Amyloidosis causes amyloid deposition within vessels in the skin and subcutaneous tissues, which may increase vascular fragility, causing purpura. Purpura typically occur on the upper extremities in contrast to immune thrombocytopenia, in which purpura occur mostly in the lower extremities. In some patients, coagulation factor X is adsorbed by amyloid and becomes deficient, but this deficiency is usually not the cause of bleeding. Periorbital purpura or a purpuric rash that develops in a nonthrombocytopenic patient after gentle stroking of the skin suggests amyloidosis. Some patients with amyloidosis have macroglossia (enlarged tongue).

Most patients have elevated levels of serum free light chains. The diagnosis is confirmed by tissue biopsy (eg, Congo red birefringence staining of fat pad aspirate).

Cryoglobulinemia produces immunoglobulins that precipitate when plasma is cooled (ie, cryoglobulins) while flowing through the skin and subcutaneous tissues of the extremities. Monoclonal immunoglobulins formed in Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma) or in multiple myeloma occasionally behave as cryoglobulins, as may mixed IgM-IgG immune complexes formed in some chronic infectious diseases, most commonly hepatitis C. Cryoglobulinemia can also lead to small-vessel vasculitis, which can cause purpura. Cryoglobulins can be detected by laboratory testing.

Hypergammaglobulinemic purpura is a vasculitic purpura that primarily affects women. Recurrent crops of small, palpable purpuric lesions develop on the lower legs. These lesions leave small residual brown spots. Many patients have manifestations of an underlying immunologic disorder (eg, Sjögren syndrome, SLE). The diagnostic finding is a polyclonal increase in IgG.

Hyperviscosity syndrome, usually resulting from a markedly elevated plasma IgM concentration, may also result in purpura and other forms of abnormal bleeding (eg, profuse epistaxis) in patients with macroglobulinemia. Marked elevations of other immunoglobulins (especially IgA and IgG₃) can also be associated with hyperviscosity syndrome.