History

Individuals with hereditary protein C deficiency can present with venous thromboembolism (VTE), warfarin-induced skin necrosis in adults, and neonatal purpura fulminans in newborns who are homozygous or compound heterozygous for protein C mutation. Obtaining a detailed history that focuses on personal history—including previous history of thrombosis and any abnormal laboratory results—family history, and obstetric history is paramount.

Venous Thromboembolism

The most common sites of VTE are the deep veins of the leg (DVT), mesenteric veins, and pulmonary veins. Other sites, including cerebral veins, portal veins, superficial veins, or other unusual sites are also reported.^{[61, 62]}

In patients who present with VTE or warfarin-induced skin necrosis, family history is the best predictor for congenital thrombophilia. The initial episode of VTE in individuals with protein C deficiency is apparently spontaneous in approximately two-thirds of cases, and the other third usually have typical risk factors such as pregnancy, oral contraceptives, surgery, or trauma. Among patients with a positive family history, the risk is as high as 75% in those with severely affected families and closer to 30% in members of other families.^[62]

Warfarin-induced skin necrosis

Wafarin-induced skin necrosis (WISN) typically develops in the first few days of warfarin therapy, often in patients given large loading doses of 10 mg or more per day. If the patient is on warfarin and heparin, the lesions may appear upon discontinuation of the heparin. If a product containing protein C is not rapidly administered, the affected cutaneous area typically becomes edematous, develops central purpura, and eventually becomes necrotic.

WISN is not pathognomonic for protein C deficiency. It has been described in individuals with other inherited thrombophilias (factor V Leiden mutation, protein S deficiency) and transient reduction of protein C levels.^{[40, 41]}

Neonatal purpura fulminans

Purpura fulminans is a rare life-threatening condition in newborns characterized by disseminated intravascular coagulation (DIC), extensive venous and arterial thrombosis, and hemorrhagic skin necrosis. Laboratory testing reveals evidence of DIC and extremely low protein levels of less than 1% of normal.

Physical Examination

Patients with symptomatic hereditary protein C deficiency may present with VTE or WISN. Homozygotes and compound heterozygotes frequently present with neonatal purpura fulminans during the first hours of life.

Venous thromboembolism

Findings of acute VTE on physical examination are discussed in topics elsewhere (see Further Reading). Deep venous thrombosis of the lower extremity may be complicated by postthrombotic syndrome, a chronic condition associated with swelling, pain, discoloration, and venous insufficiency of the lower extremity.

Warfarin-induced skin necrosis

The skin lesions of WISN occur on the extremities, torso, breasts, and penis. They begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic bullae. See image below.

A patient with warfarin-induced skin necrosis.

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Neonatal purpura fulminans

Affected neonates present with diffuse ecchymoses that, like the lesions of WISN, progress to form necrotic bullae if appropriate therapy is not rapidly instituted. See image below.

A patient with neonatal purpura fulminans.

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Differential Diagnoses

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Media Gallery

The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.
A patient with warfarin-induced skin necrosis.
A patient with neonatal purpura fulminans.

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Author

Shamudheen Rafiyath, MD Medical Oncologist, Hematologist, Arizona Blood and Cancer Specialists

Shamudheen Rafiyath, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Eleanor S Pollak, MD Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania

Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, AMDA - The Society for Post-Acute and Long-Term Care Medicine, American Society of Hematology, Infectious Diseases Society of America, Phi Beta Kappa

Disclosure: Nothing to disclose.

Adam Cuker, MD, MS Assistant Professor of Medicine, Assistant Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania

Adam Cuker, MD, MS is a member of the following medical societies: American College of Physicians, American Society of Hematology, Anticoagulation Forum, Hemostasis and Thrombosis Research Society, International Society on Thrombosis and Haemostasis

Disclosure: Received research grant from: Alexion; Bayer; Bioverativ; Novo Nordisk; Pfizer; Shire; Spark; Syntimmune<br/>Received income in an amount equal to or greater than $250 from: Genzyme; Kedrion; Synergy.