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

Lab Med. 2016;47(3):223-240.

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.

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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

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

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

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

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.

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

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.