Table of Contents  
CASE REPORT
Year : 2015  |  Volume : 8  |  Issue : 1  |  Page : 48-51  

Protein C and S deficiency presenting as acute abdomen


1 Department of Medicine, KIMS, Karad, Maharashtra, India
2 Department of Biochemistry, S.R.T.R.G.M.C, Ambejogai, Maharashtra, India

Date of Web Publication8-Jan-2015

Correspondence Address:
Amit A Bharadiya
Medicine Resident, Room No.102, I.H.R, Krishna Institute of Medical Sciences, Karad - 415 110, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.148844

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  Abstract 

Protein C and S are essential in limiting the activation of coagulation in vivo. Their deficiencies predispose the patient to thrombophilia and leads to thrombosis, often at unusual sites. Arterial thrombosis is rarely observed. We report a case of a patient with abdominal arteriovenous thrombosis leading to multiorgan infarction secondary to deficiency of protein C and protein S and presenting as acute abdomen.

Keywords: Acute abdomen, arterial thrombosis, protein C deficiency, protein S deficiency, venous thrombosis


How to cite this article:
Bharadiya AA, Aundhakar SC, Panpalia NG, Jaju JB. Protein C and S deficiency presenting as acute abdomen. Med J DY Patil Univ 2015;8:48-51

How to cite this URL:
Bharadiya AA, Aundhakar SC, Panpalia NG, Jaju JB. Protein C and S deficiency presenting as acute abdomen. Med J DY Patil Univ [serial online] 2015 [cited 2024 Mar 29];8:48-51. Available from: https://journals.lww.com/mjdy/pages/default.aspx/text.asp?2015/8/1/48/148844


  Introduction Top


There are few situations in clinical medicine which demand prompt and decisive action as frequently as does acute abdominal pain. Acute conditions of the abdomen are produced by inflammatory, obstructive, or vascular mechanisms. The urgency of managing such conditions usually restricts prolonged investigation and there are few specific tests or examinations which may be relied upon to give clear-cut answers as to the exact cause of the acute condition. While gathering the evidence, in the form of history, physical examination, lab investigations, and imaging studies, changes should be evaluated in terms of pathophysiologic alterations rather than specific diagnoses so as not to miss the rare conditions. Protein C and S deficiency is inherited in an autosomal dominant manner and is associated with familial venous thrombosis. The gene for protein C is located on chromosome 2 (2q13-14) and appears to be closely related to the gene for factor IX. [1] The primary effect of activated protein C (APC) is to inactivate coagulation factors Va and VIIIa, which are necessary for efficient thrombin generation and factor X activation. [2] The inhibitory effect of APC is markedly enhanced by protein S, another vitamin K-dependent protein. Two major subtypes of heterozygous protein C deficiency have been delineated using immunologic and functional assays. Over 160 different gene abnormalities have been associated with the two subtypes. [3] Type I deficiency - The type I deficiency state is more common. Most affected patients are heterozygous, having a reduced plasma protein C concentration at approximately 50% of normal in both immunologic and functional assays. [4] Type II deficiency - Individuals with the type II deficiency state have normal plasma protein C antigen levels with decreased functional activity. A variety of different point mutations affecting protein function have been identified in this disorder. [3] Homozygotes can develop a severe thrombotic tendency in infancy characterized as purpura fulminans. [5] Heterozygotes for protein C deficiency have an increased risk of developing warfarin-induced skin necrosis. [6] Protein C deficiency has been implicated in adverse pregnancy outcomes such as DVT, preeclampsia, intrauterine growth restriction, and recurrent pregnancy loss. [7] Protein S serves as a cofactor for activated protein C. It was originally discovered and purified in Seattle, leading to the designation protein S. There are two homologous genes for protein S: PROS1 and PROS2, which both map to chromosome 3. [8] Three phenotypes of protein S deficiency have been defined on the basis of total protein S antigen concentrations, free protein S concentrations, and protein S functional activity. Type I - The classic type of protein S deficiency is associated with a decreased level of total S antigen (approximately 50% of normal), and marked reductions in free protein S antigen and protein S functional activity. [9] Type II - This type of protein S deficiency is characterized by normal total and free protein S levels, but diminished protein S functional activity. Interestingly, all five mutations originally described were missense mutations located in the N-terminal end of the protein S molecule, which includes the domains that interact with activated protein C. [10] Type III - Also known as type IIa, this is characterized by total protein S antigen measurements in the normal range and selectively reduced levels of free protein S and protein S functional activity to less than approximately 40% of normal. [11] The clinical manifestations are similar to those seen with antithrombin and protein C deficiency. Thrombosis occurs in heterozygotes whose levels of functional protein S are in the range of 15 to 50% of normal.


  Case Report Top


A 65-year-old female was admitted to our hospital with the complaints of sudden onset abdominal pain and vomiting. Pain was generalized, colicky, and non-radiating in nature. Abdominal pain was associated with vomiting containing food particles and non-projectile. History of constipation, trauma, or any intoxication was absent.

Patient had intestinal perforation two months ago. Laparotomy showed distal gangrenous ileal loops. Resection and anastomoses were done. Her father had died of myocardial infarction.

On examination, she was conscious and well oriented. Her vitals were stable. No pallor, icterus, clubbing, cyanosis, lymphadenopathy, or edema was seen. On abdominal examination, she had generalized tenderness and peristaltic sounds were sluggish. Rest of the systemic examination was unremarkable.

Her X-ray erect abdomen ruled out obstruction. With her history of intestinal ischemia, vascular pathology was strongly suspected and a MDCT-abdomen was done immediately [Figure 1]. It revealed a 2 cm (longitudinal) × 0.7 cm (transverse) thrombus along posterior wall of abdominal aorta at the level of origin of renal arteries. 1 × 1 cm floating thrombus was noted in distal abdominal aorta just below inferior mesenteric artery's origin, which was partially attached to left posterior wall. Right renal artery thrombosis had caused right renal infarction of around 90%. Small right renal parenchyma noted was perfused by collaterals. Left splenic vein was thrombosed. Spleen was abnormal in shape and showed focal acute infarction. Abnormal shape of spleen was due to previous infarction. Proximal right hepatic artery was thrombosed. Celiac artery was almost completely thrombosed. Superior and inferior mesenteric arteries were normal. Left proximal renal artery showed mild stenosis. No calculopathy was noted.
Figure 1: Image showing the arterial thrombosis

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Coagulation profile of this patient revealed; Protein C - 45%, protein S - 45% while factor V leiden mutation was negative. Clot-based assays were used for detection of protein C and S deficiencies while polymerase chain reaction method was used for detecting factor V leiden mutation. The reference range for protein C levels in adults is in the range of 65 to 135 IU/dL whereas for protein S they were: Males >73 U/dL and Females >63 U/dl. Activated partial thromboplastin, serum homocystein, antithrombin activity, lipid profile, antiphospholipid antibodies, lupus anticoagulant, and INR were normal. Hemogram, renal and liver function tests were normal.

No surgical intervention was required and the patient was managed conservatively. Patient was kept nil by mouth for three days with continuous Ryles tube aspiration. The patient was started on injectable low-molecular-weight heparin [LMWH] 0.6 mg subcutaneous 12 hourly. Warfarin was overlapped with LMWH on the third day at a dosage of 5 mg/day targeting an INR in the range of 2 to 3. She was started on oral feeds by day 3 and eventually discharged on day 6. Follow-up was advised after 5 days with her INR status.


  Discussion Top


Protein C and protein S are vitamin K-dependent factors. Protein S deficiency occurs at a slightly greater frequency than protein C deficiency. Heterozygous protein C or S abnormalities cause hypercoagulability, whereas homozygous protein C or S abnormalities can result in purpura fulminans. [12,13] They exert their anticoagulatory activity by inhibiting factor V and VIII. Protein C deficiency is transmitted in an autosomal dominant form. Protein C and S deficiency are commonly associated with venous thrombosis [14,15] than arterial. [16] Thrombotic events are precipitated by trauma, surgery, or childbirth. There is no relationship between degrees of protein C or S deficiency and degree of severity of symptoms. [17] All deficient individuals will not experience thrombotic events. [18] The varying degrees to which family members carry a certain defect has raised the possibility of individuals carrying more than 1 defect being more susceptible to thromboembolic events. In 1998, Mustafa et al. suggested that there appeared to be an increased incidence of a second thrombophilic defect, particularly factor V Leiden, among patients who presented with thrombosis and were primarily found to have deficiencies of protein S or protein C. [19] In a study in Austria, factor V Leiden was present in four of fourteen patients with protein S deficiency and six of fifteen with protein C deficiency. [19] Carriers of two defects seem to be at a higher risk for thrombosis than their relatives with a single defect. In 1995, Koelman et al. showed that APC-R was an additional risk factor for Dutch patients with protein C deficiency. [20] They found that 73% of the family members who had factor V Leiden combined with the protein C deficiency experienced a thromboembolic event, compared with 31% and 13% of carriers with a single defect of protein C deficiency or factor V, respectively. Complete deficiency of protein C or S (homozygous individuals) cause neonatal purpura fulminans and disseminated intravascular coagulation with an incidence of about 1 in 16,000 to 360,000. [21] While significant advances have been made in understanding congenital thrombophilias, there may still be many more heritable forms of thrombophilia as yet undiscovered. Thus, it is not possible to determine the true prevalence of congenital thrombophilia. Pediatric disorders associated with genetic thrombophilia include neonatal purpura fulminans, renal vein thrombosis, vena cava thrombosis, and hepatic venous thrombosis. Pulmonary embolism, Legg Calve Perthes, and cerebral palsy have all been linked to genetic thrombophilia. [22] [Table 1] shows the prevalence of genetic defects among Caucasians with venous thrombosis. [23]
Table 1: Prevalence of genetic defects among Caucasians[23]

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Presenting symptoms of patients depend upon the site and severity of the thrombosis. Treatment includes LMWH and oral anticoagulation targeting an INR ranging 2-3. It can be continued till it is contraindicated. Patients with hypercoagulable states have a three times higher incidence of failed arterial reconstructions. [24,25] Surgical management should be considered wisely.


  Conclusion Top


Protein C and S deficiency, a rare disorder, led to thrombotic involvement of abdominal aorta, right renal artery, right coeliac artery, right hepatic artery along with splenic vein in our patient, which is extremely rare. Patient recovered with parenteral as well as oral anticoagulants and supportive management.

 
  References Top

1.
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2.
Clouse LH, Comp PC. The regulation of hemostasis: The protein C system. N Engl J Med 1986;14:1298-304.  Back to cited text no. 2
    
3.
Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, et al. Protein C deficiency: A database of mutations, 1995 update. Thromb Haemost 1995;73:876-89.  Back to cited text no. 3
    
4.
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7.
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8.
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9.
Simmonds RE, Ireland H, Kunz G, Lane DA. Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group. Blood 1996;88:4195-204.  Back to cited text no. 9
    
10.
Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C, et al. Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 1995;85: 130-8.  Back to cited text no. 10
    
11.
Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V mutation in 47 out of 60 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994;94:2521-4.  Back to cited text no. 11
    
12.
Mahasandana C, Suvatte V, Marlar RA, Manco-Johnson MJ, Jacobson LJ, Hathaway WE. Neonatal purpura fulminans associated with homozygous protein S deficiency. Lancet 1990;1:61-2.  Back to cited text no. 12
    
13.
Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: A genetic disorder related to the absence of protein C in blood. Blood 1985;65:15-20.  Back to cited text no. 13
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14.
Rharrit D, Harmouche H, Baroudi S, Mezalek ZT, Adnaoui M, Aouni M, et al. Protein C deficiency and mesenteric venous thrombosis. Can J Surg 2009;52:E35-7.  Back to cited text no. 14
    
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Choi BK, Yang SH, Suh KH, Hwang JA, Lee MH, Si WK, et al. A case of portal vein thrombosis by protein C and S deficiency completely recanalized by anticoagulation therapy. Chonnam Med J 2011;47:185-8.  Back to cited text no. 15
    
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Onwuanyi A, Sachdeva R, Hamirani K, Islam M, Parris R. Multiple aortic thrombi associated with protein C and S deficiency. Mayo Clin Proc 2001;76:319-22.  Back to cited text no. 16
    
17.
Gouault-Heilmann M, Leroy-Matheron C, Levent M. Inherited protein S deficiency: Clinical manifestations and laboratory findings in 63 patients. Thromb Res 1994;76:269-79.  Back to cited text no. 17
    
18.
Esmon CT. The regulation of natural anticoagulant pathways. Science 1987;235:1348-52.  Back to cited text no. 18
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19.
Mustafa S, Mannhalter C, Rintelen C, Kyrle PA, Knöbl P, Lechner K, et al. Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden. Blood Coagul Fibrinolysis 1998;9:85-9.  Back to cited text no. 19
    
20.
Koeleman BP, van Rumpt D, Hamulyák K, Reitsma PH, Bertina RM. Factor V Leiden: An additional risk factor for thrombosis in protein S deficient families? Thromb Haemost 1995;74:580-3.  Back to cited text no. 20
    
21.
Chalmers EA. Heritable thrombophilia and childhood thrombosis. Blood Rev 2001;15:181-9.  Back to cited text no. 21
    
22.
Feero WG. Genetic Thrombophilia. Prim Care 2004;31:685-709.  Back to cited text no. 22
    
23.
Press RD, Bauer KA, Kujovich JL, Heit JA. Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med 2002;126:1304-18.  Back to cited text no. 23
    
24.
Curi MA, Skelly CL, Baldwin ZK, Woo DH, Baron JM, Desai TR, et al. Long-term outcome of infrainguinal bypass grafting in patients with serologically proven hypercoagulability. J Vasc Surg 2003;37:301-6.  Back to cited text no. 24
    
25.
Ray SA, Rowley MR, Bevan DH, Taylor RS, Dormandy JA. Hypercoagulable abnormalities and postoperative failure of arterial reconstruction. Eur J Vasc Endovasc Surg 1997;13:363-70.  Back to cited text no. 25
    


    Figures

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    Tables

  [Table 1]


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