Evidence for a theory of physical fragmentation of megakaryocytes, implying that all platelets are produced in the pulmonary circulation

Trowbridge, E. A.; Martin, John F.; Slater, David

doi:10.1016/0049-3848(82)90163-3

Cited by 111 publications

(47 citation statements)

References 24 publications

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“…Since MKs are large cells, they would not be expected to pass unchanged through the normal lung vasculature. Commonly only the nuclei of MKs, denuded of cytoplasm, are seen in arterial blood [53]. Megakaryocytes can often be observed apparently stuck in lung capillaries [47,52,56].…”

Section: J Dickinsonmentioning

confidence: 99%

“…They are relatively abundant in mixed venous blood and scarce in arterial blood [47-521, whereas platelets are more abundant in arterial than in venous blood [5 11. Calculations relating MK size (25000 fl; 20-50 , u diameter in stained sections), content of platelets (about 3000 per cell), and MK and platelet numbers in venous and arterial blood led to the proposition that most platelets are produced in the lungs, in pulmonary capillaries, by physical fragmentation of megakaryocytes [51,53,54,55]. Normal lung capillaries are narrow.…”

Section: J Dickinsonmentioning

confidence: 99%

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The aetiology of clubbing and hypertrophic osteoarthropathy

Dickinson

1993

Eur J Clin Investigation

133

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Abstract. The evidence is reviewed for the hypothesis that clubbing and hypertrophic osteoarthropathy are due to the peripheral impaction of megakaryocytes and platelet clumps in the fingers and toes, to which this particulate matter has passed in an axial stream. The normal pulmonary vascular bed retains these large particles, which fragment before entering the systemic circulation. A right-to-left shunt allows them to bypass the pulmonary vascular bed. A preliminary histological report of platelet clumps seen at necropsy in nail bed capillaries of clubbed fingers supports the hypothesis. Platelets contain and release platelet-derived growth factor, whose known effects could explain all the pathological changes in clubbing. In addition to explaining why clubbing should occur in cyanotic congenital heart disease, clubbing in sub-acute bacterial endocarditis and distal to infected arterial grafts and aneurysms can be understood in terms of platelet clumps breaking off valves or arterial walls, and passing distally. Clubbing in liver disease is associated with multiple small pulmonary arteriovenous anastomoses which allow large particles through. Hypertrophic osteoarthropathy probably shares the same mechanism, and is mainly attributable to PDGF release; but there may also be altered platelet function and an additional growth factor derived from the lungs.

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Section: J Dickinsonmentioning

confidence: 99%

Section: J Dickinsonmentioning

confidence: 99%

The aetiology of clubbing and hypertrophic osteoarthropathy

Dickinson

1993

Eur J Clin Investigation

133

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“…These proplatelets insinuate between bone marrow sinusoidal cells to enter the circulation (2). Circulatory shear force within the marrow or possibly in the pulmonary circulation results in the fragmentation of these proplatelets, thereby releasing platelets into the circulation (3,4). Moreover, Italiano and colleagues have recently demonstrated that the number of platelets released per megakaryocyte is enhanced by coordinated bending and bifurcation of proplatelet processes (5).…”

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confidence: 99%

Induction of platelet formation from megakaryocytoid cells by nitric oxide

Battinelli

Willoughby

Foxall

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Although the growth factors that regulate megakaryocytopoiesis are well known, the molecular determinants of platelet formation from mature megakaryocytes remain poorly understood. Morphological changes in megakaryocytes associated with platelet formation and removal of senescent megakaryocytes are suggestive of an apoptotic process. Previously, we have established that nitric oxide (NO) can induce apoptosis in megakaryocytoid cell lines. To determine whether there is an association between NO-induced apoptosis and platelet production, we exposed Meg-01 cells to S-nitrosoglutathione (GSNO) with or without thrombopoeitin (TPO) pretreatment and used flow cytometry and electron microscopy to assess platelet-sized particle formation. Meg-01 cells treated with TPO alone produced few platelet-sized particles (<3% of total counts), whereas treatment with GSNO alone produced a significant percentage of platelet-sized particles (22 ؎ 4% of total counts); when combined with TPO pretreatment, however, GSNO led to a marked increase in platelet-sized particle production (48 ؎ 3% of total counts). Electron microscopy confirmed that Meg-01 cells treated with TPO and GSNO yielded platelet-sized particles with morphological features specific for platelet forms. The platelet-sized particle population appears to be functional, because addition of calcium, fibrinogen, and thrombin receptor-activating peptide led to aggregation. These results demonstrate that NO facilitates platelet production, thereby establishing the essential role of NO in megakaryocyte development and thrombopoiesis.thrombopoiesis ͉ apoptosis ͉ guanylyl cyclase T he mechanism by which platelets are produced from megakaryocytes (thrombocytopoiesis) is not well understood. Megakaryocytes differentiate from pluripotent hematopoietic stem cells in a process orchestrated by a series of growth factors that regulate distinct stages of megakaryocyte maturation. These stages include proliferation of progenitor cells, nuclear polyploidization (via endomitosis), cytoplasmic maturation, and, ultimately, proplatelet formation and platelet release (1). Cytoplasmic maturation is characterized by the formation of platelet-specific granules and the development of a demarcation membrane system that delineates the platelet fields in the cytoplasm. In recent years, a theory of proplatelet development has emerged in which long cytoplasmic exvaginations form from the mature megakaryocyte cytoplasm in the terminal phase of megakaryocyte development. These proplatelets insinuate between bone marrow sinusoidal cells to enter the circulation (2). Circulatory shear force within the marrow or possibly in the pulmonary circulation results in the fragmentation of these proplatelets, thereby releasing platelets into the circulation (3, 4). Moreover, Italiano and colleagues have recently demonstrated that the number of platelets released per megakaryocyte is enhanced by coordinated bending and bifurcation of proplatelet processes (5).The recently discovered growth factor thrombopoeitin (TPO) i...

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“…Studies on patients on cardiopulmonary bypass have shown that the lungs are net removers of MK from the circulation (25). Using a mathematical model based on the quantity of MK plasma volume reduction and platelet released in the postpulmonary circulation, Trowbridge et al have provided evidence that all circulating platelets are produced in the pulmonary circulation (26). More recently, the importance of the lung in platelet homeostasis is confirmed by the direct observation under electron microscopy the release of platelets from MK cells in the pulmonary capillary bed (13).…”

mentioning

confidence: 99%

Effects of Oxygen-Induced Lung Damage on Megakaryocytopoiesis and Platelet Homeostasis in a Rat Model

Yang

et al. 2003

Pediatr Res

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The association between lung injury and thrombocytopenia was investigated by comparing the megakaryocyte and platelet counts, and platelet activation using P-selectin as a marker, between the prepulmonary (right atrial) and postpulmonary (left atrial) blood in adult and neonatal (preterm and term) rats with and without hyperoxic lung injury. In the healthy controls, the postpulmonary blood had lower megakaryocyte count (prepulmonary versus postpulmonary: Preterm: 8.7[0.6] platelets, p ϭ 0.003). Peripheral platelet and intrapulmonary megakaryocyte counts in the lung-damaged rats were significantly lower than those in their respective controls. Intrapulmonary thrombi or platelet aggregation were detected in the lung-damaged rats but not in the controls. These findings showed that hyperoxic lung damage reduced circulating platelets through (1) failure of the lungs to retain and fragment megakaryocytes to release platelets, and (2) platelet activation leading to platelet aggregation, thrombi formation and platelet consumption. The magnitude of platelet reduction was physiologically significant, as demonstrated by higher counts of megakaryocyte colony forming units in the bone marrow culture of the animals in the hyperoxia group when compared with the controls. Thrombocytopenia is a common complication in neonates and may affect up to 7.6% of all newborns (1, 2). The condition is particularly prevalent in sick infants. In a survey by Castle et al. 58% and 22% of infants receiving intensive care had platelet count Ͻ150ϫ10 9 /L and 100ϫ10 9 /L, respectively (3). Congenital or early onset (Ͻ72 h of birth) neonatal thrombocytopenia may be caused by immunologic causes including isoimmune or maternal autoimmune thrombocytopenia, failure of platelet production such as that in the thrombocytopeniaabsent-radii syndrome, congenital infection, and bone marrow suppression due to maternal hypertension, preeclampsia, and diabetes mellitus (1, 4). The etiology however remains unclear in a large proportion of cases (3, 5, 6). The late onset (Ͼ72 h of birth) type of thrombocytopenia is often attributed to sepsis (7), although an infective cause is often not identifiable in the affected infants. Previous workers have observed that this category of thrombocytopenia is particularly common in newborns with lung disease such as respiratory distress syndrome (5, 8 -11), and the degree of platelet reduction is directly related to the severity of the underlying lung disease, the concentration of inspired oxygen (9, 11), and the ventilation pressure (8, 11). In a study on rabbits, mechanical ventilation

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Evidence for a theory of physical fragmentation of megakaryocytes, implying that all platelets are produced in the pulmonary circulation

Cited by 111 publications

References 24 publications

The aetiology of clubbing and hypertrophic osteoarthropathy

The aetiology of clubbing and hypertrophic osteoarthropathy

Induction of platelet formation from megakaryocytoid cells by nitric oxide

Effects of Oxygen-Induced Lung Damage on Megakaryocytopoiesis and Platelet Homeostasis in a Rat Model

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