A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liverkidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre-and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liverkidney transplantation combined with pre-and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.
The evolution of coagulation and fibrinolysis has not been thoroughly evaluated in allogeneic SCT. In this pilot study, we characterized the adaptive mechanisms of coagulation and fibrinolysis during allogeneic SCT and 3-month followup and studied possible associations with outcome, including acute GVHD. Thirty patients underwent SCT for a haematological malignancy after myeloablative conditioning. Nineteen patients received the transplant from an HLAidentical sibling and 11 from an unrelated donor. GVHD prophylaxis consisted of CYA and MTX, with methylprednisolone in sibling transplants. Serial coagulation and fibrinolytic activity markers were assessed, including prothrombin fragments 1 þ 2 (F1 þ 2), thrombin time, D-dimer, tissue-type plasminogen-activator (tPA) and plasminogenactivator inhibitor (PAI-1). Early during conditioning therapy, F1 þ 2 and D-dimer increased threefold indicating thrombin generation and fibrin turnover. TPA activity peaked before engraftment, concurring with diminished PAI-1. At 10 days after transplantation shortened thrombin time (o15 s), F1 þ 2 exceeding 0.7 nmol/L and PAI-1 3.0 IU/mL were associated with the development of GVHD. In conclusion, early maladaptation, that is, upregulated thrombin generation and inhibition of fibrinolysis, occurred in one-third of the SCT patients associating with the development of GVHD, a finding suggesting an interplay between coagulation and immunology during SCT.
The clinical manifestations of severe haemophilia, an X-linked hereditary bleeding disorder, include spontaneous and trauma-related articular and muscular bleeds. Recurring bleeds in the target joints lead to haemophilic arthropathy and the need for endoprothesis. We report a case of a sudden intra-articular pseudoaneurysm formation in a synovial artery after endoprosthesis surgery of a knee. This event occurred in a haemophilia A patient with an inhibitor to factor VIII (FVIII).A 29-year-old man with a diagnosis of severe haemophilia A underwent an elective endoprosthesis reoperation of his left knee. The patient had developed a FVIII inhibitor in his youth, but had never undergone immune tolerance induction therapy. He had been treated with recombinant FVIIa (rFVIIa, NovoSeven Ò ; Novo Nordisk Inc, Princeton, NJ, USA) on an on-demand basis. According to his history, activated prothrombin complex concentrate (aPCC, Feiba Ò ; Baxter AG, Volketswil, Switzerland) had not cured his bleeds effectively. The patient had chronic hepatitis C infection that was eradicated successfully in 2006. He experienced recurrent joint haemorrhages, particularly into the knees and ankles, but also into his elbows and hips. In 2005, he had undergone his first endoprosthesis operation of the left knee under activated rFVIIa coverage. The insertion of the endoprothesis was complicated and an extension defect of 15°remained after the operation. Furthermore, in association with his rehabilitation he experienced an intra-articular bleed and a 20°extension deficit led to a functionally unsatisfactory result.To correct the extension deficit, a revision arthroplasty was performed in May 2009. In preoperative laboratory tests no anaemia or thrombocytopenia was found and his liver enzymes and prothrombin time were normal. All other coagulation factors, with the exception of FVIII (<1%), were normal. The inhibitor titre was 3 BU mL )1 prior to the operation and it remained at that level. At 30 min prior to surgery, the patient received 7 mg (115 lg kg )1 , patientÕs weight was 60 kg) of rFVIIa and 500 mg tranexamic acid (Caprilon Ò ; Leiras, Finland) intravenously. Throughout surgery and during the following two postoperative days, he received repetitive infusions of rFVIIa 5 mg (90 lg kg )1 ) every 2 h and tranexamic acid 500 mg three times a day. The operation and early recovery period were uneventful. There were no perioperative bleeding problems and pain was manageable. On the first postoperative day his haematocrit was 30% and he received two units of red blood cells.During postoperative days 3-6, the patient developed a progressive pain in the operated knee upon mobilization. He was receiving rFVIIa 5 mg (90 lg kg )1 ) every 3 h and tranexamic acid 500 mg three times a day. At first, an intra-articular bleed was suspected and he was switched to 5000 IU aPCC 3 h after the administration of rFVIIa. The pressure and pain on leg lowering continued during the postoperative day 6 and during the following day. He could
BackgroundAllogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD.Patients and methodsThis prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6–8 time points over three months.ResultsOverall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64–0.82, p<0.001) and between PC and AT (r = 0.62–0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation.ConclusionThe coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
Allogeneic stem cell transplantation (SCT) seems to result in activation of coagulation and fibrinolysis. We characterised the outcome of SCT and graft versus host disease (GvHD) in association with the adaptive mechanisms of coagulation and fibrinolysis. 30 patients given myeloablative conditioning with cyclophosphamide and total body irradiation underwent allogeneic SCT for a hematological malignancy. 19 patients received the transplant from a sibling and 11 from an unrelated donor. GvHD prophylaxis consisted of cyclosporine and methotrexate, and in addition methylprednisolone in case of a sibling donor. Eight patients developed GvHD during the 3-month follow-up. Several coagulation and fibrinolysis activities were serially assessed: antithrombin, protein C (PC), FVIII, prothrombin fragments 1+2 (F1+2), D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1). During the conditioning therapy as an early sign of thrombin generation, F1+2 increased 3-fold and D-dimer 4-fold, compatible with enhanced fibrin turnover. The activity of tPA reached its maximum already before the engraftment and that of PAI-1 diminished accordingly. FVIII increased steadily from normal to reach maximum (up to 273% ±104%, median ±SD, p<0.001) after engraftment. Interestingly, the natural anticoagulant, PC rose (up to 189% ± 63%) in parallel with FVIII, but showed a 5-fold individual variability. After the engraftment the FVIII, PC and antihrombin levels were highly interrelated. Clinically relevant prognostic association was observed between early low PC activity and the appearance of GvHD: the level of PC lower than 90% during the conditioning therapy was associated and even predicted (p=0.007) acute GvHD (OR=16.7). After the transplantation the level of F1+2 over 2.5 nmol/l associated and predicted the non-relapse mortality (p=0.024). Three patients with the largest early thrombin generation all died during a longer follow-up (6–24 months). Also, elevated PAI-1 activity (>10 U/ml) predicted the non-relapse mortality (p=0.013). In conclusion, early activation of coagulation and fibrinolysis is followed by increased FVIII and PC activities in SCT. Early marked thrombin generation and elevated PAI-1 associated with the non-relapse mortality and low PC activity with the appearance of acute GvHD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.