A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman

Jansen N Seheult; Irina Chibisov

doi:10.1093/labmed/lmw023

. 2016 Jun 10;47(3):233–240. doi: 10.1093/labmed/lmw023

A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman

Jansen N Seheult ^1,^*, Irina Chibisov ^1,²

PMCID: PMC4985772 PMID: 27287941

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.

Keywords: plasminogen activator inhibitor 1, hypofibrinolysis, cerebral sinus thrombosis, plasminogen inactivators, venous thrombosis, gene promoter regions

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.

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, 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).

Activators and inhibitors of the fibrinolytic system. tPA indicates tissue plasminogen activator; uPA, urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1; TAFI, thrombin activatable fibrinolysis inhibitor; and FDPs, fibrin degradation products.

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.

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	31 cm H₂O	< 25 cm H₂O
Closing pressure	25 cm H₂O	< 15 cm H₂O
CSF appearance	Clear	NA
RBC count	58 mL	mL
WBC count	0 mL	mL
CSF glucose	67 mg/dL	40-75 mg/dL
CSF protein	25 mg/dL	15-45 mg/dL

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NA, nonapplicable; RBC, red blood cells; WBC, white blood cells; CSF, cerebrospinal fluid.

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.

Structure of *SERPINE1* gene (OMIM: 613329), which encodes for *PAI-1* gene, showing the site of 4G/5G polymorphism 675 bp upstream of the transcriptional start site and the possible mechanism of transcriptional control.

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 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.

Table 2.

Results of Initial Laboratory Work-Up to Determine Presence or Absence of a Hypercoagulable State in Our Patient, a 22-Year-Old Obese Caucasian Woman

Test	Result/Units	Reference Range/Units
PT	10.7 s	9.8-11.5 s
INR	1.0	NA
APTT	21.8 s^a	30.0-42.0 s
TT	16.9 s	16.0-22.0 s
Factor VIII:C	5.54 U/mL^b	0.60-1.50 U/mL
dRVV ratio	1.1	0.9-1.3
Hexagonal phase lipid neutralization	Negative	Negative
TTI 1:50	1.1	0.7-1.3
TTI 1:500	1.0	0.7-1.3
Antithrombin III activity	114%	85%-140%
Protein C activity	64%^a	70%-150%
Protein S activity	80%	58%-128%
Beta-2-glycoprotein-I IgG	<9.4 SGU	<16.1 SGU
Beta-2-glycoprotein-I IgM	<9.4 SMU	<17.1 SMU
Beta-2-glycoprotein-I IgA	<9.4 SAU	<20.1 SAU
Anticardiolipin IgM	<9.4 MPL	<15.0 MPL
Anticardiolipin IgG	<9.4 GPL	<12.5 GPL
APC resistance ratio	2.6	2.1-3.0
Factor V leiden mutation	Negative	NA
Prothrombin gene G20210A variant	Negative	NA

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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.

^aDenotes low value.

^bDenotes high value.

Due to the age of the patient and her extensive clot burden, we performed further tests to investigate for an underlying 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.

Table 3.

Results of Testing of the Fibrinolytic Pathway in Our Patient, a 22-Year-Old Obese Caucasian Woman

Date	Test	Result/Units	Reference Range/Units
December 30, 2014	Plasminogen activity	144%	75%-150%
	PAI-1 activity^a	10.8 ng/mL	<5.0 ng/mL
	PAI-1 4G/5G testing^b	Homozygous for 4G/4G	5G/5G
	JAK2 V617F	Negative	NA
February 3, 2015	Protein C activity	96%	70%-150%
	PAI-1 activity	16.8 ng/mL	<5.0 ng/mL
June 24, 2015	PAI-1 activity	12.8 ng/mL	<5.0 ng/mL
	PAI-1 antigen^c	53.1 ng/mL	1.0-25.0 ng/mL

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PAI, plasminogen activator inhibitor; JAK2, Janus kinase 2; NA, nonapplicable; ELISA, enzyme-linked immunosorbent assay.

^aPAI-1 activity level measured using the ZYMUTEST PAI-1 activity ELISA-based assay (Aniara Corporation).

^bPAI-1 4G/5G genotype determined using allele-specific polymerase chain reaction (PCR), as described by Falk et al in Cesarman-Maus et al.¹

^cPAI-1 antigen level measured using the ZYMUTEST PAI-1 antigen ELISA-based assay.

Final Diagnosis

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.

Discussion

Fibrinolysis

The fibrinolytic cascade is a complex system of serine proteases and their inhibitors, activators, and receptors, which act to regulate the activation of plasminogen to plasmin.¹ The final steps in the coagulation cascade lead to thrombus formation by conversion of fibrinogen to fibrin monomers and covalent cross-linking of fibrin strands to form cross-linked fibrin (Figure 1).²

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).

Plasminogen is a circulating plasma zymogen, which can be converted on cell surfaces or on the surface of a thrombus to active plasmin by the action of 2 activators, namely, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA).¹^,³ Whereas tPA is mainly involved in the dissolution of a thrombus, the major role of uPA is in pericellular proteolysis during tissue remodeling.⁴ The catalytic activity of tPA is greatly enhanced when it is complexed with plasminogen on lysine-binding sites of fibrin.¹ Plasmin is the major fibrinolytic protease, which degrades cross-linked fibrin and fibrinogen into soluble fibrin degradation products, D-dimers, and fibrinogen degradation products.⁵ In this regard, fibrin is a product of the coagulation cascade and a substrate for the fibrinolytic cascade (Figure 1). On cleavage of fibrin, additional C-terminal lysine residues are exposed, which creates positive feedback for the activation of plasminogen.¹ A recent study by Hur et al⁶ also showed that plasmin can cleave plasma- and platelet-derived Factor XIIIa (FXIIIa) during clot lysis, leading to its inactivation. These findings suggest that the fibrinolytic cascade can also have downstream effects on cross-linking of blood proteins.

Inhibitors of Fibrinolysis

Inhibitors of fibrinolysis can be divided into 3 main categories: plasmin inhibitors, plasminogen activator inhibitors, and attenuators.¹ The main inhibitors of plasmin are α2-antiplasmin, α2-macroglobulin and protease nexin, of which α2-antiplasmin is the most important. α2-antiplasmin is a serine protease inhibitor or serpin that binds in a 1:1 stoichiometric reaction with the active site serine of plasmin, forming an irreversible complex.⁷ Both molecules subsequently lose their catalytic activity and are cleared from the circulation. Plasmin and α2-antiplasmin have half-lives of approximately 50 hours, and the plasma concentration of plasmin (0.2 mg/mL) is approximately twice that of α2-antiplasmin (0.07 mg/mL).⁸

The most important class of fibrinolysis inhibitors is the plasminogen activator inhibitors. In order of reaction-rate constants, these include PAI-1, PAI-2, protease nexin, and PAI-3.⁹ The most ubiquitous plasminogen activator inhibitor is PAI-1.

Thrombin activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis attenuator, which is activated to TAFIa by thrombin/thrombomodulin and by plasmin.¹⁰^,¹¹ TAFIa can cleave lysine residues from fibrin, thus decreasing the binding of plasminogen to fibrin and reducing the fibrinolysis-enhancing effect of these residues.¹²

PAI-1

PAI-1 is a 52-kDa single-chain, labile, glycoprotein serpin that is produced by endothelial cells, platelets, megakaryocytes, monocytes, macrophages, hepatocytes, and adipocytes.^13-17 PAI-1 is present at a concentration of 60 ng per mL in plasma—approximately 5 to 10 times higher than the concentration of tPA and 50 times higher than the concentration of uPA.⁸ Platelet PAI-1 accounts for approximately half of circulating PAI-1 activity but is less active than plasma PAI-1.¹⁸ PAI-1 is also an acute-phase reactant that likely results from increased hepatocyte production.¹⁹ The plasma half-life of PAI-1 has been reported to be approximately 5 to 7 minutes,⁸ and the active form of PAI-1 is stabilized in the circulation by noncovalent binding to the glycoprotein vitronectin.²⁰ Four different conformations of PAI-1 have been described, namely, the active form that reacts with plasminogen activator, a latent form that is nonreactive but can be converted to the active form, a substrate form that can be cleaved by plasminogen activators but is noninhibitory, and the inert form of PAI-1 generated by the cleavage of the reactive site.²¹

PAI-1 inhibits tPA (single-chain and 2-chain) and uPA (2-chain only) by forming a stable 1:1 complex that causes loss of activity.²² Elevations in PAI-1 levels can lead to hypofibrinolysis. Increased plasma levels of PAI-1 have been associated with venous and arterial thrombosis.23-25

PAI-1 concentrations are higher in older patients, in men, in current/former smokers, in obese patients, in patients with evidence of proteinuria or a chronic inflammatory state (elevated C-reactive protein levels), and in patients with metabolic syndrome.²⁶ It is likely that the production of PAI-1 by adipose tissue, in particular by tissue from the omentum, could be an important contributor to the elevated plasma PAI-1 levels observed in patients with insulin resistance.²⁷

The PAI-1 Gene and 4G/5G Polymorphism

The SERPINE1 gene (OMIM: 613329), alternatively referred to as the PAI-1 gene, is located on chromosome 7 and is 12 kb long, consisting of 9 exons and 8 introns. The transcription start point is located 142 nucleotides upstream from the start codon.²⁸ The most frequently described polymorphism in the PAI-1 gene is the 4G/5G single base pair insertion/deletion polymorphism (allele frequency, 0.53/0.47), which is located 675 bp upstream of the transcriptional start site (Figure 2).²⁹ The 5G polymorphism is more common and allows a transcriptional repressor to bind to the transcriptional activator, thus reducing messenger RNA (mRNA) transcription and PAI-1 levels. The 4G polymorphism causes inhibition of binding of the transcriptional repressor, allowing unopposed action of the transcriptional activator and elevated PAI-1 levels.³⁰^,³¹

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).

The PAI-1 4G/4G polymorphism has been associated with an elevated risk of certain venous thromboembolic disorders. Sartori et al³² found an association between the 4G/4G genotype and a greater risk of thrombosis in patients with symptomatic thrombophilia (odds ratio [OR], 2.85; 95% confidence interval [CI], 1.26-6.46) and in patients with idiopathic DVT (3.1; 1.26-7.59). Balta et al³³ found an association between the 4G/4G and the 4G/5G genotypes with an increased risk of internal organ thrombosis, especially portal-vein thrombosis. Seguí et al³⁴ studied 190 genetically unrelated patients with DVT and 152 healthy control individuals and found no significant difference in allele frequencies between the groups. The authors reported that in the DVT group, PAI-1 antigen levels were influenced by the 4G allele dosage, triglyceride levels, and BMI. The 4G/4G genotype has also been associated with pregnancy complications due to placental insufficiency³⁵^,³⁶ and with myocardial infarction.³⁷^,³⁸ In all of the aforementioned studies, the PAI-1 4G/4G genotype was associated with elevated PAI-1 activity and/or antigen levels.

The evidence for the association between PAI-1 4G/5G genotype and cerebral sinus thrombosis is conflicting. Although several case reports have highlighted a possible relationship between the 4G allele and cerebral sinus thrombosis,^39-41 case-control studies to date have failed to find a significant independent relationship.³³^,⁴² One study that examined PAI-1 4G/5G genotypes in carriers of the Factor V Leiden (FVL) mutation found that the concurrence of FVL and homozygosity for the 4G allele lead to an increased risk for cerebral sinus thrombosis. This finding supports the assumption that in carriers of the FVL mutation, a further prothrombotic factor may be necessary for the development of a manifest thrombotic event.⁴³

Conclusion

A detailed thrombophilia work-up of the patient demonstrated persistently elevated PAI-1 activity levels, with an elevated PAI-1 antigen concentration and homozygosity for the PAI-1 4G allele (4G/4G genotype). She was treated with indefinite warfarin anticoagulation due to the unprovoked nature of her thrombotic event. A follow-up brain MRI and angiogram performed in January 2015 showed patent cerebral venous sinuses and normal venous drainage. However, the patient was left with permanent vision loss in her left eye and only partial visual acuity in her right eye. Her most recent ophthalmology examination in January 2016 showed no new optic disc edema but did show optic neuropathy and visual loss bilaterally. She remains neurologically stable on warfarin anticoagulation.

Disturbances in the fibrinolytic system, particularly in PAI-1, have been related to an increased risk of arterial and venous thrombosis. There also appears to be a relationship between PAI-1 levels and obesity, the metabolic syndrome, and insulin resistance. Although the evidence for a link between the 4G/4G genotype and cerebral sinus thrombosis is weak, we were unable to find any other inherited or acquired cause of the thrombotic event that our patient experienced. PAI-1 gene analysis and PAI-1 activity tests are not considered to be standard tests for evaluation of patients with thrombosis. However, in young patients with an otherwise unexplained thrombotic event, additional investigation, including evaluation of the fibrinolytic system, should be considered.

Glossary

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: thrombin-activatable 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

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PERMALINK

A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman

Jansen N Seheult, MB, BCh, BAO, MSc

Irina Chibisov, MD

Abstract

Clinical and Laboratory Data