RARE DISEASE
Acquired prothrombin deficiency
Acquired prothrombin deficiency
Acquired prothrombin deficiency
Synonyms: Acquired hypoprothrombinemia
Synonyms: Acquired hypoprothrombinemia
Synonyms: Acquired hypoprothrombinemia
Drug discovery
0
drugs
With orphan designations
Overview
Acquired prothrombin deficiency is a hemorrhagic disorder caused by reduced factor II activity due to underlying conditions such as severe liver disease, vitamin K deficiency (from malnutrition, malabsorption, or antibiotics), autoimmune disorders (e.g., systemic lupus erythematosus, antiphospholipid syndrome), or anticoagulant therapy. Patients present with mucocutaneous bleeding (epistaxis, menorrhagia), postoperative hemorrhage, or life-threatening intracranial/GI bleeding. Diagnosis requires prolonged PT/PTT with normal mixing studies and exclusion of inherited forms [1][4][12][16].
Categories: rare hematological diseases
Research Papers
42 drug discovery papers about Acquired prothrombin deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
42 drug discovery papers about Acquired prothrombin deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-03-01 | Twenty Years of the Four-Factor Prothrombin Complex Concentrate Octaplex/Balfaxar: A Narrative Review
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4 F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4 F-PCC beyond its approved indications.
2023-12-20 | THE STATE OF THE HEMOCOAGULATION LINK IN THE HEMOSTASIS SYSTEM OF MICE AFTER PARTIAL LIVER RESECTION UNDER ADMINISTRATION OF PLATELET AUTOMESOCONCENTRATE
The purpose of the study is to evaluate the indicators of the hemocoagulation link in the hemostasis system of mice after partial resection of the liver under the platelet automesoconcentrate administration.
Materials and methods. 2/3 of the liver was resected in wild-type mice. The animals were divided into three groups: I - control; II – mice that underwent partial hepatectomy; ІІІ – mice that were injected with automesoconcentrate of platelets in a dose of 1 ml/kg during surgery into the liver remnant.
Results and discussion. The study has shown that during the first day following the liver resection, hemocoagulation processes decrease that was indicated by a reduction in the content of platelets and fibrinogen in the blood and a simultaneous increase in the parameters of thrombin time, prothrombin time, and International Normalized Ratio. In the period from the 4th to the 7th day of the study, an increase in the levels of platelets and fibrinogen and a decrease in the indicators of thrombin time, prothrombin time, and Activated Partial Thromboplastin Timer were revealed, however, the studied indicators did not acquire the values of the control group of animals. Administration of automesoconcentrate is a dose of 1 ml/kg directly into the liver remnant during the hepatectomy procedure helps to normalize the hemocoagulation system on the seventh day after the procedure.
Administration of automesoconcentrate also prevents the development of hypocoagulation, vascular wall defects (vasculitis, reduction in the thickness of the walls of microvessels), deficiency of blood coagulation factors. The high concentration of platelets in the automesoconcentrate enables to effectively avoid the loss of platelets and fibrinogen, coagulation factor V, coagulation factor VIII and other coagulation components. Along with this, the automesoconcentrate helps to restore the functional capacity of the liver after resection of a significant part of it, since hepatectomy damages the liver function of patients.
Conclusions. Administering platelet automesoconcentrate effectively prevents the loss of platelets, fibrinogen, coagulation factor V, coagulation factor VIII, and other crucial coagulation components.
2023-12-14 | 188: TWENTY YEARS OF 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE: REVIEW AND ADVANCES OF OCTAPLEX/BALFAXAR
Introduction: Octaplex®/Balfaxar® (Octapharma AG, Switzerland) is an intravenously administered four-factor freeze-dried human prothrombin complex concentrate (4F-PCC) available since 2003 and approved in 87 countries, including the USA. 4F-PCC is used for the treatment and perioperative prophylaxis of bleeding in congenital or acquired vitamin K-dependent coagulation factor deficiency, and is being investigated for direct oral anticoagulant (DOAC)-associated bleeds and coagulation factor deficiency during cardiac surgery. We review the efficacy and safety of Octapharma's 4F-PCC and recent advances in clinical research. Methods: We reviewed all studies of Octaplex®/Balfaxar®, including literature searches of "octaplex" using PubMed, Google Scholar and Clinicaltrials.gov to capture studies reporting clinical safety and efficacy. Results: The Octapharma clinical trial program for Octaplex®/Balfaxar® included 7 studies: 5 completed (n=444) and 2 ongoing in DOAC reversal and cardiac surgery. Five published studies of urgent reversal of vitamin K antagonists (VKA) for bleeding or perioperative prophylaxis are reported. In a head-to-head Phase III randomized double-blind study (n=208), Octaplex®/Balfaxar® was non-inferior to control 4F-PCC (Kcentra®, CSL Behring) in achieving hemostatic efficacy with similar INR correction and safety profiles. Additionally, other studies of 4F-PCC in patients treated for urgent reversal of VKA, showed effective hemostasis and rapid correction of INR. Proportions of TEEs were low and not significantly different between groups. In a study of 20 patients, excellent hemostatic efficacy was achieved for 85% after a single infusion and in another study (n=56), the timely correction of INR to target levels was achieved for 91% of patients. A randomized, phase II investigator-led study (FARES) evaluated Octaplex® and FFP in patients undergoing cardiac surgery with cardiopulmonary bypass. The Octaplex® group (n=54) required significantly reduced additional hemostatic therapy compared with the FFP group (n=47) and used fewer allogeneic blood products. Conclusions: Multiple clinical studies have shown that Octaplex®/Balfaxar® is an effective hemostatic agent for various indications including VKA reversal, with a favorable safety profile. Ongoing studies are expanding the role of 4F-PCC.
2023-09-14 | Role of individual factor X concentrate pharmacokinetic studies in perioperative management of AL amyloidosis-associated acquired factor X deficiency.
AL amyloidosis is associated with acquired factor X (FX) deficiency. Experience related to its management is limited to case reports and series using prothrombin complex concentrate, fresh frozen plasma, plasma exchange, recombinant activated factor seven, and desmopressin with limited and variable efficacy. FX concentrate has not been widely used in its management. We report our experience with the perioperative use of FX concentrate (Coagadex) in two patients with AL amyloidosis-associated acquired FX deficiency requiring surgery, using their individual pharmacokinetic studies to manage perioperative hemostasis. Pharmacokinetic studies involved obtaining post-infusion FX activity at 10 min, 2, and 4 h following the administration of FX concentrate to calculate the FX half-life. Both patients' plasma FX activity was successfully increased to provide perioperative hemostatic support. Monitoring FX activity post-surgery was also utilized to maintain FX activity levels to prevent post-operative bleeding. Pharmacokinetic studies have a useful role in tailoring preoperative FX repletion in patients with AL amyloidosis associated with acquired FX deficiency.
2020-09-29 | Plasma-derived factors VIIa and X mixtures (Byclot®) significantly improve impairment of coagulant potential ex vivo in plasmas from acquired hemophilia A patients.
A combined product of plasma-derived factor (F)VIIa and FX (pd-FVIIa/FX; Byclot®) is currently available for the hemostatic treatment of hemophilia A and B patients with inhibitors in Japan. Limited information is available, however, on its coagulant effect in acquired hemophilia A (AHA). In the present study, we assessed the coagulant effect of pd-FVIIa/FX on impairment of coagulation potentials in AHA. The bypassing agents, pd-FVIIa/FX, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrates (aPCC) were spiked with normal plasma preincubated with anti-FVIII monoclonal antibody (AHA-model plasma), and added to plasmas from AHA patients. Clot waveform analysis (CWA) triggered by the mixture of tissue factor and ellagic acid was subsequently performed. In the AHA-model, pd-FVIIa/FX improved all of the CWA parameters in a dose-dependent manner, irrespective of epitope specificity, with significant improvements relative to rFVIIa and aPCC. The coagulant effect of pd-FVIIa/FX at 1.6 µg/mL (corresponding to 120 µg/kg infusion) at the maximum therapeutic dose was outside the normal range. Moreover, the addition of pd-FVIIa/FX led to a greater improvement in the coagulant potentials in AHA plasmas than those of rFVIIa and/or aPCC. These data suggest that pd-FVIIa/FX significantly improves the impaired coagulant potentials in AHA and is potentially therapeutic.
small molecules
2026-07-06 | Using Preoperative Therapeutic Plasma Exchange in Lupus Anticoagulant Hypoprothrombinemia Syndrome to Achieve Hemostatic Factor II Activity: A Case Report
Lupus anticoagulant hypoprothrombinemia syndrome (LA-HPS) is a rare cause of acquired factor II deficiency associated with lupus anticoagulant due to antiprothrombin antibody, which predisposes to bleeding rather than thrombosis. We report a case of a 48-year-old female with LA-HPS resulting in a bleeding diathesis due to acquired prothrombin or factor II (FII) deficiency in the context of very high titers of anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT). In preparation for elective mitral valve replacement surgery due to infective endocarditis, she received four sessions of therapeutic plasma exchange (TPE) preoperatively, followed by IVIG (2 g/kg total in divided doses). Her FII activity improved from 7% to 53% on the morning of her surgery, and her IgM anti-PS/PT decreased from greater than 150 units to a nadir of 26.4 units. She completed the surgery without bleeding complications. She has since been maintained on immunosuppression with mycophenolate and without bleeding. We illustrate one of the few reported successful uses of TPE to effectively remove the anti-PS/PT antibodies and optimizing hemostasis by increasing FII activity before a surgical procedure to mitigate the high bleeding risk. We also add to the limited existing evidence that immunosuppression is a reasonable long-term treatment in patients with anti-prothrombin antibodies causing severe hypoprothrombinemia with bleeding.
2024-10-29 | Clinical features and treatment of 70 children with lupus anticoagulant-hypoprothrombinemia syndrome: a retrospective study from a single center in China.
Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare acquired bleeding disorder characterized by the presence of lupus anticoagulant (LA) and acquired hypoprothrombinemia. To summarize the experience of diagnosis, clinical features, and treatment of lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). A retrospective study of 70 children diagnosed with LAHPS from January 2019 to February 2024 at a single center was conducted. A total of 70 subjects (32 boys and 38 girls), with a mean age of 5.58 years, were included in the study. Among these subjects, 15 had autoimmune diseases (AIDs), 51 had infections, and 4 had unknown causes. Fifty-six of 70 (80%) subjects experienced bleeding with the median bleeding score of 4, 1 of 70 (1.4%) presented with thrombosis, and 13 of 70 (18.6%) were asymptomatic. All patients exhibited prolonged prothrombin time, significantly prolonged activated partial thromboplastin time, decreased factor (F)II activity (FII:C), and positive lupus anticoagulant. There was a weak negative correlation between the severity of bleeding and FII:C level (rs = -0.4283; P < .001). Patients with infection-associated LAHPS were younger than those with AIDs-associated LAHPS (P < .0001). In the study, LAHPS subjects are treated with corticosteroids as the first-line therapy, or in combination with immunosuppressants. Coagulation factor replacement therapy can effectively prevent and control bleeding events. After follow-up, lupus anticoagulant of all patients had turned negative within 12 weeks. And, prothrombin time and FII:C were completely normalized of all patients without recurrence of bleeding and without thrombosis. Children develop LAHPS most commonly after AIDs and infection. Most patients presented with mild to moderate bleeding. The severity of bleeding symptoms was not exactly parallel to the decreased FII:C level.
2021-09-30 | The Glasgow Outcome Scale-Extended Pediatric Scores of Intracranial Bleeding Patients with Acquired Prothrombin Complex Deficiency Post Craniotomy and Duraplasty.
Surgical evacuation of intracranial bleeding in pediatric patients due to acquired prothrombin complex deficiency (APCD) is a life-saving surgery when conservative treatment insufficient and impending brain herniation. This study aimed to evaluate the Glasgow outcome scale-extended pediatric (GOS-ePed) score of the pediatric intracranial bleeding patients with APCD after craniotomy and duraplasty. This was a retrospective study in the last 5 years of our experience. All of the pediatric patients with intracranial bleeding due to APCD who needed surgery were investigated. The data were collected from medical records after their parents have given their written informed concern and approved by the Ethics Review Committee, Faculty of Medicine, Universitas Kristen Indonesia. The inclusion criteria were patients who operated on by craniotomy and duraplasty. The patient with a second disease was excluded. Blood tests include hemoglobin, prothrombin time, activated prothrombin time, and platelets were investigated before and after intravenous vitamin K injection, transfusion packed red cells (PRCs), and fresh frozen plasma (FFP) administration. The Glasgow coma scale (GCS) pre- and postoperatively was evaluated using a modified GCS for infants and children. The outcome was evaluated by the GOS-ePed score. All data were analyzed with the normality test and paired t test. There were 5 patients age between 37 and 60 days, and all patients did not get vitamin K prophylaxis after birth. The blood tests of all patients revealed anemia, prothrombin, and activated prothrombin time increased, but platelets were normal. All these values returned to normal after vitamin K injection, transfusion of PRCs, and FFP. The paired t tests were p < 0.05. The GCS of all patients before surgery was 8 or below. After surgery, the GCS of 4 patients was increased become 12 and 15. One patient did not change significantly. The GOS-ePed score showed 4 patients (80%) had upper or lower good recovery, and 1 patient (20%) was in a vegetative state. The GOS-ePed score of the pediatric intracranial bleeding with APCD after craniotomy and duraplasty was mostly in upper or lower good recovery.
2021-08-23 | Feasibility of therapeutic plasma exchange-based combination therapy in the treatment of acquired hemophilia A: A retrospective 6 case series.
Poor availability and a lack of affordability of bypassing agents (recombinant activated factor VII and activated prothrombin complex concentrate) in west China prompted us to investigate an alternative cost-effective combination therapy. We aimed to explore the feasibility of therapeutic plasma exchange (TPE)-based combination therapy in the treatment of acquired hemophilia A (AHA).We retrospectively investigated the clinical features of AHA in 6 patients who were treated with a combination of TPE, corticosteroids, and rituximab in our department for 9 years between January, 2011 and December, 2019.We examined 1 male and 5 female patients. The median age at diagnosis of AHA was 51 years (18-66 years). In all patients, FVIII activity levels were low (median: 1.5%; 1-3%), FVIII inhibitor titers were high (median: 24.5 BU/mL; 13.2-48.6 BU/mL), and activated partial thromboplastin time was markedly prolonged (median: 99.4 s; 60.9-110.1 s). They underwent 2 to 8 cycles of plasma exchange and were given varying combinations of dexamethasone, methylprednisolone, prednisone, and rituximab. After TPE bleeding gradually stopped, and activated partial thromboplastin time decreased. After 3 months of treatment, FVIII inhibitors completely disappeared.TPE when combined with corticosteroids and rituximab, as adjunctive immunosuppressive agents, may be an effective and reliable treatment for AHA. When there is no alternative, intensive first-line treatment including TPE may be lifesaving.
2021-03-12 | Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.
Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.
antibodies
2026-02-24 | Lupus anticoagulant hypoprothrombinemia syndrome successfully treated with rituximab – case report
Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare, acquired coagulation disorder where antiphospholipid antibodies (aPL) target prothrombin. LAHPS should be suspected in patients with aPL presenting with bleeding rather than thrombotic events or prolonged prothrombin time. Prompt assessment of factor II levels is crucial to prevent life-threatening hemorrhage. Given its rarity, there is currently no established treatment guidelines. Management of bleeding episodes involves transfusion of fresh frozen plasma or prothrombin complex concentrate (PPC), activated factor concentrates such as FEIBA or recombinant factor VIIa could be considered if initial interventions fail. Concurrent immunosuppressive therapy is essential to suppress pathogenic anti-prothrombine antibodies, with corticosteroids typically serving as first-line treatment, either alone or in combination with other immunosuppressive agents. Here, we present a case of a newly diagnosed LAHPS in a patient with active systemic lupus erythematosus who was successively treated with PCCs and immunosuppression with corticosteroids and rituximab.
2025-08-05 | PO27 | B-cell lymphoproliferative disorder and acquired coagulopathy: an insidious link
Background: Acquired coagulation factor inhibitors are autoantibodies that may develop in individuals with autoimmune or neoplastic disorders and should be assessed in patients without personal or familiar history of bleeding disorders. These inhibitors most commonly target factor VIII (FVIII) or von Willebrand factor (VWF), resulting in acquired haemophilia A or acquired von Willebrand disease, respectively and may occasionally interfere with the normal activity of other coagulation factors. Case Report: An 81-year-old female presented with recurrent episodes of anterior epistaxis and ecchymoses, without history of personal bleeding disorders. Laboratory testing revealed deficiencies in vitamin K–dependent factors (except for factor IX) in the absence of liver dysfunction or other known causes of coagulopathy, raising suspicion of an acquired haemorrhagic disorder. Past medical history included an indolent B-cell lymphoproliferative disorder, under haematological follow-up and arterial hypertension. Clinically, the patient exhibited persistent mucocutaneous bleeding associated with progressive anaemia and transient memory deficits. Due to suspected central nervous system involvement, an MRI was performed, revealing a small haemorrhagic area in the fornix of the limbic system. At the admission, coagulation studies confirmed markedly abnormal coagulation parameters: PT/INR 5.36 and aPTT 1.56. The mixing test showed suboptimal correction. The laboratory evaluation revealed: Factor IX 171%, Factor II 5%, Factor VII 17%, Factor X 7%, Protein S 51%, and Protein C 24%. Mixing studies for Factors II and VII demonstrated suboptimal correction, suggesting the presence of inhibitors. Lupus anticoagulant and antiphospholipid antibodies were negative. According to these results, we hypnotized the presence of a poly-specific serum para-protein interfering with clotting factors. Intravenous vitamin K (Konakion 10 mg) induced a not significant resolution of PT prolongation followed by a rebound increase to 4.66 and 5.27. PIVKA-II levels were 41 AU/mL (negative), supporting the lack of a functional vitamin K deficiency. Immunosuppressive steroid therapy with prednisone was started at the time of admission. Given the known lymphoproliferative disorder, the possibility of a neoplastic trigger for the coagulation abnormality was considered. Flow cytometry confirmed the presence of a B-cell clone expressing CD20, with a 2% blast count. After 15 days of steroid therapy without clinical improvement, a pharmacokinetic assessment was conducted following the administration of a 4-factor prothrombin complex concentrate (PCC). Factor levels were measured at baseline and several time points post-infusion (30 min, 1h, 2h, 4h, 12h, 24h). A marked decline in circulating coagulation factors was noted after 4 hours, with the greatest reduction observed for Factor II, suggesting preferential inhibitory activity against this factor, likely due to the presence of a neoplastic paraprotein. Therapy with rituximab (anti-CD20 monoclonal antibody) was then introduced at the standard dose of 375 mg/m² weekly for four weeks with complete normalisation of coagulation. Conclusions: This case highlights the diagnostic and therapeutic challenges posed by rare coagulation inhibitors. The successful use of rituximab underscores the relevance of B-cell–directed immunosuppression in managing such complex cases, particularly in the context of clonal B-cell disorders.
2012-09-19 | Resolution of Hypoprothrombinemia‐Lupus Anticoagulant Syndrome (HLAS) after multidrug therapy with rituximab: a case report and review of the literature
Summary Hypoprothrombinemia associated with a lupus anticoagulant ( LA ) was first reported in the literature over 50 years ago. The hypoprothrombinemia‐lupus anticoagulant syndrome ( HLAS ) is a rare bleeding diathesis that has been associated with LA s in adult and paediatric patients with systemic lupus erythematosus ( SLE ) and with transient LA s due to other causes. There are no standard recommendations for treating haemorrhage associated with this syndrome. Herein, we report a patient with SLE and HLAS who achieved a durable remission following treatment with intravenous immune globulin ( IVIG ), prednisone and rituximab.
2001-01-01 | Acquired bleeding disorder in a patient with malignant lymphoma
BACKGROUND Bleeding manifestations secondary to acquired hemostatic abnormalities in cancer patients have been well described. Bleeding due to the development of hemostatic inhibitors is observed less frequently. In this report, the authors describe a patient with a low grade lymphoma who presented with an acquired bleeding disorder and abnormal hemostatic screening tests. METHODS Patient plasma samples were collected initially and during the course of treatment. Mixing studies and specific coagulation factor assays were performed to detect and confirm any deficiencies. Patient immunoglobulin G was isolated from plasma, and binding to prothrombin was demonstrated by immunoblot method and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS Initial prolongations in the prothombin time and the activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Factor assays confirmed that the coagulation abnormality in this patient was the result of an acquired prothrombin (factor II) deficiency. This was confirmed by an immunoassay for prothrombin antigen. Further studies demonstrated the presence of a noninhibitory antibody to prothrombin that interacted with a calcium dependent epitope. CONCLUSIONS Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of all hemostatic abnormalities and manifestations. An acquired prothrombin deficiency has not been reported previously in association with a malignancy, and this patient represents the first such documented case. Cancer 2001;91:636–41. © 2001 American Cancer Society.
proteins
2025-03-01 | Twenty Years of the Four-Factor Prothrombin Complex Concentrate Octaplex/Balfaxar: A Narrative Review
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4 F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4 F-PCC beyond its approved indications.
2023-12-20 | THE STATE OF THE HEMOCOAGULATION LINK IN THE HEMOSTASIS SYSTEM OF MICE AFTER PARTIAL LIVER RESECTION UNDER ADMINISTRATION OF PLATELET AUTOMESOCONCENTRATE
The purpose of the study is to evaluate the indicators of the hemocoagulation link in the hemostasis system of mice after partial resection of the liver under the platelet automesoconcentrate administration.
Materials and methods. 2/3 of the liver was resected in wild-type mice. The animals were divided into three groups: I - control; II – mice that underwent partial hepatectomy; ІІІ – mice that were injected with automesoconcentrate of platelets in a dose of 1 ml/kg during surgery into the liver remnant.
Results and discussion. The study has shown that during the first day following the liver resection, hemocoagulation processes decrease that was indicated by a reduction in the content of platelets and fibrinogen in the blood and a simultaneous increase in the parameters of thrombin time, prothrombin time, and International Normalized Ratio. In the period from the 4th to the 7th day of the study, an increase in the levels of platelets and fibrinogen and a decrease in the indicators of thrombin time, prothrombin time, and Activated Partial Thromboplastin Timer were revealed, however, the studied indicators did not acquire the values of the control group of animals. Administration of automesoconcentrate is a dose of 1 ml/kg directly into the liver remnant during the hepatectomy procedure helps to normalize the hemocoagulation system on the seventh day after the procedure.
Administration of automesoconcentrate also prevents the development of hypocoagulation, vascular wall defects (vasculitis, reduction in the thickness of the walls of microvessels), deficiency of blood coagulation factors. The high concentration of platelets in the automesoconcentrate enables to effectively avoid the loss of platelets and fibrinogen, coagulation factor V, coagulation factor VIII and other coagulation components. Along with this, the automesoconcentrate helps to restore the functional capacity of the liver after resection of a significant part of it, since hepatectomy damages the liver function of patients.
Conclusions. Administering platelet automesoconcentrate effectively prevents the loss of platelets, fibrinogen, coagulation factor V, coagulation factor VIII, and other crucial coagulation components.
2023-12-14 | 188: TWENTY YEARS OF 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE: REVIEW AND ADVANCES OF OCTAPLEX/BALFAXAR
Introduction: Octaplex®/Balfaxar® (Octapharma AG, Switzerland) is an intravenously administered four-factor freeze-dried human prothrombin complex concentrate (4F-PCC) available since 2003 and approved in 87 countries, including the USA. 4F-PCC is used for the treatment and perioperative prophylaxis of bleeding in congenital or acquired vitamin K-dependent coagulation factor deficiency, and is being investigated for direct oral anticoagulant (DOAC)-associated bleeds and coagulation factor deficiency during cardiac surgery. We review the efficacy and safety of Octapharma's 4F-PCC and recent advances in clinical research. Methods: We reviewed all studies of Octaplex®/Balfaxar®, including literature searches of "octaplex" using PubMed, Google Scholar and Clinicaltrials.gov to capture studies reporting clinical safety and efficacy. Results: The Octapharma clinical trial program for Octaplex®/Balfaxar® included 7 studies: 5 completed (n=444) and 2 ongoing in DOAC reversal and cardiac surgery. Five published studies of urgent reversal of vitamin K antagonists (VKA) for bleeding or perioperative prophylaxis are reported. In a head-to-head Phase III randomized double-blind study (n=208), Octaplex®/Balfaxar® was non-inferior to control 4F-PCC (Kcentra®, CSL Behring) in achieving hemostatic efficacy with similar INR correction and safety profiles. Additionally, other studies of 4F-PCC in patients treated for urgent reversal of VKA, showed effective hemostasis and rapid correction of INR. Proportions of TEEs were low and not significantly different between groups. In a study of 20 patients, excellent hemostatic efficacy was achieved for 85% after a single infusion and in another study (n=56), the timely correction of INR to target levels was achieved for 91% of patients. A randomized, phase II investigator-led study (FARES) evaluated Octaplex® and FFP in patients undergoing cardiac surgery with cardiopulmonary bypass. The Octaplex® group (n=54) required significantly reduced additional hemostatic therapy compared with the FFP group (n=47) and used fewer allogeneic blood products. Conclusions: Multiple clinical studies have shown that Octaplex®/Balfaxar® is an effective hemostatic agent for various indications including VKA reversal, with a favorable safety profile. Ongoing studies are expanding the role of 4F-PCC.
2023-09-14 | Role of individual factor X concentrate pharmacokinetic studies in perioperative management of AL amyloidosis-associated acquired factor X deficiency.
AL amyloidosis is associated with acquired factor X (FX) deficiency. Experience related to its management is limited to case reports and series using prothrombin complex concentrate, fresh frozen plasma, plasma exchange, recombinant activated factor seven, and desmopressin with limited and variable efficacy. FX concentrate has not been widely used in its management. We report our experience with the perioperative use of FX concentrate (Coagadex) in two patients with AL amyloidosis-associated acquired FX deficiency requiring surgery, using their individual pharmacokinetic studies to manage perioperative hemostasis. Pharmacokinetic studies involved obtaining post-infusion FX activity at 10 min, 2, and 4 h following the administration of FX concentrate to calculate the FX half-life. Both patients' plasma FX activity was successfully increased to provide perioperative hemostatic support. Monitoring FX activity post-surgery was also utilized to maintain FX activity levels to prevent post-operative bleeding. Pharmacokinetic studies have a useful role in tailoring preoperative FX repletion in patients with AL amyloidosis associated with acquired FX deficiency.
2020-09-29 | Plasma-derived factors VIIa and X mixtures (Byclot®) significantly improve impairment of coagulant potential ex vivo in plasmas from acquired hemophilia A patients.
A combined product of plasma-derived factor (F)VIIa and FX (pd-FVIIa/FX; Byclot®) is currently available for the hemostatic treatment of hemophilia A and B patients with inhibitors in Japan. Limited information is available, however, on its coagulant effect in acquired hemophilia A (AHA). In the present study, we assessed the coagulant effect of pd-FVIIa/FX on impairment of coagulation potentials in AHA. The bypassing agents, pd-FVIIa/FX, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrates (aPCC) were spiked with normal plasma preincubated with anti-FVIII monoclonal antibody (AHA-model plasma), and added to plasmas from AHA patients. Clot waveform analysis (CWA) triggered by the mixture of tissue factor and ellagic acid was subsequently performed. In the AHA-model, pd-FVIIa/FX improved all of the CWA parameters in a dose-dependent manner, irrespective of epitope specificity, with significant improvements relative to rFVIIa and aPCC. The coagulant effect of pd-FVIIa/FX at 1.6 µg/mL (corresponding to 120 µg/kg infusion) at the maximum therapeutic dose was outside the normal range. Moreover, the addition of pd-FVIIa/FX led to a greater improvement in the coagulant potentials in AHA plasmas than those of rFVIIa and/or aPCC. These data suggest that pd-FVIIa/FX significantly improves the impaired coagulant potentials in AHA and is potentially therapeutic.
small molecules
2026-07-06 | Using Preoperative Therapeutic Plasma Exchange in Lupus Anticoagulant Hypoprothrombinemia Syndrome to Achieve Hemostatic Factor II Activity: A Case Report
Lupus anticoagulant hypoprothrombinemia syndrome (LA-HPS) is a rare cause of acquired factor II deficiency associated with lupus anticoagulant due to antiprothrombin antibody, which predisposes to bleeding rather than thrombosis. We report a case of a 48-year-old female with LA-HPS resulting in a bleeding diathesis due to acquired prothrombin or factor II (FII) deficiency in the context of very high titers of anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT). In preparation for elective mitral valve replacement surgery due to infective endocarditis, she received four sessions of therapeutic plasma exchange (TPE) preoperatively, followed by IVIG (2 g/kg total in divided doses). Her FII activity improved from 7% to 53% on the morning of her surgery, and her IgM anti-PS/PT decreased from greater than 150 units to a nadir of 26.4 units. She completed the surgery without bleeding complications. She has since been maintained on immunosuppression with mycophenolate and without bleeding. We illustrate one of the few reported successful uses of TPE to effectively remove the anti-PS/PT antibodies and optimizing hemostasis by increasing FII activity before a surgical procedure to mitigate the high bleeding risk. We also add to the limited existing evidence that immunosuppression is a reasonable long-term treatment in patients with anti-prothrombin antibodies causing severe hypoprothrombinemia with bleeding.
2024-10-29 | Clinical features and treatment of 70 children with lupus anticoagulant-hypoprothrombinemia syndrome: a retrospective study from a single center in China.
Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare acquired bleeding disorder characterized by the presence of lupus anticoagulant (LA) and acquired hypoprothrombinemia. To summarize the experience of diagnosis, clinical features, and treatment of lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). A retrospective study of 70 children diagnosed with LAHPS from January 2019 to February 2024 at a single center was conducted. A total of 70 subjects (32 boys and 38 girls), with a mean age of 5.58 years, were included in the study. Among these subjects, 15 had autoimmune diseases (AIDs), 51 had infections, and 4 had unknown causes. Fifty-six of 70 (80%) subjects experienced bleeding with the median bleeding score of 4, 1 of 70 (1.4%) presented with thrombosis, and 13 of 70 (18.6%) were asymptomatic. All patients exhibited prolonged prothrombin time, significantly prolonged activated partial thromboplastin time, decreased factor (F)II activity (FII:C), and positive lupus anticoagulant. There was a weak negative correlation between the severity of bleeding and FII:C level (rs = -0.4283; P < .001). Patients with infection-associated LAHPS were younger than those with AIDs-associated LAHPS (P < .0001). In the study, LAHPS subjects are treated with corticosteroids as the first-line therapy, or in combination with immunosuppressants. Coagulation factor replacement therapy can effectively prevent and control bleeding events. After follow-up, lupus anticoagulant of all patients had turned negative within 12 weeks. And, prothrombin time and FII:C were completely normalized of all patients without recurrence of bleeding and without thrombosis. Children develop LAHPS most commonly after AIDs and infection. Most patients presented with mild to moderate bleeding. The severity of bleeding symptoms was not exactly parallel to the decreased FII:C level.
2021-09-30 | The Glasgow Outcome Scale-Extended Pediatric Scores of Intracranial Bleeding Patients with Acquired Prothrombin Complex Deficiency Post Craniotomy and Duraplasty.
Surgical evacuation of intracranial bleeding in pediatric patients due to acquired prothrombin complex deficiency (APCD) is a life-saving surgery when conservative treatment insufficient and impending brain herniation. This study aimed to evaluate the Glasgow outcome scale-extended pediatric (GOS-ePed) score of the pediatric intracranial bleeding patients with APCD after craniotomy and duraplasty. This was a retrospective study in the last 5 years of our experience. All of the pediatric patients with intracranial bleeding due to APCD who needed surgery were investigated. The data were collected from medical records after their parents have given their written informed concern and approved by the Ethics Review Committee, Faculty of Medicine, Universitas Kristen Indonesia. The inclusion criteria were patients who operated on by craniotomy and duraplasty. The patient with a second disease was excluded. Blood tests include hemoglobin, prothrombin time, activated prothrombin time, and platelets were investigated before and after intravenous vitamin K injection, transfusion packed red cells (PRCs), and fresh frozen plasma (FFP) administration. The Glasgow coma scale (GCS) pre- and postoperatively was evaluated using a modified GCS for infants and children. The outcome was evaluated by the GOS-ePed score. All data were analyzed with the normality test and paired t test. There were 5 patients age between 37 and 60 days, and all patients did not get vitamin K prophylaxis after birth. The blood tests of all patients revealed anemia, prothrombin, and activated prothrombin time increased, but platelets were normal. All these values returned to normal after vitamin K injection, transfusion of PRCs, and FFP. The paired t tests were p < 0.05. The GCS of all patients before surgery was 8 or below. After surgery, the GCS of 4 patients was increased become 12 and 15. One patient did not change significantly. The GOS-ePed score showed 4 patients (80%) had upper or lower good recovery, and 1 patient (20%) was in a vegetative state. The GOS-ePed score of the pediatric intracranial bleeding with APCD after craniotomy and duraplasty was mostly in upper or lower good recovery.
2021-08-23 | Feasibility of therapeutic plasma exchange-based combination therapy in the treatment of acquired hemophilia A: A retrospective 6 case series.
Poor availability and a lack of affordability of bypassing agents (recombinant activated factor VII and activated prothrombin complex concentrate) in west China prompted us to investigate an alternative cost-effective combination therapy. We aimed to explore the feasibility of therapeutic plasma exchange (TPE)-based combination therapy in the treatment of acquired hemophilia A (AHA).We retrospectively investigated the clinical features of AHA in 6 patients who were treated with a combination of TPE, corticosteroids, and rituximab in our department for 9 years between January, 2011 and December, 2019.We examined 1 male and 5 female patients. The median age at diagnosis of AHA was 51 years (18-66 years). In all patients, FVIII activity levels were low (median: 1.5%; 1-3%), FVIII inhibitor titers were high (median: 24.5 BU/mL; 13.2-48.6 BU/mL), and activated partial thromboplastin time was markedly prolonged (median: 99.4 s; 60.9-110.1 s). They underwent 2 to 8 cycles of plasma exchange and were given varying combinations of dexamethasone, methylprednisolone, prednisone, and rituximab. After TPE bleeding gradually stopped, and activated partial thromboplastin time decreased. After 3 months of treatment, FVIII inhibitors completely disappeared.TPE when combined with corticosteroids and rituximab, as adjunctive immunosuppressive agents, may be an effective and reliable treatment for AHA. When there is no alternative, intensive first-line treatment including TPE may be lifesaving.
2021-03-12 | Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.
Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.
antibodies
2026-02-24 | Lupus anticoagulant hypoprothrombinemia syndrome successfully treated with rituximab – case report
Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare, acquired coagulation disorder where antiphospholipid antibodies (aPL) target prothrombin. LAHPS should be suspected in patients with aPL presenting with bleeding rather than thrombotic events or prolonged prothrombin time. Prompt assessment of factor II levels is crucial to prevent life-threatening hemorrhage. Given its rarity, there is currently no established treatment guidelines. Management of bleeding episodes involves transfusion of fresh frozen plasma or prothrombin complex concentrate (PPC), activated factor concentrates such as FEIBA or recombinant factor VIIa could be considered if initial interventions fail. Concurrent immunosuppressive therapy is essential to suppress pathogenic anti-prothrombine antibodies, with corticosteroids typically serving as first-line treatment, either alone or in combination with other immunosuppressive agents. Here, we present a case of a newly diagnosed LAHPS in a patient with active systemic lupus erythematosus who was successively treated with PCCs and immunosuppression with corticosteroids and rituximab.
2025-08-05 | PO27 | B-cell lymphoproliferative disorder and acquired coagulopathy: an insidious link
Background: Acquired coagulation factor inhibitors are autoantibodies that may develop in individuals with autoimmune or neoplastic disorders and should be assessed in patients without personal or familiar history of bleeding disorders. These inhibitors most commonly target factor VIII (FVIII) or von Willebrand factor (VWF), resulting in acquired haemophilia A or acquired von Willebrand disease, respectively and may occasionally interfere with the normal activity of other coagulation factors. Case Report: An 81-year-old female presented with recurrent episodes of anterior epistaxis and ecchymoses, without history of personal bleeding disorders. Laboratory testing revealed deficiencies in vitamin K–dependent factors (except for factor IX) in the absence of liver dysfunction or other known causes of coagulopathy, raising suspicion of an acquired haemorrhagic disorder. Past medical history included an indolent B-cell lymphoproliferative disorder, under haematological follow-up and arterial hypertension. Clinically, the patient exhibited persistent mucocutaneous bleeding associated with progressive anaemia and transient memory deficits. Due to suspected central nervous system involvement, an MRI was performed, revealing a small haemorrhagic area in the fornix of the limbic system. At the admission, coagulation studies confirmed markedly abnormal coagulation parameters: PT/INR 5.36 and aPTT 1.56. The mixing test showed suboptimal correction. The laboratory evaluation revealed: Factor IX 171%, Factor II 5%, Factor VII 17%, Factor X 7%, Protein S 51%, and Protein C 24%. Mixing studies for Factors II and VII demonstrated suboptimal correction, suggesting the presence of inhibitors. Lupus anticoagulant and antiphospholipid antibodies were negative. According to these results, we hypnotized the presence of a poly-specific serum para-protein interfering with clotting factors. Intravenous vitamin K (Konakion 10 mg) induced a not significant resolution of PT prolongation followed by a rebound increase to 4.66 and 5.27. PIVKA-II levels were 41 AU/mL (negative), supporting the lack of a functional vitamin K deficiency. Immunosuppressive steroid therapy with prednisone was started at the time of admission. Given the known lymphoproliferative disorder, the possibility of a neoplastic trigger for the coagulation abnormality was considered. Flow cytometry confirmed the presence of a B-cell clone expressing CD20, with a 2% blast count. After 15 days of steroid therapy without clinical improvement, a pharmacokinetic assessment was conducted following the administration of a 4-factor prothrombin complex concentrate (PCC). Factor levels were measured at baseline and several time points post-infusion (30 min, 1h, 2h, 4h, 12h, 24h). A marked decline in circulating coagulation factors was noted after 4 hours, with the greatest reduction observed for Factor II, suggesting preferential inhibitory activity against this factor, likely due to the presence of a neoplastic paraprotein. Therapy with rituximab (anti-CD20 monoclonal antibody) was then introduced at the standard dose of 375 mg/m² weekly for four weeks with complete normalisation of coagulation. Conclusions: This case highlights the diagnostic and therapeutic challenges posed by rare coagulation inhibitors. The successful use of rituximab underscores the relevance of B-cell–directed immunosuppression in managing such complex cases, particularly in the context of clonal B-cell disorders.
2012-09-19 | Resolution of Hypoprothrombinemia‐Lupus Anticoagulant Syndrome (HLAS) after multidrug therapy with rituximab: a case report and review of the literature
Summary Hypoprothrombinemia associated with a lupus anticoagulant ( LA ) was first reported in the literature over 50 years ago. The hypoprothrombinemia‐lupus anticoagulant syndrome ( HLAS ) is a rare bleeding diathesis that has been associated with LA s in adult and paediatric patients with systemic lupus erythematosus ( SLE ) and with transient LA s due to other causes. There are no standard recommendations for treating haemorrhage associated with this syndrome. Herein, we report a patient with SLE and HLAS who achieved a durable remission following treatment with intravenous immune globulin ( IVIG ), prednisone and rituximab.
2001-01-01 | Acquired bleeding disorder in a patient with malignant lymphoma
BACKGROUND Bleeding manifestations secondary to acquired hemostatic abnormalities in cancer patients have been well described. Bleeding due to the development of hemostatic inhibitors is observed less frequently. In this report, the authors describe a patient with a low grade lymphoma who presented with an acquired bleeding disorder and abnormal hemostatic screening tests. METHODS Patient plasma samples were collected initially and during the course of treatment. Mixing studies and specific coagulation factor assays were performed to detect and confirm any deficiencies. Patient immunoglobulin G was isolated from plasma, and binding to prothrombin was demonstrated by immunoblot method and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS Initial prolongations in the prothombin time and the activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Factor assays confirmed that the coagulation abnormality in this patient was the result of an acquired prothrombin (factor II) deficiency. This was confirmed by an immunoassay for prothrombin antigen. Further studies demonstrated the presence of a noninhibitory antibody to prothrombin that interacted with a calcium dependent epitope. CONCLUSIONS Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of all hemostatic abnormalities and manifestations. An acquired prothrombin deficiency has not been reported previously in association with a malignancy, and this patient represents the first such documented case. Cancer 2001;91:636–41. © 2001 American Cancer Society.
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