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Background and Objectives: Deficiencies of protein C (PC) or protein S (PS) are rare diseases, characterized by mutations in the PC or PS genes, which encode plasma serine proteases with anti-coagulant activity. Severe PC or PS deficiencies manifest in early life as neonatal purpura fulminans, a life-threatening heamorrhagic condition requiring immediate treatment. First-line treatment involves replacement therapy, followed by maintenance with anti-coagulants. Replacement therapy with specific protein concentrates is currently only limited to PC, and therefore, a PC + PS concentrate represents a useful addition to therapeutic options, particularly for severe PS deficiency. Further, the production of a PC + PS concentrate from unused plasma fractionation intermediates would impact favourably on manufacturing costs, and consequently therapy prices for patients and health systems., Materials and Methods: Several chromatographic runs were performed on the same unused plasma fractionation intermediates using different supports to obtain a PC/PS concentrate. The best chromatographic mediums were chosen, in terms of specific activity and recovery. A full process of purification including virus inactivation/removal and lyophilization steps was set up., Results: The final freeze-dried product had a mean PC concentration of 47.75 IU/mL with 11% of PS, and a mean specific activity of 202.5 IU/mg protein, corresponding to over 12,000-fold purification from plasma., Conclusion: The development of a novel concentrated PC/PS mixture obtained from a waste fraction of other commercial products could be used for its potential therapeutic role in the management of neonatal purpura fulminans pathology., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Objectives: Protein C (PC) deficiency is an inherited thrombophilia with a prevalence of 0.5% in the general population and 3% in subjects with a first-time deep vein thrombosis (DVT). Here we report a series of 14 PC-deficient Polish patients with comprehensive clinical and molecular characteristics, including long-term follow-up data and a deep mutational analysis of the PROC gene. Patients and Methods: Fourteen unrelated probands (mean ± SD age 43.8 ± 13.0 years) with suspicion of PC deficiency, who experienced thromboembolic events and a majority of whom received anticoagulants (92.8%), were screened for PROC mutations by sequencing the nine PROC exons and their flanking intron regions. Results: Ten probands (71.4%) had missense mutations, two patients (14.3%) carried nonsense variants, and the other two subjects (14.3%) had splice-site mutations, the latter including the c.401-1G>A variant, reported here for the very first time. The proband carrying the c.401-1A allele had a hepatic artery aneurysm with a highly positive family history of aneurysms and the absence of any mutations known to predispose to this vascular anomaly. Conclusion: A novel detrimental PROC mutation was identified in a family with aneurysms, which might suggest yet unclear links of thrombophilia to vascular anomalies, including aneurysms at atypical locations in women. The present case series also supports data indicating that novel oral anticoagulants (NOACs) are effective in PC deficient patients.

Perioperative management of severe congenital protein C deficiency remains unestablished. This deficiency is often treated with anticoagulants, such as warfarin. Although anticoagulants need to be perioperatively discontinued, there are few methods for the management of such patients. We adopted a method for administering prothrombin complex concentrates (PCC), which includes intermittent administration of inactive protein C (PPSB-HT), and examined its outcome as a perioperative management approach for severe congenital protein C deficiency. Three patients underwent our perioperative management six times. We monitored activity levels of protein C, factor IX, and so forth. These patients could be perioperatively managed with PCC treatment., (© 2021 Wiley Periodicals LLC.)

Patients with severe congenital protein (P)C deficiency require long-term anticoagulant management. Recombinant PC concentrates for prophylactic use are not available in Japan; prothrombin complex concentrates (PCC), containing factors (F)II, VII, IX, X, and PC (PPSB-HT ® ), have been used 'off-label' in a few patients. We investigated the combined use of prophylactic PCC and Warfarin (VKA; PT-INR 2.0-2.5) in a severely PC-deficient patient in whom VKA alone did not prevent recurrent purpura. Plasma VKA-dependent factor levels and global PC function (Thrombopath ® ) were assessed. Plasma activity levels of FII/FVII/FIX/FX post-infusion of PCC (6.3 unit/kg) increased 35/27/27/35 (initial level) to 59/60/38/83 IU/dl, respectively. FVII:C and FIX:C rapidly returned to baseline levels 12-24 h post-infusion, but FII:C and FX:C returned more slowly. PC antigen (< 5%) increased to ~ 15%, followed by return to baseline levels 24 h post-infusion. Global PC function was very low (%PiCi 24%), but improved post-PCC infusion. This potential was slightly detectable even at an undetectable PC level. At day 3, high levels of D-dimer and FDP were observed without thrombotic event, but these improved post-infusion. Although PCC restored VKA-dependent coagulation factors, PC contained in PCC significantly improved global anticoagulation, and was clinically beneficial in this severely deficient patient.

A male patient diagnosed with severe congenital protein C (PC) deficiency during the neonatal period was treated with long-term warfarin but frequently developed purpura fulminans and bleeding. At four years of age, edoxaban was initiated (direct oral anticoagulant [DOAC]). His d-dimer and fibrin/fibrinogen degradation product levels were closely monitored. His PC activity increased from below the sensitivity range to 17%; this increase was thought to be due to a reduction in PC consumption during edoxaban therapy. After edoxaban introduction, he experienced just one episode of purpura fulminans over two years without any adverse events. Thus, DOAC may be a promising alternative for the management of congenital PC deficiency., (© 2019 Wiley Periodicals, Inc.)

Neonatal severe protein C deficiency is a serious disease. There is no uniform approach for long-term preventive treatment of thrombotic events. We report the case of neonatal severe protein C deficiency treated with warfarin oral suspension. An international normalized ratio (INR) from 2.5 to 3.5 was expected. The INR was measured by home monitoring using the Coaguchek XS ® (Roche Diagnostics, Mannheim, Germany) monitor. During 2years of warfarin treatment, there were only two minor episodes of purpuric access and no bleeding was reported. This case suggests that the early introduction of warfarin oral suspension, home-care monitoring, and parental education programs may be a beneficial treatment option for children with protein C deficiency., (Copyright © 2017. Published by Elsevier SAS.)

Subcutaneous (SC) protein C (PC) was used in a child with purpura fulminans secondary to severe congenital PC deficiency. For maintenance, PC 80-120 IU/kg, given over 60-90 min SC Q48hr, has been successful as a home therapy for more than 3 years. The treatment was monitored by measuring trough PC chromogenic activity (target ≥15%) and D-dimer levels. No change in clinical course was appreciated after discontinuing enoxaparin (and leaving the patient on prophylactic PC replacement alone). A significant discrepancy between clotting-based and chromogenic-based PC activity is shown., (© 2016 Wiley Periodicals, Inc.)

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Pre-defined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate-treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.

It is imperative to maintain normal blood flow to provide adequate oxygen supply to specific organs and cells, as well as for the removal of metabolic byproducts. Therefore, any situation that results in blood clotting can injure or kill living tissues. In this paper, we describe a case where a protein C deficient subject who would, by all medical indicators, be at 100 % risk of experiencing thrombophlebitis, deep vein thrombosis, and or lung emboli, is able to escape all pathologies by using perioperative zymogen protein C (ZPC). This protein C deficient patient has a long history of blood clotting, particularly from surgical procedures. The patient is 81 years old and first experienced clotting due to hernia surgery in 1964, when he was hospitalized for 16 days post-surgery with life threatening complications. It was later determined in 1980, after many episodes, that the patient had hereditary protein C deficiency at the 38 % level. In his hernia surgery, perioperative ZPC was used along with accepted anticoagulation procedures with no blood clots or other related side effects occurring. This procedure can greatly benefit protein C deficient patients, and could potentially find use for non-PC deficient patients in surgeries and a variety of other medical treatments. This particular case helps to validate the importance of ZPC in effecting safer surgery in high-risk patients. It also supports the mechanism of ZPC acting as an anticoagulant without causing bleeding. Most importantly, each clinical case study represents a unique combination of surgeon, hematologist, medical staff, and patient functioning as a coordinated team. In this case, smaller amounts of very expensive ZPC achieved safe and efficacious results, which is hugely important for future clinical applications when considering the production cost of ZPC. More studies must be done to establish minimum dosing while achieving safe and efficacious outcomes.

Obscure gastrointestinal bleeding is an uncommonly encountered and difficult-to-treat clinical problem in gastroenterology, but advancements in endoscopic and radiologic imaging modalities allow for greater accuracy in diagnosing obscure gastrointestinal bleeding. Ectopic varices account for less than 5% of all variceal bleeding cases, and jejunal variceal bleeding due to extrahepatic portal hypertension is rare. We present a 47-year-old man suffering from obscure gastrointestinal bleeding. Computed tomography of the abdomen revealed multiple vascular tufts around the proximal jejunum but no evidence of cirrhosis, and a visible hypodense filling defect suggestive of thrombus was visible in the superior mesenteric vein. Enteroscopy revealed several serpiginous varices in the proximal jejunum. Serologic data disclosed protein C deficiency (33.6%). The patient was successfully treated by therapeutic balloon-assisted enteroscopy and long-term anticoagulant therapy, which is normally contraindicated in patients with gastrointestinal bleeding. Diagnostic modalities for obscure gastrointestinal bleeding, such as capsule endoscopy, computed tomography enterography, magnetic resonance enterography, and enteroscopy, were also reviewed in this article.

History and Clinical Findings: A 51-year-old female patient with history of longterm drug abuse, was admitted to our hospital with large, stocking-shaped areas of painful, non-displaceable confluent bruising reaching up to the groin., Investigations: The emergency laboratory tests showed leucopenia, thrombocytopenia and anemia as well as a distinct protein C deficiency., Diagnosis, Treatment and Course: Purpura fulminans was diagnosed and treated with an initial dose of protein C. The patient survived and the skin necrosis can be treated., Conclusion: Purpura fulminans is an internistic and dermatological emergency situation which can lead to shock through consumptive coagulopathy. The serious course of disease can be prevented by rapid treatment with protein C., (© Georg Thieme Verlag KG Stuttgart · New York.)

We describe the case of a newborn presenting with multicystic encephalomalacy, hydrocephalus and bilateral hemovitreous. An underlying coagulation disorder was suspected and laboratory tests revealed severe protein C deficiency. At 25 days of life, after the appearance of purpura fulminans, replacement therapy with intravenous protein C concentrate (Ceprotin; Baxter, Vienna, Austria) was started.Due to difficulties in getting peripheral venous access and to repeated loss of the venous access, continuous subcutaneous infusion of protein C was started with an insulin pump (VEO 754; Medtronic, Minneapolis, Minnesota, USA), normally adopted in patients with type 1 diabetes mellitus. Protein C values increased into the normal range and the resolution of the purpuric skin lesion was achieved. Chronic prophylaxis with low-molecular-weight heparin failed and, due to cutaneous and cerebral recrudescence, replacement therapy with the pump was started again. The insulin pump allowed us to reduce the number of injections per day and to deal with the difficulties in getting peripheral venous access, permitting medical and paramedical staff an easier management of the therapy. The dosing schedule could be easily adapted with the insulin pump and the continuous subcutaneous administration of small amounts of protein C concentrate prevented fluctuation in trough levels of protein C. This is the first reported case of a novel, successful use of an insulin pump in an extremely rare disease, to administer a drug different from insulin, which needs to be further analyzed, underlining the importance of a multidisciplinary team approach in order to provide effective and efficient care in high-complexity diseases.

Thrombotic events occurring in the course of celiac disease are frequently reported in the literature. The localization is often unusual, mainly affecting the hepatic veins. To our knowledge, this is the first report of intracardiac thrombosis occurring in a patient with celiac disease. A 32-year-old patient with celiac disease adhered poorly to his gluten-free diet. He suffered an ischemic stroke revealing an intracardiac thrombus, which, on radiological imaging, simulated a multiple myxoma. Histological examination of the resected tumor enabled the correct diagnosis. Biological findings revealed severe protein C and S deficiency. The patient improved with anticoagulant therapy and gluten-free diet., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Since the first description of subcutaneous protein C concentrate as treatment for severe protein C deficiency in 1996, further cases have been reported but there is no uniform approach to this form of treatment. In order to assess the safety and effectiveness of subcutaneous protein C concentrate and suggest recommendations for future use, patients who had received subcutaneous protein C concentrate were identified from the literature, by contacting the manufacturers and by personal communication. Treatment details were available from 14 cases. Apart from one case where the infusion interval was inadvertently increased, no thrombotic events occurred even when doses were subsequently reduced. Initially, a trough protein C level of >0·25 iu/ml should be aimed for. Subsequently, a smaller dose of subcutaneous protein C concentrate, especially if taken with an oral anticoagulant, may be protective maintenance treatment. The treatment was well tolerated with few side effects. Subcutaneous protein C concentrate on its own or combined with an oral anticoagulant appears to be safe and effective as maintenance treatment of severe protein C deficiency. A major advantage is the avoidance of central venous access devices. The incidence of neurodevelopmental handicap was high with blindness affecting the majority of patients., (© 2013 John Wiley & Sons Ltd.)

The patient was a 41-year-old female with chronic thromboembolism. She was admitted to an affiliated hospital with exertional dyspnea, leg swelling, and hemoptysis, and she was treated medically with tissue plasminogen activator and warfarin therapy. When transferred to our hospital, she was oxygen-dependent with severe dyspnea. A pulmonary arteriogram showed occlusion and stenosis of the pulmonary arteries. Cardiac catheterization revealed marked pulmonary hypertension. The lung perfusion scintigram showedmultiple defects in the right and left lungs. Preoperative laboratory data showed a markedly decreased protein C antigen level. Magnetic resonance angiography showed that a myoma uteri compressed the pelvic vein and that she had deep vein occlusion of the left leg. After the administration of an epoprostenol infusion and the insertion of an inferior vena cava filter, she underwent an operation. Under deep hypothermia, the bilateral pulmonary artery was opened and an endarterectomy was performed during intermittent circulatory arrest. After surgery, her pulmonary vascular resistance was in the normal range. Her New York Heart Association functional classification changed from class IV to class I. She has been in good condition for 7 years since the surgery.

A 41-year-old male with a history of human immunodeficiency virus (HIV) infection developed motor aphasia, dysarthria, and right hemiparesis. A magnetic resonance imaging scan of the brain revealed a cerebral infarction in the territory of the left middle cerebral artery. The laboratory data showed decreased levels of protein S and protein C. Transesophageal contrast-enhanced echocardiography revealed a patent foramen ovale (PFO). Prothrombotic states, such as protein S and C deficiency, have been reported in HIV-infected patients. In addition, previous studies have reported prothrombotic states to be risk factors for PFO-related cerebral infarction. An association between combined protein S and C deficiency caused by HIV infection and PFO-related cerebral infarction was suggested in our patient., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Protein C and S are vitamin K-dependent natural anticoagulants. They play a major role in hemostasis by degrading the activated factor V and factor VIII. Deficiencies of protein C and protein S are associated with increased risk of thrombotic events. The combined occurrence of protein C and S deficiency has been rarely reported. We report a 6-year-old boy with Budd-Chiari syndrome due to combined protein C and protein S deficiency. He was managed with low molecular weight heparin and discharged on long-term warfarin therapy.

Background & Aims: Cirrhosis is associated with a plasmatic procoagulant imbalance, detected in vitro by thrombin generation tests performed in the presence vs. absence of such activators of protein C as thrombomodulin or Protac. This imbalance is thought to be due to decreased protein C and increased factor VIII, but this has never been directly demonstrated. To test this hypothesis we analyzed plasma from 50 patients with cirrhosis before and after in vitro addition of purified protein C meant to restore normal levels., Methods: Results for two thrombin generation assays were expressed as ratios of endogenous thrombin potential (ETP) with-to-without thrombomodulin or as Protac-induced coagulation inhibition (PICI%). By definition, high ETP ratios or low PICI% reflect a resistance to the anticoagulant action of thrombomodulin or Protac, respectively, and can be taken as indexes of in vitro procoagulant imbalance., Results: The median (range) protein C level before addition was 40% (4-101%) and increased to 156% (110-305) after addition (p<0.001). The procoagulant imbalance, which was high before protein C addition [ETP ratio=0.83 (0.44-1.00)], was reduced after addition [ETP ratio=0.60 (0.14-0.84)], p<0.001. ETP-ratios were inversely correlated with protein C activity (rho=-0.46, p<0.001). Similar results were obtained with the Protac assay., Conclusions: The results provide evidence that low protein C contributes to the procoagulant imbalance in plasma from patients with cirrhosis. The findings may have clinical implications for the treatment or prophylaxis of thrombosis in these patients., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Genetic predisposition of thromboembolism depends on the racial background. Factor V Leiden (G1691A) and factor II mutation (G20210A) are the leading causes of inherited thrombophilias in Caucasians, but are not found in Asian ancestries. Protein S (PS), protein C (PC) and antithrombin (AT) activity are reportedly low in 65% of adult Japanese patients with deep vein thrombosis. Approximately half of the patients with each deficiency carry the heterozygous mutation of PS (PROS1; 20%), PC (PROC; 10%), and AT genes (SERPINC1: 5%). Recently, several studies have revealed an outline of inherited thrombophilias in Japanese children. Congenital thrombophilias in 48 patients less than age 20 years consisted of 45% PC deficiency, 15% PS deficiency and 10% AT deficiency, along with other causes. All PS- and AT-deficient patients had a heterozygous mutation of the respective gene. On the other hand, PC-deficient patients were considered to carry the homozygous or compound heterozygous mutation in 50%, the heterozygous mutation in 25%, and unknown causes in the remaining 25% of patients. Half of unrelated patients with homozygous or compound heterozygous PROC mutations carried PC-nagoya (1362delG), while their parents with its heterozygous mutation were asymptomatic. Most of the PC-deficient patients developed intracranial lesion and/or purpura fulminans within 2 weeks after birth. Non-inherited PC deficiency also conveyed thromboembolic events in early infancy. The molecular epidemiology of thrombosis in Asian children would provide a clue to establish the early intervention and optimal anticoagulant therapy in pediatric PC deficiency., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC(aPC) concentrate (Anact(®)C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency., (© 2013 Blackwell Publishing Ltd.)

The aim of this study is to evaluate the frequency of protein C deficiency in venous thromboembolism in black African patients of Benin. It is a descriptive study. Inclusion criteria were: acceptance- having a venous thromboembolism. No exlusion criteria was retained. Protein C deficiency was diagnosed by quantitative technic with a Minividas materiel in the blood. Protein C dosage has been done before antivitamin k therapy and a second dosage has been done if the first one demonstrated a low level of protein C. Acuired aetiology have been research. For the 54 patients of this study mean age was 52.7±14.1 and sex-ratio 1.08. The frequency of protein C deficiency was 9.3% in all patients and 12.5% in those with clinical thrombophily (p=1). No acquired deficit has been found., (Copyright © 2011. Published by Elsevier SAS.)

A 23-year-old young adult, who had no previous illness, suffered from anterior wall acute myocardial infarction, right renal infarction and occlusion of the left distal brachial artery, popliteal artery, and tibioperoneal trunk artery within six months. He had a habit of smoking but denied a history of drug abuse. Protein C deficiency was diagnosed via the examination of a hypercoagulable panel. The investigation of the hypercoagulable state is essential in young adults with an unusual presentation of artery occlusion.

We describe here the case of a boy who presented 2 days after birth with purpura fulminans on his feet and scalp. Laboratory investigations revealed signs of disseminated intravascular coagulation. An underlying coagulation disorder was suspected, and therapy with recombinant tissue plasminogen activator, fresh-frozen plasma, and unfractionated heparin was started. On the basis of plasma protein C activity and antigen levels of 0.02 and 0.03 IU/mL, respectively, after administration of fresh-frozen plasma, a diagnosis of severe protein C deficiency was established, and therapy with intravenous protein C concentrate (Ceprotin [Baxter, Deerfield, IL]) was started. Because of difficulties with venous access, we switched to subcutaneous administration after 6 weeks. The precise dosing schedule for subcutaneously administered protein C concentrate is unknown. In the literature, a trough level of protein C activity at >0.25 IU/mL is recommended to prevent recurrent thrombosis. During 1 year of follow-up our patient frequently had protein C activity levels at <0.25 IU/mL. Clinically, however, there was no recurrent thrombosis, and we kept the dosage unchanged. This report highlights 2 important points: (1) subcutaneously administered protein C concentrate is effective in treating severe protein C deficiency; and (2) in accordance with previous studies, after the acute phase trough levels of protein C activity at >0.25 IU/mL may not be necessary to prevent recurrent thrombosis. However, further research on the dosing, efficacy, and safety of protein C concentrate for prophylaxis and treatment of severe protein C deficiency is needed.

Background: Perioperative management of patients with heterozygous protein C deficiency is challenging because of the competing risks of bleeding and recurrent thrombosis., Case Description: We report the case of a 74-year-old man with protein C deficiency and heterozygous prothrombin G20210A gene mutation who had a successful left THA with perioperative administration of human zymogen protein C concentrate in addition to anticoagulation with enoxaparin., Literature Review: Several studies have reported the use of protein C concentrate in severe sepsis-associated purpura fulminans in patients with severe congenital protein C deficiency who have had thrombotic events. We reviewed studies and case reports pertinent to the treatment of patients with protein C deficiency, especially in the perioperative setting. We report the case of a patient undergoing THA in whom we used human zymogen protein C concentrate., Purposes and Clinical Relevance: THA, a particularly high-risk procedure, is associated with a 40% to 70% incidence of venographic deep venous thrombosis and a 2% to 3% incidence of symptomatic deep venous thrombosis. These risks are greater in people with thrombophilic defects such as protein C deficiency. The use of human zymogen protein C in our patient with heterozygous protein C deficiency during the perioperative period of a THA was associated with no evidence of excessive bleeding, hematoma, deep venous thrombosis, or pulmonary embolism.

Levels of protein C, low at birth, physiologically Increase until six months of age and achieve the adult range after puberty. Protein C deficiency may be congenital or acquired. Severe protein C deficiency is a rare autosomal recessive disorder that usually presents in neonatal period with purpura fulminans. Acquired protein C deficiency may be caused by increased consumption (e.g., asphyxia, overt DIC, severe infection without overt DIC, acute VTE) or by decreased synthesis of the active carboxylated protein (e.g. administration of vitamin K antagonists, severe hepatic synthetic disfunction). Two different formulations of protein C are available: recombinant human activated protein C (rhAPC) and human plasma-derived viral-inactivated protein C. It is known that in septic patients replacement therapy with rhAPC reduces mortality but is associated with an increased risk of bleeding. During the neonatal period, when a higher risk of bleeding exists, the human plasma-derived viral-inactivated protein C concentrate may represent an effective therapeutic option. In fact, its administration results effective both in severe congenital and acquired forms of protein C deficiency.

A 13-month-old Japanese female with Haemophilus influenzae type b meningitis presented with unusually severe septic shock and cerebral infarction in half a day of fever. The initial therapy of plasma-derived activated protein C (Anact C) led to an impressive effect on the aggressive condition. However, purpura fulminans and the consistent decline of plasma protein C activity (<20%) required prolonged activated protein C therapy and gene analysis. The patient carried a novel heterozygous mutation of PROC (exon 4; 335 GAC>TAC, Asp46Tyr). This is the first report of infectious purpura fulminans in a protein C-deficient heterozygote. The clinical onset and treatment course adequately corroborated the aggravated immune/hemostatic reactions and the cytoprotective effects of activated protein C replacement in human heterozygous protein C deficiency. The monitoring of plasma protein C activity and sufficient administration of activated protein C product could improve the outcome of severe sepsis in children.

Homozygous protein C deficiency is an autosomal recessive disorder often presenting with purpura fulminans. Fresh frozen plasma and oral anticoagulation have been used in the treatment of this disease. Lately, protein C concentrate has become the treatment of choice. However, protein C concentrate is not yet widely available in many countries. We report a six-month-old girl with homozygous protein C deficiency who had suffered from frequent thrombotic episodes. She was successfully treated with living donor liver transplantation. Eight years after the transplantation, she remains symptom free. As described here, the liver transplantation offers an alternative curative treatment for children with homozygous protein C deficiency.

Hereditary deficiencies of protein S, protein C and antithrombin are known risk factors for first venous thromboembolism. We assessed the absolute risk of recurrence, and the contribution of concomitant thrombophilic defects in a large cohort of families with these deficiencies. Annual incidence of recurrence was estimated in 130 deficient patients, with separate estimates for those with each of protein S, protein C, and antithrombin deficiency, and in eight non-deficient patients with prior venous thromboembolism. All patients were also tested for factor V Leiden, prothrombin G20210A, high levels of factors VIII, IX and XI, and hyperhomocysteinemia. There were 81 recurrent events among 130 deficient patients. Median follow-up was 4.6 years. Annual incidences (95% confidence interval) of recurrent venous thromboembolism were 8.4% (5.8-11.7) for protein S deficiency, 6.0% (3.9-8.7) for protein C deficiency, 10.0% (6.1-15.4) for antithrombin deficiency, and overall 7.7% (6.1-9.5). Relative risk of recurrence in patients with a spontaneous versus provoked first event was 1.5 (0.95-2.3). Cumulative recurrence rates at 1, 5 and 10 years were 15%, 38% and 53%. Relative risk of recurrence with concomitant defects was 1.4 (0.7-2.6) (1 defect) and 1.4 (0.8-2.7) (> or =2 defects). Annual incidence was 1.0% (0.03-5.5) in eight non-deficient patients. Annual incidence of major bleeding in deficient patients on oral anticoagulant treatment was 0.5% (0.2-1.0). We conclude that patients with a hereditary protein S, protein C or antithrombin deficiency appear to have a high absolute risk of recurrence. This risk is increased after a first spontaneous event, and by concomitance of other thrombophilic defects.

We report the case of a 19-year-old woman who consulted for low-back pain 3 weeks after her first delivery. This young woman had a personal history of protein C deficiency and was treated daily during her pregnancy with low-molecular-weight heparin. Her body mass index was 34 and she only gained 10 kg during her pregnancy. Since the delivery - which occurred without any complication - she had suffered from a gradually increasing right-buttock pain and limp. Magnetic resonance imaging (MRI) revealed a fracture of the right sacral ala. After analgesia and 1 month of home relative bed rest, the patient recovered her functional capacities. Regarding our patient, who had no potential clinical risk factors for osteoporosis, the causal effect of heparin is thus possible but not certain. This case report illustrates the fact that clinicians should have a high suspicion of pelvic fracture in post-partum women, even in very young ones, presenting sudden onset of low back and pelvic pain, especially when they have received heparin during pregnancy. MRI seems to be the key exam because it is able to detect and stage fractures or microfractures.

Severe protein C deficiency (i.e. protein C activity <1 IU dL(-1)) is a rare autosomal recessive disorder that usually presents in the neonatal period with purpura fulminans (PF) and severe disseminated intravascular coagulation (DIC), often with concomitant venous thromboembolism (VTE). Recurrent thrombotic episodes (PF, DIC, or VTE) are common. Homozygotes and compound heterozygotes often possess a similar phenotype of severe protein C deficiency. Mild (i.e. simple heterozygous) protein C deficiency, by contrast, is often asymptomatic but may involve recurrent VTE episodes, most often triggered by clinical risk factors. The coagulopathy in protein C deficiency is caused by impaired inactivation of factors Va and VIIIa by activated protein C after the propagation phase of coagulation activation. Mutational analysis of symptomatic patients shows a wide range of genetic mutations. Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation; protein C replacement is also used for prevention of these complications around surgery. Long-term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency are born with evidence of in utero thrombosis and experience multiple further events, intensive treatment and monitoring can enable these individuals to thrive. Further research is needed to better delineate optimal preventive and therapeutic strategies.

A 6-month-old girl with a diagnosis of double-outlet right ventricle and pulmonary stenosis had a left modified Blalock-Taussig shunt. Chest computed tomography (CT) performed on postoperative day 11 showed good patency of the shunt. However, on postoperative day 16, oxygen saturation suddenly dropped below 40%, and chest CT showed thrombotic occlusion of the shunt. Urgent thrombectomy was performed successfully. Examination of coagulation factors revealed low levels of both the amount and activity of protein C (27% and 31%, respectively). Diagnosis of heterozygous hereditary protein C deficiency was made, and the patient was placed on warfarin. She is currently in good condition.

Priapism is a rare disorder defined as a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation. There are two types of priapism; ischemic low-flow type or non-ischemic high flow, with differing etiologies. Priapism associated with thrombophilia is a well-recognized entity. However, the pathogenesis of this association is not fully understood. We report a rare case of recurrent (stuttering) priapism in a patient with protein C deficiency while maintained on Warfarin therapy. This therapy was also complicated by Warfarin-induced skin necrosis.

The protein C pathway has an important function in regulating and modulating blood coagulation and ensuring patency of the microcirculation. Protein C deficiency leads to macro- or microvascular thrombosis. Hereditary severe protein C deficiency is a life-threatening state with neonatal purpura fulminans. Patients with heterozygous protein C deficiency have an increased risk for thromboembolic events or coumarin-induced skin necrosis. Secondary protein C deficiency occurs during disseminated intravascular coagulation (DIC), sepsis (especially meningococcal sepsis with purpura fulminans), liver failure and vitamin K deficiency. Replacement with protein C concentrates is an established treatment for congenital protein C deficiency. The high-purity, plasma-derived protein C concentrate Ceprotin (Baxter AG, Vienna, Austria) is approved for this indication, but its use in acquired deficiency states is not approved. Several case series demonstrated beneficial effects in infectious purpura fulminans and DIC, but no controlled studies for these indications exist. Protein C concentrate may therefore be given off-label in such cases. Protein C concentrate has an excellent safety profile: no drug interactions, overdose or bloodborne infections, bleeding or prothrombotic complications have been observed. As with all protein preparations, a potential risk of hypersensitivity reactions exists.

Painful pink or magenta colored skin lesions characterized by a clear line of demarcation between the affected area and surrounding tissue appearing under therapy with coumarins may be a sign for evolving coumarin-necrosis. Immediate treatment with a protein C preparation in patients with protein C deficiency can prevent necrosis.

The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency.

Protein C (PC) is a vitamin K-dependent proenzyme with anticoagulant activity, and patients with congenital PC deficiency are at high risk for thrombotic episodes. In patients with PC deficiency, starting treatment with oral anticoagulant drugs is associated with a transient hypercoagulable state and clinically overt thromboembolic complications before reaching a full anticoagulant effect. This report describes a successful supplementation with PC concentrate in two adult patients with moderately severe PC deficiency during the initiation of oral anticoagulation and a course of therapeutic dose of low-molecular-weight heparin for acute venous thromboembolism. Plasma PC levels above 50% were observed in both patients and maintained during the entire supplementation treatment period with PC concentrate until a stable therapeutic anticoagulation level has been reached. These results have been obtained within a short time, thus allowing a safe administration of a loading dose of warfarin. No adverse reactions to the PC concentrate, i.e. skin necrosis and other thromboembolic complications, bleedings or allergic reactions, were observed. We conclude that PC concentrate seems to be effective for the prevention of thromboembolic complications and safe in patients with congenital PC deficiency while initiating oral anticoagulants., (Copyright 2009 S. Karger AG, Basel.)

Thromboembolic events in preterm infants constitute a serious problem in neonatal intensive care. In most cases, treatment with low-molecular-weight heparin offers a sufficient therapy of thrombotic events. We report the case of a severely sick male preterm infant with a heterozygous factor V Leiden mutation and protein C deficiency. The infant developed multiple thromboses despite adequate anticoagulation with enoxaparin and was in a life-threatening situation. Treatment with hirudin prevented the occurrence of new thromboses without causing bleeding complications. After 2 weeks hirudin was discontinued and low-molecular-weight heparin therapy was started again. A successive recanalization of the vast majority of affected vessels was observed within the following 6 months. Despite some minor neurologic sequelae and a slight delay in neuro-motor development, the 2.5-year-old boy is in a healthy condition. This case demonstrates that hirudin can be an effective alternative anticoagulant in neonates and infants refractory to heparin treatment. Efficacy and safety issues of hirudin treatment, however, need to be evaluated in randomized trials.

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous tromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analysed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% confidence interval 0.001-0.7; P = 0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin, protein C or protein S.

A right-to-left shunt in the presence of normal pulmonary artery pressure is an unusual cause of hypoxemia in an adult who has a patent foramen ovale. We report a rare case of such a shunt-the result of a right atrial thrombus that formed in a hypercoagulable patient after placement of an indwelling central venous catheter for chemotherapy. In order to ascertain the nature of the right atrial mass and to decrease the risk of systemic embolization, the thrombus was surgically removed with the patient on cardiopulmonary bypass.