Our Patient, a 22-YearOld Obese Caucasian Woman Test PT INR APTT TT Factor VIII:C dRVV ratio Hexagonal phase lipid neutralization TTI 1:50 TTI 1:500 Antithrombin III activity Protein C activity Protein S activity Beta-2-glycoprotein-I IgG Beta-2-glycoprotein-I IgM Beta-2-glycoprotein-I IgA Anticardiolipin IgM Anticardiolipin IgG APC resistance ratio Factor V leiden mutation Prothrombin gene G20210A variant
Result/Units
Reference Range/Units
10.7 s 1.0 21.8 sa 16.9 s 5.54 U/mLb 1.1 Negative 1.1 1.0 114% 64%a 80%
A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman Jansen N. Seheult, MB, BCh, BAO, MSc,1* Irina Chibisov, MD1,2 Laboratory Medicine 47:3:233-240 DOI: 10.1093/labmed/lmw023
ABSTRACT Herein, we present the case of a 22-year old obese Caucasian woman female with no acquired thrombophilic risk factors who was diagnosed with extensive cerebral sinus thrombosis. A detailed thrombophilia workup demonstrated persistently elevated plasminogen activator inhibitor 1 (PAI-1) activity levels, with an elevated PAI-1 antigen concentration and homozygosity for the PAI-1 4G allele (4G/4G genotype). The patient was treated with indefinite warfarin anticoagulation medication due to the unprovoked nature of her thrombotic event. Disturbances in the fibrinolytic system, in particular
PAI-1, have been related to an increased risk of arterial and venous thrombosis. In this article, we discuss the pathophysiology of hypofibrinolysis associated with elevated PAI-1 levels and the PAI-1 4G/5G polymorphism.
A 22-year old obese Caucasian woman with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 34.3 kg per m2 and no
significant past medical history arrived at the emergency department (ED) in early September 2014 seeking treatment for left-sided facial droop. She was diagnosed with Bell’s palsy and started on oral corticosteroid therapy. A routine laboratory workup for conditions such as Lyme disease testing yielded negative results. During the next 2 to 3 weeks, the patient developed left-sided ptosis, left lateral and upper gaze paralysis, progressive left-sided visual loss, and partial right-sided visual obscuration. She also reported pulsating tinnitus and bifrontal morning headaches. Her primary care physician referred her to the ED, where she underwent an extensive workup.
Abbreviations BMI, body mass index, ED, emergency department; CNS, central nervous system; DVT, deep venous thrombosis; MRI, magnetic resonance imaging; APTT, activated partial thromboplastin time; GPI, glycosylphosphatidylinositol; FLAER, fluorescent aerolysin; PAI, plasminogen activator inhibitor; JAK2, Janus kinase 2; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; FXIII:A, Factor XIII A; TAFI, thrombinactivatable fibrinolysis inhibitor; mRNA, messenger RNA; FVL, Factor V Leiden; CT, computed tomography; NA, nonapplicable; RBCs, red blood cells; WBCs, white blood cells; CSF, cerebrospinal fluid; PT, prothrombin time; INR, international normalized ratio; NA, nonapplicable; APTT, activated partial thromboplastin time; TT, thrombin time; dRVV, dilute Russell viper venom; TTI, tissue thromboplastin inhibition; Ig, immunoglobulin; SGU, standard IGM beta-2 glycoprotein unit; SMU, standard IgM beta-2 glycoprotein unit; SAU, standard IgA beta-2 glycoprotein unit; MPL, IgM phospholipid units; GPL, IgG phospholipid units; APC, activated protein C 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, and 2Institute for Transfusion Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, PA
*To whom correspondence should be addressed. [email protected]
Keywords: plasminogen activator inhibitor 1, hypofibrinolysis, cerebral sinus thrombosis, plasminogen inactivators, venous thrombosis, gene promoter regions
The patient reported no fever, chills, sweating, or other systemic symptoms. She had no history of recent travel and no previous pregnancies; she reported that she was not sexually active. She also reported that she was not taking oral contraceptive pills, any other estrogen containing contraceptive chemicals, or other medications. A careful history did not identify any other provoking factors for thrombosis. She has a family history of type II diabetes mellitus and provoked deep venous thrombosis (DVT) postoperatively in her maternal grandfather. The differential diagnosis featured a space-occupying lesion; infection,
C American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: [email protected] V
233
Case Study
Image 1 Axial magnetic resonance imaging (MRI) scan of our patient, a 22-year-old obese Caucasian woman. The image shows sections at the levels of the lateral ventricles and the cerebellum/optic nerves. On initial review, the images were reported as being unremarkable. Further review demonstrated the presence of sagittal sinus hyperintensity (short red arrow) with swirling effect and bulging of the optic nerves bilaterally (long red arrows).
including fungal disease; cerebral sinus thrombosis; paraneoplastic syndrome; central nervous system (CNS) autoimmune disease, and vasculitis.
Clinical and Laboratory Data A magnetic resonance imaging (MRI) scan with contrast was performed on the patient. The results were initially reported as being unremarkable (Image 1). A spinal tap demonstrated an elevated opening pressure of 31 cm H2O, but the results were otherwise unremarkable (Table 1). Due to the evidence of intracranial hypertension on lumbar puncture, the clinical team sought a second opinion on the results of the MRI that had been performed earlier. Further review demonstrated the presence of sagittal sinus hyperintensity with a swirling effect and bulging of the optic nerves bilaterally, which was indicative of cerebral venous sinus thrombosis. A computed tomography (CT) scan with contrast was ordered to evaluate the extent of thrombosis (Image 2). The CT scan revealed extensive left-sided subtotal dural venous sinus thrombosis, involving the superior sagittal sinus, straight sinus, and transverse sinus; partial empty sella; and buckling of the optic nerves bilaterally, all of which were suggestive of intracranial hypertension.
234
Lab Medicine 2016;47:3;233–240
234
DOI: 10.1093/labmed/lmw023
Table 1. Results of Cerebrospinal Fluid Analysis of our Patient, a 22-Year-Old Obese Caucausian Woman Test
Result/Units
Reference Range/Units
Opening pressure Closing pressure CSF appearance RBC count WBC count CSF glucose CSF protein
31 cm H2O 25 cm H2O Clear 58 mL 0 mL 67 mg/dL 25 mg/dL
< 25 cm H2O < 15 cm H2O NA mL mL 40-75 mg/dL 15-45 mg/dL
NA, nonapplicable; RBC, red blood cells; WBC, white blood cells; CSF, cerebrospinal fluid.
A complete blood count revealed a microcytic, hypochromic anemia on admission, with a hemoglobin level of 6.3 g per dL; 2 units of packed red blood cells were transfused to correct the anemia. Further treatment included anticoagulation with warfarin, using a heparin bridge and intracranial thrombectomy due to the high clot burden. Four days later, bilateral optic nerve fenestration was performed to address the worsening visual acuity and a ventriculoperitoneal shunt was inserted for management of intracranial hypertension. A coagulation work-up was conducted in parallel to these treatment measures, to investigate for the underlying cause of
www.labmedicine.com
Case Study
defect in fibrinolysis. Repeat testing revealed a persistently elevated plasminogen activator inhibitor (PAI)–1 activity level with a corresponding elevation in PAI-1 antigen concentration (Table 3). The patient was also found to be homozygous for the PAI-1 4G/4G polymorphism. In addition, Janus kinase 2 (JAK2) mutation test results were negative, and repeat protein C activity levels were within the normal range.
Final Diagnosis
Image 2 Computed tomography (CT) scan of our patient, a 22-year-old obese Caucasian woman. The contrast shows extensive left subtotal dural venous sinus thrombosis involving the superior sagittal sinus, straight sinus, and transverse sinus (red arrows).
cerebral sinus thrombosis in the patient. The results of the initial investigations are shown in Table 2. The hypercoagulable work-up results were negative for lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoprotein-I antibodies on 2 separate occasions in September 2014 and early October 2014. On initial testing, the patient was noted to have elevated Factor VIII:C activity with a peak level of 5.54 U per mL; however, repeat testing in the steady state demonstrated normal levels (1.47 U per mL). The low activated partial thromboplastin time (APTT) results were likely secondary to the elevated Factor VIII:C as part of the acute-phase response. Protein C activity was mildly decreased at 64%; however, repeat testing while the patient had temporarily stopped taking warfarin demonstrated normal protein C activity (96%). The rest of the hypercoagulable work-up results were unremarkable. Flow cytometric tests performed for glycosylphosphatidylinositol (GPI)–linked antigens and fluorescent aerolysin (FLAER) on peripheral blood cells to rule out paroxysmal nocturnal hemoglobinuria (due to the combination of anemia and thrombosis) yielded negative results. Due to the age of the patient and her extensive clot burden, we performed further tests to investigate for an underlying
www.labmedicine.com
We diagnosed the patient with extensive cerebral venous sinus thrombosis secondary to hypofibrinolysis, due to her homozygous PAI-1 4G/4G polymorphism and elevated PAI-1 antigen activity levels.
Table 2. Results of Initial Laboratory Work-Up to Determine Presence or Absence of a Hypercoagulable State in Our Patient, a 22-YearOld Obese Caucasian Woman Test PT INR APTT TT Factor VIII:C dRVV ratio Hexagonal phase lipid neutralization TTI 1:50 TTI 1:500 Antithrombin III activity Protein C activity Protein S activity Beta-2-glycoprotein-I IgG Beta-2-glycoprotein-I IgM Beta-2-glycoprotein-I IgA Anticardiolipin IgM Anticardiolipin IgG APC resistance ratio Factor V leiden mutation Prothrombin gene G20210A variant
Result/Units
Reference Range/Units
10.7 s 1.0 21.8 sa 16.9 s 5.54 U/mLb 1.1 Negative 1.1 1.0 114% 64%a 80%
