A case of protein S deficiency type 2 presenting as cerebral venous thrombosis (CVT) in an 18-year-old woman


Protein S deficiency is an autosomal dominant disease caused by mutations in the FOR 1 , a large gene on chromosome 3. It is associated with an increased risk of thromboembolism. Protein S is mainly synthesized by hepatocytes and undergoes vitamin K-dependent gamma-carboxylation [1]. The gamma-carboxylated mature protein S circulates in two states: free and bound to the complement component C4b-binding protein (C4b-BP). The free form comprises 30-40% of total protein S and is the only form of protein S that has cofactor activity for activated protein C. [1,2]. Total protein S values ​​differ with age, while free protein S values ​​remain relatively constant.

Protein S was named after Seattle, Washington, where it was first discovered and purified. It is a vitamin K-dependent glycoprotein and serves as a cofactor for activated protein C, which in turn inactivates procoagulant factors Va and VIIIa, reducing thrombin generation [3]. Protein S also serves as a cofactor for activated protein C in enhancing fibrinolysis and can directly inhibit prothrombin activation via interactions with other coagulation factors [4-8]. Protein S deficiency interferes with the normal control mechanism and thus increases the risk of thrombosis.

A young 18-year-old woman presents as an outpatient with complaints of headaches for five days, of the holocranial type (left > right), of the continuous type with no aggravating or relieving factor. It was associated with two episodes of vomiting two days earlier. The vomitus was non-projectile, non-blood-tinged, non-bilious, and contained food particles. As a result, she developed abnormal sensation over the left half of her body, including her face, trunk, upper limbs, and lower limbs. She denied having visual disturbances, seizures, fever, neck pain, loss of consciousness, fall or head trauma. She denied having had similar complaints in the past. She had never been hospitalized before.

Her family history was insignificant and she denies taking medication or treatment for any ailments. She is unmarried and had her first period when she was 14, her last menstrual cycle having started 18 days earlier. She was not sexually active and did not take any medications such as oral contraceptive pills.

She was conscious and oriented to time, place and person. His vital signs were blood pressure (BP) 90/60 mm Hg, pulse 92/minute, respiratory rate 20/minute with oxygen saturation 97% on room air, and afebrile. The pallor was present with no other abnormalities on his general physical examination.

Upon examination of his central nervous system, higher mental functions were found to be normal; she showed decreased perception of touch when examining her trigeminal nerve (maxillary and mandibular divisions). All other cranial nerves were normal. Her motor system examination showed no abnormalities with normal reflexes. His sensory system examination revealed a deficit on the left side with decreased pain perception and tactile sensation on the left upper limb and lower limb. Joint position sense was intact. Cerebellar function was intact. No abnormalities were found on examination of his respiratory, abdominal and cardiovascular systems.

She was mistaken for a CT brain, which showed “hyperdense inferior sagittal and left transverse sinuses.” A possibility of cerebral venous thrombosis was considered. His laboratory parameters showed hemoglobin of 6.9 g/dl, mean corpuscular volume (MCV) of 54 fl, mean corpuscular hemoglobin (MCH) of 13 pg, mean corpuscular hemoglobin concentration (MCHC) of 24 g/dl, a total white blood cell count of 11,440 cells. /cumm with a predominance of neutrophils of 61.3% and lymphocytes of 33%. During the presentation, it was discovered that she suffered from mild transaminitis, which later resolved. His kidney parameters and electrolytes were found to be normal. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were also within normal limits. Antinuclear antibodies (ANA) and rheumatoid factor (RF) were negative.

Brain MRI with magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) (Figure 1) showed “an early acute venous infarction in the right thalamus with thrombosis of the deep cerebral veins and dural venous sinuses and multiple acute lacunar infarctions in the bilateral semiovale centrum and corona radiata”.

The patient was put on anticoagulant therapy. Other causes of cerebral vein thrombosis such as dehydration, smoking, and infection have been ruled out. Procoagulation studies have been delayed because acute thrombosis may give an erroneous reading of decreased values.

A repeat MRI was performed six months after the start of treatment and the findings were “discontinuous, serpiginous, flow-related signals at locations in the left transverse sinus, characteristic suggestive of chronic cerebral venous sinus thrombosis with partial recanalization” (Figure 2).

Procoagulation studies (table 1) were performed at this stage after stopping anticoagulant treatment for two weeks; it showed a lupus anticoagulant screening ratio of 1.13; homocysteine ​​levels were normal with a value of 8.73 µmol/L, and phospholipid IgG and IgM antibodies were normal with values ​​of 3.57 IgG phospholipid (GPL) U/ml and 5.35 IgM phospholipid units (MPL) U/ml, respectively. Her beta 2 glycoprotein IgG and IgM levels were also found to be normal. She had slightly elevated functional antithrombin activity with a value of 122% (normal range: 80-120%) and decreased functional protein S activity with a value of 6% (normal range: 55-123%) . Her free protein S antigen values ​​were found to be normal, ie 71% (normal range: 60-140%). His functional protein C values ​​were normal. Genetic testing revealed no mutations in factor V Leiden and the prothrombin gene.

Test Results normal range
Lupus Anticoagulation Screening Report 1.13
Serum homocysteine 8.73 µmol/L 4.44-13.56
Serum phospholipid antibody, IgG 3.57 LPG units/ml
Serum phospholipid antibodies, IgM 5.35 MPL U/ml
Beta 2 serum glycoprotein, IgG 1.21 SKU
Beta 2 serum glycoprotein, IgM 3.42 EMS
Free protein S antigen 71% 60-140%
Protein S Functional/Activity 6% 55-123%
Functional protein C 107% 70-140%
Functional antithrombin activity 122% 80-120%
Factor V Leiden Mutation Analysis Not detected Not detected
Prothrombin gene mutation Not detected Not detected

She continued her anticoagulant therapy and improved significantly over time with full recovery from her sensory deficits.

Until the mid-1960s, recurrent venous thrombosis was recognized on a clinical basis with no apparent cause. After which, antithrombin III (AT-III) deficiency was recognized as a possible cause by Egeberg in 1965 [8]. Protein C and protein S deficiencies were recognized nearly 16 years later by Griffin et al. and Comp et al. In 1981, Griffin et al. [9] reported familial protein C deficiency in association with venous thromboembolism, and in 1984, Comp and Esmon [10] reported protein S deficiency in six patients; five had appeared between the ages of 15 and 27. These studies demonstrated that congenital protein S, protein C, and AT-III deficiencies are inherited in an autosomal dominant fashion.

In our particular case, the patient is young with no risk factor for a thrombotic event. His family history was uneventful, which posed a dilemma in the clinical diagnosis of any of the above-mentioned impairments. This warranted a detailed evaluation and, after further review of the literature, it was discovered that she suffered from protein S type 2 deficiency, which is considered to be one of the rarest forms.

Protein S deficiencies have been classified into three types [11]; type 1 is the classic type of hereditary deficiency. Total protein S, free protein S and protein S function are reduced. Type 2 represents a qualitative defect and is one of the rarest forms of this deficiency where only protein S function is reduced as evidenced by our case. Type 3 represents the selective reduction of free protein S and functional protein S with normal values ​​of total protein S.

Regarding protein S deficiency type 2, in a case series of 118 French patients with thromboembolism associated with protein S deficiency, 26 had a substitution from serine to proline at the amino acid level. 460 (the Heerlen polymorphism), which affects protein S metabolism [12,13]. Low plasma free protein S may result from increased binding of abnormal protein S to C4b-binding protein [14,15]. Most patients with protein S type 2 deficiency do not manifest with thrombophilic episodes, but in our case, this was the only abnormality found that could be attributed to said manifestation.

With this case report, we would like to emphasize the importance of a detailed evaluation in a young patient presenting with a thromboembolic event with no apparent cause and with a negative family history. Although thrombophilic events in protein S deficiency type 2 have been questioned, this case had no other alternative causes. The patient’s clinical manifestation and supporting evidence of decreased protein S activity levels support the etiology of qualitative protein S deficiency. The patient has been followed regularly and is in good health with oral anticoagulant therapy.

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