fibrin and Multiple-Myeloma

Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

Topics: Drug Therapy; Female; Fibrin; Fibrinolysis; Humans; Male; Multiple Myeloma; Venous Thromboembolism

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication resulting from the long-term application of bisphosphonates. In most cases, BRONJ occurs after a surgical procedure involving the jawbone. Currently, the management of BRONJ remains controversial, and there is no definitive treatment other than palliative methods. Platelet-rich fibrin (PRF) represents a relatively new biotechnology for the stimulation and acceleration of tissue healing and bone regeneration. This technical note describes the total closure of moderate bone exposure in persistent BRONJ in 2 weeks with a double-layer PRF membrane. PRF may stimulate gingival healing and act as a barrier membrane between the alveolar bone and the oral cavity. PRF may offer a fast, easy, and effective alternative method for the closure of bone exposure in BRONJ.

Topics: Aged; Bisphosphonate-Associated Osteonecrosis of the Jaw; Blood Platelets; Diphosphonates; Fibrin; Humans; Imidazoles; Male; Membranes, Artificial; Multiple Myeloma; Pamidronate; Zoledronic Acid

Multiple myeloma (MM) is associated with increased risk of venous and arterial thromboembolism. Formation of denser and poorly lysable fibrin clots is observed in patients with arterial and venous thromboembolism. We investigated fibrin clot properties and their determinants in MM patients.. Ex vivo plasma fibrin clot permeability, turbidity and susceptibility to lysis were evaluated in 106 MM patients at the time of diagnosis vs. 100 age- and sex-matched controls. MM patients had lower clot permeability (Ks ), compaction, indicating denser fibrin clots, impaired fibrin polymerization with longer lag phase and lower final turbidity (D-Dmax ), combined with hypofibrinolysis reflected by longer lysis time and slower rate of D-dimer release from fibrin clots (D-Drate ) compared with controls (all P < 0·001).. Patients with IgG MM had lower Ks compared with IgA MM [5·9 (5·1-6·4) vs. 6·3 (5·9-7·2) 10(-9)  cm(2) ; P = 0·007] and longer lysis time compared with light-chain-disease patients [11·4 (10·9-12·3) vs. 10·7 (9·8-11·9) min; P = 0·022]. Of the fibrin variables, only Ks was significantly lower in patients with International Staging System (ISS) grade III than in those with ISS grade I and II [5·9 (4·9-6·6) vs. 6·2 (5·7-6·8) 10(-9)  cm(2) ; P = 0·015]. Multivariate analysis adjusted for age and fibrinogen showed that in MM patients elevated peak thrombin levels determine Ks and D-Dmax , while thrombin-activatable fibrinolysis inhibitor (TAFI) activity predicts Ks , t50% , D-Drate and lag phase.. Our study demonstrates prothrombotic fibrin clot phenotype in patients with MM, with a significant impact of increased thrombin formation and TAFI activity.

Topics: Aged; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Multiple Myeloma; Phenotype; Thrombin

Abnormal coagulation properties indicative of a dysfibrinogen were found in the plasma of a 72-year-old male with multiple myeloma (IgGkappa, stage IIIA). The patient had high paraprotein concentration (85.75 g/l) and prolonged thrombin time (76.8 s), activated partial thromboplastin time (39.5 s), prothrombin time (23.5 s) and reptilase time (72.0 s). The fibrinogen level was increased. The fibrin polymerization induced by both thrombin and reptilase was impaired. Scanning electron microscopy revealed abnormal clot morphology. After six months of treatment, the paraprotein level decreased (19.48 g/l) and coagulation normalized as well as fibrin polymerization and fibrin clot morphology. It was found that the paraprotein interacts with the gamma-chain of fibrinogen. Acquired dysfibrinogenemia associated with multiple myeloma was diagnosed in the 72-year-old patient.

Topics: Afibrinogenemia; Aged; Blood Coagulation Tests; Fibrin; Fibrinogen; Humans; Male; Microscopy, Electron, Scanning; Multiple Myeloma; Paraproteins; Peptide Fragments; Treatment Outcome

We describe a 56-year-old patient with multiple myeloma and very high paraprotein concentration (IgG kappa). Coagulation studies showed unclottable thrombin and reptilase times caused by impaired fibrin polymerization presumably due to the paraproteinemia. There was no obvious bleeding tendency. The differential diagnosis of thrombin time prolongation includes inhibition of the added thrombin by exogenous heparin, hirudin or seldom by endogenous heparin-like anticoagulants or by acquired (bovine) thrombin antibodies, qualitative fibrinogen disorders (congenital and acquired dysfibrinogenemia), quantitative fibrinogen disorders (severe hypo- and afibrinogenemia) and delayed fibrin polymerization due to fibrin/fibrinogen degradation products, paraproteins and antibodies against fibrin(ogen). In multiple myeloma, thrombin time prolongation may seldom be due to endogenous heparin-like anticoagulants or antibodies to thrombin and more frequently to impaired fibrin polymerization by paraproteins. Simultaneous reptilase time prolongation as present in this case hints to this latter possibility.

Topics: Diagnosis, Differential; Fibrin; Hemorrhagic Disorders; Humans; Immunoglobulin kappa-Chains; Male; Middle Aged; Multiple Myeloma; Thrombin Time

Abnormal clot structures have been reported in patients with multiple myeloma, and purified immunoglobulin G (IgG) has been shown to influence fibrin assembly in purified systems. Recently fibrin structure has been demonstrated to be a major determinant of fibrinolytic rates. This study examined the effects of purified polyclonal and monoclonal myeloma IgG on fibrin structure and fibrinolysis in plasma clots. Clotting was initiated by the addition of thrombin (1.0 NIH units/ml) and calcium (10 mmol/L). Gelation was monitored as a time-dependent increase in optical density (633 nm). Fibrin fiber size (mu = mass-length ratio) was measured by scanning the gel from 800 to 400 nm. Two preparations of polyclonal IgG and plasma samples from 10 patients with myeloma were studied. Both Sandoglobulin (Sandoz Pharmaceuticals Corp.) and Gamimmune (Miles Inc., Cutter Biological) decreased final gel turbidity as the IgG concentration increased from 0 to 15 mg/ml. Because of its high maltose content, Gamimmune produced more-pronounced effects. Over a concentration range of 0 to 15 mg IgG per milliliter, mu decreased from 1.25 to 0.59 x 10(13) daltons/cm for Sandoglobulin and from 1.30 to 0.18 x 10(13) daltons/cm for Gamimmune. Polyclonal IgG at 15 mg/ml prolonged clot lysis induced by tissue-type plasminogen activator (tPA) from 800 seconds to > 12 hours. Similar effects were noted in myeloma clots. mu values in myeloma clots were significantly smaller than mu values in comparable normal clots. mu became smaller and lysis times became increasingly prolonged as the IgG level increased. High IgG concentrations induce thin fiber formation and impair fibrinolysis in plasma gels. These results demonstrate that fibrinolysis is inhibited in myeloma clots and that the degree of inhibition is correlated with IgG-mediated alterations in fibrin structure. Thin fibrin fibers may contribute to thrombotic risk in myeloma.

Topics: Blood Coagulation; Fibrin; Fibrinolysis; Humans; Immunoglobulin G; Kinetics; Multiple Myeloma; Time Factors; Tissue Plasminogen Activator

Clot retraction, measured by serum expression, is absent in some cases of multiple myeloma. Decreased clot retraction has been attributed to platelet dysfunction. A new instrument allows simultaneous measurement of platelet-mediated force development during clot retraction and of clot elastic modulus. We report 10 patients with immunoglobulin (Ig) G myeloma in whom the abnormalities of fibrin structure were quantitatively defined and platelet-fibrin interactions were assessed. Fiber mass-to-length ratios were calculated from gel turbidity. Platelet force development and clot elastic modula were measured in platelet-rich plasma gels. Fiber mass-to-length ratios for IgG myeloma patients were smaller (means +/- SE) (0.98 +/- 0.19 x 10(13) Da/cm) than for normal controls (1.36 +/- 0.06 x 10(13) Da/cm), indicating thinner fiber formation. Elastic modula of myeloma clots (51,013 +/- 14,660 dyn/cm2) were strikingly larger than modula for normal controls (23,355 +/- 1,887 dyn/cm2), indicating that such clots are mechanically less flexible. Platelet force development 1,200 s after thrombin addition was not diminished in myeloma patients (8,315 +/- 1,155 dyn) vs. controls (6,906 +/- 606 dyn). Abnormal clot retraction in myeloma appears to be primarily due to altered clot structure rather than platelet dysfunction.

Topics: Aged; Blood Coagulation; Blood Platelets; Clot Retraction; Elasticity; Electrophysiology; Fibrin; Humans; Immunoglobulin G; Male; Middle Aged; Multiple Myeloma; Reference Values; Waldenstrom Macroglobulinemia

Myelomatosis was diagnosed in a 64 year old man on the basis of a serum paraprotein band (type IgG lambda, 42 g/l), plasma cell infiltration of bone marrow, and multiple lytic lesions evident on skull x ray picture. Blood specimens taken into plain glass tubes showed bulky gelatinous clot formation with minimal clot retraction. Coagulation tests were significantly abnormal with an increase in thrombin time, prothrombin time, and reptilase time. The possibility that the paraprotein was interfering with fibrin production was investigated. The rate of fibrin monomer polymerisation (measured turbidometrically) was reduced in patient plasma compared with control plasma. Although purified fibrin monomer prepared from the patient's fibrinogen polymerised normally, the addition of purified paraprotein caused a dose dependent reduction in the rate of polymerisation. These results suggest that the paraprotein was impairing fibrin formation by inhibiting fibrin monomer polymerisation. After chemotherapy the paraprotein concentration decreased and the coagulation results returned to normal.

Topics: Blood Coagulation Tests; Fibrin; Fibrinogen; Humans; Immunoelectrophoresis; In Vitro Techniques; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Time Factors

We show that the mouse gamma 2b heavy chain or human beta-globin 3' untranslated region can greatly enhance protein expression in myeloma cells transfected by genes coding for antibody-plasminogen activator fusion proteins. Expression plasmids were constructed containing a cloned genomic heavy chain variable region from fibrin-specific monoclonal antibody 59D8, a cloned genomic constant region of the mouse gamma 2b heavy chain, and DNA sequence coding for either tissue-type plasminogen activator (tPA) or a segment of urokinase (UK) and their respective 3' untranslated sequences. Cell lines transfected with these constructs, pSVtPA (tPA) and pSVUKG(UK), produced extremely low levels of mRNA and protein (0.008-0.06 micrograms/ml) in comparison with the parental 59D8 myeloma cell line (7.6-10 micrograms/ml). In vitro nuclear run-off analysis indicated that the low steady-state levels of mRNA encoded by pSVUKG(UK) did not result from a lower rate of transcription of the transfected gene (relative to the rate of transcription of the endogenous heavy chain gene in the 59D8 parent cells). In an attempt to increase protein secretion, we assembled the expression plasmids pSVtPA(Ig), pSVUKG(Ig), and pSVUKG(beta), in which the 3' untranslated region of the mouse gamma 2b heavy chain or human beta-globin gene was substituted for the 3' untranslated region of the plasminogen activator gene. Analysis of supernatant media from cell lines transfected with these constructs showed an increase in recombinant protein secretion of 68 to 100 fold in comparison with that from cell lines transfected with pSVtPA(tPA) or pSVUKG(UK).

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Clone Cells; Fibrin; Humans; Hybridomas; Immunoblotting; Immunoglobulin Heavy Chains; Mice; Molecular Sequence Data; Multiple Myeloma; Neoplasm Proteins; Plasminogen Activators; Recombinant Fusion Proteins; RNA, Messenger; RNA, Transfer; Transcription, Genetic

A 58-year-old man with multiple myeloma and paraproteinemia (IgG kappa) acquired cryoglobulinemia 2 years after the initial diagnosis of the disease. This cryoglobulin interfered specifically with fibrin aggregation. The patient's fibrinogen was functionally normal; however, clotting times (thrombin clotting time, reptilase clotting time) were prolonged in the untreated plasma and in the supernatant after removal of the cryoglobulins. Untreated patient's serum, and even more pronounced, the cryoprecipitate inhibited the association of fibrin monomers obtained from healthy controls. The inhibitory activity on fibrin aggregation diminished upon treatment-induced reduction of plasma protein levels.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Cryoglobulinemia; Fibrin; Fibrinogen; Humans; Immunoglobulin kappa-Chains; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Plasmapheresis; Polymers; Temperature

A 64-year-old woman complained of reddish plaques that had suddenly appeared on her upper arms and trunk. Histological investigation revealed perivascular distribution of a neutrophilic infiltrate in the upper and mid-dermis; direct immunofluorescence showed deposits of C3 and fibrin in and around the vessels. Laboratory values in the blood, X-ray of the head and fine-needle biopsy of the hip showed the typical pattern of multiple myeloma. After chemotherapy the dermatological lesions improved rapidly, and the plasmocytoma reached remission stage. The diagnosis of Sweet's syndrome was established on the basis of the clinical and histological changes and the improvement observed after steroid therapy. The coincidence with plasmocytoma confirms the interpretation of Sweet disease as a paraneoplastic syndrome.

Topics: Bone Marrow; Complement C3; Female; Fibrin; Fluorescent Antibody Technique; Humans; Middle Aged; Multiple Myeloma; Muscle, Smooth, Vascular; Neutrophils; Skin; Sweet Syndrome

Topics: Aged; Blood Coagulation; Blood Proteins; Clot Retraction; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Immunoglobulins; Male; Multiple Myeloma; Myeloma Proteins

Bleeding is a common complication in patients suffering from multiple myeloma. In some cases a defect in fibrin formation has been suggested as one possible cause of haemorrhagic tendency. As shown in this investigation the defect in fibrin formation, ascertained using PAGE, is due to a lack of alpha-chain polymerization of fibrin monomers in 5/11 patients with IgG myeloma and in 2/5 patients with IgM paraproteinaemia. No disturbed fibrin polymerization could be observed in IgA myeloma (n = 6). Factor XIII concentrations of subunit A and to a lesser extent of subunit S (Laurell technique) were highly elevated in all cases with regular fibrin formation. comparable values were obtained by measuring the transamidase activity of factor XIII by incorporation of 14C-labelled purtrescin into casein. Levels up to 600% of normal could be recorded. In contrast, all patients with a lack of alpha-chain polymerization had a factor XIII activity within the normal range. Addition of factor XIII concentrate to plasma from patients with defective fibrin formation led in 5/8 cases to a partial cross-linking of alpha-monomers. we conclude that in some cases paraproteins can inhibit the factor XIII and prevent its action on fibrin.

Topics: Blood Coagulation Tests; Electrophoresis, Polyacrylamide Gel; Factor XIII; Fibrin; Hemorrhage; Humans; Immunodiffusion; Immunoglobulins; Multiple Myeloma; Paraproteinemias

Topics: Bence Jones Protein; Fibrin; Humans; Immunoglobulin G; Immunoglobulin lambda-Chains; Male; Middle Aged; Multiple Myeloma

Studies were performed to analyse the inhibitory effect of a myeloma globulin (IgG) on fibrin formation. This inhibitory activity was very intense and caused a severe bleeding disorder which proved fatal. The isolated myeloma globulin inhibited all three stages of fibrin formation: the proteolytic action of thrombin on fibrinogen, the aggregation of fibrin monomers and the stabilization of fibrin by cross-linkages in the gamma and alpha chains. Purified factor XIII, even in excess, previously activated by the addition of thrombin and calcium, did not correct this defect in cross linking. Our results suggest that this myeloma globulin induced a blockage of some receptors near the cross linking sites.

Topics: Blood Coagulation Tests; Calcium; Edetic Acid; Factor XIII; Fibrin; Fibrinogen; Humans; Immunoglobulin G; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Platelet Adhesiveness; Platelet Aggregation; Protein Binding; Prothrombin Time; Thrombin

In 15 out of 35 patients with myelomatosis histological examination showed intravascular fibrin within the glomeruli, and this was associated with proliferation of the mesangial complex in 12. The presence of intravascular fibrin and mesangial proliferation was not associated with any specific immunoglobulin abnormality or with the presence or absence of Bence Jones proteinuria. In addition to fibrin being present within glomerular capillaries it was also shown in intertubular capillaries in three cases of myelomatosis with acute tubular necrosis. It is suggested that intraglomerular coagulation and fibrin deposition may contribute to the genesis of renal failure in myelomatosis.

Topics: Acute Kidney Injury; Autopsy; Bence Jones Protein; Biopsy, Needle; Capillaries; Disseminated Intravascular Coagulation; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin A; Immunoglobulin D; Immunoglobulin G; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Microscopy; Multiple Myeloma; Proteinuria; Retrospective Studies; Thromboembolism; Urea

Topics: Agglutination; Blood Coagulation; Erythrocyte Aggregation; Fibrin; Humans; In Vitro Techniques; Microcirculation; Microscopy, Phase-Contrast; Multiple Myeloma; Photomicrography; Platelet Adhesiveness; Rheology

Topics: Adult; Aged; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Middle Aged; Multiple Myeloma; Myeloproliferative Disorders; Plasminogen; Trypsin Inhibitors

Topics: Adult; Aged; Antifibrinolytic Agents; Disseminated Intravascular Coagulation; Factor V; Factor VII; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Multiple Myeloma; Plasminogen; Thromboembolism

Topics: Acute Kidney Injury; Biopsy; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Epithelium; Fibrin; Fibrinolysis; Humans; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Multiple Myeloma; Plasminogen

Topics: Fibrin; Humans; Kidney; Kidney Failure, Chronic; Multiple Myeloma

Topics: Afibrinogenemia; Aged; Blood Coagulation Tests; Blood Platelets; Blood Protein Disorders; Factor VIII; Female; Fibrin; Hemorrhagic Disorders; Humans; Immunoglobulin G; Japan; Male; Middle Aged; Multiple Myeloma; Thromboplastin; Waldenstrom Macroglobulinemia

Topics: Adenocarcinoma; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Blood Protein Disorders; Carcinoma; Colonic Neoplasms; Fibrin; Hemostatics; Humans; Immunoelectrophoresis; Kidney Neoplasms; Male; Middle Aged; Multiple Myeloma; Papain; Plasmapheresis

Topics: Aged; Blood Coagulation Tests; Blood Platelets; Clot Retraction; Fibrin; Fibrinogen; Humans; Male; Microscopy, Electron; Middle Aged; Multiple Myeloma; Prothrombin Time; Thrombin

Topics: Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Protein Disorders; Calcium; Collagen; Connective Tissue; Fibrin; Fibrinogen; gamma-Globulins; Hemorrhagic Disorders; Humans; Male; Multiple Myeloma; Nitrogen Mustard Compounds; Plasmapheresis; Prothrombin Time; Thromboplastin; Tryptophan

Topics: Anemia; Anemia, Hypochromic; Biomedical Research; Blood Chemical Analysis; Collagen Diseases; Enzyme Inhibitors; Fibrin; Hemophilia A; Hepatitis; Hepatitis A; Jaundice; Jaundice, Obstructive; Leukemia; Liver Cirrhosis; Multiple Myeloma; Nephritis; Nephrotic Syndrome; Physiology; Purpura; Thrombin; Uremia

Topics: Coagulants; Fibrin; Fibrinogen; Fibrinolysis; Hemostatics; Humans; Multiple Myeloma; Plasma Cells

Topics: Blood Proteins; Coagulants; Fibrin; Fibrinogen; Hemostatics; Humans; Multiple Myeloma; Plasma Cells

Topics: Fibrin; Fibrinogen; Hemostatics; Humans; Multiple Myeloma; Plasma Cells

Topics: Blood Proteins; Body Fluids; Fibrin; Humans; Multiple Myeloma; Plasma Cells; Proteinuria; Urine