Deep‐vein thrombosis and coumarin skin necrosis associated with a factor V inhibitor with lupus‐like features

Kamphuisen, Pieter Willem; Haan, Joost; Rosekrans, Peter C.M.; Meer, F. J. M. Van Der

doi:10.1002/(sici)1096-8652(199802)57:2<176::aid-ajh14>3.3.co;2-w

Cited by 16 publications

(21 citation statements)

References 10 publications

(11 reference statements)

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“…12 Only 3 cases of patients with antibodies to factor V have been associated with thrombotic events. However, 2 of the 3 cases had an autoimmune syndrome where lupuslike anticoagulant activity was demonstrated in association with anticardiolipin antibodies, 13,14 whereas the antifactor V antibody in the third case was associated with Sjögren syndrome. 15 It is interesting to note that in all 3 cases prolongation of the basal clotting time was present, suggesting an interference with the procoagulant function of factor V. It has been demonstrated in one case (Sjögren syndrome 15 ) that although the antibody in vitro did not inhibit activated protein C activity toward factor Va, it was able to inhibit the procoagulant function of factor V. It is well established that the binding to a membrane surface is necessary for both normal procoagulant expression of factor Va cofactor activity as well as efficient down-regulation of its activity by APC.…”

Section: Discussionmentioning

confidence: 99%

“…Only 3 antifactor V antibodies have been demonstrated to cause thrombotic manifestations. However, these antibodies were not well characterized and, whereas 2 of them were associated with lupuslike symptoms, 13,14 the third antifactor V antibody was associated with Sjögren syndrome. 15 In the present manuscript, we present data from an individual with an antifactor V antibody that interferes with the anticoagulant pathway of blood coagulation.…”

Section: Introductionmentioning

confidence: 99%

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Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Kalafatis

Simioni²,

Tormene³

et al. 2002

Blood

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A 44-year-old woman with a history of severe thrombotic manifestations presented with a markedly reduced activated protein C-sensitivity ratio (APC-SR). DNA sequencing of and around the regions encoding the APC cleavage sites in the factor Va molecule excluded the presence of the factor VLeiden mutation and of other known genetic mutations. No antiphospholipid antibodies were present in the patient's plasma and both prothrombin time and activated partial thromboplastin time were normal. The total immunoglobulin fraction was isolated from the patient's plasma and found to induce severe APC resistance when added to normal plasma and to factor V-deficient plasma supplemented with increasing concentrations of factor V. Immunoblotting and immunoprecipitation experiments with the total immunoglobulin fraction purified from the patient's plasma demonstrated that the antibody recognizes factor V, is polyclonal, and has conformational epitopes on the entire factor V molecule (heavy and light chains, and B region). Thus, the immunoglobulin fraction interferes with the anticoagulant pathway involving factor V. The inhibitor was isolated by sequential affinity chromatography on protein G-Sepharose and factor V-Sepharose. The isolated immunoglobulin fraction inhibited factor Va inactivation by APC because of impaired cleavage at Arg306 and Arg506 of the heavy chain of the cofactor. The isolated immunoglobulin fraction was also found to inhibit the cofactor effect of factor V for the inactivation of factor VIII by the APC/ protein S complex. Our data provide for the first time the demonstration of an antifactor V antibody not related to the presence of antiphospholipid antibodies, which is responsible for thrombotic rather than hemorrhagic symptoms. IntroductionCoagulation factor V circulates in plasma as a large single-chain protein with a M r 330 000. 1,2 ␣-Thrombin cleaves single-chain factor V to give rise to the active cofactor (factor Va) and to 2 heavily glycosylated activation fragments. The factor Va resulting from ␣-thrombin cleavage of human factor V is composed of a heavy chain of M r 105 000 containing the NH 2 -terminal part of the factor V molecule (A1-A2 domains) and a light chain of M r 74 000 that is derived from the COOH-terminal end of the cofactor (A3-C1-C2 domains). Once formed, ␣-thrombin binds to the endothelial cell receptor thrombomodulin and initiates the protein C pathway leading to the formation of APC. Proteolytic cleavage of factor Va by APC is required for complete inactivation of the cofactor and arrest of its contribution to the procoagulant process. 3 Factor Va is inactivated by activated protein C (APC) following 3 cleavages of the heavy chain: Arg506, Arg306, and Arg679. Cleavage at Arg306 efficiently occurs on the membrane-bound cofactor and is responsible for complete inactivation of factor Va. 3 Thus, irregularities in the mechanism of inactivation of factor Va by APC are associated with thrombotic episodes because of sustained prothrombin activation.Individuals with a 1691GϾA substitu...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Kalafatis

Simioni²,

Tormene³

et al. 2002

Blood

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“…However, the overlapping APC resistance results between controls and patients makes it difficult to apply this concept to individual patient care [41]. Patients have been reported to develop autoantibodies against factor V after exposure to bovine thrombin leading to APC resistance, with subsequent thrombosis of unclear etiology [42][43][44]. One study has also observed APC resistance (as measured by endogenous thrombin potential without dilution into factor V-deficient plasma) in unselected patients with untreated hematological malignancies, which may contribute to the increased risk of venous thrombosis observed in these patients [45].…”

Section: Apc Resistance Without Factor V Leidenmentioning

confidence: 99%

Factor VLeiden

2015

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Factor V Leiden (FV Leiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance. This review describes many of the most fascinating features of FV Leiden , including background features, mechanisms of hypercoagulability, the founder mutation concept, the "FV Leiden paradox," synergistic interaction with other thrombotic risk factors, the intertwined relationship between FV Leiden and APC resistance testing, and other, uncommon mutations implicated in causing APC resistance. In addition, there are several conditions where laboratory tests for APC resistance and FV Leiden are or can be discrepant, including lupus anticoagulants, anticoagulants such as direct thrombin inhibitors (dabigatran, argatroban, and bivalirudin) and rivaroxaban, as well as pseudohomozygous, pseudo-wildtype, liver transplant, and bone marrow transplant patients. The laboratory test error rate for FV Leiden is also presented.

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“…[2,3] For 3 patients, the AFVI appeared after the prescription of anti-vitamin K. A few case reports also described the onset of AFVI after treatment with anti-vitamin K, raising the question of its immutability. [5,6] Anti-vitamin K should thus be used with caution in the context of AFVI.…”

Section: Discussionmentioning

confidence: 99%

“…The remaining six patients were treated with heparin (LMWH or unfractionated heparin) during the initial phase followed by anti-vitamin K or oral anticoagulants. [6,[13][14][15] The treatment with heparin helped towards a favorable evolution of thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Transient FV inhibitor of unknown origin in difficult clinical situation

Pointeau

Marot

Suhl

et al. 2017

CRIM

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Acquired Factor V inhibitors are a rare condition, associated frequently with at times severe bleeding. Patients can show no symptoms and in exceptional cases thrombosis can be reported. In this article we report two cases of acquired FV inhibitors associated with thrombosis. We systematically reviewed the literature on FV inhibitors and thrombosis. A patient had acquired FV inhibitors and thrombosis. He had no bleeding and was treated with anticoagulant. Despite initial improvement, he died from legionaire's disease. The second patient had septicemia, acquired FV inhibitors and deep vein thrombosis. The patient's condition improved with anticoagulation and antibiotic therapy. Ten case reports were considered in the systematic review. The median age at admission was 67. Seven patients had bleeding episodes. The median peak inhibitor titer was 2.7 BU (0.62-8) while the median FV activity was 2% (1-75). Except for 2 patients, all recovered. FV has two activities: a procoagulant action activating prothrombin, as well as an anticoagulant action activating protein C. This property could be associated with thrombosis activity. Inhibitor could also have a through effect on activated protein C. In our study, because of underlying diseases, it was not possible to clearly demonstrate that inhibitors give thrombosis. Immunosuppressive therapies were administered in cases of severe bleeding. Heparin seemed efficient for thrombosis without major bleeding. The prognosis of acquired FV inhibitors appeared to be related to the underlying disease.

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Deep‐vein thrombosis and coumarin skin necrosis associated with a factor V inhibitor with lupus‐like features

Cited by 16 publications

References 10 publications

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations

Factor VLeiden

Transient FV inhibitor of unknown origin in difficult clinical situation

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