Acquired Multiple Coagulation Factor Inhibitors Associated Bleeding Disorder

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4511-4511
Author(s):  
Qin-fen Chen ◽  
Pei Li ◽  
Yi Xie ◽  
Bao-An Chen

Abstract Objective: To inquire into the clinical features of acquired multiple coagulation factors inhibitors associated bleeding disorder. Methods: A case of acquired multiple coagulation factors inhibitors in clinical manifestations, diagnosis, treatment and result was described and related literatures were reviewed. Results: A 74-year-old man developed sustained wound bleeding after implantation of heart pacemaker. Prothrombin time (PT), activated partial thromboplastin time (APTT) were prolonged significantly. But thrombin time (TT), fibrinogen (Fg), platelet count(PLT) and liver function were normal. 3P test was negative. Further tests revealed that the activities of factor 2, 5, 7,8,9,10,11,12 were all less than 10%, and the inhibitors of these factors could be detected, with the titers ranging from 8~64 Bu. So acquired multiple coagulation factor inhibitors was diagnosed. Transfusion with frozen plasma and cryoprecipitate was ineffective, whereas the combination therapy with glucocorticoid plus plasma exchange seemed to be successful. The patient was cured. Conclusion: Acquired multiple coagulation factors inhibitors is a rare bleeding disorder. In fact, this is the first case, as far as we are aware. It may develop serious bleeding. Immunosuppressive agents, such as corticosteroids, used for suppression of autoantibodies formation and plasma exchange, used for eradication of inhibitors may have beneficial effects.

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Allan M. Klompas ◽  
Noud van Helmond ◽  
Justin E. Juskewitch ◽  
Rajiv K. Pruthi ◽  
Matthew A. Sexton ◽  
...  

AbstractConvalescent plasma is used to treat COVID-19. There are theoretical concerns about the impact of pro-coagulant factors in convalescent plasma on the coagulation cascade particularly among patients with severe COVID-19. The aim of this study was to evaluate the coagulation profile of COVID-19 convalescent plasma. Clotting times and coagulation factor assays were compared between fresh frozen plasma, COVID-19 convalescent plasma, and pathogen-reduced COVID-19 convalescent plasma. Measurements included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, von Willebrand factor activity, von Willebrand factor antigen, coagulation factors II, V, VII–XII, protein S activity, protein C antigen, and alpha-2 plasmin inhibitor. Clotting times and coagulation factor assays were not different between COVID-19 convalescent plasma and fresh frozen plasma, except for protein C antigen. When compared to fresh frozen plasma and regular convalescent plasma, pathogen reduction treatment increased activated partial thromboplastin time and thrombin time, while reducing fibrinogen, coagulation factor II, V, VIII, IX, X, XI, XII, protein S activity, and alpha-2 plasmin inhibitor. The coagulation profiles of human COVID-19 convalescent plasma and standard fresh frozen plasma are not different. Pathogen reduced COVID-19 convalescent plasma is associated with reduction of coagulation factors and a slight prolongation of coagulation times, as anticipated. A key limitation of the study is that the COVID-19 disease course of the convalesced donors was not characterized.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4149-4149
Author(s):  
Jean-Pierre Cazenave ◽  
Hervé Isola ◽  
Marie-Louise Wiesel ◽  
Daniel Kientz ◽  
Michel Laforêt ◽  
...  

Abstract Background. A photochemical treatment (PCT) using amotosalen HCl (S-59) and UVA light was developed to inactivate pathogens and leukocytes in therapeutic plasma (INTERCEPT™, I-FFP) frozen within 8 hr of collection. Previous studies demonstrated a broad spectrum of pathogen inactivation (Transfusion2006;46:1168) and clinical efficacy of I-FFP for support of coagulopathies (Transfusion2005;45:1362; Blood2006; 107:3753), and plasma exchange of TTP (Transfusion 2006;46). Preparation of therapeutic plasma from whole blood would complement blood center logistics and reduce the cost of therapeutic frozen plasma provided sufficient coagulation factors were retained. Aims. We measured coagulation factors in plasma isolated from whole blood held overnight at controlled temperature (21 ± 3°C), processed with pathogen inactivation, and frozen within 18 hr of blood collection. Methods. Whole blood units, approximately 460 mL, anticoagulated with CPD (Baxter, La Chatre, France) were drawn from group A, O, B and AB donors. Units were processed after 16 hr storage, and plasma was isolated by centrifugation. Two to 3 plasma units of matched blood group were pooled (n = 30: A = 14, O = 14, B = 1, AB =1) to a final volume of 635 mL. Baseline samples for assay of coagulation factors were withdrawn. Each of 30 pools was mixed with 15 mL of 6 mM amotosalen (150 uM: final concentration) and illuminated with a 3 J/cm2 UVA treatment. Following illumination (~ 8 min) and passage through a flow compound adsorption device (~20 min) to reduce levels of residual S-59, treated plasma units (650 mL) were divided into 3 equal storage units of ≥ 200 mL. Before freezing, post-treatment samples for assay of coagulation factors were withdrawn for assay of coagulation factors. Treated plasma units were flash frozen at -80°C, and transferred to −30°C for 12-month storage. Treated units were withdrawn after 1 month to measure total protein, albumin, IgG, IgM, IgA, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, VIII-vWF, Proteins C and S, AT III, plasminogen, alpha-2 antiplasmin, D-dimers, PT, and APTT. Results. Baseline coagulation factor levels (Mean ± SD) were in suitable therapeutic ranges. After PCT, all units had residual platelets < 1×109/L, WBC < 1×104/L, and RBC < 1 × 109/L. After PCT and frozen storage for 1 month, total protein (59 ± 2 g/L), albumin (38 ± 1 g/L), IgG (8.9 ± 1.1g/L), IgA (1.8 ± 0.4 g/L) and IgM (0.9 ± 0.3 g/L) were unchanged from baseline. Mean values for fibrinogen (g/L), coagulation factors (IU/dL), coagulation inhibitors (IU/dL), were variably reduced from baseline, but within ranges defined as suitable for therapeutic plasma (Table). There was no evidence of plasma activation. Conclusions. Plasma prepared from whole blood after storage on cooling plates before processing with the INTERCEPT system for pathogen inactivation retained coagulation factor activity levels after frozen storage (−30°C) in conformance with French national standards for therapeutic frozen plasma (FP). Approximately 36 units (200 mL) could be prepared per hr of illumination time with this system.


2002 ◽  
Vol 9 (2) ◽  
pp. 482-484 ◽  
Author(s):  
Kai-Chung Tse ◽  
Pok-Siu Yip ◽  
King-Men Hui ◽  
Fu-Keung Li ◽  
Kwok-Yung Yuen ◽  
...  

ABSTRACT Leptospirosis is a common zoonosis seen worldwide, but it is rare in our locality (Hong Kong). Clinical manifestations of leptospirosis are variable and may range from subclinical infection to fever, jaundice, hemorrhagic tendency, and fulminant hepato-renal failure. Severe hyperbilirubinemia and acute renal failure have been associated with high mortality. We report our experience with a patient who developed severe Weil's syndrome with marked conjugated hyperbilirubinemia and oliguric acute renal failure. These complications persisted despite treatment with penicillin and hemodiafiltration. Plasma exchange was instituted in view of the severe hyperbilirubinemia (970 μmol/liter). This was followed by prompt clinical improvement, with recovery of liver and renal function. The beneficial effects of plasma exchange could be attributed to amelioration of the toxic effects of hyperbilirubinemia on hepatocyte and renal tubular cell function. We conclude that plasma exchange should be considered as an adjunctive therapy for patients with severe icteric leptospirosis complicated by acute renal failure who have not shown rapid clinical response to conventional treatment.


2020 ◽  
Vol 17 (3) ◽  
pp. 101-108
Author(s):  
A. V. Kuligin ◽  
A. V. Lushnikov ◽  
E. E. Zeulina

Massive obstetric hemorrhage is one of the most threatening complications of pregnancy, delivery and early postpartum period, which are part of the triad of leading causes of maternal mortality both in the world and in the Russian Federation. In recent years, to stop coagulopathy, which is one of the clinical manifestations of massive obstetric hemorrhage, recombinant and plasma factors of the blood coagulation system are successfully used, which include a concentrate of prothrombin complex and activated coagulation factor VII (eptacog alfa activated). The authors present results of successful consistent use of the blood coagulation system factors within comprehensive intensive care of coagulopathy in a patient with massive obstetric hemorrhage.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 942-942
Author(s):  
Markus M. Mueller ◽  
Hans-Ulrich Pfeiffer ◽  
Margaret Rheinschmidt ◽  
Bernd Poetzsch ◽  
Johannes Oldenburg ◽  
...  

Abstract Continuous emergence of known or new pathogens as well as increasing complexity of pathogen testing challenge the provision of safe blood products. Pathogen inactivation using amotosalen + UVA effectively reduces a number of different pathogens including viruses, bacteria and parasites (Transfusion2006;46:1168). We determined the impact of pathogen inactivation on the coagulation activity of frozen plasma (FP) using amotosalen (150μM) and UVA (3 J/cm2) in the operational setting of a large blood bank. Plasma (650mL) was collected as single-donor apheresis plasma processed within 8h (arm A) and whole blood derived plasma pooled from three different, but ABO and Rh identical donors after an initial storage time of 8h (arm B) or after 22h (arm C) before photochemical treatment (PCT). Each 650mL unit of treated plasma was divided into 3 units of 200mL each prior to freezing at −40°C. Eight subsequent FP units (200mL) from individual collections were analyzed per arm, representing different blood groups. Samples for coagulation analysis were taken at baseline, after PCT and absorption of amotosalen (post-inactivation), and after six weeks of storage at −40°C (post-storage). Global coagulation tests (PT, aPTT), thrombin time, fibrinogen activity (Clauss) and fibrinogen antigen levels remained within normal ranges at all time points in all three arms. Similarly, activities of coagulation factors II, V, VII, IX, X, XI, XII, XIII, as well as von Willebrand factor (vWF) antigen, ristocetin cofactor, vWF-collagen binding capacity, antithrombin, protein C levels, protein S activity, plasmin-antiplasmin-complexes (PAP), plasminogen levels, and D-dimers did not show significant alterations. Median factor VIII activities were diminished compared to baseline (= 100%) in all three groups post-inactivation and post-storage, respectively (A: 84% and 80%; B: 74% and 65%; C: 84% and 93%). Significant differences in thrombin-antithrombin-complex (TAT) levels were seen between apheresis plasma (< 0.1 ng/ml) and plasma processed from whole blood after 8h (7.25 ng/ml) and 22h (57 ng/ml) of storage time prior to PCT. During pathogen inactivation, there was no increase in TAT levels ruling out that thrombin was formed through the inactivation process. In summary, pathogen inactivation of FP using amotosalen + UVA does not significantly influence coagulation parameters with the exception of FVIII. The decrease in FVIII activity might be explained in part by an additional freeze-thawing cycle included in the protocol due to technical reasons. Increased TAT levels, especially in arm C, were not reflected in decreased AT activity or an increase in other markers of coagulation activation, but indicate continuous, although moderate activation of the coagulation cascade during storage time. We conclude that the described inactivation procedure for whole blood derived and apheresis FP can be performed in a large blood bank setting without significant decreases in coagulation factor activities and thus without major impairment of the functional capacity of therapeutic plasma.


Author(s):  
Marion Sternbach

This chapter describes therapeutic plasma exchange, as well as cytapheresis for hyperleukocytosis and essential thrombocythemia, as well as harvesting haematological stem cells (HSC) for transplantation. Instrumentation and techniques are mostly density centrifugation, much less column adsorption for antibodies or membrane filtration for noxious molecules. Pathophysiology of apheresis is dealt with in great detail with emphasis on prevention and treatment of side effects, much more critical in the intensive care unit (ICU) setting. Main manifestations are: hypocalcaemia due to chelation by anticoagulants, hypo- and less hypervolaemia, allergic reactions to sedimenting and volume replacement starches or plasma, depletion of coagulation factors, vitamin K, immunoglobulins, lymphocytes with long lifespan and platelets. Wash-out of drugs for comorbid or underlying conditions occurs inadvertently. Main indications for plasma exchange are thrombotic thrombocytopenic purpura (TTP)/haemolytic uraemic syndrome (HUS) with plasma or cryo-poor supernatant (based on RCT), hyperviscosity syndromes, post-transfusion purpura (PTP) and auto-immune haemolytic anaemia (AIHA), where all other treatments have failed. In cold agglutinin disease, cryoglobulinaemia, coagulation factor inhibitors and ABO incompatible HSC transplants, plasmapheresis has proven useful. Myeloma with renal failure does not seem to benefit significantly from plasma exchange (randomized controlled trials proven).


Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 266-270 ◽  
Author(s):  
Francesco Dentali ◽  
Mark A. Crowther

Abstract Unexpectedly elevated INR values are commonly encountered in clinical practice. In the absence of bleeding, such values may be treated with either simple warfarin withdrawal or the administration of low doses of oral vitamin K. Oral vitamin K will more rapidly return the INR to the therapeutic reference interval; however, its impact on bleeding is unknown. If the INR is in excess of 10, most experts would recommend the administration of vitamin K and, in the case of active bleeding, additional administration of coagulation factors either in the form of fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC). Coagulation factor replacement is required given the need to urgently correct the INR; however, vitamin K should not be forgotten since it is required to antagonize the effect of warfarin, preventing “rebound” anticoagulation after transfused coagulation factors are consumed. This paper will review the evidence supporting various treatment modalities and will provide suggestions for treatment. Future advances in this area will likely focus on evaluations of the relative merits of FFP and PCCs.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 940-940
Author(s):  
Jean-Pierre Cazenave ◽  
Hervé Isola ◽  
Marie-Louise Wiesel ◽  
Daniel Kientz ◽  
Michel Laforêt ◽  
...  

Abstract Background. A photochemical treatment (PCT) using amotosalen HCl (S-59) and UVA light inactivates pathogens and leukocytes in therapeutic single donor apheresis fresh frozen plasma (INTERCEPT™, I-FFP) prepared within 8 hr of collection. Previous studies demonstrated a broad spectrum of pathogen inactivation (Transfusion2006;46:1168) and clinical efficacy of I-FFP for support of coagulopathies (Transfusion2005;45:1362; Blood2006; 107:3753), and plasma exchange of TTP (Transfusion2006;46). Preparation of therapeutic plasma up to 18 hr after collection would improve production logistics of frozen plasma provided sufficient levels of coagulation factors were retained. Aims. We measured coagulation factors in apheresis plasma stored for 18 hr at ambient temperature, processed with pathogen inactivation, and frozen. Methods. Fifteen jumbo plasma units (650 mL), were collected by apheresis with AB16 anticoagulant from group A, B, AB and O donors (MCS+. Haemonetics, Braintree, MA). Plasma collections were held at ambient blood bank temperature (20 – 24 °C) prior to further processing. After 18 hr, baseline samples for assay of coagulation factors were withdrawn before PCT. Plasma (635 mL plasma) was mixed with 15 mL of 6 mM amotosalen (150 uM: final concentration) and illuminated with a 3 J/cm2 UVA treatment. Following illumination (~ 8 min) and passage through a flow compound adsorption device (~20 min) to reduce levels of residual S-59, treated plasma units (650 mL) were divided into 3 equal storage units of ≥ 200 mL. Before freezing, post-treatment samples were withdrawn for factor assays. Treated plasma units were flash frozen at −80°C, and transferred to −30°C for 12-month storage. Plasma units were withdrawn to measure total protein, albumin, IgG, IgM, IgA, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, VIII-vWF, Proteins C and S, AT III, plasminogen, alpha-2 antiplasmin, D-dimers, PT, and APTT. Results. Baseline coagulation factor levels (Mean ± SD) were in therapeutic ranges after 18 hr storage at ambient temperature. After PCT, all units had residual platelets < 1x109/L, WBC < 1x104/L, and RBC < 1 x 109/L. After PCT, total protein (59 ± 4 g/L), albumin (38 ± 2 g/L), IgG (9.0 ± 1.7g/L), IgA (1.6 ± 0.8 g/L) and IgM (0.9 ± 0.5 g/L) were unchanged from baseline. Mean values for fibrinogen (g/L), coagulation factors (IU/dL), coagulation inhibitors (IU/dL) were variably reduced from baseline, but within the ranges defined for therapeutic plasma (Table). Treated plasma showed no evidence of activation. Conclusions. Apheresis plasma held for 18 hr before processing with the INTERCEPT system for pathogen inactivation retained coagulation factor activity levels in conformance with French national standards for therapeutic frozen plasma (FP). Approximately 36 units (200 mL) could be prepared per hr with this system. A single UVA platform is compatible with the operational requirements of a regional blood center producing 12,000 doses (200 mL) of therapeutic FP and 12,000 doses of platelets per year.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4934-4934 ◽  
Author(s):  
Alona A. Merkulova ◽  
Steven C. Mitchell ◽  
Sergei Merkulov ◽  
Alisa S. Wolberg ◽  
Neerman-Arbez Marguerite ◽  
...  

A 45 yo woman with a medical history of common variable immunodifficiency (CVID) was referred for a bleeding disorder. The bleeding was manifested daily with ecchymosis and epistaxis, but prior to the visit, she developed a lower pelvic mass that was a massive hematoma requiring transfusion. In 2011 she had a splenectomy for thrombocytopenia. After splenectomy, her liver enlarged and one year prior to being seen, she was started on everolimus as part of a protocol to reduce her liver size. Bleeding started 3-6 months after starting everolimus treatment, first manifesting with recurrent lower gastrointestinal hemorrhage. In 2011 she had normal PT and aPTT. At the present time her PT remains normal at 11.43+0.67 (Mean+SD) (normal 9.7-12.7 sec); but her aPTT is abnormal at 43+6.1 (normal 28-38 sec); clottable fibrinogen (Fb) 305+72 (normal 200-400 mg/dl); Fb antigen, 428+115 mg/dl (normal 196-441); ratio of clottable Fb/Fb antigen = 0.71+ 0.06; reptilase time 20+2.2 (normal 14-23 sec); and her thrombin time of 19+1.6 is prolonged (normal 10-16 sec). Blood coagulation factors XI, IX, VIII, VII, X, V, II, and XIII were normal. Further, she did not have excess alpha-1-antitrypin, antithrombin, or protein C to suppress thrombin generation. On a 1:1 mixing study of normal plasma:patient plasma, her thrombin time corrected to normal. Since the patient had an abnormal thrombin time with serious, spontaneous, clinical bleeding with a normal reptilase time, we postulated a fibrin polymerization defect. On a fibrin polymerization assay, the patient required 4-fold greater amounts (32 nM vs 8 nM) of human alpha thrombin to achieve complete fibrin polymerization (See Figure 1 below). On complete fibrinogen sequencing, the patient was found to have a pathologic mutation [Fb gamma chain exon 3, 124G>A, Gly42Ser (Gly16Ser in the mature gamma chain without the signal peptide)]. This defect had been previously described as Fibrinogen Krakow III (Pietrys D et al. Thromb Haemost. 2011;106:558-60). However, neither parent of the patient has a bleeding disorder. Sequencings of her parents' Fb gamma chains show no mutation. Since first being seen, the patient had a serious bleed into her right sacral plexus leaving her with a permanent foot drop. We managed her bleeding with cryoprecipitate replacement acutely and oral tranexamic acid as an outpatient. Everolimus is an mTor inhibitor which is a regulator of protein synthesis. We postulated that everolimus therapy produced the acquired abnormal Fb gamma synthesis, producing the fibrin polymerization defect associated with bleeding. Upon urging, the patient stopped everolimus therapy and has not had a major bleeding incident in 8 months although the abnormal thrombin time persists. Figure 1 Disclosures Wolberg: Novo Nordisk: Research Funding.


1970 ◽  
Vol 23 (03) ◽  
pp. 593-600
Author(s):  
P Pudlák ◽  
I Farská ◽  
V Brabec ◽  
V Pospíšilová

Summary1. The following coagulation changes were found in rats with experimental hypersplenism: a mild prolongation of the recalcification time, shortened times in Quick’s test, a lowered activity in plasma thrombin time and shortened times in the partial thromboplastin test. Concentrations of factor II, V, VII (+X), VIII and X did not differ from those of normal control rats.2. The administration of adrenaline to hypersplenic rats induced the correction of the partial thromboplastin test, Quick’s test and plasma thrombin time to normal values. Concentrations of coagulation factors were not significantly changed. An increase was found in factor V.3. Splenectomy performed in hypersplenic rats was followed by a shortened recalcification time, a prolongation of the partial thromboplastin test and of the test with partial thromboplastin and kaolin. A prolongation was also observed in Quick’s test. Complete correction of plasma thrombin time was not observed. The concentration of factor VII increased.4. The administration of adrenaline to splenectomized rats with experimental hypersplenism did not induce any significant changes with the exception of a corrected plasma thrombin time and a decreased concentration of factor VIII.5. A different reaction of factor VIII to adrenaline in normal and hypersplenic rats is pointed out.


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