Thrombosis in Brothers With Protein S Deficiency: Case Series

ABSTRACT

Hereditary protein S deficiency is a rare thrombophilia that increases the risk of venous thromboembolism (VTE), including thrombosis in unusual sites. Early diagnosis, familial screening, and long‐term anticoagulation are essential for preventing complications and improving outcomes.

1. Introduction

Protein S is a vitamin K‐dependent glycoprotein that plays a crucial role in anticoagulation by serving as a cofactor for activated protein C (APC), which inactivates clotting factors Va and VIIIa. Additionally, protein S exerts direct anticoagulant effects by binding to factors Xa and Va, thereby inhibiting factor Xa activity [1, 2]. Deficiency of protein S disrupts this regulatory process, leading to an increased risk of abnormal clot formation and venous thromboembolism (VTE) [1].

Protein S deficiency can be either hereditary or acquired. In the hereditary form, it is caused by mutations in the PROS1 gene, which is located on chromosome 3q11.1, leading to reduced levels of functional protein S. These mutations, which can be either homozygous or heterozygous, are inherited in an autosomal semi‐dominant pattern. Acquired protein S deficiency, on the other hand, can result from conditions such as liver disease, vitamin K deficiency, vitamin K antagonist therapy like warfarin, systemic lupus erythematosus, pregnancy, or the use of oral contraceptives [1, 3].

Combined with protein C deficiency, protein S deficiency accounts for approximately 19% of plasma protein deficiencies that lead to venous thrombosis [4]. Although exact prevalence in the general population remains uncertain, some studies have estimated the prevalence of protein S deficiency to be 0.03%–0.13% in healthy individuals [5, 6]. While both men and women share a similar lifetime risk, women with protein S deficiency may develop VTE at an earlier age (< 30 years), due to factors such as the use of oral contraceptives, pregnancy, or the postpartum period, compared to men with protein S deficiency [7, 8].

Clinically, protein S deficiency often presents with VTE, most commonly presenting as recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE), though less frequent cases involve superficial, cerebral, visceral, or axillary vein thrombosis, with 29 years being the median age of presentation [1]. Around half of these thromboembolic events are unprovoked. Some women may have fetal loss as their only manifestation of protein S deficiency [7, 9]. In extremely rare cases of homozygous or compound heterozygous protein S deficiency, neonates may present with life‐threatening conditions such as massive VTE or purpura fulminans, and in some instances, severe retinopathy of prematurity is observed as the predominant initial symptom [7, 10, 11].

Screening for inherited thrombophilia, such as protein S deficiency, is recommended in individuals who experience VTE without a clear cause, especially those younger than 45–50 years. Once diagnosed, long‐term anticoagulation is often required due to the persistent prothrombotic risk [12, 13].

Here, we present two brothers with hereditary protein S deficiency, each experiencing distinct thrombotic events—one with portal vein thrombosis (PVT) and acute mesenteric ischemia, the other with DVT of the lower limb.

2. Case 1—History/Examination

A 28‐year‐old male presented to the outpatient department (OPD) at Adera Medical and Surgical Center with complaints of vague abdominal pain, bloating, and mucoid loose stools for 5 months. The symptoms were associated with a 5 kg weight loss but were not accompanied by vomiting, hematochezia, or overt gastrointestinal bleeding. His medical history was unremarkable, with no prior history of thrombotic events, major surgeries, or chronic illnesses. There was no known family history of thrombophilia or clotting disorders at the time of presentation.

On physical examination, the patient was hemodynamically stable, with blood pressure at 118/78 mmHg, a pulse rate of 82 bpm, a respiratory rate of 16 breaths per minute, and oxygen saturation of 98% on room air. His abdomen was soft but exhibited mild epigastric and lower abdominal tenderness on deep palpation without rebound tenderness or guarding. No hepatomegaly or splenomegaly was appreciable on palpation. The rest of his systemic examination was unremarkable.

2.1. Methods (Diagnosis, Investigations, and Treatment)

Routine laboratory workup, including complete blood count (CBC), renal function tests, and serum electrolytes, was within normal ranges. Liver function tests revealed mild transaminitis with Alanine aminotransferase (ALT) of 64 U/L, Aspartate aminotransferase (AST) of 44 U/L and Alkaline phosphatase (ALP) of 65 U/L. Serologic tests for hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti‐HCV), and human immunodeficiency virus (HIV, ELISA) were all negative. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were normal. Contrast‐enhanced abdominal CT scan revealed splenomegaly with intra‐abdominal collaterals, suggestive of chronic PVT. Upper gastrointestinal (GI) endoscopy demonstrated Grade 1 esophageal varices without red color signs and mild portal hypertensive gastropathy. Colonoscopy was unremarkable.

While under observation, the patient developed severe diffuse abdominal pain, progressive abdominal distension, and nausea. A repeat abdominal CT scan a week later revealed contrast non‐enhancing tissue completely filling the lumen of the main portal vein (PV) and the whole length of the Superior Mesenteric Vein (SMV) (suggesting acute complete PV and SMV thrombosis) (Figure 1) and a moderately thickened contrast hypo‐enhancing small bowel loop with mesenteric edema suggesting acute mesenteric ischemia (Figure 2).

FIGURE 1.

Contrast non‐enhancing tissue completely filling the lumen of main portal vein (yellow arrow) and the whole length of SMV (red arrow).

FIGURE 2.

Moderately thickened contrast hypo enhancing small bowel loop (yellow arrow) with mesenteric edema (red arrow).

He was subsequently started on unfractionated heparin and intravenous broad‐spectrum antibiotics, along with bowel rest and close monitoring of his abdominal condition. Despite these measures, the patient’s condition deteriorated, with worsening abdominal pain, distention, and failure to pass feces or flatus. An emergency laparotomy was performed, which revealed 30 cm of infarcted small bowel in the SMV territory, necessitating segmental resection with ileostomy.

Further testing for inherited thrombophilia was conducted 3 months after his acute thrombotic event and anticoagulation washout (Table 1). The functional assays for Protein S, Protein C, and Antithrombin III were performed using a clot‐based chromogenic method on the STA Compact Max coagulation analyzer (Diagnostica Stago, France). Unfortunately, genetic testing to identify the specific PROS1 variant was not performed due to a lack of local availability and high costs.

TABLE 1.

Thrombophilia Screening results for Case 1.

Test name	Result	Units	Reference interval
Protein S activity	< 28.00	%	77.00–143.00
Protein C activity	73.00	%	70.00–140.00
Factor V Leiden mutation	Not detected
Prothrombin gene mutation	Not detected
MTHFR gene mutation	Not detected
Antithrombin III activity	95.00	%	83.00–128.00

Abbreviation: MTHFR, Methylenetetrahydrofolate Reductase.

2.2. Conclusion and Results (Outcome and Follow‐Up)

The patient had an uneventful postoperative recovery and was discharged on the seventh day after surgery. Warfarin therapy was initiated with ongoing INR monitoring, and indefinite anticoagulation was advised. His ileostomy was reversed after 3 months, and he has remained free of thrombotic events over the past year. Due to limited availability of resources, repeat testing of Protein S and Protein C levels could not be conducted.

3. Case 2—History/Examination

A 32‐year‐old male, the elder brother of the patient in Case 1, presented to the OPD at Adera Medical and Surgical Center with a one‐week history of right leg and thigh swelling, associated with pain and progressive limitation of movement. His symptoms started while he was attending to his brother (Case 1), who was recovering from his surgery. He denied any preceding trauma, recent surgeries, prolonged immobilization, or travel. He also reported no history of chest pain, cough, hemoptysis, or shortness of breath.

The patient's vital signs were stable, with a blood pressure of 124/82 mmHg, pulse rate of 80 bpm, respiratory rate of 16 breaths per minute, and oxygen saturation of 98% on room air. Examination of the right lower limb revealed diffuse swelling and erythema over the entire leg and thigh, increased warmth and tenderness along the femoral and popliteal veins, a 4 cm circumference discrepancy between the right and left calf, and positive Homan's sign.

3.1. Methods (Diagnosis, Investigations, and Treatment)

The initial workup revealed a Hemoglobin of 16.6 g/dL, White blood cell count of 5.9 × 10³/μL (neutrophils 64.9%, lymphocytes 29.5%), Platelet count of 196 × 10³/μL, Erythrocyte sedimentation rate (ESR) of 10 mm/h, Renal function tests, serum electrolytes, PT, aPTT, and INR were within normal limits. Serologic testing for HIV, hepatitis B, and hepatitis C yielded negative results. A Doppler ultrasound of the right lower limb revealed mild soft tissue edema and non‐compressible superficial femoral, popliteal, anterior tibial, posterior tibial, and fibular veins, with echogenic thrombus within the vessel lumen and absent color flow Doppler signal in the occluded segment.

Hence, with the diagnosis of right lower extremity DVT, the patient was started on unfractionated heparin, followed by transition to warfarin therapy until a target INR was achieved. Given the confirmed diagnosis of DVT, his age, and his brother's recent thrombotic event, further thrombophilia screening was done 12 weeks later after discontinuation of anticoagulant (Table 2).

TABLE 2.

Thrombophilia screening results for Case 2.

Test name	Result	Units	Reference interval
Protein S activity	< 10.00	%	77.00–143.00
Protein C activity	78.00	%	70.00–140.00
Factor V Leiden mutation	Not detected
Prothrombin gene mutation	Not detected
MTHFR gene mutation	Homozygous mutation detected
Antithrombin III activity	99.00	%	83.00–128.00
Plasma homocysteine level	32	μmol/L	< 15

Abbreviation: MTHFR, Methylenetetrahydrofolate Reductase.

However, similar to the first case, genetic sequencing could not be performed due to cost and availability constraints in our setting. As a result, we were unable to identify the specific mutation. Nonetheless, the diagnosis of DVT secondary to protein S deficiency and homozygous MTHFR mutation with moderate hyperhomocysteinemia, was established based on the clinical presentation supported by the reported laboratory findings.

3.2. Conclusion and Results (Outcome and Follow‐Up)

The patient's symptoms, including limb swelling, gradually subsided, and he was discharged with indefinite anticoagulation therapy with close INR monitoring. He has had no thrombotic events in the past year. Similar to the above case, repeat testing of Protein S and Protein C was not done due to cost and availability limitations.

4. Discussion

Protein S is a natural anticoagulant protein that was first identified in Seattle, Washington, in 1979. In 1984, Schwarz et al. published the first clinical report linking protein S deficiency to an increased risk of VTE, describing a family with hereditary protein S deficiency. Since then, over 200 different mutations in the PROS1 gene have been identified, primarily consisting of missense or nonsense mutations [3].

Among individuals who are heterozygous for protein S deficiency, approximately 50% develop VTE, while the remaining 50% remain asymptomatic and never develop VTE [9]. Furthermore, individuals with a PROS1 gene defect in first‐degree relatives face a 5‐fold increased risk of thrombosis compared to the general population [14], with an annual incidence of first venous thrombosis at 0.7% and a recurrence risk of 6%–10% [15, 16]. Exposure to precipitating factors, such as surgery or trauma, can trigger thrombosis in these individuals [17].

In the presence of additional thrombophilic factors and a positive family history, protein S deficiency can predispose individuals to an increased risk of VTE. A case–control study by den Heijer et al. demonstrated that hyperhomocysteinemia, when combined with other thrombophilic factors such as protein S deficiency, can further elevate the risk of DVT [18]. Interestingly, the second patient in our case series was also found to have a homozygous mutation in the MTHFR gene with moderate hyperhomocysteinemia, which has been linked to an increased risk of VTE, particularly when combined with other thrombophilic factors.

The increased occurrence of thrombotic events in families with protein S deficiency, including unusual sites such as the axillary, mesenteric, and cerebral veins, supports the autosomal dominant inheritance pattern of this condition. A study evaluating 136 members from 12 families with protein S deficiency found that 71 were heterozygous for the disorder, inherited in an autosomal dominant manner. Among these 71 individuals, 39 (55%) experienced venous thrombotic events, with 77% of these events being recurrent. The symptoms included DVT (74%), superficial thrombophlebitis (72%), and PE (38%). Additionally, thrombosis occurred in unusual sites, including the axillary, mesenteric, and cerebral veins, on 5 occasions [19].

The variability in the clinical presentation of protein S deficiency, such as the occurrence of PVT and mesenteric ischemia in one of the brothers, is a rare but important manifestation of the condition. A systematic review and meta‐analysis by Qi et al. reported that inherited protein S deficiency was present in 2.6% of patients with PVT [20]. Mesenteric venous thrombosis, though uncommon, can lead to significant morbidity and mortality if not diagnosed and treated promptly. Early diagnosis and anticoagulation therapy have been shown to improve outcomes in such cases [21]. A case report by Gigante et al. described a 50‐year‐old patient with low protein S and C levels who presented with vague dyspeptic symptoms and bowel obstruction diagnosed with acute mesenteric ischemia, emphasizing the need for a high index of suspicion in these cases [22].

Current evidence suggests that screening for inherited thrombophilia is appropriate in several situations, including cases of VTE with no obvious cause in individuals under 45 to 50 years of age, VTE in patients with a family history of thrombosis, recurrent VTE, thrombosis occurring in unusual locations, and VTE developing during pregnancy or with the use of oral contraceptives or hormone replacement therapy [23].

Laboratory testing for protein S includes both total and free protein S immunoassays, functional assays, and mutational analysis of the PROS1 gene to identify any underlying deficiencies [24]. Approximately 40% of protein S circulates in its free form, while the remaining 60% is bound to C4b‐binding protein (C4BP) [5, 7, 10]; free protein S is a more accurate marker of thrombosis risk than total protein S levels [3]. Testing for thrombophilia should be conducted at least several weeks after an acute clotting event to allow acute‐phase reactant proteins to return to baseline [25]. Additionally, Protein S deficiency should not be diagnosed or excluded based on assays performed while the patient is taking a vitamin K antagonist. Plasma samples should be collected after temporarily discontinuing oral anticoagulant therapy for at least 10 days. For pregnant women, testing should be conducted after the postpartum period [26].

The management of VTE in patients with inherited thrombophilia, such as protein S deficiency, typically involves anticoagulation therapy. The duration of anticoagulation in these patients is often indefinite, as the underlying thrombophilic disorder persists, and the risk of recurrent VTE remains high [13, 24]. Thromboprophylaxis should be provided to all individuals with protein S deficiency in high‐risk situations, such as surgery, trauma, immobilization, long‐duration air travel (more than 4 h), and low‐molecular‐weight heparin during pregnancy or the puerperium [7]. In the presented cases, the patients were treated with unfractionated heparin and warfarin, with close monitoring of their INR to ensure a therapeutic range.

5. Conclusion

These two cases illustrate the importance of recognizing protein S deficiency as a potential cause of both common and rare thrombotic events, particularly in patients with a family history of thrombosis, unprovoked, or unusual‐site thrombotic events. Early detection, appropriate familial screening, and personalized anticoagulation strategies are critical in preventing further thrombotic events and improving patient outcomes.

Author Contributions

Abate Bane Shewaye: conceptualization, data curation, investigation, methodology, project administration, resources, supervision, validation, writing – original draft, writing – review and editing. Seifu Kebede: conceptualization, data curation, methodology, validation, visualization, writing – original draft, writing – review and editing. Amsalework Daniel: conceptualization, data curation, investigation, methodology, project administration, resources, validation, visualization, writing – original draft, writing – review and editing. Kaleb Assefa Berhane: conceptualization, data curation, investigation, methodology, project administration, resources, supervision, validation, visualization, writing – original draft, writing – review and editing. Asteraye Tsige Minyilshewa: conceptualization, data curation, methodology, resources, visualization, writing – original draft, writing – review and editing. Besufikad Girma Kebede: conceptualization, data curation, methodology, writing – original draft, writing – review and editing.

Ethics Statement

The ethical approval for the present study was obtained from the institutional review board of Adera Medical and Surgical Center. All the information obtained was held confidential and used only for the intended purpose.

Consent

Written informed consent was obtained from the patients for publication of this case report and the accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Shewaye A. B., Kebede S., Daniel A., Berhane K. A., Minyilshewa A. T., and Kebede B. G., “Thrombosis in Brothers With Protein S Deficiency: Case Series,” Clinical Case Reports 13, no. 9 (2025): e70824, 10.1002/ccr3.70824.

Data Availability Statement

The datasets used during the study are available from the corresponding author up on reasonable request.