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Formation of the cellular constituents of blood; normal adult production is chiefly associated with bone marrow.

Leucocythaemia was the historical description of a persistent excess of white corpuscles in the blood, commonly accompanied by enlargement of blood-forming or lymphoid organs. The corresponding modern disease group is leukaemia, but a raised leukocyte count alone is not a sufficient modern diagnosis.

A period investigation would compare the proportions and appearances of the white and red corpuscles in a fresh blood preparation and examine the spleen, lymph nodes and liver. Splenic enlargement could be striking, and enlarged lymphatic glands supplied another important pattern. The white material was not simply pus circulating from an unnoticed abscess; microscopic resemblance between a leukocyte and a pus corpuscle does not establish suppuration. A persistent excess must also be distinguished from a temporary reactive rise during infection or inflammation.

In present terms, leukaemia comprises malignant disorders of blood-forming cells. Acute and chronic forms, and myeloid and lymphoid lineages, differ in the maturity and identity of their abnormal cells and in their course. Bone marrow disease can interfere with normal production of red blood cells, platelets and functioning leukocytes. Thus pallor, fatigue and breathlessness may reflect anaemia; bruising or bleeding may reflect inadequate platelets; recurrent infection can occur despite a large total white count. Infiltration or enlargement of the spleen, lymph nodes and liver can produce swelling, early satiety or abdominal discomfort.^[ref]

The useful modern examination includes a complete blood count and differential, a stained blood film, and investigation of bone marrow and cellular markers when indicated. The morphology and proportions of mature and immature cells matter. A count can be normal or low in some leukaemias, while a high count can have a non-malignant cause.^[ref] The historical appearance suggests a disorder of blood formation, but classification requires more than counting white cells.

“Leukhæmia” denotes leukaemia: historically a persistent excess of colourless corpuscles in the blood, now understood as a group of malignant disorders of blood-forming biological cells. It is distinct from a temporary rise of ordinary leukocytes during inflammation or infection.

The historical laboratory finding was an unusually large proportion of colourless blood corpuscles on microscopy, often accompanied by enlargement of the spleen or lymph nodes. Such a blood appearance did not mean that ordinary pus had simply entered the circulation. The present classification separates acute and chronic disorders and myeloid and lymphoid lineages. The abnormal population can interfere with production of normal red blood cells, platelets and effective leukocytes in the bone marrow. A high total white-cell count is common, but some acute leukaemias present with a normal or low count; the count alone is neither a complete definition nor a modern subtype diagnosis.^[ref]

The symptoms follow several mechanisms:

These are possible manifestations, not a required syndrome in every affected person.^[ref][ref]

For an 1866 explanation, the important connection is between the persistent abnormal blood picture, enlargement of blood-forming or lymphatic organs, progressive debility and bleeding. Modern diagnosis goes further: a complete blood count with differential and a stained blood film establish which cellular populations are abnormal; selected bone marrow studies, immunophenotyping and genetic tests identify the disease. A microscope image of numerous white corpuscles is the beginning of that distinction, not proof of every later molecular category. The dominant clinical problem can be failure of normal blood formation despite an apparent abundance of white cells.

An answer appropriate to 1867 must distinguish the early nucleated embryonic red blood cells from later populations, and report uncertainty about their origin. Simply stating the modern bone marrow account would miss the historical force of the request for the views then held.

Early embryonic life. In the pre-exam account of William Senhouse Kirkes, a first generation of red corpuscles arose from embryonic cells in the early vascular territory before or around the establishment of blood circulation. The initially colourless cellular material acquired colour, and the early corpuscles were relatively large and nucleated. Division of these early nucleated forms was among the processes considered capable of increasing their number. A second generation subsequently replaced the first. His embryological terminology, including the vegetative layer, should not be silently treated as an exact statement of modern germ layer derivation.^[ref]

Later fetal and adult life. A widely taught hypothesis made pale corpuscles in lymph and chyle precursors of the later red blood cells. In this scheme the pale cells entered the blood, acquired colouring matter and underwent changes associated with loss or alteration of the cell nucleus. Lymph nodes, the spleen and, during development, the liver were consequently central candidates for sites of renewal. Other opinions proposed multiplication of pre-existing red corpuscles by division or segmentation. These were competing interpretations of microscopic appearances, not demonstrations that every adult leukocyte can become a red blood cell. The pre-exam historical record explicitly documents both the pale-corpuscle hypothesis and the alternative multiplication hypotheses.^[ref]

The modern correction is successive developmental waves of haematopoiesis, followed chiefly by bone marrow production after birth, with distinct committed precursors. Primitive erythropoiesis begins in extra-embryonic yolk sac blood islands. Definitive blood-forming populations emerge through additional embryonic processes, including haemogenic endothelium in the aorta-gonad-mesonephros region, and expand in the fetal liver. Bone marrow becomes a major site later in fetal development and is the normal main adult site. The sequence is not a single already mature cell population merely migrating unchanged from organ to organ.^{[ref][ref][ref]}

During definitive erythropoiesis, erythroblasts divide and accumulate haemoglobin; the late precursor extrudes its cell nucleus, producing a reticulocyte, which matures into a red blood cell. The large primitive mammalian erythroblasts also ultimately undergo enucleation; their transient nucleation does not make them adult leukocytes.^[ref] A mature human red blood cell does not normally divide. Adult haematopoietic stem cells maintain progenitor populations giving rise to red blood cells, leukocytes and megakaryocytes; platelets are fragments produced by the last of these, not equivalent nucleated cells. Lymphocytes have their own differentiation and maturation pathways, including development in lymphoid organs. Thus a precursor's pale or lymphoid appearance under a nineteenth-century microscope is insufficient to identify it as an ordinary mature circulating leukocyte.

Two observations explain both the attraction and the weakness of the older theories. Comparing embryonic and adult blood under a microscope reveals genuine differences in corpuscle size, colour and nuclear appearance. But a series of different-looking cells in separate samples is not direct observation of one changing into another. Mixing developmental stages, species or preparations can create a false apparent sequence; reagents that reveal or damage the cell nucleus add another complication. A stronger test samples the proposed blood-forming organs and identifies proliferating precursors there, then connects them experimentally to their descendants. The explicit identification of adult bone marrow as a blood-forming organ in 1868 is therefore a subsequent development, not established background to the December 1867 paper.^[ref]