200-147 million years ago


During the evolution of the synapsid reptiles and the early mammals (a period of more than 150 million years), a number of changes evolved in the cardiovascular and lymphatic systems. Red blood cells lost their nuclei, the ancestral ventricle was divided in two, the blood vessels were reorganized, new antibodies evolved, and lymph nodes and tonsils were added to the lymphatic system.

In mammals, the red bone marrow became the site of red blood cell and granulocyte synthesis while sites such as the thymus and spleen are important for the maturation and proliferation of agranulocytes. Mammals were the first to develop the blood cell known as platelets. In mammals, circulating red blood cells lack nuclei (although a percentage of the red blood cells in reptiles are also anucleate).
In the mammalian heart, an interventricular septum completely divided the ancestral ventricle to creates right and left ventricles. The intrinsic conduction system of the heart developed an AV node. Mammals evolved vagal pathways from the nucleus ambiguous to regulate the heart.
Mammals developed complex coiled masses of blood vessels called rete mirable which occur in many mammalian tails, perhaps as a heat-saving device; humans still have the coccygeal glomus in their tail. Mammals lost their lateral head veins which were replaced by internal jugular veins. Mammals lost the ancestral renal portal system. Iliac veins now emptied into the posterior vena cava (as opposed to the lateral abdominal veins or renal portal veins). Mammals also lost the carotid duct connecting the carotid artery to dorsal aorta. In mammals, the right branch of the fourth aortic arch degenerated (its only remnant being the base of the right subclavian artery) and the left branch of the fourth aortic arch composes the aorta.

Valves (present in primitive lymph "hearts") developed in lymphatic vessels. Mammals evolved true lymph nodes, increased the number of lymph nodes sites over ancestral lymphatic tissue concentrations and evolved palatine and lingual tonsils only in mammals. The thymus forms from the ventral portions of pouches 3 and 4 instead of dorsal portions.
It seems that there was a duplication of the IgY gene in the ancestors of mammals and the two forms were modified to form IgG and IgY. All mammals use IgM, IgG, IgA, and IgE and lack the IgY used in reptiles. IgE only exists in mammals but present in all 3 groups groups of mammals. Much of the expansion of the expansion of the interleukin family has occurred mammals. Interleukin-6 evolved in mammals.