Cryofibrinogenemia Summary



Cryofibrinogenemia Epidemiology:

 • 40-70 years with a modest female predominance



Cryofibrinogenemia:

 • The precipitation of a complex when plasma is cooled from the normal body temperature of 37°C to the near-freezing temperature of 4°C.

 • This precipitating complex contains fibrinogen, fibrin, fibronectin, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins which can plug blood vessels.

 • Cryofibrinogen is distinguished from cryoglobulin (CG) since, it precipitates only in plasma and not in serum.

 • Cryoglobulins precipitate in serum + plasma



Cryofibrinogen - Cryofibrinogen is a cold insoluble complex of:

 • Fibrin

 • Fibrinogen

 • Fibrin split products with:

	- Albumin

	- Cold insoluble globulin

	- Factor VIII

	- Plasma proteins



Cryofibrinogenemia Symptoms:

 • Asymptomatic or combination of:

	- Hyperviscosity,

	- Vascular reactivity (Skin necrosis)

	- Thrombosis (Thrombotic vasculopathy)

 • Paradoxical spontaneous bleeding may occur due to the depletion of clotting factors



Cryofibrinogenemia Can Be Divided Into Two Types:

1. Primary (essential)

2. Secondary form associated with autoimmune diseases, malignancies, vasculitis, sepsis or cryoglobulinemia

Associated Disorders:

 • Malignancy

 • Infections including coronavirus disease 2019 (COVID-19)

 • Inflammatory processes:

 • Systemic rheumatic diseases

 • Thromboembolic conditions



Cryofibrinogenemia Clinical Manifestations - Findings may include:

 • Cold sensitivity

 • Painful ulcers

 • Skin necrosis

 • Purpura

 • Livedo reticularis

 • Painful or pruritic erythema (perniosis) of the extremities

 • Arthralgias

 • Raynaud phenomenon

 • Simulates calciphylaxis clinicopathologically,

	- Related conditions: Stroke, myocardial infarction, limb and bowel ischemia or infarction, thrombophlebitis, pulmonary emboli, and ocular thrombi including retinal arterial and/or venous occlusions, as well as gangrene



Cryofibrinogenemia Diagnosis:

 • + Clinical findings/Presentation

 • Asymptomatic: Plasma (CF) cryofibrinogen levels < than 50 mg/L

	- Significant levels >1g/L

 • Negative cryoglobulins

 • Negative causes of secondary cryofibrinogenemia.

 • Biopsy: Typical pathologic findings on biopsy of affected tissue

 • Angio: Occlusion of small to medium-sized arteries

 • Secondary CF: Presence of associated disease



Cryofibrinogenemia DDX:

 • Calciphylaxis

 • Cryoglobulinemia

 • TTP, HUS and HIT

 • Antiphospholipid syndrome

 • Warfarin-induced skin necrosis

 • DIC

 • Septic emboli

 • Frostbite

 • Atherosclerotic PVD

 • Atheroemboli



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