Polycythaemia vera: bone marrow histopathology under treatment with interferon, hydroxyurea and busulphan

Little is known about long-term effects of myelosuppressive therapy on bone marrow of patients with polycythaemia vera, since histopathology from follow-up biopsies has not been frequently reported. Thus we conducted a retrospective morphometrical analysis of diagnostic and follow-up biopsies of 62 patients, evaluating fibre content, megakaryocytes and bone marrow cellularity. 8/62 patients were treated with interferon-alpha (INF), 11/62 with hydroxyurea (HU) and 11/62 with busulphan (BU). 32/62 served as controls; they were not treated with myelosuppressive drugs but with phlebotomy only. The median observation time was 2.3 yr. Results were compared on the basis of change per time. The bone marrow of the patients with phlebotomies only was characterised by increasing cellularity of haematopoesis, number and volume ratio of megakaryocytes and fibre content. In BU- and HU-treated patients, the haematopoesis was significantly reduced. The IFN patients revealed a reduction of cellularity which was not significant. The fibre content was reduced by BU only, but not significantly. No correlation between megakaryocytes and fibres was found. It could be concluded therefore that: 1) fibre proliferation within the bone marrow was not significantly altered by IFN, HU or BU. 2) Cellularity of haematopoesis was reduced significantly by HU and BU but only partly by IFN, corresponding with haematological remission.     

Renal diagnosis without renal biopsy. Nephritis and sensorineural deafness.

Two examples of hereditary nephropathy within the context of clinical syndromes are described. Emphasis is put on the ability to make a renal diagnosis without renal biopsy and the benefits of screening relatives once a diagnosis is achieved. A variant of Alport's syndrome with associated macrothrombocytic thrombocytopenia, known as Epstein's syndrome, is reported. In addition siblings with Alstr?m's syndrome characterized by pigmentary retinal degeneration (causing blindness in early childhood), progressive sensorineural hearing loss, and progressive renal failure are reported. Both cases had previously presented for non-renal pathology in advance of the onset of symptomatic renal failure and may have benefited from appropriate screening.     

急性放射病患者骨髓巨核细胞中出现其它血细胞现象的观察

本文对l0例急性放射病;3倒亚急性放射病及4例一次超剂量外照射病人的骨髓涂片进行了观察与分析。发现巨核细胞中出现其它血细胞的规律与病情轻重及病期有关, 有助于急性放射病的分度诊断。巨核细胞中出现其它血细胞现象是血细胞落入巨核细胞分界膜系统内的一种共生现象, 但不排除有少数巨核细胞有吞噬作用。未见巨核细胞被噬现象。另外对产生上述现象的机理进行了讨论。     

Adhesive receptors,extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes

Summary. Background: Megakaryocytes release platelets from the tips of cytoplasmic extensions, called proplatelets. In humans, the regulation of this process is still poorly characterized. Objective: To analyse the regulation of proplatelet formation by megakaryocyte adhesion to extracellular adhesive proteins through different membrane receptors. Methods: Human megakaryocytes were obtained by differentiation of cord blood‐derived CD34⁺ cells, and proplatelet formation was evaluated by phase contrast and fluorescence microscopy. Results: We found that human megakaryocytes extended proplatelets in a time‐dependent manner. Adhesion to fibrinogen, fibronectin or von Willebrand factor (VWF) anticipated the development of proplatelets, but dramatically limited both amplitude and duration of the process. Type I, but not type III or type IV, collagen totally suppressed proplatelet extension, and this effect was overcome by the myosin IIA antagonist blebbistatin. Integrin αIIbβ3 was essential for megakaryocyte spreading on fibrinogen or VWF, but was not required for proplatelet formation. In contrast, proplatelet formation was prevented by blockade of GPIb‐IX‐V, or upon cleavage of GPIbα by the metalloproteinase mocarhagin. Membrane‐associated VWF was detected exclusively on proplatelet‐forming megakaryocytes, but not on round mature cells that do not extend proplatelets. Conclusions: Our findings show that proplatelet formation in human megakaryocytes undergoes a complex spatio‐temporal regulation orchestrated by adhesive proteins, GPIb‐IX‐V and myosin IIA.     

Survival of motor neurone protein is required for normal postnatal development of the spleen

Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the ‘Taiwanese’ murine model of severe SMA (Smn^−/−;SMN2^tg/0), correlated to low levels of cell proliferation and increased cell death. Spleen lacks its distinctive red appearance and presents with a degenerated capsule and a disorganised fibrotic architecture. Histologically distinct white pulp failed to form and this was reflected in an almost complete absence of B lymphocytes necessary for normal immune function. In addition, megakaryoctyes persisted in the red pulp. However, the vascular density remained unchanged in SMA spleen. Assessment of the spleen in SMA patients with the infantile form of the disease indicated a range of pathologies. We conclude that development of the spleen fails to occur normally in SMA mouse models and human patients. Thus, further analysis of immune function is likely to be required to fully understand the full extent of systemic disease pathology in SMA.     

The unique contribution of ion channels to platelet and megakaryocyte function

Summary. Ion channels are transmembrane proteins that play ubiquitous roles in cellular homeostasis and activation. In addition to their recognized role in the regulation of ionic permeability and thus membrane potential, some channel proteins possess intrinsic kinase activity, directly interact with integrins or are permeable to molecules up to ≈1000 Da. The small size and anuclear nature of the platelet has often hindered progress in understanding the role of specific ion channels in hemostasis, thrombosis and other platelet‐dependent events. However, with the aid of transgenic mice and ‘surrogate’ patch clamp recordings from primary megakaryocytes, important unique contributions to platelet function have been identified for several classes of ion channel. Examples include ATP‐gated P2X1 channels, Orai1 store‐operated Ca²⁺ channels, voltage‐gated Kv1.3 channels, AMPA and kainate glutamate receptors and connexin gap junction channels. Furthermore, evidence exists that some ion channels, such as NMDA glutamate receptors, contribute to megakaryocyte development. This review examines the evidence for expression of a range of ion channels in the platelet and its progenitor cell, and highlights the distinct roles that these proteins may play in health and disease.     

Circulating human megakaryocytes in cardiac diseases

Abstract Both bone marrow and circulating megakaryocytes may produce platelets. Changes in number and properties of the circulating megakaryocytes in cardiac diseases may provide information about thrombopoiesis in these disease states. Circulating megakaryocytes were obtained by retrograde aspiration through wedged pulmonary artery catheters from patients without cardiac abnormalities, patients with cardiac diseases and patients with disorders known to affect the megakaryocyte-platelet axis or marrowblood barrier. Their number, ploidy distribution and expression of the β₁-integrin adhesion antigens were estimated. We found evidence for an increased number of circulating megakaryocytes during acute myocardial infarction and in patients with triple vessel disease. A significantly higher proportion of circulating megakaryocytes obtained within 60 h after acute myocardial infarction, expressed CDw49b (α-chain of VLA2), CDw49e (α-chain of VLA5), and CDw49f (α-chain of VLA6) compared to megakaryocytes of patients without cardiac diseases. In myocardial infarction the increase in number of circulating megakaryocytes together with the higher proportion that expressed the β₁-integrin adhesion antigens favour the hypothesis that these megakaryocytes are acutely released from the bone marrow. This could reflect either a selective response to an increased demand for circulating platelets or be the result of an aselective mechanism resulting from damage to the marrow-blood barrier following the acute infarction or thrombolytic therapy administered.