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Canadian Journal of Anesthesia 48:1070-1074 (2001)
© Canadian Anesthesiologists' Society, 2001
General Anesthesia

Perioperative management of a patient with purpura fulminans syndrome due to protein C deficiency

[La démarche anesthésique périopératoire adoptée chez une patiente atteinte du syndrome de purpura fulminans causé par un déficit en protéine C]

Kojiro Kumagai, MD*, Kimitoshi Nishiwaki, MD PhD{dagger}, Kosei Sato, MD{dagger}, Hanae Kitamura, MD{ddagger}, Kayo Yano, MD{ddagger}, Toru Komatsu, MD PhD* and Yasuhiro Shimada, MD PhD{dagger}

* From the Department of Anesthesiology, Aichi Medical University School of Medicine, Aichi;
{dagger} the Department Of Anesthesiology, Nagoya University School of Medicine and
{ddagger} the Department Of Anesthesiology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.

Dr. Kojiro Kumagai, Department of Anesthesiology, Aichi Medical University School of Medicine, Nagakute-cho Aichi, 480-1195, Japan. Phone: +81-561-62-3311; Fax: +81-561-63-6621; E-mail: kkumagai{at}aichi-med-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Case report
 Discussion
 References
 
Purpose: Protein C is a vitamin K-dependent anticoagulant and homozygous protein C deficiency is a rare fatal thrombotic disease. This report describes the perioperative management of homozygous protein C deficiency in a patient who underwent a total of three surgical procedures under general anesthesia and the successful use of activated protein C concentrate.

Clinical features: A female baby, who developed disseminated intravascular coagulation and purpura fulminans shortly after birth, was diagnosed as purpura fulminans syndrome due to homozygous protein C deficiency. At one month of age, she suffered bilateral retinal detachment and glaucoma due to retinal hemorrhage. After marked improvement of her condition after administration of activated protein C concentrate, she underwent a left iridectomy and implantation of a Broviak catheter under general anesthesia. Her intraoperative course was uncomplicated but, on postoperative day four, she presented another episode of massive cutaneous necrosis and gangrene. Activated protein C concentrate was administered again, with good results. She underwent replacement of a Broviak catheter at four months of age, and right iridectomy for glaucoma at eight months. Both were uneventful.

Conclusion: The perioperative management of homozygous protein C deficiency and purpura fulminans requires appropriate measures for thromboembolic prophylaxis. Sufficient iv fluid administration is necessary. Attention should be paid to decrease the risk of tissue compression such as that associated with positioning, blood pressure cuff, and endotracheal intubation, which may cause necrosis over pressure points. Replacement therapy with activated protein C concentrate appears safe and effective. The anesthetic management is reviewed and discussed.


   Introduction
TOP
 Abstract
 Introduction
Case report
 Discussion
 References
 
PROTEIN C is a vitamin-K dependent plasma glycoprotein which, when activated, exerts its anticoagulant effect by inactivating activated factor V and activated factor VII and promotes fibrinolysis by neutralizing a plasminogen activator inhibitor (Figure 1Go). In homozygous protein C deficiency, purpura fulminans syndrome may occur shortly after birth, resulting in life-threatening neonatal thrombosis. We report the perioperative management and successful use of activated protein C concentrate in a patient with congenital protein C deficiency.



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  		FIGURE 1 The site of action of protein C.

 

   Case report
TOP
 Abstract
 Introduction
 Case report
Discussion
 References
 
The patient was a female baby, born at 37 weeks and one day of gestation, after a normal delivery (birth weight, 2430 g). Her Apgar score was 9 at one and 10 at five minutes respectively. At 15 hr of life, she presented ecchymosis and hemorrhagic bullae which culminated in gangrene on her buttock and inguinal region. She was transferred to our hospital. Laboratory values on admission are given in the TableGo.


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  		TABLE Laboratory findings on admission
 
Disseminated intravascular coagulation (DIC) was diagnosed and treated with human anti-thrombin III, gabexate mesilate, fresh-frozen plasma (FFP) and platelet concentrates. Although the infant's condition improved at first, a new purpuric lesion developed on the right arm at seven days of age. Further tests revealed that the protein C activity of the infant was 3% (normal range 80–130%) with a protein C antigen activity <5% (normal range 80–130%). The protein C activities of both of parents were 44% with protein C antigen activities of 41%. The diagnosis of purpura fulminans syndrome due to homozygous protein C deficiency was made on the patient's ninth day of life. In addition to treatment with FFP and warfarin potassium, administration of activated protein C concentrate, affinity-purified from human plasma, (Teijin Co .Ltd., Osaka, Japan and the Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan) was initiated on the 11th day of life after informed consent was obtained from the parents. An infusion of 600 U•kg-1•day-1 of activated protein C concentrate for six days followed a bolus injection of 100 U•kg-1. After initiation of activated protein C concentrate therapy, the cutaneous manifestations of purpura fulminans stopped. However, bilateral retinal detachment and glaucoma due to retinal hemorrhage was diagnosed. At 43 days of age, she presented new ecchymosis on her precordia and left thigh and new petechial hemorrhage on her face. At the same time, left intraocular pressure was increased. Therefore left iridectomy for glaucoma and implantation of an indwelling Broviak catheter through the right jugular vein were planned under general anesthesia, after a bolus injection of 100 U•kg-1 of activated protein C concentrate and an infusion of 600 U•kg-1•day-1 for three days and of 900 U•kg-1•day-1 for three days. The treatment with warfarin potassium was continued until the day before the operation.

The infant was not premedicated. Thiamylal and vecuronium bromide were used for a rapid sequence induction of anesthesia. Endotracheal intubation was achieved easily with a 3.0-mm tube. We selected a small endotracheal tube to decrease the risk of tracheal compression, and there was an air leak at a pressure of 10 cmH2O. Gauze was put into laryngopharynx to create a seal around the endotracheal tube. Anesthesia was maintained with nitrous oxide, oxygen and 1%–2% sevoflurane. The intraoperative course was uneventful. At the end of the procedure, residual neuromuscular block was reversed with neostigmine and atropine, and the trachea was extubated. The treatment with warfarin potassium was reintroduced on the second postoperative day. Yet, another purpuric lesion developed on the right foot on the fourth postoperative day. She was treated with FFP and activated protein C concentrate. On the first day of treatment, an infusion of 800 U•kg-1•day-1 of activated protein C concentrate followed a bolus injection of 100 U•kg-1. From day two to day six, 900 U•kg-1•day-1 of activated protein C concentrate were infused continuously. After the treatment, she experienced an immediate improvement in clinical symptoms with disappearance of skin erythema and the plasma concentration of activated protein C was increased from 1.6 ng•mL-1 to 118.2 ng•mL-1 (Figure 2Go).



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  		FIGURE 2 Administration of exogenous activated protein C increased activated protein C plasma concentration and was accompanied by an increase in platelet count and a decrease in D-dimer concentration. See text for details.

 
She was treated with warfarin potassium and FFP postoperatively, and her condition remained stable. At four months, she weighed 5.4 kg and underwent replacement of an indwelling Broviak catheter via the left jugular vein. No premedication was administered. After rapid induction of anesthesia with thiamylal and vecuronium bromide, the trachea was intubated with a 3.5-mm tube, with an air leak at a pressure of 10 cmH2O. Anesthesia was maintained with 50%–100% oxygen and 1%–2.5% sevoflurane. The intraoperative and postoperative courses were uneventful.

At eight months, she weighed 6.9 kg and underwent right iridectomy for glaucoma. Her general condition was stable. Again, no premedication was given, and thiamylal and vecuronium bromide were used for rapid induction of anesthesia. The trachea was intubated with a 3.5-mm tube, with an air leak at a pressure of 7 cmH2O. Anesthesia was maintained with 50%–100% oxygen and 2%–3.5% sevoflurane. The intraoperative and postoperative courses were uneventful.

No postoperative complications and no adverse effects related to the use of activated protein C concentrate were noted.


   Discussion
TOP
 Abstract
 Introduction
 Case report
 Discussion
References
 
This is one of the first reports of the perioperative management of a patient with purpura fulminans syndrome due to protein C deficiency with activated protein C concentrate.

Protein C is the central protein in a major antithrombotic regulatory system of hemostasis, the protein C pathway.1–5 Protein C is a vitamin K-dependent glycoprotein circulating in plasma as an inactive zymogen. This zymogen is activated on the endothelium of the cell wall by a complex of thrombin and the endothelial thrombin receptor thrombomodulin. Activated protein C exerts its anticoagulant effects by inactivating activated factor V and activated factor VII, and it facilitates fibrinolysis by neutralizing a circulating inhibitor of tissue-type plasminogen activator. In the large vessels most of the thrombin is free and therefore catalyses clotting. In the microcirculation, most of the thrombin is bound to thrombomodulin, clotting activity is depressed, and protein C activation is enhanced. Therefore protein C activation probably occurs primarily in the microcirculation.6

Congenital protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease.2,4 Patients with heterozygous protein C deficiency are at risk for superficial thrombophlebitis, deep venous thrombosis and pulmonary embolism, which may occur without apparent cause at a young age.7,8 Patients with homozygous protein C deficiency present shortly after birth with life-threatening neonatal thrombosis, hemorrhagic necrosis due to vascular thrombosis, retinal hemorrhage and purpura fulminans. The site of mutation in this patient was found recently.9

Purpura fulminans defines an acute, often lethal syndrome of DIC with rapidly progressive hemorrhagic necrosis of the skin due to dermal vascular thrombosis.10,11 Pathological specimens in purpura fulminans reveal microvascular thrombosis involving the dermis with perivascular hemorrhage. Clinically, skin lesions are characterized by a progression from ecchymotic areas to circumscribed lesions of purplish-black skin containing hemorrhagic bullae, eventually culminating in gangrene.

A precautious atraumatic anesthetic technique is indispensable. To decsrease the risk of tissue compression, attention should be paid to intraoperative positioning and possible pressure points such as the blood pressure cuff. A water bed would have been useful but was not available in our institute. In addition, intravascular volume should be expanded adequately to avoid dehydration, which increase the risk of thromboembolism.

We have found only one report of the anesthetic management of purpura fulminans due to homozygous protein C deficiency.12 In line with that report we selected a small endotracheal tube to decrease the risk of tracheal compression, submucosal thrombosis, and necrosis. A seal with gauze between the endotracheal tube and laryngopharyngeal mucosa minimized the risk of aspiration and provided adequate oxygenation and ventilation.

Previously reported treatments such as FFP, prothrombin-complex concentrates, or oral anticoagulants, have many disadvantages.10 Administration of FFP can lead to hyperproteinemia, fluid overload and hypertension, and carries an increased risk of infection. The use of prothrombin-complex concentrates is controversial.13,14 Vitamin K antagonist therapy carries the risk of breakthrough bleeding. Casella et al. reported the successful treatment by orthotopic hepatic transplantation,15 but the long-term benefits and complications are unknown. Recently the availability of monoclonal antibody purified protein C concentrates allows specific replacement of protein C, avoiding the above-mentioned problems.16–20

We used activated protein C concentrate preoperatively and postoperatively in the first operation for treatment of thrombosis and thromboembolic prophylaxis with, apparently, good results. To our knowledge, this patient is the first case of purpura fulminans treated with activated protein C concentrate and the effective dosage of activated protein C concentrate has not been determined. In view of the disadvantages of previously reported therapies, we suggest that the perioperative use of activated protein C concentrate is a safe and effective treatment for infants with severe homozygous protein C deficiency.


   Footnotes
 
This work was conducted in the Department of Anesthesiology, Japanese Red Cross Nagoya First Hospital.

Revision received August 29, 2001. Accepted for publication June 6, 2001.


   References
TOP
 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298–304.[Medline]

2 Aiach M, Borgel D, Gaussem P, Emmerich J, Alhenc-Gelas M, Gandrille S. Protein C and protein S deficiencies. Semin Hematol 1997; 34: 205–17.[Medline]

3 Mannucci PM, Vigano S. Deficiencies of protein C, an inhibitor of blood coagulation. Lancet 1982; 2: 463–7.[Medline]

4 Reitsma PH. Protein C deficiency: from gene defects to disease. Thromb Haemost 1997; 78: 344–50.[Medline]

5 Reitsma PH, Bernardi F, Doig RG, et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the subcommittee on plasma coagulation inhibitors of the scientific and standardization committee of the ISTH. Thromb Haemost 1995; 73: 876–89.[Medline]

6 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743–6.[Free Full Text]

7 Broekmans AW. Hereditary protein C deficiency. Haemostasis1985;15:233–40.[Medline]

8 Sternberg TL, Bailey MK, Lazarchick J, Brahen NH. Protein C deficiency as a cause of pulmonary embolism in the perioperative period. Anesthesiology 1991; 74: 364–6.[Medline]

9 Nakayama T, Matsushita T, Hidano H, et al. A case of purpura fulminans is caused by homozygous 8857 mutation (protein C-Nagoya) and successfully treated with activated protein C concentrate. Br J Haematol 2000; 110: 727–30.[Medline]

10 Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. Report of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, international committee on thrombosis and haemostasis. J Pediatr 1989; 114: 528–34.[Medline]

11 Sills RH, Marlar RA, Montgomery RR, Deshpande GN, Humbert JR. Severe homozygous protein C deficiency. J Pediatr 1984; 105: 409–16.[Medline]

12 Wetzel RC, Marsh BR, Yaster M, Casella JF. Anesthetic implications of protein C deficiency. Anesth Analg 1986; 65: 982–4.[Free Full Text]

13 Bertina RM, Broekmans AW. Protein C concentrates for therapeutic use (Letter). Lancet 1982; 2: 1348.

14 Mannucci PM, Vigano S. Protein C concentrates for therapeutic use (Letter). Lancet 1983; 1: 875.

15 Casella JF, Lewis JH, Bontempo FA, Zitelli BJ, Markel H, Starzl TE. Successful treatment of homozygous protein C deficiency by hepatic transplantation (Letter). Lancet 1988; 1: 435–8.[Medline]

16 Dreyfus M, Magny JF, Bridey F, et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325: 1565–8.[Medline]

17 De Stefano V, Mastrangelo S, Schwarz HP, et al. Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency. Thromb Haemost 1993; 70: 247–9.[Medline]

18 Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993; 91: 418–22.[Abstract/Free Full Text]

19 Schramm W, Spannagl M, Bauer KA, et al. Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. Arch Dermatol 1993; 129: 753–6.[Abstract]

20 Müller F-M, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr 1996; 155: 20–5.[Medline]





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