Warfarin necrosis
Encyclopedia
Warfarin-induced skin necrosis (or, more generally, coumadin-induced skin necrosis) is a condition in which skin
and subcutaneous tissue
necrosis
(tissue death) occurs due to acquired protein C deficiency
following treatment with anti-vitamin K
anticoagulant
s (coumarin
s, such as warfarin
).
Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants. The typical patient appears to be an obese, middle aged woman (median age 54 years, male to female ratio 1:3). This drug eruption
usually occurs between the third and tenth days of therapy with warfarin derivatives. The first symptoms are pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechia
l, then hard and purpuric
. They may then resolve or progress to form large, irregular, bloody bullae
with eventual necrosis and slow-healing eschar
formation. Favored sites are breasts, thighs, buttocks and penis. In rare cases, the fascia
and muscle
are involved.
Development of the syndrome is associated with the use of large loading doses at the start of treatment.
In warfarin's initial stages of action, inhibition of protein C
and Factor VII
is stronger than inhibition of the other vitamin K
-dependent coagulation factors II, IX
and X
. This results from the fact that these proteins have different half-lives
: 1.5 to six hours for factor VII and eight hours for protein C, versus one day for factor IX, two days for factor X and two to five days for factor II. The larger the initial dose of vitamin K-antagonist, the more pronounced these differences are. This coagulation factor imbalance leads to paradoxical activation of coagulation, resulting in a hypercoagulable state and thrombosis
. The blood clots interrupt the blood supply to the skin, causing necrosis. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it can lead to massive thrombosis with necrosis and gangrene of limbs.
Notably, the prothrombin time
(or international normalized ratio, INR) used to test the effect of coumarins is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state.
In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. The condition is related to purpura fulminans
, a complication in infants with sepsis
(blood stream infection) which also involves skin necrosis. These infants often have protein C deficiency as well. There have also been cases in patients with other deficiency, including protein S deficiency
, activated protein C resistance
(Factor V Leiden) and antithrombin III deficiency
.
Although the above theory is the most commonly accepted theory, others believe that it is a hypersensitivity reaction or a direct toxic effect.
or its low molecular weight heparin
(LMWH) can be used in an attempt to prevent further clotting. None of these suggested therapies have been studied in clinical trial
s.
Heparin and LMWH act by a different mechanism than warfarin, so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis (this is called 'bridging').
Because low levels of protein C are involved in the underlying mechanism, fresh frozen plasma
or pure activated protein C has been used in this setting.
The necrotic skin areas are treated as in other conditions, sometimes healing spontaneously with or without scarring, sometimes going on to require surgical debridement
or skin grafting. The risk of death is mainly related to underlying disorders for which anticoagulation is started (for example, recurrent pulmonary embolism
).
Since the clot-promoting effects of coumarins are transitory, patients with protein C deficiency or previous warfarin necrosis can still be restarted on these drugs if appropriate measures are taken. These include gradual increase starting from low doses and supplemental administration of protein C (pure or from fresh frozen plasma).
or necrotizing fasciitis
. Warfarin necrosis is also different from another drug eruption associated with warfarin, purple toe syndrome, which usually occurs three to eight weeks after the start of anticoagulation therapy. No report has described this disorder in the immediate postpartum period in patients with protein S deficiency.
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
and subcutaneous tissue
Subcutaneous tissue
The hypodermis, also called the hypoderm, subcutaneous tissue, or superficial fascia is the lowermost layer of the integumentary system in vertebrates. Types of cells that are found in the hypodermis are fibroblasts, adipose cells, and macrophages...
necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
(tissue death) occurs due to acquired protein C deficiency
Protein C deficiency
Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population...
following treatment with anti-vitamin K
Vitamin K antagonist
Vitamin K antagonists are a class of anticoagulants. They reduce blood clotting by inhibiting the recycling of vitamin K epoxide back to the active reduced form of vitamin K. The term Vitamin K antagonists is a misnomer. These drugs do NOT antagonize the action of Vitamin K...
anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
s (coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...
s, such as warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
).
Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants. The typical patient appears to be an obese, middle aged woman (median age 54 years, male to female ratio 1:3). This drug eruption
Drug eruption
In medicine, a drug eruption is an adverse drug reaction of the skin. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn. Drugs can also cause hair and nail changes, affect the mucous membranes, or cause itching without outward skin...
usually occurs between the third and tenth days of therapy with warfarin derivatives. The first symptoms are pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechia
Petechia
A petechia is a small red or purple spot on the body, caused by a minor hemorrhage ."Petechiae" refers to one of the three major classes of purpuric skin conditions. Purpuric eruptions are classified by size into three broad categories...
l, then hard and purpuric
Purpura
Purpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin...
. They may then resolve or progress to form large, irregular, bloody bullae
Blister
A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...
with eventual necrosis and slow-healing eschar
Eschar
An eschar is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, necrotizing spider bite wounds, and exposure to cutaneous anthrax....
formation. Favored sites are breasts, thighs, buttocks and penis. In rare cases, the fascia
Fascia
A fascia is a layer of fibrous tissue that permeates the human body. A fascia is a connective tissue that surrounds muscles, groups of muscles, blood vessels, and nerves, binding those structures together in much the same manner as plastic wrap can be used to hold the contents of sandwiches...
and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
are involved.
Development of the syndrome is associated with the use of large loading doses at the start of treatment.
Disease mechanism
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
and Factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
is stronger than inhibition of the other vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
-dependent coagulation factors II, IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
and X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
. This results from the fact that these proteins have different half-lives
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
: 1.5 to six hours for factor VII and eight hours for protein C, versus one day for factor IX, two days for factor X and two to five days for factor II. The larger the initial dose of vitamin K-antagonist, the more pronounced these differences are. This coagulation factor imbalance leads to paradoxical activation of coagulation, resulting in a hypercoagulable state and thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. The blood clots interrupt the blood supply to the skin, causing necrosis. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it can lead to massive thrombosis with necrosis and gangrene of limbs.
Notably, the prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
(or international normalized ratio, INR) used to test the effect of coumarins is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state.
In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. The condition is related to purpura fulminans
Purpura fulminans
Purpura fulminans is a haemorrhagic condition usually associated with sepsis or previous infection. It occurs mainly in babies and small children.It was first described by Guelliot in 1884.- Presentation :...
, a complication in infants with sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
(blood stream infection) which also involves skin necrosis. These infants often have protein C deficiency as well. There have also been cases in patients with other deficiency, including protein S deficiency
Protein S deficiency
Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa...
, activated protein C resistance
Activated protein C resistance
Activated protein C resistance is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C . This results in an increased risk of venous thrombosis, which can cause heart attacks, strokes, and other problems with circulation.The disorder can be acquired or...
(Factor V Leiden) and antithrombin III deficiency
Antithrombin III deficiency
Antithrombin III deficiency is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism...
.
Although the above theory is the most commonly accepted theory, others believe that it is a hypersensitivity reaction or a direct toxic effect.
Treatment and prevention
The first element of treatment is usually to discontinue the offending drug, although there have been reports describing how the eruption evolved little after it had established in spite of continuing the medication. Vitamin K can be used to reverse the effects of coumarins, and heparinHeparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
or its low molecular weight heparin
Low molecular weight heparin
In medicine, low-molecular-weight heparin is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis....
(LMWH) can be used in an attempt to prevent further clotting. None of these suggested therapies have been studied in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Heparin and LMWH act by a different mechanism than warfarin, so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis (this is called 'bridging').
Because low levels of protein C are involved in the underlying mechanism, fresh frozen plasma
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...
or pure activated protein C has been used in this setting.
The necrotic skin areas are treated as in other conditions, sometimes healing spontaneously with or without scarring, sometimes going on to require surgical debridement
Debridement
Debridement is the medical removal of a patient's dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue...
or skin grafting. The risk of death is mainly related to underlying disorders for which anticoagulation is started (for example, recurrent pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
).
Since the clot-promoting effects of coumarins are transitory, patients with protein C deficiency or previous warfarin necrosis can still be restarted on these drugs if appropriate measures are taken. These include gradual increase starting from low doses and supplemental administration of protein C (pure or from fresh frozen plasma).
Differential diagnosis
Many conditions mimic or may be mistaken for warfarin necrosis, including pyoderma gangrenosumPyoderma gangrenosum
Pyoderma gangrenosum is a disease that causes tissue to become necrotic, causing deep ulcers that usually occur on the legs. When they occur, they can lead to chronic wounds. Ulcers usually initially look like small bug bites or papules, and they progress to larger ulcers. Though the wounds...
or necrotizing fasciitis
Necrotizing fasciitis
Necrotizing fasciitis , commonly known as flesh-eating disease or Flesh-eating bacteria syndrome, is a rare infection of the deeper layers of skin and subcutaneous tissues, easily spreading across the fascial plane within the subcutaneous tissue.Necrotizing fasciitis is a quickly progressing and...
. Warfarin necrosis is also different from another drug eruption associated with warfarin, purple toe syndrome, which usually occurs three to eight weeks after the start of anticoagulation therapy. No report has described this disorder in the immediate postpartum period in patients with protein S deficiency.