Abstract: 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.

Abstract: 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 & gt;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 & lt;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 & gt;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.

Abstract: Background Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). It is treated by infusion of FVIII clotting factor concentrate with dosing based primarily on bodyweight. Previous studies evaluating perioperative dosing strategies in hemophilia conclude that improvement with regard to consumption of clotting factor concentrates is possible. However, the magnitude and complexity of the problem has not yet been addressed. Moreover, guidelines to optimize treatment have been lacking. Methods In a retrospective multicenter study, we evaluated perioperative management in hemophilia A patients with clotting factor VIII (FVIII) plasma levels below 0.05 IUml-1 by quantification of perioperative infusion of clotting factor concentrate and achieved FVIII plasma levels, while exploring possible modifiers of clotting factor concentrate consumption. Results Data was collected in a total of 198 surgical procedures in 119 patients; 75 adults (140 surgical procedures; median age: 48 years; median weight: 80 kg) and 44 children (58 surgical procedures; median age: 4 years; median weight: 19 kg). In adults, mainly medium risk surgical procedures (n=86; 61%) were performed, which were most often orthopedic procedures (n=91; 65%). Children mainly underwent low risk surgical procedures (n=47; 81%), most frequently an insertion or removal of a central venous device (n=31; 53%). The median duration of hospitalization in adults and children was respectively nine (IQR 5-14) and seven (IQR 6-10) days; p=0.09. The median amount of clotting factor concentrate infused per surgical procedure was 26,100 IU (69 IUkg-1day-1). Depending on post-operative day, 67-81% of achieved FVIII plasma levels were outside of the predefined target range recommended by National Hemophilia Consensus. Moreover, 45% of FVIII plasma levels were below target range between 0-24 hours after surgery with the median deviation below the lowest required target level of 0.17 IUml-1. More than six days after surgery, 75% of the FVIII plasma levels were above target range with the median deviation above the highest target level of 0.31 IUml-1. No significant difference in frequency of under dosing or overdosing was demonstrated in adults or children. Neither was mode of administration of replacement therapy (continuous or bolus), or type of surgical procedure (low or medium risk), significantly related with under dosing or overdosing (Figure 1A-D). Moreover, under dosing was not correlated with clinical bleeding and overdosing did not lead to observed cases of vascular thrombosis. Overall, in this study population the total amount of clotting factor concentrate under dosed amounted to 422,000 IU and overdosed amounted to 3,320,300 IU, when calculated using the median deviation of achieved FVIII levels in comparison to the predefined target range and an in vivo recovery of 2.0 IUml-1 per 1 IUkg-1, a crude median half-life of FVIII concentrate of 12 hours and an overall median hospitalization period of nine days. Importantly, a reduction of clotting factor concentrate consumption of approximately 49% would have been realized if predefined plasma target levels could have been achieved. Conclusion Targeting of clotting FVIII levels in the perioperative setting is complex and forms a “moving target” for treating professionals. Optimization of dosing strategies by construction of algorithms with minimization of both under dosing and overdosing is obligatory to improve quality of care with a reduction of bleeding risk, a possible decrease of clotting factor concentrate consumption and potential cost reduction of treatment. Figure 1: Achieved FVIII plasma levels in adults (1A and 1C) and children (1B and 1D) receiving FVIII clotting factor replacement therapy. Figure 1A and 1B: Achieved FVIII plasma levels of patients treated by continuous infusion (blue dots) and by bolus infusions (red dots). Figure 1C and 1D: Achieved FVIII plasma levels of patients treated for a medium risk surgical procedure (blue dots) and patients treated for a low risk surgical procedure (red dots). Predefined target levels (green line) as stated by the Dutch Hemophilia Consensus are depicted as green boxes (Leebeek et al. 2009) Figure 1: Achieved FVIII plasma levels in adults (1A and 1C) and children (1B and 1D) receiving FVIII clotting factor replacement therapy. Figure 1A and 1B: Achieved FVIII plasma levels of patients treated by continuous infusion (blue dots) and by bolus infusions (red dots). Figure 1C and 1D: Achieved FVIII plasma levels of patients treated for a medium risk surgical procedure (blue dots) and patients treated for a low risk surgical procedure (red dots). Predefined target levels (green line) as stated by the Dutch Hemophilia Consensus are depicted as green boxes (Leebeek et al. 2009) Disclosures Lock: ZonMW: Research Funding; Baxter: Research Funding. Hazendonk:ZonMW: Research Funding; Baxter: Research Funding. Meijer:Bayer Schering Pharma: Research Funding, speakers fee, travel support, outside the submitted work Other; Sanquin: Research Funding, speakers fee, outside the submitted work, speakers fee, outside the submitted work Other; Boehringer Ingelheim: speakers fee, outside the submitted work, speakers fee, outside the submitted work Other; Baxter: Research Funding, travel support, outside the submitted work, travel support, outside the submitted work Other. Driessens:Baxter: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Bayer Schering Pharma: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; CSL Behring: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Eurocept: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Novo Nordisk: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Pfizer: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Sanquin: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other. Fijnvandraat:Baxter: European Hemophilia Treatment and Standardisation Board sponsored by Baxter Other; CSL Behring: Research Funding; Pfizer: has given lectures at educational symposiums organized by Pfizer, outside the submitted work, has given lectures at educational symposiums organized by Pfizer, outside the submitted work Other, Research Funding; Bayer Schering Pharma: has given lectures at educational symposiums organized by Bayer, outside the submitted work, has given lectures at educational symposiums organized by Bayer, outside the submitted work Other. Leebeek:CSL Behring: has served on advisory boards of CSL Behring, outside the submitted work Other, Research Funding; Baxter: has served on advisory boards of Baxter, outside the submitted work, has served on advisory boards of Baxter, outside the submitted work Other. Cnossen:Novo Nordisk: Educational funding Other, Research Funding; Bayer Schering Pharma: Educational funding and travel support, Educational funding and travel support Other, Research Funding; Baxter: Research Funding, Travel support, Travel support Other; Pfizer: Educational funding and travel support, Educational funding and travel support Other, Research Funding; ZonMW: Research Funding; Novartis: Educational funding and travel support Other, Research Funding.

Abstract: During recent years, our understanding of the pathogenesis of inherited microcytic anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis, and management of these diseases. Integration of these insights into daily clinical practice will reduce delays in establishing a proper diagnosis, invasive and/or costly diagnostic tests, and unnecessary or even detrimental treatments. To assist the clinician, we developed evidence-based multidisciplinary guidelines on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages, and therefore these guidelines are relevant for pediatricians as well as clinicians who treat adults. This article summarizes these clinical practice guidelines and includes background on pathogenesis, conclusions, and recommendations and a diagnostic flowchart to facilitate using these guidelines in the clinical setting.