Long-term Subcutaneous Protein C Replacement inNeonatal Severe Protein C Deficiency

abstractWe describe here the case of a boy who presented 2 days after birthwith purpura fulminans on his feet and scalp. Laboratory investiga-tions revealed signs of disseminated intravascular coagulation. An un-derlying coagulation disorder was suspected, and therapy with recom-binant tissue plasminogen activator, fresh-frozen plasma, andunfractionated heparin was started. On the basis of plasma protein Cactivity and antigen levels of 0.02 and 0.03 IU/mL, respectively, afteradministration of fresh-frozen plasma, a diagnosis of severe protein Cdeficiency was established, and therapy with intravenous protein Cconcentrate (Ceprotin [Baxter, Deerfield, IL]) was started. Because ofdifficulties with venous access, we switched to subcutaneous adminis-tration after 6 weeks. The precise dosing schedule for subcutaneouslyadministered protein C concentrate is unknown. In the literature, atrough level of protein C activity at �0.25 IU/mL is recommended toprevent recurrent thrombosis. During 1 year of follow-up our patientfrequently had protein C activity levels at�0.25 IU/mL. Clinically, how-ever, there was no recurrent thrombosis, and we kept the dosageunchanged. This report highlights 2 important points: (1) subcutane-ously administered protein C concentrate is effective in treating severeprotein C deficiency; and (2) in accordance with previous studies, afterthe acute phase trough levels of protein C activity at�0.25 IU/mL maynot be necessary to prevent recurrent thrombosis. However, furtherresearch on the dosing, efficacy, and safety of protein C concentratefor prophylaxis and treatment of severe protein C deficiency is needed.Pediatrics 2011;127:e1338–e1342

AUTHORS: Ellen H. M. de Kort, MD,a Sabine L. A. G.Vrancken, MD,a Arno F. J. van Heijst, MD, PhD,a MathijsBinkhorst, MD,a Marcel P. J. M. Cuppen, MD, PhD,b andPaul P. T. Brons, MD, PhDa

aDepartment of Pediatrics, Radboud University NijmegenMedical Centre, Nijmegen, Netherlands; and bDepartment ofPediatrics, Slingeland Hospital, Doetinchem, Netherlands

KEY WORDSinherited protein C deficiency, purpura fulminans, protein Cconcentrate, replacement therapy, neonate

www.pediatrics.org/cgi/doi/10.1542/peds.2009-2913

doi:10.1542/peds.2009-2913

Accepted for publication Jan 18, 2011

Address correspondence to Paul P.T. Brons, MD, PhD,Department of Pediatrics, Radboud University Nijmegen MedicalCentre, PO Box 9101, 6500 HB Nijmegen, Netherlands. E-mail:p.brons@cukz.umcn.nl

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

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Protein C is a vitamin K–dependent an-ticoagulant glycoprotein that is pro-duced by the liver and circulates as aninactive zymogen. It is activated by thethrombin/thrombomodulin complexon the vascular endothelial surfaceand displays 2 main functions. First, itimpairs thrombin generation by inhib-iting the conversion of factor X to fac-tor Xa and prothrombin to thrombin.Second, it enhances fibrinolysis by in-hibiting plasminogen activator inhibi-tor 1 and decreasing thrombin-activatable fibrinolysis inhibitor.1–6

There are 2 types of protein C defi-ciency. With the most common type(type 1), plasma concentrations ofboth protein C antigen and activity arereduced. With type 2 protein C defi-ciency, patients have normal concen-trations of protein C antigen but de-creased levels of protein C activity.1–3,5,7

Severe protein C deficiency is a raredisorder caused by a homozygousor compound heterozygous geneticanomaly. Patients usually present inthe neonatal period with purpura ful-minans andmassive thrombosis.1,2 Theage of onset of the first symptoms canrange from a few hours to 2 weeks.1,8

If untreated, the condition is life-threatening. However, despite earlytreatment, infants with severe proteinC deficiency often have central ner-vous system involvement as a result ofthrombosis, which causes neurodevel-opmental delay.1–3 In almost every pa-tient there is retinal thrombosis thatresults in vitreous hemorrhage andretinal detachment, which lead to par-tial or complete blindness.1,2,8,9 Theseabnormalities can be present at birthand, thus, could not be prevented byearly treatment.

In this report we present the case of aterm newborn boy with severe proteinC deficiency and a review of the litera-ture concerning this disease and itstreatment. We present our experiencewith subcutaneously administered

protein C concentrate and discuss theparameters for evaluating the effec-tiveness of this therapy.

CASE REPORT

Our patient is a boy born at 38 weeks ofgestation after an uneventful preg-nancy and delivery. He is the secondchild of consanguineous parents. Pre-natal ultrasound revealed no abnor-malities. His birth weight was 3195 g.Physical examination directly afterbirth revealed no abnormalities, andhe was discharged from the hospital.

On the first day of life the boy devel-oped rapidly progressive purplish-black, painful lesions on the soles ofhis feet and on his scalp (Fig 1), forwhich he was admitted to our NICU.Laboratory studies revealed a plateletcount of 73� 109/L, fibrinogen level of1100 mg/L, D-dimer level of 20 950 ng/mL, prothrombin time of 22 seconds(normal: 11–17 seconds), and acti-vated thromboplastin time of 42 sec-onds (normal: 28–42 seconds). Thesevalues indicated the presence of dis-seminated intravascular coagulation.

An underlying coagulation disorderwas suspected, and intravenous ther-apy with fresh-frozen plasma, recom-binant tissue plasminogen activator,and unfractionated heparin wasstarted. Coagulation studies revealedprotein C activity of 0.02 IU/mL (nor-mal: 0.42 IU/mL) and protein C antigenactivity of 0.03 IU/mL (measured with acoagulant technique after administra-tion of fresh-frozen plasma). On the ba-sis of these results, the diagnosissevere protein C deficiency was estab-lished. Other coagulation-inhibitor levelswere normal according to age. On day 5,treatment with intravenous protein Cconcentrate (Ceprotin [Baxter, Deerfield,IL]) was started at an initial dose of 500IU (180 IU/kg) 3 times daily. On the basisof his plasma concentrations of proteinC, the dose was changed to 250 IU (90IU/kg) 4 times daily.

The lesions on the boy’s feet and scalphealed slowly but completely. He devel-oped a central venous catheter–related infection for which he wastreated with antibiotics and catheter

FIGURE 1Purpuric lesions on both feet and scalp at presentation.

CASE REPORTS

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replacement. Ophthalmologic exami-nation at the age of 1 week (2 daysafter starting therapy with protein Cconcentrate) revealed bilateral vitre-ous hemorrhage. It was not possible tojudge the retinas at that time. At theage of 5 weeks the ophthalmologic ex-amination was repeated and revealedbilateral retinal detachment, which re-sulted in complete blindness. At theage of 2 weeks a cerebral MRI revealedno abnormalities; repeat MRI at theage of 6 months was also normal.Apart from his blindness, the boyshowed normal neurologic develop-ment at 1 year.

Because of problems with venous ac-cess after several weeks, we adminis-tered protein C concentrate subcuta-neously: we started with 750 IU oncedaily administered by a subcutaneouscatheter (Insuflon [IntraPump, Grape-vine, TX]) for 10 hours overnight. Thesite of infusion was changed every 2 to3 days. His parents were instructed togive the protein C subcutaneously athome. Up to the time of this report,there have been no new episodes ofpurpura fulminans or thrombosis, andlaboratory investigations have re-vealed no signs of disseminated intra-vascular coagulation. Trough levels ofprotein C activity were between 0.14and 0.31 IU/mL. Figure 2 shows the pa-tient’s D-dimer levels and trough levelsof protein C activity at different timesduring treatment.

Because of the severe protein C defi-ciency in our patient, protein C activitylevels in his parents and sibling weremeasured. His parents showed a de-creased protein C activity of 36% in thefather and 50% in the mother, whichindicates that both parents haveheterozygous protein C deficiency.The sibling was unaffected (protein Cactivity: 98%). In light of these re-sults, the consanguinity of the par-ents and the nearly undetectable lev-els of protein C activity and antigen

in the patient, the most probable di-agnosis for this patient is homozy-gous protein C deficiency.

DISCUSSION

During the last few decades the treat-ment of protein C deficiency haschanged considerably. In the past, var-ious treatments including intravenousheparin, aspirin, dipyridamole, factorVIII concentrate, platelet concentrates,and sulfinpyrazone were evaluated butnot proven to be successful.1,10–13 Until2 decades ago, the only available treat-ment for the acute phase has beenfresh-frozen plasma or prothrombincomplex concentrate, both of whichhave numerous disadvantages.1,4–6,14–16

The best way to manage protein C defi-ciency would be to provide an exoge-nous source of protein C.17 Sills et al12

described the case of the first patientsuccessfully treated with purified pro-tein C from factor IX concentrate. Afterthat, several authors published casereports of homozygous protein C defi-ciency successfully treated with pro-tein C concentrate.3–7,14,15,18,19 Protein Cconcentrate has proven to be muchmore effective in the treatment of se-vere protein C deficiency, and the dis-

advantages of fresh-frozen plasmaand prothrombin complex concentrateare eliminated except for the need forvenous access.1,3,5,6

For the long-term treatment of se-vere protein C deficiency, numeroustherapeutic modalities have beenused. Oral anticoagulants whichavoid spontaneous thrombosis inthese patients are still the long-termtreatments of choice.1,3,17,20,21 How-ever, the difficulty of maintaining astable international normalized ratioin young children is a serious disad-vantage.3–5,15,16,20,22–26 Low molecularweight heparin has also been used asa long-term treatment.23 Another appli-cable but not easy long-term treat-ment option is auxiliary liver trans-plantation, after which protein C levelsare restored and the thrombotic disor-der is eliminated.17,27,28 Disadvantagesof transplantation are the need for life-long immunosuppression and the pos-sibility of forming autoantibodiesagainst the foreign protein C.27 Forour patient an auxiliary liver trans-plant was rejected because of hisyoung age and the disadvantages ofimmunosuppression.

FIGURE 2Relation between protein C activity and D-dimer levels during the treatment course. Protein C activitylevels are always measured just before the next dosage and, thus, always represent minimal residual(trough) levels.

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Several authors have reported suc-cessful treatment of severe protein Cdeficiency with long-term intravenousprotein C concentrate.3–6,18 To avoidsubstantial problems with venous ac-cess, the subcutaneous route was ex-plored.4,6,20,24 To prevent purpura fulmi-nans and recurrent thrombosis,several authors have stated that atrough level of protein C activity of atleast 0.25 IU/mL should be main-tained.4,25 Three cases of homozygousprotein C deficiency successfullytreated with subcutaneous protein Cconcentrate are described in the liter-ature.20,24,25 These studies showed thatwith a dose of 250 IU/kg, protective lev-els are present 1 hour after infusionand peak levels are present 12 hoursafter infusion; the calculated half-life is�16 hours. Protective levels (�0.25IU/mL) can be achieved for up to 48hours after infusion.20,25

In our case, we decided to switch tosubcutaneous administration of pro-tein C concentrate (Ceprotin) after sev-eral weeks because of substantialproblemswith venous access. We usedthe above-mentioned pharmacologicdata to determine the precise dosing

schedule. We preferred to administerprotein C concentrate every day to pre-vent significant fluctuations in troughlevels of protein C concentrate and tominimize the effect of forgetting 1 dos-age on trough levels. We decided tostart subcutaneous protein C infusionin a dosage of 750 IU (187.5 IU/kg) oncedaily. During long-term follow-up, thepatient’s trough levels of protein C ac-tivity were frequently �0.25 IU/mL(range: 0.14–0.31 IU/mL). Clinically,however, there was no recurrentthrombosis or relapse of purpura ful-minans, and laboratory investigationsalways revealed normal D-dimer levels(�500 ng/mL). Because signs of dis-seminated intravascular coagulationwere absent despite a protein C activ-ity level of �0.25 IU/mL, we kept thedosage of protein C concentrate un-changed. We concluded that protein Cactivity levels much lower than 0.25IU/mL are sufficient to prevent throm-bosis. Dreyfus et al18 showed that aprotein C activity level of 0.25 IU/mLwas required to prevent purpura ful-minans and recurrent thrombosis inthe acute phase. However, supportingour findings, after the acute phase, aprotein C activity level of only 0.12 to

0.16 IU/mL was required to prevent re-current thrombosis. Because of thesefindings we would recommend consid-eration of both protein C activity levelsand clinical and biochemical signs ofthrombosis in evaluating the effective-ness of therapy with subcutaneousprotein C concentrate.

CONCLUSIONS

The satisfactory follow-up of our pa-tient suggests that subcutaneouslyadministered protein C concentratemay be a good therapeutic tool forthe long-term treatment of severeprotein C deficiency. Our results indi-cate that, in accordance with the re-sults of several previous studies,protein C activity levels can be muchlower than 0.25 IU/mL after the acutephase to prevent recurrent thrombo-sis. To evaluate the effectiveness oftreatment with protein C concen-trate, not only protein C activity lev-els but also clinical and biochemicalsigns of thrombosis should be takeninto account. However, further re-search on the dosing, efficacy, andsafety of protein C concentrate forprophylaxis and treatment of severeprotein C deficiency is needed.

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PROTEXEL Study Group. Treatment of inher-ited protein C deficiency by replacementtherapy with the French purified plasma-derived protein C concentrate (PROTEXEL).Vox Sanguinis. 2007;93(3):233–240

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DOI: 10.1542/peds.2009-2913; originally published online April 11, 2011; 2011;127;e1338Pediatrics

Binkhorst, Marcel P. J. M. Cuppen and Paul P. T. BronsEllen H. M. de Kort, Sabine L. A. G. Vrancken, Arno F. J. van Heijst, Mathijs

DeficiencyLong-term Subcutaneous Protein C Replacement in Neonatal Severe Protein C

  

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DeficiencyLong-term Subcutaneous Protein C Replacement in Neonatal Severe Protein C

  

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