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A 9-year-old Caucasian boy presented in 1994 with severe headache, attacks of migraine, aggressive behavior and minor bleeding symptoms. Initial abnormal laboratory data were a platelet count of 1596 × 109/L and slight splenomegaly on echogram. Low-dose aspirin 100 mg/day relieved the cerebral symptoms, but a pronounced spontaneous bleeding tendency became evident. Severe epistaxis, bruises, hematomas and gum bleedings resulted in an iron deficiency state (hemoglobin 5.7 mmol/L,hematocrit 0.30, MCV 77 fl, ferritine 6 ug/l) in November 1995. The combination of mucocutaneous bleeding, high platelet counts (1946 × 109/L), and increase of enlarged megakaryocytes in a bone marrow smear was consistent with the diagnosis of hemorrhagic thrombocythemia. Coagulation studies revealed the presence of an acquired von Willebrand syndrome type 2A featured by a prolonged Ivy bleeding time, near normal factor VIII coagulant activity (0.53 u/ml) and von Willebrand factor (VWF) antigen (0.55 u/ml), low VWF ristocetine cofactor activity (0.29), very low VWF collagen binding activity (0.16 u/ml) and absence of large VWF multimers. A severe epistaxis lasting for several hours stopped immediately after correction of the VWF parameters by substitution of 3000 units Bone marrow histopathology showed a pronounced increase of large immature megakaryocytes with hyperlobulated nuclei and maturation defects of nuclei and cytoplasm, and absence of reticuline fibrosis consistent with the diagnosis of JAK2 wild type thrombocythemia in primary megakaryocytic granulocytic myeloproliferation (PMGM). Initial treatment with hydroxyurea (500 mg daily) followed by anagrelide resulted in correction of platelet count from 2000 × 109/L to near normal (400-600 × 109/L) by), which was associated with relief of bleeding symptoms, and correction of plasma VWF values and VWF multimeric pattern to normal. The subsequent natural history was featured by spontaneous reduction of platelet count to near normal and no progression of JAK2 wild type myeloproliferative neoplasms for more than 13 years follow-up.

In 1934, Epstein and Goedel used the term hemorrhagic thrombocythemia to describe a disorder characterized by permanent elevation of a platelet count to more than three times normal, hyperplasia of megakaryocytes, and the tendency for venous thrombosis and spontaneous hemorrhage. Over the last 75 years, and particularly in the past 6 years, major progress has been made in our understanding of essential thrombocythemia (ET) and its pathogenesis with the identification of the highly prevalent JAK-2 V617F and other mutations. Current management of this condition is based upon historical data and with treatments that have not changed significantly for nearly two decades. This study discusses this and recent progress, highlighting exciting new data with old and new drugs, as well as which patients in particular should be evaluated for these new therapies.

We analysed between 1908 and 1985 of two hundred cases of thrombocythemia from the literature between 1908 and 1985. Erythromelalgic, acrocyanotic ischemia and digital gangrene, cerebral or coronary ischemic events (erythromelalgic thrombotic thrombocyhemia: ETT) in 99 thrombocythemia patients (essential thrombocythemia: ET N=67 and polycythemia vera: PV N=32) occured at platelet counts in excess of 400 × 10 9 /L. Hemorrhagic complications at time of presentation of hemorrhagic thrombocythemia (HT) in 100 HT patients included melana and/or hematemesis, skin bleedings (bruises, subcutaneous hematomas, painfull hematomas after trauma, ecchymoses, but not petechiae, epistaxis and gum bleeding and secondary bleeding after trauma or surgery. ETT occurred at an early stage of thrombocythemia with a mean platelet count of 1110+477 × 10 9 /L, whereas HT occurred at significantly higher platelet counts in excess of 1000 × 10 9 /L with a mean platelet count of 2016+1070 × 10 9 /L. HT patients frequently had a previous history of ETT or paradoxical occurrences of both thrombosis and bleeding (ETT/PHT). The degree of thrombocythosis determined the sequential occurrence of ETT, HT in ET and PV patients. Hypersensitive thrombocythemic platelets (sticky platelets) are involved in the etiology of platelet-mediated thrombosis at platelet counts above 400 × 10 9 /L whereas bleedings at high platelet count is related to an acquired von Willebrand syndrome processes on top of a blood clot retraction disturbance with erythrocyte fall out, that causes painful subcutaneous hematomas with a central swelling (clot) after a blow, trauma and secondary bleeding after surgery in thrombocythemia patients.

Aspirin responsive erythromelalgia is the presenting symptom of thrombocythemia in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Skin punch biopsies taken from the affected areas of erythromelalgia and acrocyanotic compications show typical arteriolar inflammation, fibromuscular intimal proliferation and thrombotic occlusions. If left untreated both microvascular and major thrombosis frequently do occur in thrombocythemia in ET and PV patients, but can easily be cured and prevented by low dose aspirin. The stratification as low, intermediate and high thrombotic risk in the retrospective Bergamo studies has been performed in ET patients not treated with aspirin. The risk of thrombosis in aspirin treated ET and PV is not age dependent when on low dose aspirin, and does recur when not on low dose aspirin during follow-up. The persistence of the Bergamo definition of low, intermediate and high thrombotic risk in the 2012 International Prognostic Score of Thrombosis in ET (IPSET) is applicable for JAK2 mutated ET and PV patients not on aspirin and has led to significant overtreatment with hydroxyurea. MPN disease burden in patients with JAK2V617F positive ET and PV is related to JAK2 allele burden and associated leukocytosis, thrombocytosis, constitutional symptoms and splenomegaly. Low dose peglyated interferon (PegasysR, 45 μg/ ml once per week or every two weeks) is becoming the first line myeloreductive treatment option to postpone the useof hydroxyurea as long as possible. Von Willebrand factor (VWF) mediated platelet thrombi formation, as well as increased proteolysis of the VWF multimers in one and the same patient do occur simultaneously or in sequence leading to the paradoxical occurrence of thrombosis at platelet count aboe 400x109/L and bleeding at platelet counts above 1000x109/L due to an acquired von Willebrand disease type 2A.

With these uncertainties, which patients with ET and PV should receive myelosuppressive therapy and accept its possible risks? Remembering the generalization from the literature that most patients with ET who are to have a catastrophic thrombosis either have it at the time of diagnosis or after preceding, less severe thrombotic symptoms, it is acceptable to omit myelosuppressive therapy in asymptomatic patients with ET. Young patients with PV and no thrombotic manifestations can similarly be managed with phlebotomy alone. There is no evidence in the literature to show that myelosuppressive therapy should be used simply because the platelet count is high or to prevent transition to myeloid metaplasia. In patients with ET or PV with previous thrombotic manifestations, the risk/benefit ratio probably favors myelosuppressive therapy. The PVSG studies also suggest that patients over the age of 70 with PV are at particular risk for thrombosis and should be treated with myelosuppression. No myelosuppressive agent has been shown to be superior to hydroxyurea. Patients who fail on hydroxyurea should not be treated with 32P or alkylating agents. Anagrelide or interferon would be more appropriate. The PVSG-05 study suggests that high doses of aspirin, i.e. approximately 1.0 grams per day, are not indicated. Trials of low dose aspirin to prevent thrombosis are encouraged. There is no way to predict which patients will have hemorrhagic complications and, as mentioned, one study suggests that there will be few (44). Patients with thrombocytosis and pathological bleeding, i.e. hemorrhagic thrombocythemia, generally improve with myelosuppressive therapy. This syndrome is to be distinguished from patients who bleed with normal or low platelet counts, generally in the setting of myeloid metaplasia (14). These patients have an acquired disorder of platelet function due to platelet production from abnormal megakaryocytes. An occasional patient will benefit from increasing the platelet count by splenectomy.

Essential thrombocythemia (ET) is a risk factor for ischemic stroke and, far more rarely, hemorrhage. We report the case of an untreated 32-year-old woman with a history of JAK2 V617F–positive ET with cerebellar and subarachnoid hemorrhages without evidence of sinus vein thrombosis. She was commenced on oral cytotoxic and antiplatelet therapy. This case report discusses the underlying mechanism of hemorrhagic thrombocythemia and the management dilemma presented by the recommended treatment implications.

According to strict morphological, biochemical and cytogenetic criteria Philadelphia chromosome positive essential thrombocythemia and chronic granulocytic leukemia constitute a separate malignant and individual disease entity, whereas Philadelphia chromosome negative essential thrombocythemia, polycythemia vera and agnogenic or megakaryocytic myeloid metaplasia form a chronic proliferation of three hematopoietic cell lines. Histopathology from bone marrow biopsies permits the characterization and diagnostic differention of the various myeloproliferative disorders and appears to be a main and specific diagostic criterion for polycythemia vera and essential thrombocythemia. Hemorrhagic thrombocythemia is a clinical syndrome of recurrent spontaneous mucocutaneous and secondary hemorrhages often preceded by thromboses, extremely high platelet counts, pseudohyperkalemia, increased bone marrow cellularity and frequently splenomegaly. The diagnostic criteria of essential thrombocythemia with paradoxical occurrence of thrombotic events and hemorrhagic manifestations are a platelet count in excess of 1000 x 10(9)/L and increased bone marrow cellularity in the majority of the cases. Erythromelalgia and other microcirculatory ischemic or thrombotic events or accidents in essential thrombocythemia and polycythemia vera already occur at platelet counts in excess of the upper limit of normal. First line treatment options in essential thrombocythemia and polycythemia vera are control of platelet function with low-dose aspirin and reductive control of platelet count and erythrocytes by bloodletting, interferon and busulfan or hydroxyurea monochemotherapy.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by isolated overproduction of platelets, thrombohemorrhagic complications, and a median age of 50-60. When it occurs in younger patients, the incidence of complications has been reported to be quite low, with a good long-term prognosis. We report a retrospective review of 13 patients with ET between the ages of 22 and 35 in which 11 were symptomatic at diagnosis, with only one remaining asymptomatic during follow-up. Three patients presented with potentially life-threatening complications (two myocardial infarctions, one stroke), although no deaths were observed. The majority of the nonlife-threatening complications were vaso-occlusive in nature, including erythromelalgia and transient neurologic symptoms. We conclude that ET in young adults is not always a benign disease and that potentially life-threatening complications are not rare. The optimum approach to treatment in this or any other age group remains uncertain.

Essential thrombocythemia and thrombocythemia in polycythemia vera manifest itself in two clinical pictures: thrombotic thrombocythemia and hemorrhagic thrombocythemia. The broad spectrum of microcirculatory events including erythromelalgia and neurological, ocular or coronary ischemic manifestations reflect a novel platelet-dependent thrombophilia in thrombocythemia at platelet counts in excess of 400 × 109/1, which is exquisitely sensitive to low dose aspirin. At platelet count below 1000 × 109/1, low dose aspirin usually does not elicit bleeding symptoms. The arterial thrombophilia in thrombocythemia changes into an overt hemorrhagic diathesis at increasing platelet count from below to far in excess of 1000 × 109/1, which is accompanied by the acquisition of a von Willebrand factor (vWF) deficiency simulating type II von Willebrand disease.

1. Editoral: Myelofibrosis, Lancet 1:127, 1980. 2. Say B, and Berkel t: Idiopathic myelofibrosis in an infant, J PEDIATR 64:580, 1964. 11. 3. Boxer LA, Camitta BM, Berenberg W, and Fanning JP: Myelofibrosis-myeloid metaplasia in childhood, Pediatrics 55:861, 1975. 4. Laszlo J: Myeloproliferative disorders (MPD): Myelofibro12. sis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia, Semin Hematol 12:409, 1975. 13. 5. Tobin MS, Tan C, and Argano S: Myelofibrosis in the pediatric age group, NY State J Med 1:1080, 1969. 6. Schlackman N, Green AA, and Naiman JL: Myelofibrosis 14. in children with chronic renal insufficiency, J PEDIATR 87:720, 1975. 15. 7. Crisser SD, and Chung KB: Acute myelofibrosis in progressive systemic sclerosis, Am J Med 67:151, 1979. 8. Evans DIK: Acute myelofibrosis in children with Down's syndrome, Arch Dis Child 50:458, 1975. Teasdale JM, Worth AT, and Corey MT: A missing C chromosome in the bone marrow cells of three children with myeloproliferative disease, Cancer 25:1468, 1970. Myers CE, Chabner BA, DeVita VT, and Gralnick HR: Bone marrow involvement in Hodgkin's disease: Pathology and response to MOPP chemotherapy, Blood 44:197, 1974. Smith CM, McKenna R, Hedlund B, Nesbit ME, and Krivit W: Transient myeloid metaplasia associated with an unusual hemoglobin in a newborn infant, Am J Pediatr Hematol/Oncol 1:291, 1979. Charron D, Ladislas R, Couty MC, and Binet JL: Biochemical and histological analysis of bone marrow collagen in myelofibrosis, Br J Haematol 41:151, 1979. Lewis CM, and Pegrum GD: Immune complexes in myelofibrosis: A possible guide to management, Br J Haematol 39:233, 1978. Balfanz JR, Nesbit ME, and Krivit W: Bone marrow curettage in childhood myelofibrosis, J PEDIATR 87:578, 1979. Rappeport J, Parkman R, Belli J, Levey R, Rosen F, and Nathan D: Reversibility ofmyelofibrosis after bone marrow transplantation, Blood 52(Suppl):271, 1978.

SummaryA new case of primary hemorrhagic thrombocythemia is presented, in which ferrokinetic studies were performed 3 times in different phases of the illness.The 84 years old patient fitted all the clinical and hematological criteria of these disease : repeated spontaneous hemorrhages, splenomegaly, persistent thrombocythemia, severe and prolonged anemia, leukocytes not in excess of 50.000 and a rich bone marrow with pronounced megakaryocytic preponderance.Radioactive phosporous treatment produced several remissions, but the patient died 2 years after the diagnosis was established, showing a transformation to acute monocytic leukemia.The quantitative determinations of iron kinetics in the hemorrhagic phase, in remission and in hematologic relapse showed an highly increased erythropoiesis despite of the existent anemia and an important ineffective erythropoiesis.Therefore, the authors feel that primary hemorrhagic thrombocythemia is a myeloproliferative disorder with a predominant platelet elevation.

Hemorrhagic thrombocythemia is a relatively well-defined myeloproliferative disease in which the major abnormality is the excessive production of megakaryocytes and platelets. In its natural evolution acute and chronic bleeding from the gastrointestinal tract, thromboembolic phenomena, gastric and esophageal varices, and infarction atrophy of the spleen are the important clinical features. Disastrous complications may follow splenectomy. Removal of the spleen by surgery, or infarction and atrophy allows masses of platelets to circulate which produce thrombi or emboli in small vessels and ultimately hemorrhage. Effective treatment requires the suppression of megakaryocyte growth and thrombopoiesis. In four patients who developed severe postsplenectomy hemorrhagic thrombocythemia, melphalan (L-phenylalanine mustard) therapy effectively controlled the abnormal thrombocytosis and clinical evidence of disease.

Agnogenic myeloid metaplasia is an uncommon disease included in the myeloproliferative disorders along with polycythemia vera, chronic granulocytic leukemia, and primary hemorrhagic thrombocythemia. It is characterized by anemia, hepatosplenomegaly, and extramedullary hematopoiesis. The disease usually follows a chronic course with ultimate demise related to hemorrhage, infection, or cardiovascular disease [1 , 2]. At autopsy extramedullany hematopoiesis is often found scattered throughout nearly all body tissues as an incidental finding. In some cases, however, clinically significant and life-threatening complications can result from extramedullary hematopoiesis in critical organ systems. The following cases and discussion review the clinical and radiologic findings associated with extramedullary hematopoiesis.

We have presented a retrospective study of 129 patients with platelet counts of 1,000 X 10(9)/L or more--72 with myeloproliferative disorders (MPD), and 57 with reactive thrombocytosis (RT)--in an effort to determine the incidence of thrombohemorrhagic complications. Thrombotic disorders occurred with approximately equal frequency in the two groups, being found in three patients (4%) with MPD and three (5%) with RT when the platelet count was over 1,000 X 10(9)/L and in 11% of the patients in each group when the platelet count was less than 1,000 X 10(9)/L. In contrast, bleeding manifestations were more common in MPD, where 36% of patients were affected on one or more occasions versus only 4% of those with RT. However, bleeding was generally not severe, with only six patients requiring transfusions, and three of these patients had been receiving aspirin or corticosteroids when they developed severe gastrointestinal bleeding.

EVEN BEFORE Nygaard's and Brown's inclusion of a patient with thrombocytosis in their series of five patients with "essential thrombophilia" in 1937, 1 scattered reports of patients with thrombohemorrhagic phenomena and increased numbers of circulating platelets had appeared in the English and foreign medical literature under such names as piastrinemia, primary thrombocythemia, essential thrombocythemia, hemorrhagic thrombocythemia, megakaryocytic leukemia, hyperthrombocytic myelosis, and essential thrombophilia. 2 The present report describes an instance of hemorrhagic thrombocythemia studied at the Eugene Talmadge Memorial Hospital of the Medical College of Georgia. It is the first report, to the author's knowledge, to include definition of patient karyotype. The reader is referred to the reviews of hemorrhagic thrombocythemia by Ozer et al 2 and Gunz. 3 Report of a Case A 52-year-old Negro woman (ETMH 018-900) was admitted to the Eugene Talmadge Memorial Hospital for the sixth time on Jan 30, 1964, with the complaint of abdominal

Recently there has been increasing recognition of hemorrhagic thrombocythemia as a clinical entity, although its status as a distinct pathological disorder is questioned. 1,2 Synonyms are essential thrombocytosis, essential thrombophilia, thrombocythemia hemorrhagica, and hyperthrombotic myelosis. We concur with those who classify this disease with granulocytic leukemia, polycythemia vera, myeloid metaplasia, and myelosclerosis in the general category of "myeloproliferative disorders." There may be no sharp dividing line between the different conditions; indeed, there are known cases of transformation from one form into another. Characteristic findings include recurrent episodes of hemorrhage and/or thrombosis, megakaryocytic hyperplasia of the marrow, and a striking increase in circulating platelets. Present in some, but not all, patients have been splenomegaly, neutrophilic leukocytosis, erythrocytosis, and a variety of coagulation defects, showing no consistent pattern. The interested reader is referred to several comprehensive reviews of the subject for further details. 1,3-7 The purpose of this report is to show

1.1. Six new cases of primary hemorrhagic thrombocythemia are reported. All six patients exhibited thrombohemorrhagic phenomena in one form or another. Purpura, epistaxis, and bleeding of the gums and gastrointestinal tract were common. All had hepatosplenomegaly. In the patient with gastrointestinal bleeding, sources could not be found. All had persistent elevation of thrombocyte count above 800,000/ cu. mm. (indirect method). Acute myeloblastic leukemia finally developed in one patient. 2.2. The literature is critically surveyed. On the basis of this survey and from personal experience new diagnostic criteria are outlined. These include: (a) a history of thrombohemorrhagic phenomena; (b) the presence of the spleen, which is usually enlarged; (c) erythrocyte level of not more than 6 million/cu. mm., hemoglobin not to exceed 18 gm. per cent, hematocrit not above 54 per cent, leukocytes not exceeding 50,000/cu. mm., and a platelet count persistently above 800,000/cu. mm. (indirect method); (d) hyperplasia of all marrow elements with megakaryocytic preponderance and platelet masses plus eosinophilia and/or basophilia; and (e) absence of leukemic tissue infiltration. 3.3. It is emphasized that primary hemorrhagic thrombocythemia is a myeloproliferative syndrome in which elevation of platelets predominates, thus constituting a separate entity apart from polycythemia vera, chronic granulocytic leukemia and secondary thrombocytoses. 4.4. The recognition of this entity is clinically important in guiding management. Radioactive phosphorus appears to be the treatment of choice at the present time.

AS WOULD BE anticipated, disorders with moderately increased blood platelet levels are often characterized by thrombotic complications. Paradoxically, massive increases in the platelet count are more frequently associated with a hemorrhagic disorder.1Thus, such diseases as polycythemia vera, chronic granulocytic leukemia, and essential thrombocythemia may present a hemophilia-like syndrome when the platelets exceed a million per cubic millimeter. The mechanism by which thrombocythemia leads to bleeding has been the subject of much speculation, but few of the suggested theories have been implemented by experimental verification. The present study concerns a case of thrombocythemia resulting from polycythemia vera. Data to be presented indicate that excess platelets display anticoagulant activity. Both thrombocythemic and normal platelets were found to be similarly anticoagulant at comparable concentrations. The findings suggest that the platelet anticoagulant effect may be at least partially responsible for the hemorrhagic manifestations of thrombocythemia. Report of Case A 71-year-old woman was

Excerpt Transitory thrombocytosis is seen following splenectomy, during the postpartum period and accompanying certain infections and malignant processes.1More persistent elevations of circulating ...

Fifteen patients with primary thrombocythemia were seen at the Mayo Clinic from 1960 through 1966. Nine patients presented with hemorrhagic manifestations, especially gastrointestinal bleeding. Three patients presented with thrombotic phenomena, including one patient with the nephrotic syndrome. Platelet counts in excess of 1 million/cu mm were seen in all patients. In this series, 9 patients had hypochromic anemia, and 12 had mature neutrophilic leukocytosis. In three patients there was no splenomegaly in association with Howell-Jolly bodies and target cells in peripheral blood, findings suggestive of infarction atrophy of the spleen. Three patients died within 24 months of diagnosis. Four of the six deaths were related to thrombotic mechanisms. Sodium phosphate P 32 produced more rapid and longer remissions than did busulfan.