Prolonged Anticoagulation

Indefinite anticoagulation is recommended for many patients with an unprovoked thromboembolism event, especially those with a strong family history of VTE. However, this does expose the patient to an increased risk of bleeding. Indefinite anticoagulation is most useful for patients who are at low risk for bleeding.

Prophylactic Anticoagulation

Prophylactic anticoagulation may be used in certain cases of PS deficiency, in patients with a strong family history, and in situations with VTE risk factors, including pregnancy, prolonged immobilization, or impending surgical interventions. In pregnancy, anticoagulation should be initiated in the first trimester because the risk of VTE increases in early pregnancy. For example, in pregnant patients, the prophylactic dose is given from the first trimester to 6-weeks postpartum. The postpartum stage puts a woman at even higher risk for VTE; therefore, treatment should be as or even more aggressive than during the antepartum stage.

Thrombotic episodes during pregnancy can be prevented using LMWH or aspirin.15-17 For example, enoxaparin thromboprophylaxis of 40 mg once a day and therapeutic dosage of 1 mg/kg every 12 hours at least 24 hours before delivery was used in one study.16 The optimal dosage during pregnancy has to be readjusted for weight gain. Warfarin is a known teratogen and is not given in early pregnancy. Low-dose aspirin is also given for thromboprophylaxis.15 


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Clinical Case Examples

A number of selected cases of clotting reported in the literature illustrate the clinical manifestations of PS deficiency, diagnostic measures, and management choices. The cases summarized in Tables 3 and 4.27-34 Common characteristics of these cases include patient age younger than 50 years, clotting in unusual sites, neurologic and abdominal manifestations, and low levels of PS. The majority of the cases with known ethnicity are of Asian or African descent.

Table 3. Cases of PS Deficiency With Neurological Manifestations34-37

PatientClinical ManifestationsLaboratory FindingsThrombosis SiteInterventions/Outcomes
13-year-old boy34  Proteinuria, fever, and productive cough; after admission, he developed generalized seizures and became unstableHigh fibrinogen and fibrinogen degradation products; type II PS deficiency (normal PS antigen level and low PS functional activity)Cerebral angio-MRI showed thrombosis of the superior sagittal, left transverse, and straight sinusesSystemic thrombolysis with tPA. Heparin infusion switched to LMWH and eventually to warfarin (following phenobarbital discontinuation) for 6 months  
22-year-old Black woman35Two-week history of occipital headache, fever, and projectile vomiting of recently ingested food; neck rigidity and papilledema found on examinationMalaria parasites, hemoglobin C trait; PS deficiency (level -8%); CSF negative for meningitisCT with contrast showed left transverse sinus thrombosis  Delay in diagnosis; treated with LMWH and discharged on oral dabigatran with symptom resolution after 3 weeks  
23-year-old Asian man36Presents to dental clinic with bifrontal occipital pulsatile headache, facial numbness on the right side; reports photophobia and pulsatile tinnitus in both ears for the past 2 weeks; grade III papilloedema found on fundus exam Initial laboratory results were all normal; PS deficiencyMRI-MR venogram showed dural venous sinus thrombosis involving the superior sagittal sinus, straight sinus, and bilateral transverse sinus without venous infarcts  Anticoagulant therapy with warfarin for 10 days; discharged on  warfarin daily for 6 months  
32-year-old  woman37Sudden onset of headache, projectile vomiting, slight neck stiffness, and altered consciousness  PS 11%CT showed extensive primary intraventricular hemorrhage; cerebral angiography compatible with  Moyamoya syndrome with internal caroid artery narrowing and extracranial collateralsTreated conservatively with intraventricular drainage and ICP monitoring; anticoagulants are controversial in Moyamoya syndrome because of intracranial hemorrhage risk  
CSF, cerebrospinal fluid; LMWH, low-molecular-weight heparin; MRI, magnetic resonance imaging; PS, protein S; tPA, tissue plasminogen activator

Table 4. Cases of PS Deficiency With Abdominal Symptoms38-41

PatientClinical ManifestationsWorkupThrombosis SiteInterventions/Outcomes
16-year-old boy38Priapism with scrotal edema appeared 1 week after an influenza-like illness; multiple extensive venous necrotic lesions of legs and feet  Low level of both PS-free antigen (7%) and PS activity (14%)Corpora cavernosaUFH, corticosteroids, and plasmapheresis; priapism lasted for 4 days, erective function returned in 3 months, and full recovery of the skin was established in 6 months
38-year-old Asian woman39        Beaded swelling over abdominal area, large tortuous veins in the legs, back, and abdomen that were increasing in sizePS 13.1% PC 56%Thromboses in multiple sites including inferior vena cava and hepatic, portal, and renal veinsLMWH for 1 week followed by warfarin; discharged on warfarin  
46-year-old Black man40Acute pancreatitis with diffuse abdominal pain, vomiting, and abdominal distention.Abdominal Doppler showed massive venous thrombosis of the splenic, hepatic, and mesenteric veins; contrast-enhanced CT showed inflammatory flows in the peritoneum and infiltration of proximal pancreas; PC 25%; PS 50%  Portosplenomesenteric vein  Treated with LMWH followed by warfarin on day 10 
65-year-old Asian woman41Presented with sudden onset of abdominal pain and tachycardia, mild tenderness of the abdomen, and diminished peristalsis; obstruction rule out by radiographCT of the abdomen suggested vascular compromise; PS 45%; PC 45%Thrombosis in abdominal, hepatic, renal-celiac artery, and splenic vein; splenic and renal infarction LMWH was given, warfarin daily was started on day 3; patient discharged on day 6
CT, computed tomography; LMWH, low-molecular-weight heparin; PC, protein C; PS, protein S; SQ, subcutaneous; UFH, unfractionated heparin

Conclusion

Protein S deficiency is an uncommon anomaly in primary care. A history of a precipitating event coupled with a strong family history of abnormal clotting should raise the suspicion in clinicians to investigate clotting anomalies, especially PS/PC deficiency. An episode of clotting in young patients should prompt further workup. Appropriate diagnosis and referral to a hematologist for further investigation and management are essential steps to prevent premature death and complications.

Elizabeth Simon, PhD, RN, ANP-BC, is a professor of nursing, has over 25 years of nursing education experience and over 30 years of clinical experience. Dr. Simon is a board-certified adult health nurse practitioner. She has authored and reviewed books on critical care nursing. She was a Fulbright Scholar in 2015-16 academic year; Anoma Zehra Ahmed, PA-C, MBBS, is an associate professor in the Department of Physician Assistant Studies at New York Institute of Technology; Sara Winter, PA-C, MS, SLP, is an assistant professor in the Department of Physician Assistant Studies at New York Institute of Technology. She is also a practicing PA and her clinical experience includes neurosurgery, emergency medicine, and family practice.

References

1. Khare S, Kushwaha R, Kumar A, et al. Prothrombotic state in HIV: a study on protein C, protein S, homocysteine and correlation with CD4 counts. Indian J Med Microbiol. 2018;36(2):201-206. doi:10.4103/ijmm.IJMM_15_414

2. Carroll R, Rebarber A, Booker W, et al. Double versus single thrombophilias during pregnancy. J Matern Fetal Neonatal Med. 2018;31:2590-2593. doi:10.1080/14767058.2017.1349745

3. Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol. 2019;12(3):147-158. doi: 0.1080/17474086.2019.1583555

4. Simon E, Hwang I. Causes of clotting unmasked. MEDSURG Nursing. 2019;28(6):363-366.

5. Pahuja M, Ainapurapu B, Abidov A. Large left ventricular thrombus in a patient with systemic and venous thromboembolism secondary to protein C and S deficiency. Case Rep Cardiol. 2017;2017:7576801. doi:10.1155/2017/7576801

6. Gantayet M, Singh M. Acute pulmonary embolism in protein S deficiency: 2 rare case reports of young male presenting with breathlessness. J Med Allied Sci. 2018;8(2):86-90.

7. van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2016;14:1393-1403. doi:10.1111/jth.13349

8. Satpanich P, Rojnuckarin P. Risk factors for venous thromboembolism (VTE) recurrences in Thai patients without cancer. Hematology. 2019;24:159-165. doi:10.1080/10245332.2018.1535535

9. Miyata T, Maruyama K, Banno F, Neki R. Thrombophilia in East Asian countries: are there any genetic differences in these countries? Thromb J. 2016;14(Suppl 1):25. doi:10.1186/s12959-016-0109-x

10. de Moerloose P, Boehlen F. Inherited thrombophilia in arterial disease: a selective review. Semin Hematol. 2007;44(2):106-113. doi:10.1053/j.seminhematol.2007.01.008

11. National Organization for Rare Disorders. Protein S deficiency. Accessed 6/14 2021. https://rarediseases.org/rare-diseases/protein-s-deficiency/

12. Chen TY, Lin L, Hsieh MY, Chen CH, Chen MK, Wu CC. Thrombophilia associated with early post-angioplasty thrombosis of dialysis vascular access. Cardiovasc Intervent Radiol. 2018;41(11):1683-1690. doi:10.1007/s00270-018-2046-5

13. Konishi T, Yamamoto T, Funayama N, et al. Stent thrombosis caused by metal allergy complicated by protein S deficiency and heparin-induced thrombocytopenia: a case report and review of the literature. Thromb J. 2015;13:25. doi:10.1186/s12959-015-0055-z

14. Berceanu C, Diana V, Sorin V, et al. Incidence of fetal loss in women with inherited thrombophilia. J Perinat Med. 2017;45:268. https://doi.org/10.1515/jpm-2017-3002

15. Khalafallah AA, Ibraheem AR, Teo QY, et al. Review of management and outcomes in women with thrombophilia risk during pregnancy at a single institution. ISRN Obstet Gynecol. 2014;2014:381826. doi:10.1155/2014/381826

16. Shen MC, Wu WJ, Cheng PJ, et al. Low-molecular-weight-heparin can benefit women with recurrent pregnancy loss and sole protein S deficiency: a historical control cohort study from Taiwan. Thromb J. 2016;14:44. doi:10.1186/s12959-016-0118-9

17. Mekaj Y, Lulaj S, Daci F, et al. Prevalence and role of antithrombin III, protein C and protein S deficiencies and activated protein C resistance in Kosovo women with recurrent pregnancy loss during the first trimester of pregnancy. J Hum Reprod Sci. 2015;8(4):224-249. doi:10.4103/0974-1208.170407

18. Özdemir HH, Varol S, Akıl E, Acar A, Demir CF. Evaluation of cerebral venous thrombosis secondary to oral contraceptive use in adolescents. Neurol Sci. 2015;36(1):149-153. doi:10.1007/s10072-014-1914-2

19. Marlar RA, Gausman JN, Tsuda H, Rollins-Raval MA, Brinkman HJM. Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH. J Thromb Haemost. 2021;19(1):68-74. doi:10.1111/jth.15109.

20. Senst B, Tadi P, Goyal A, et al. Hypercoagulability. In: StatPearls [Internet]. StatPearls Publishing; 2021 Jan-. Updated July 8, 2021. Accessed August 28, 2021. https://www.ncbi.nlm.nih.gov/books/NBK538251/

21. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830

22. Senyei G, Fernandes T. Duration of anticoagulation Post-PE: things to consider. March 22, 2019. Accessed August 26, 2021. https://www.acc.org/latest-in-cardiology/articles/2019/03/22/07/45/duration-of-anticoagulation-post-pe

23. Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA; Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost. 2016;14(7):1480-1483. doi:10.1111/jth.13336

24. Scutelnicu A, Gica C, Botezatu R, et al. Screening for inherited thrombophilias and prophylaxis of venous thromboembolism in pregnancy and puerperium. Romanian J Med Prac. 2020;15(4):400-404. doi:10.37897/RJMP.2020.4.6

25. Chen GC, Gao H, Zhang L, Tong T. Evaluation of therapeutic efficacy of anticoagulant drugs for patients with venous thromboembolism during pregnancy: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2019;238:7-11. doi:10.1016/j.ejogrb.2019.04.038

26 Smythe MA, Priziola J, Dobesh PP, Wirth D, Cuker A, Wittkowsky AK. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):165-86. doi:10.1007/s11239-015-1315-2

27. Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. doi:10.1182/bloodadvances.2018024489.

28. Ameku K, Higa M. Rivaroxaban Treatment for warfarin-refractory thrombosis in a patient with hereditary protein S deficiency. Case Rep Hematol. 2018;2018:5217301. doi:10.1155/2018/5217301.

29. Liaw TY, Chang CH. Skin necrosis complicated by warfarin-induced protein S deficiency. J Formos Med Assoc. 2014;113:758-759. doi:10.1016/j.jfma.2012.09.005

30. Shikdar S, Vashisht R, Bhattacharya PT. International Normalized Ratio (INR) [Updated 2021 May 10]. In: StatPearls [Internet]. StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507707/

31. Gupta A, Tun AM, Gupta K, et al. Protein S deficiency. In: StatPearls [Internet]. StatPearls Publishing; 2021 Jan-. Updated Septmber 13, 2020. Accessed August 26, 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544344/

32. Maryamchik E, Rosenbaum MW, Van Cott EM. Rivaroxaban causes missed diagnosis of protein S deficiency but not of activated protein C resistance (factor V Leiden). Arch Pathol Lab Med. 2018;142(1):70-74. doi:10.5858/arpa.2016-0616-OA

33. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-13. doi:10.1111/jth.13323

34. Artoni A, Passamonti SM, Edefonti A, Gianniello F, Civelli V, Martinelli I. Antithrombotic prophylaxis in a patient with nephrotic syndrome and congenital protein S deficiency. Ital J Pediatr. 2016;42:22. doi:10.1186/s13052-016-0227-x

35. Ogun OA, Ogbole G, Owolabi M. An “uncommon” headache at our doorsteps: cerebral venous sinus thrombosis from combined haemoglobinopathy and protein S deficiency, presenting with papilledema. J Neurol Sci. 2015;32(1):237-242.

36. Kumar MH, Deepthi DA, Singh DN, Virupakshappa B, Rahul R. Dangerous headache: a case of dural venous sinus thrombosis with protein S deficiency. J Clin Diagn Res. 2017;11(1):ZD50-ZD52. doi:10.7860/JCDR/2017/24959.9303

37. Cevik B, Acu B, Aksoy D, Kurt S. Protein S deficiency and an adult case with moyamoya syndrome that presented with primary intraventricular haemorrhage. Balkan Med J. 2014;31(2):180-183. doi:10.5152/balkanmedj.2014.13028

38. Boissier E, Durant C, Vildy S, et al. An unexpected etiology of priapism: infection-related anti-protein s antibodies. J Sex Med. 2014;11(11):2830-2833. doi:10.1111/jsm.12660

39. Kodali VU, Borra S, Mandarapu SB, Sanda MR, Bolla SR. Multiple abdominal veins thrombosis secondary to protein s deficiency — a case report. J Clin Diagn Res. 2014;8(6):MD07-8. doi:10.7860/JCDR/2014/5879.4509

40. Ankouane F, Kowo M, Ngo Nonga B, Magny E, Hell Medjo E, Ndjitoyap Ndam EC. Clinical outcome of a portosplenomesenteric venous thrombosis in necrotizing acute pancreatitis with protein C and S deficiency treated by anticoagulation therapy alone. Case Rep Gastrointest Med. 2015;2015:934784. doi:10.1155/2015/934784

41. Bharadiya AA, Aundhakar SC, Panpalia NG, Jaju JB. Protein C and S deficiency presenting as acute abdomen. Med J DY Patil Univ. 2015;8(1):48-51.