All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

Cryoglobulinemia, cryoglobulinaemia, or cryoglobulinemic disease, is a medical condition in which the blood contains large amounts of cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

Cryoglobulins typically precipitate at temperatures below normal body temperatureand will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.

In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins.

Paraproteinemia, also known as monoclonal gammopathy, is the presence of excessive amounts of paraprotein or single monoclonal gammaglobulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia.

Paraproteinemias may be categorized according to the type of monoclonal protein found in blood:

- Light chains only (or Bence Jones protein). This may be associated with multiple myeloma or AL amyloidosis.

- Heavy chains only (also known as "heavy chain disease");

- Whole immunoglobulins. In this case, the paraprotein goes under the name of "M-protein" ("M" for monoclonal). If immunoglobulins tend to precipitate within blood vessels with cold, that phenomenon takes the name of cryoglobulinaemia.

The three types of paraproteins may occur alone or in combination in a given individual. Note that while most heavy chains or whole immunoglobulins remain within blood vessels, light chains frequently escape and are excreted by the kidneys into urine, where they take the name of Bence Jones protein.

It is also possible for paraproteins (usually whole immunoglobulins) to form polymers by aggregating with each other; this takes the name of macroglobulinemia and may lead to further complications. For example, certain macroglobulins tend to precipitate within blood vessel with cold, a phenomenon known as cryoglobulinemia. Others may make blood too viscous to flow smoothly (usually with IgM pentamer macroglobulins), a phenomenon known as Waldenström macroglobulinemia.

A number of conditions may cause the appearance of livedo reticularis:

- Cutis marmorata telangiectatica congenita, a rare congenital condition

- Sneddon syndrome – association of livedoid vasculitis and systemic vascular disorders, such as strokes, due to underlying genetic cause

- Idiopathic livedo reticularis – the most common form of livedo reticularis, completely benign condition of unknown cause affecting mostly young women during the winter: It is a lacy purple appearance of skin in extremities due to sluggish venous blood flow. It may be mild, but ulceration may occur later in the summer.

- Secondary livedo reticularis:

- Vasculitis autoimmune conditions:

- Livedoid vasculitis – with painful ulceration occurring in the lower legs

- Polyarteritis nodosa

- Systemic lupus erythematosus

- Dermatomyositis

- Rheumatoid arthritis

- Lymphoma

- Pancreatitis

- Chronic pancreatitis

- Tuberculosis

- Drug-related:

- Adderall (side effect)

- Amantadine (side effect)

- Bromocriptine (side effect)

- Beta IFN treatment, "i.e." in multiple sclerosis

- Livedo reticularis associated with rasagiline

- Methylphenidate and dextroamphetamine-induced peripheral vasculopathy

- Gefitinib

- Obstruction of capillaries:

- Cryoglobulinaemia – proteins in the blood that clump together in cold conditions

- Antiphospholipid syndrome due to small blood clots

- Hypercalcaemia (raised blood calcium levels which may be deposited in the capillaries)

- Haematological disorders of polycythaemia rubra vera or thrombocytosis (excessive red cells or platelets)

- Infections (syphilis, tuberculosis, Lyme disease)

- Associated with acute renal failure due to cholesterol emboli status after cardiac catheterization

- Arteriosclerosis (cholesterol emboli) and homocystinuria (due to Chromosome 21 autosomal recessive Cystathionine beta synthase deficiency)

- Intra-arterial injection (especially in drug addicts)

- Ehlers-Danlos syndrome – connective tissue disorder, often with many secondary conditions, may be present in all types

- Pheochromocytoma

- Livedoid vasculopathy and its association with factor V Leiden mutation

- FILS syndrome (polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature)

- Primary hyperoxaluria, oxalosis (oxalate vasculopathy)

- Cytomegalovirus infection (very rare clinical form, presenting with persistent fever and livedo reticularis on the extremities and cutaneous necrotizing vasculitis of the toes)

- Generalized livedo reticularis induced by silicone implants for soft tissue augmentation

- As a rare skin finding in children with Down syndrome

- Idiopathic livedo reticularis with polyclonal IgM hypergammopathy

- CO angiography (rare, reported case)

- A less common skin lesion of Churg-Strauss syndrome

- Erythema nodosum-like cutaneous lesions of sarcoidosis showing livedoid changes in a patient with sarcoidosis and Sjögren's syndrome

- Livedo vasculopathy associated with IgM antiphosphatidylserine-prothrombin complex antibody

- Livedo vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity and prothrombin G20210A heterozygosity

- As a first sign of metastatic breast carcinoma (very rare)

- Livedo reticularis associated with renal cell carcinoma (rare)

- Buerger's disease (as an initial symptom)

- As a rare manifestation of Graves hyperthyroidism

- Associated with pernicious anaemia

- Moyamoya disease (a rare, chronic cerebrovascular occlusive disease of unknown cause, characterized by progressive stenosis of the arteries of the circle of Willis leading to an abnormal capillary network and resultant ischemic strokes or cerebral hemorrhages)

- Associated with the use of a midline catheter

- Familial primary cryofibrinogenemia.

Other than identifying and treating any underlying conditions in secondary livedo, idiopathic livedo reticularis may improve with warming the area.

Meltzer’s triad describes the classical symptoms suggesting the diagnosis of cryoglobulinaemia of polyclonal CGs seen in essential-, viral-, or connective tissue disease-associated cryoglobulinaemia. The triad consists of:

- palpable purpura

- arthralgia (joint pain)

- weakness.