Factor V Leiden mutation

* Inherited thrombophilia is a risk factor for dural sinus thrombosis (DST). To our knowledge, this is the first description with autopsy findings of a patient with DST associated with heterozygous factor V Leiden and a short activated partial thromboplastin time (aPTT). A 51-year-old woman presented with a 3-day history of headache, nausea, right-sided weakness, and focal motor seizure; she died 3 days after admission. At autopsy, a gross examination showed hemorrhage of bilateral parietal lobes and left primary motor cortex, uncal and tonsillar herniation, and pulmonary embolus of the right upper lobe. A microscopic examination of the brain showed an organizing thrombus in the superior sagittal sinus, diffuse cerebral edema, and extensive venous congestion. Laboratory studies showed heterozygous factor V Leiden by polymerase chain reaction and a very short aPTT of 17 seconds (reference range, 22-30 seconds). The combination of a heterozygous factor V Leiden mutation and a short aPTT may have contributed to the fatal DST in this patient.

Dural sinus thrombosis (DST) is an uncommon but serious medical disorder.1 It usually occurs in the fourth decade of life, although it can occur at all ages. The spectrum and duration of symptoms/signs at presentation, as well as the clinical course after diagnosis and treatment, are highly variable. The overall mortality is 5% to 15%, and the frequency of permanent neurologic deficit is 14% to 43%.

There are multiple inherited risk factors for venous thrombosis,2 and many of these have been reported in DST.3 The most common inherited abnormality is the heterozygous factor V Leiden mutation, seen in 15% to 20% of cases.4,5 To our knowledge, a short activated partial thromboplastin time (aPTT) has never been reported as a risk factor for DST; however, it is associated with increased risk of venous thrombosis.6 In this study, we describe a patient with rapidly fatal DST who had a combination of both coagulation abnormalities: a heterozygous factor V Leiden mutation and a short aPTT.

REPORT OF A CASE

A 51-year-old white woman in previously good health presented with a 3-day history of worsening headache, neck pain, nausea, and right-sided weakness. On the day of presentation, she developed a focal motor seizure on the right side. Noncontrast computed tomography and magnetic resonance imaging of the head showed bilateral parietal mass lesions with surrounding edema. The patient was admitted for clinical management and further diagnostic evaluation.

The patient's medical history was negative for venous thrombosis, trauma, recent surgery, malignancy, prolonged immobilization, oral contraceptive use, estrogen replacement therapy, and diabetes mellitus. The parents had a negative history for venous thrombosis. The patient had no siblings or children.

The laboratory studies are summarized in Table 1. The most notable abnormalities were the heterozygosity for the factor V Leiden mutation and the very short aPTT. A stereotactic brain biopsy showed hemorrhage, necrosis, and gliosis. On hospital day 3, noncontrast computed tomography and magnetic resonance imaging showed hemorrhagic infarcts in the right and left parietal lobes, diffuse edema, and uncal herniation with a left-to-right shift (Figure, A). Magnetic resonance venography showed a flow void of the superior sagittal sinus, confirming the diagnosis of superior sagittal sinus thrombosis.

The patient continued to deteriorate, and she required mechanical ventilation. She did not receive anticoagulant therapy. Life support measures were withdrawn at the request of the family, and the patient died on hospital day 3. An autopsy was performed.

RESULTS

Autopsy Findings

The brain showed a thrombus in the superior sagittal sinus with bilateral parietal softening, hemorrhage, and extensive venous congestion (Figure, B). The brain was edematous (weight, 1520 g), with mild uncal herniation, tonsillar herniation, and a left-to-right shift. The gyri were flattened with a concomitant narrowing of the sulci. The left parietal hemorrhage measured 8.5 x 5.5 x 4.5 cm, and the right parietal hemorrhage measured 3.0 x 3.0 x 2.5 cm. There was a small Duret hemorrhage in the pons measuring 0.3 x 0.2 x 0.2 cm. Hemosiderin staining of the dura accompanied the parietal infarcts.

There was mild pulmonary congestion of the lower posterior lobes. A Y-shaped thrombus was found in the right upper lobe pulmonary artery that measured 5.0 x 0.5 x 2.0 cm. Mild cardiomegaly was also present (weight, 430 g). The liver was mildly congested (weight, 2000 g). The remaining examination was noncontributory.

Microscopic Findings

There was an organized thrombus in multiple sections of the superior sagittal sinus, with the thrombus showing an ingrowth of fibroblasts (Figure, C). Brain parenchyma from the parietal lobe showed venous congestion, hemorrhage, and diffuse edema.

COMMENT

To our knowledge, this patient represents the first reported case of autopsy-documented DST associated with a combined coagulation abnormality of the heterozygous factor V Leiden mutation and the short aPTT A number of inherited and acquired coagulation abnormalities are associated with DST (Table 2). One of the most common and well documented of these is the factor V Leiden mutation G1691A.4,5 Factor V Leiden contains an Arg506[arrow right]Glu substitution, which causes delayed inactivation by the enzyme-activated protein C. This prolongs its life span and increases the duration of its procoagulant function. The mutation is frequent in the general white population, ranging from 2% to 15%.2 Heterozygous individuals have a 2.6-fold increased risk for DST.4

A shortened aPTT is a risk factor for peripheral deep venous thrombosis, carrying a 10-fold increased risk.6 To our knowledge, this coagulation test abnormality has never been reported in DST. Elevated coagulation factor VIII, which is also an independent risk factor for venous thrombosis,7 can cause a short aPTT.8 Factor VIII levels were not measured in this case, so the basis for the short aPTT is unknown. It is thought that the combination of a heterozygous factor V Leiden mutation and a short aPTT may interact to produce a greater risk for DST than either risk factor alone.

Patients who have had a DST should be tested for inherited thrombophilia.9 The main purpose is to identify abnormalities that could be inherited by other family members. If a coagulation defect is identified in the patient, then first-degree relatives should be tested. If any family members are positive, then they should be counseled about their future risk of thrombosis and about strategies for prophylaxis in high-risk situations. Regardless of the test results for inherited thrombophilia, patients with DST should receive lifelong oral anticoagulation therapy to prevent future thrombotic episodes.9

References

1. Allroggen H, Abbott RJ. Cerebral venous sinus thrombosis. Postgrad Med J. 2000;76:12-15.

2. Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost. 1999; 82:601-609.

3. Van Gijn J. Cerebral venous thrombosis: pathogenesis, presentation and prognosis. J R Soc Med. 2000;93:230-233.

4. Ludemann P, Nabavi DC, Junker R, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients. Stroke. 1998;29:2507-2510.

5. Martinelli I, Landi G, Merati G, et al. Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost. 1996;75:393-394.

6. McKenna R, Bachmann F, Miro-Quesada M. Thrombo-embolism in patients with abnormally short activated partial thromboplastin time. Thromb Haemost. 1977;38:893-899.

7. Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343:457-462.

8. Edson JR, Krivit W, White JG. Kaolin partial thromboplastin time: high levels of procoagulants producing short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants. J Lab Clin Med. 1967;70: 463-470.

9. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

10. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793-1797.

Christina L. Stephan, MD; Karen SantaCruz, MD; Corrie May, MD; Steve B. Wilkinson, MD; Mark T. Cunningham, MD

Accepted for publication May 28, 2003.

From the Departments of Pathology (Drs Stephan, May, and Cunningham) and Neurosurgery (Dr Wilkinson), University of Kansas Medical Center, Kansas City, Kan; and the Department of Pathology, University of Minnesota School of Medicine, Minneapolis, Minn (Dr SantaCruz).

Reprints: Mark T. Cunningham, MD, University of Kansas Medical Center, Department of Pathology, 3901 Rainbow Blvd, Kansas City, KS 66160 (e-mail: mcunningham@kumc.edu).

Copyright College of American Pathologists Oct 2003
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