deamino-arginine-vasopressin and Myeloproliferative-Disorders

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation Factors; Blood Loss, Surgical; Blood Transfusion; Blood Vessels; Clinical Trials as Topic; Contraindications; Deamino Arginine Vasopressin; Disease Management; Elective Surgical Procedures; Hemorrhage; Hemostatic Techniques; Humans; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Liver; Multicenter Studies as Topic; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Transfusion; Postoperative Hemorrhage; Thrombophilia; Tranexamic Acid; von Willebrand Diseases; von Willebrand Factor

Topics: Antigens; Autoimmune Diseases; Cardiovascular Diseases; Deamino Arginine Vasopressin; Disease Management; Hemorrhage; Humans; Immunosuppressive Agents; Incidence; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Myeloproliferative Disorders; Neoplasms; Prospective Studies; Registries; von Willebrand Diseases; von Willebrand Factor

Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management.

Topics: Age Distribution; Age of Onset; Aged; Autoimmune Diseases; Comorbidity; Deamino Arginine Vasopressin; Diagnosis, Differential; Factor VIII; Hemorrhage; Hemostatics; Humans; Lymphoproliferative Disorders; Myeloproliferative Disorders; Paraproteinemias; Prevalence; Risk Factors; Severity of Illness Index; Treatment Outcome; von Willebrand Diseases

Topics: Autoantibodies; Cardiovascular Diseases; Deamino Arginine Vasopressin; Diagnosis, Differential; Drug Combinations; Factor VIII; Humans; Lymphoproliferative Disorders; Myeloproliferative Disorders; Platelet Membrane Glycoproteins; Receptors, Cell Surface; von Willebrand Diseases; von Willebrand Factor

The multimeric and subunit patterns of plasma von Willebrand factor (vWF) were analyzed in eight patients with myeloproliferative syndrome (MS) in order to investigate the possible existence of heterogeneity in the "in vivo" proteolytic cleavage of the protein, previously observed in this entity. Six patients lacked large vWF multimers, five of them having normal bleeding times (BT) and clinically documented episodes of thrombotic origin, whereas one patient had long BT and bleeding symptoms. Seven patients showed a relative increase in the 176 kDa subunit fragment while the 189 kDa polypeptide was increased in only one. In addition, another patient (and prior to any therapy) showed the presence of a new fragment of approximately 95 kDa which disappeared after Busulfan therapy. The collection of blood from these patients with proteinase inhibitors did not correct the abnormalities. The infusion of DDAVP to two patients with abnormal vWF was accompanied by: the appearance of larger vWF multimers which disappeared rapidly from plasma; an increase in the relative proportion of the satellite bands of each multimer and a further increase of the 176 kDa fragment. These data point to some heterogeneity in the vWF abnormality present in MS which may be related in part to a variable degree of proteolysis of vWF occurring "in vivo" rather than "in vitro", and which may be associated to either a thrombotic or a bleeding diathesis. They also suggest that despite the presence of abnormal, already proteolyzed vWF, DDAVP-enhanced proteolysis occurs in MS to a similar extent to what is described in normal individuals.

Topics: Deamino Arginine Vasopressin; Hemorrhage; Humans; Myeloproliferative Disorders; Protein Conformation; Syndrome; Thrombosis; von Willebrand Factor

In order to evaluate the role of proteolysis in acquired von Willebrand's disease (vWD) associated with the myeloproliferative syndrome, we have determined the relative quantity of von Willebrand factor (vWF) fragments as compared with the intact 225 kDa subunit in four patients. The plasma vWF of each individual lacked large multimers; each had a prolonged bleeding time; and both platelet and leukocyte counts were elevated. Plasma was obtained from blood drawn into 1 mmol/L leupeptin, 6 mmol/L N-ethylmaleimide, and 5 mmol/L EDTA to prevent in vitro proteolysis. vWF was isolated from plasma by immunoadsorbent chromatography, reduced, subjected to SDS-5% polyacrylamide gel electrophoresis, and immunoblotted with a mixture of 55 anti-vWF monoclonal antibodies. In three patients with essential thrombocytosis (ET) the 176 and 140 kDa fragments were increased in proportion to the intact 225 kDa subunit indicating increased proteolysis. Treatment of one ET patient with CCNU (Lomustine) decreased the platelet count and, to a lesser extent, the white blood cell count. This was associated with a correction of the bleeding time, a partial correction of the multimeric abnormality, and a lessening of vWF cleavage. In a patient with polycythemia rubra vera (PRV) the proportion of the 176 kDa fragment was increased to the upper limit of normal but there was no definite evidence of increased proteolysis. These studies provide evidence that proteolysis plays a role in the acquired von Willebrand's disease associated with the myeloproliferative syndrome. However, other mechanisms must also be considered.

Topics: Bleeding Time; Blood Coagulation; Deamino Arginine Vasopressin; Humans; Macromolecular Substances; Molecular Weight; Myeloproliferative Disorders; Peptide Hydrolases; von Willebrand Factor

An acquired hemorrhagic disorder developed in two patients in association with postsplenectomy thrombocytosis and leukocytosis during the course of the myeloproliferative syndrome. The presence of acquired von Willebrand's disease in these individuals was demonstrated by a decrease or absence of the larger von Willebrand factor (vWF) multimers, alteration of the repeating vWF multimeric "triplet," decreased ristocetin cofactor activity (vWF:RCo), and prolonged bleeding time. The bleeding stopped in both patients after treatment with either 1-deamino-[8-D-arginine]-vasopressin (DDAVP) or Cohn fraction I. Treatment with thrombocytapheresis and azathioprine or busulfan resulted in reduction of the elevated platelet and white cell counts and was associated with partial correction of the vWF abnormalities and remission of the hemostatic abnormalities. In five additional patients with the myeloproliferative syndrome, but without bleeding symptoms, large multimers of plasma vWF were diminished also. These findings suggest that acquired von Willebrand's disease should be considered when a bleeding diathesis develops during the course of the myeloproliferative syndrome.

Topics: Adult; Bleeding Time; Blood Proteins; Deamino Arginine Vasopressin; Female; Humans; Male; Myeloproliferative Disorders; Postoperative Complications; Splenectomy; von Willebrand Diseases; von Willebrand Factor