Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: Relationship with platelet count

We present a 4-year follow-up of a 42-year-old patient with primary thrombocythemia whose clinical course was complicated by two major mucocutaneous bleeding episodes. On both occasions an acquired functional von Willebrand factor deficiency was demonstrated. In contrast to what is reported in the literature, an inverse relationship between platelet number and plasma high-molecular-weight multimers of von Willebrand factor was established

Cutaneous pathology in primary erythermalgia

Primary or idiopathic erythermalgia is characterized by recurrent, red, warm, and painful lower extremities. It arises at young age and persists throughout life because no treatment is available. We report the cutaneous pathology of affected skin lesions of three patients with primary erythermalgia. Biopsy specimens showed a mild perivascular mononuclear infiltrate, thickened blood vessel basement membranes, abundant perivascular edema, and moderate endothelial swelling. The thickened basal membrane of the blood vessels showed a laminar structure, and abundant perivascular edema and moderate endothelial cell swelling were evident. These histopathologic findings in primary erythermalgia appear to be nonspecific but allow diagnostic differentiation from erythromelalgia in which fibromuscular intimal proliferation and occlusive thrombi in the endarteriolar capillaries are apparent and from erythermalgia secondary to vasculitis. Histopathologic examination of affected skin lesions in patients with red, congested, warm, and painful burning extremities is a valuable tool in the diagnostic process

Erytromelalgia and Thrombocythamia

In 1878 beschrijft Mitchel onder de titel "On a rare vasomotor neurosis of the extremities and on the maladies with which it may be confounded" een aandoening van de voeten en handen, welke hij zeer bescheiden in een voetnoot aanduidde met erytromelalgie. De term is afgeleid van de Griekse woorden erythros (rood), roelos (extremiteit) en algos (pijn). Deze pijnlijke roodheid treft bij voorkeur de bal van de voet en de grote tenen. De pijn is van een brandend karakter, door Mitchel beschreven als "the pain of a burn, of mustard, of intense sun-burn", neemt altijd af of verdwijnt door rust met hoogleggen en door koude, maar neemt toe bij staan en lopen, in ernstige gevallen reeds bij afhangen van de aangedane extremiteit. Warmte geeft ook eenzelfde verergering van de klachten die altijd gepaard gaan met een "dull dusky mottled redness" met opvallende drukpijnlijkheid. Mitchel beschrijft verder dat het op den duur kan overgaan in een "dark purplish tint". In ernstige gevallen treedt blaarvorming op, is de extremiteit in rust koud en zelfs bleek. De aandoening kan jaren bestaan zonder progressie. Aanvankelijk treden de klachten alleen op na inspanning aan het einde van de dag. Uiteindelijk kan continue pijn ontstaan,die het lopen volledig belet. De aandoening wordt door Mitchel beschouwd als nauwelijks of niet behandelbaar en verschilt van jicht, reuma en syphilis

Physiopathology, etiologic factors, diagnosis, and course of polycythemia vera as related to therapy according to William Dameshek, 1940-1950

According to Dameshek, true polycythemia (polycythemia vera: PV) is a chronic myeloproliferative disorder of the total bone marrow without any evidence of invasiveness, in which erythrocytosis, leukocytosis, and thrombocytosis are all simultaneously present. A possible hereditary or transmitted tendency may be present, but actual familial polycythemia is rare. As to the etiology, Dameshek proposed 2 highly speculative possibilities in 1950: the presence of excessive bone marrow stimulation by an unknown factor or factors, and a lack or a diminution in the normal inhibitory factor or factors. Dameshek's hypothesis was confirmed in 2005 by Vainchenker in France by the discovery of the acquired JAK2V617F mutation as the cause of 3 phenotypes of classical myeloproliferative neoplasms: essential thrombocythemia, PV, and myelofibrosis. The JAK2V617F mutation induces a loss of inhibitory activity of the JH2 pseudokinase part on the JH1 kinase part of Janus kinase 2 (JAK2). This leads to enhanced activity of the normal JH1 kinase activity of JAK2, which makes the mutated hematopoietic stem cells hypersensitive to the hematopoietic growth factors thrombopoietin, erythropoietin, insulin-like growth factor-1, stem cell factor, and granulocyte colony-stimulating factor, resulting in trilinear myeloproliferation. In retrospect, the situation observed by Dameshek where all stops to blood production in the bone marrow are pulled in PV is caused by the JAK2V617F mutation. Dameshek considered PV patients as fundamentally normal and therefore the treatment should be as physiologic as possible. For this reason, a systematic phlebotomy/iron deficiency method of treatment was recommended; the use of radioactive phosphorus is reserved for refractory cases and cases of major thrombosis. If the patient lives long enough and does not succumb to the effects of thrombosis or other complications, the marrow will gradually show signs of diminished activity. The blood smear shows nucleated red cells, increased polychromatophilia, and immature granulocytes of various types. With increasing reduction of erythropoietic tissue, myelofibrosis becomes more of an organized mass of fibrous tissue. There is prominent extramedullary hematopoiesis in the spleen, which becomes extraordinarily large and in some cases occupies almost the entire abdominal cavity. The enlarged spleen is made up largely of metaplastic marrow tissue in primary myeloid metaplasia of the spleen