**4. Results**

We present eight cases of cerebral venous thrombosis in a group of young women (aged between 18.7 and 39.3 years, mean age 28.1 years), who were hospitalized between April 2004 and October 2005.

The most frequently observed manifestations of CVT (see Table 1) were headache (100%) and vertigo (87,5%). The most frequently detected objective findings were movement disorders – central hemiparesis or quadruparesis (75%), the same percentage applies to spasms, behavioural disorders, altered consciousness, sensoric disorders and aphasias (25%). CT and MRI examinations (see Table 3, 4) showed venous infarction or vasogenic inflation in 62.5% and presence of petechial haemorrhage in 25%. Digital subtraction 3D-XR venography most frequently confirmed a combination of occlusions of sinus transversus and sigmoideus (75%), sinus sagitalis superior (62,5%), cortical veins (62,5%) and deep venous system (50%).

The outcomes of the therapy were excellent in seven patients receiving the basic treatment. The treatment included administration of a combination of low weight molecular heparin in the treatment dose and subsequent coverage with warfarin. In three patients with insufficient effect of LMWH, we used local thrombolysis Actilyse ® (rt-PA). One of the women died, despite acute thrombolysis and complex therapy. The results of coagulation tests (see Table 6) showed the presence of several thrombophilic risk factors in all women in our group. Homozygous form of the MTHFR-C677T gene mutation was detected in three patients, two patients had a mutation of the gene for PAI-1 in homozygous form. A combination of both homozygous forms was detected in one patient, the combination was present in heterozygous forms in two patients. The tests further detected an elevated level of factor VIII in three patients, and five of the patients showed a deficit of protein S, always in combination with mutations of the gene responsible for MTHFR-C677T, three of these were present in homozygous form.

### **5. Discussion**

122 Venous Thrombosis – Principles and Practice

**T,U** Thrombosis of sinus sagitalis superior as seen after opening of the sinus and removal of the hard

**V** Thrombosis of confluens sinuum and sinus rectus orifice, thrombosis of Labe collector on the right

We present eight cases of cerebral venous thrombosis in a group of young women (aged between 18.7 and 39.3 years, mean age 28.1 years), who were hospitalized between April

The most frequently observed manifestations of CVT (see Table 1) were headache (100%) and vertigo (87,5%). The most frequently detected objective findings were movement disorders – central hemiparesis or quadruparesis (75%), the same percentage applies to spasms, behavioural disorders, altered consciousness, sensoric disorders and aphasias (25%). CT and MRI examinations (see Table 3, 4) showed venous infarction or vasogenic inflation in 62.5% and presence of petechial haemorrhage in 25%. Digital subtraction 3D-XR venography most frequently confirmed a combination of occlusions of sinus transversus and sigmoideus (75%), sinus sagitalis superior (62,5%), cortical veins (62,5%) and deep

**W** Thrombosis of perimesenphalic veins with hyperaemia in the area of medulla oblongata

meninges

**4. Results** 

2004 and October 2005.

venous system (50%).

and cortical veins parietally on the left

**T U**

**V W**

Fig. 4. Pathology-anatomic finding

The first clinical and pathological finding of cerebral venous thrombosis was described by Ribs in 1825 in a 45-year-old male patient with generalized malignant process. Without the possibility of angiography imaging, the diagnosis was determined on the basis of clinical findings – progreding headaches, oedema of the eye papilla, spasms, focal deficit, coma, and was most usually confirmed with pathology-anatomical findings of thrombosis in the area of dural sinuses, accompanied with haemorrhagic infarsation. In 2001, an important study "International Study of Cerebral Vein Thrombosis" - ISCVT was published; the study prospectively monitored data of 624 patients with this diagnosis. (2)

Deep vein system, including vv. cerebri internae, v. basalis Rosenthali, v. magna cerebri and sinus rectus, responsible for the drainage of diencephalon, basal ganglia and deep structures of the white matter of hemispheres, is usually affected in 10% of cerebral venous thromboses. More serious clinical cases, including hemipareses and quadrupareses are caused by compression of capsula interna, with unilateral of bilateral infliction of the thalami or basal ganglia, and can be diagnosed with non-invasive examinations, e.g. CT or MRI under the image of the oedema or haemorrhagic infarction. Limitations of venous outflow result in cerebral hyperaemia, mostly detected on MRI in patients with CVT (3,4,5).

The diagnosis of CVT in our group of patients was confirmed with MRI imaging, MR venography and subsequently also with digital subtraction angiography. Liang et al. confirm the importance of three-dimensional imaging of magnetic resonance MP-RAGE venography, supported with the use of contrast, in the diagnostics of thromboses in the area of dural sinuses. This method was also very useful in our patient group. (6) As an alternative diagnostic procedure for CVT it is also possible to perform CT venography, together with the subtraction of bone structures "Mathed Mask Bone Elimination" (MMBE). (7) 3D-Xra-digital rotation venography provides an excellent alternative, with the possibility of imaging the speed and direction of the flow in a normal section of the venous system, as well as in partially thrombotized parts of dural sinuses and deep vein system.

The treatment of patients with intracranial venous thrombosis depends on the timeliness of the clinical suspicion of CVT and subsequent confirmation of the diagnosis with imaging techniques. Purdon Martin and Sheehan (1941) were the first to recommend anticoagulation therapy for the treatment of CVT. The treatment with heparin is currently considered as a treatment of choice in patients with CVT. (2) However, the effect of heparin may be too

Cerebral Venous Thrombosis in Patients Using Oral Contraceptives 125

Gynaecology and Obstetrics JEP, prior to administration of HAK, to perform a detailed analysis of personal and family history, and in indicated cases also a detailed examination of the presence of thrombophilic states. The significance of individual thrombophile mutations is inconsistent. Absolute contraindications for HAK usage include deficit of the antithrombin III, protein C deficit, homozygous form of V Leiden factor and combination of other thrombophile mutations. Other thrombophile mutations present a relative contraindication only. Screening examination of women prior to administration of HAK is not indicated. (26) However, in our study group, although we performed a detailed retrospective analysis, the personal and family history were negative in all patients. Considering this fact there arises the question of a facultative possibility of thrombophile examination covered by the patient, based on the

As a certain surprise we may mention the high incidence of homozygous form of C677T in out study group (37,5%), which may be in consistence with the findings of Martinelli et al., who proved the risk of CVT onset in users of hormonal contraceptives with hyperhomocysteinemia OR 19,5 95% CI (5,7 – 67,3). The levels of homocystein were not monitored in our patients. Other frequently observed findings included mutations of the plasminogen activator inhibitor gene (PAI-1) and deficit of protein S, which may be also present in combinations strengthening the prothrombogenic effect. On the other hand, we did not observe an incidence of V Leiden factor in patients with CVT, however this factor is

**1. 2. 3. 4. 5. 6. 7. 8. Mean** 

Age 32.0 32.5 24.1 18.7 33.3 24.8 39.3 20.2 28.1

Symptoms 1. 2. 3. 4. 5. 6. 7. 8. % Headache + + + + + + + + 100 Vertigo + + + + + + + 87.5

and quadruparesis + + + + + 62,5

Sight disorders + + 25.0 Sensitivity disorder + + 25.0 Behavioural disorder + + 25.0

Aphasia + + 25.0 Spasms + + 25.0 Coma + + 25.0

frequently mentioned in literature as a significant thrombophilic risk factor.

patient's request, prior to administration of HAK.

Table 1. Age of patients included into the study

Table 2. Subjective and objective manifestations on admission

Central hemiparesis

**7. Tables** 

slow, especially in patients with rapidly progreding symptoms and involvement of most of the dural sinuses and deep venous system. This patient population should be referred for thrombolytic treatment, as the overall mortality of these patients reaches 10%. (8-11) Our current experiences also point towards the possibility of mechanical revascularization of the obstructed venous bed, using the techniques of rheolytic thrombectomy and mechanical disturbance of the thrombus with balloon catheters. (12,13)

Thrombophilic states are commonly observed in 25-35% of patients with venous thrombosis. (14,15) Hormonal contraceptives are currently used by more than 100 million women. Shortly after their introduction in 1960s, an increased incidence of thrombotic vascular complications was observed (16-18), together with an interaction of hormonal contraceptives and haemocoagulation system. Increased activity of coagulation factors VII, VIII, X and fibrinogen is a common finding in most cases. (19) Martinelli et al. in their work define the risk of onset of cerebral venous thrombosis in users of hormonal contraceptives OR 6,1 95% CI (3,3 – 11,00). This potential risk may be further intensified by congenital haemostatic disorders. (20)

Peroral contraceptives induce extensive changes in the fibrinolytic system. The levels of plasminogen and plazmin-alfa2-antiplazmin complex are elevated, also the activity of tissue activator of plasminogen (tPA) is increased, at the same time, the level of antigen inhibitor of the plasminogen-I activator (PAI-I) and the PAI-I activity are decreased, and many other changes occur. The fibrinolysis in the users of contraceptives is elevated, which is most probably caused by the response and compensation of the prothrombogenic state, caused by hormonal preparations. These changes are identical in preparations containing levonorgestrel, as well as third-generation gestagens. (21) Genetically conditioned thrombophilic states of the fibrinolytic system (PAI-I) increase the potential risk of the onset of thrombosis in HAK users. An increased activity and clustering of platelets was observed. (22)

Hormonal contraceptives with third-generation gestagens are connected with an increased risk of venous thromboses, in comparison with previous generations of contraceptives. This risk is also present in women without V Leiden factor mutation or a positive family history. (23)
