The aetiology of clubbing and hypertrophic osteoarthropathy

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. SUMMARY In 1987 John Martin and I proposed that clubbing was 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. A preliminary histological report of platelet clumps or microthrombi seen at necropsy in nail bed capillaries of clubbed fingers is compatible with our hypothesis. We suggested that at the site of impaction platelet-derived growth factor (PDGF) is released. This material is a general growth promoter. It is known to have effects which include all the pathological changes recognized to occur in clubbed digits, including increased vascular permeability, increased vascularity, and stimulation of smooth muscle cells and fibro-blasts. In cyanotic congenital heart disease with a macroscopic right-to-left shunt large particles can pass directly from bone marrow to the systemic arterial circulation without fragmenting in the lungs, as they normally do. In sub-acute bacterial endocarditis, and in arterial aneurysms or infected arterial grafts, platelet clumps form locally on heart valves or on the damaged arterial wall, then detach themselves and pass peripherally. This mechanism accounts well for localized clubbing. In those lung diseases in which clubbing is common, there may be not only local shunting of blood through multiple small arteriove-nous anastomotic channels, but also local platelet aggregation and in some cases altered platelet function. In severe liver disease, clubbing can be accounted for by multiple small arteriovenous shunts in the lungs. These have been demonstrated histologically and radiologically, and by tests with particulate matter of different sizes. Clubbing might be expected in the newborn, because blood largely bypasses the lungs during fetal life; but it has not been noted. The likeliest explanation is that fetal platelet PDGF release is undeveloped or inhibited, as are many other fetal platelet release functions: but this matter has not so far been investigated. Hypertrophic osteoarthropathy (HOA) in mild form can often be found in cyanotic congenital heart disease; but its special occurrence and severity in certain diseases (especially carcinoma of the bronchus) suggests that some additional factor may be operating, perhaps associated with the tumour itself. In most respects, however, HOA can be regarded as a more advanced stage of the same process that results in simple clubbing.