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 activate protein C in the degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free, only free protein S has activated protein C cofactor activity

Antithrombin III deficiency (abbreviated ATIII deficiency) is a of antithrombin III. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Inheritance is usually autosomal dominant, though a few recessive cases have been noted.

The disorder was first described by Egeberg in 1965.

The patients are treated with anticoagulants or, more rarely, with antithrombin concentrate.

In kidney failure, especially nephrotic syndrome, antithrombin is lost in the urine, leading to a higher activity of Factor II and Factor X and in increased tendency to thrombosis.

Symptoms may differ greatly, as apparently modifiers control to some degree the amount of FVII that is produced. Some affected individuals have few or no symptoms while others may experience life-threatening bleeding. Typically this bleeding disorder manifests itself as a tendency to easy bruising, nose bleeding, heavy and prolonged menstruation, and excessive bleeding after dental or surgical interventions. Newborns may bleed in the head, from the umbilicus, or excessively after circumcision. Other bleeding can be encountered in the gut, in muscles or joints, or the brain. Hematuria may occur.

While in congenital disease symptoms may be present at birth or show up later, in patients with acquired FVII deficiency symptoms typically show up in later life.

About 3-4% of patients with FVII deficiency may also experience thrombotic episodes.

Among the possibilities for differential diagnosis of protein S deficiency are- Antiphospholipid syndrome, disseminated intravascular coagulation and antithrombin deficiency (though this list is not exhaustive)

Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor (TF/factor III) in the extrinsic pathway.

The condition may be inherited or acquired. It is the most common of the rare congenital coagulation disorders.

While it is indicated that people with FXII deficiency are generally asymptomatic, studies in women with recurrent miscarriages suggest an association with FXII deficiency.

The condition is of importance in the differential diagnosis to other bleeding disorders, specifically the hemophilias: hemophilia A with a deficiency in factor VIII or antihemophilic globulin, hemophilia B with a deficiency in factor IX (Christmas disease), and hemophilia C with a deficiency in factor XI. Other rare forms of bleeding disorders are also in the differential diagnosis.

There is concern that individuals with FXII deficiency are more prone to thrombophilic disease, however, this is at variance with a long term study from Switzerland.

Warfarin-induced skin necrosis (or, more generally, Anticoagulant-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 anticoagulants (4-hydroxycoumarins, 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 petechial, 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, all areas with subcutaneous fat. 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.

Factor XII deficiency (also Hageman factor deficiency) is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.

The condition can be inherited or acquired.

The most common conditions associated with thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE), which are referred to collectively as venous thromboembolism (VTE). DVT usually occurs in the legs, and is characterized by pain, swelling and redness of the limb. It may lead to long-term swelling and heaviness due to damage to valves in the veins. The clot may also break off and migrate (embolize) to arteries in the lungs. Depending on the size and the location of the clot, this may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, shock and cardiac arrest.

Venous thrombosis may also occur in more unusual places: in the veins of the brain, liver (portal vein thrombosis and hepatic vein thrombosis), mesenteric vein, kidney (renal vein thrombosis) and the veins of the arms. Whether thrombophilia also increases the risk of arterial thrombosis (which is the underlying cause of heart attacks and strokes) is less well established.

Thrombophilia has been linked to recurrent miscarriage, and possibly various complications of pregnancy such as intrauterine growth restriction, stillbirth, severe pre-eclampsia and abruptio placentae.

Protein C deficiency may cause purpura fulminans, a severe clotting disorder in the newborn that leads to both tissue death and bleeding into the skin and other organs. The condition has also been described in adults. Protein C and protein S deficiency have also been associated with an increased risk of skin necrosis on commencing anticoagulant treatment with warfarin or related drugs.

Thrombophilia can be congenital or acquired. "Congenital thrombophilia" refers to inborn conditions (and usually hereditary, in which case ""hereditary thrombophilia"" may be used) that increase the tendency to develop thrombosis, while, on the other hand, "acquired thrombophilia" refers to conditions that arise later in life.

Many conditions mimic or may be mistaken for warfarin necrosis, including pyoderma gangrenosum 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.

Early purpura fulminans lesions look similar to traumatic skin bleeds or purpuric rashes, such as immune thrombocytopenic purpura or thrombotic thrombocytopenic purpura; however, purpura fulminans will rapidly progress to necrosis whereas other purpuric rashes do not. In most cases, differential diagnoses may be distinguished from purpura fulminans by other clinical and laboratory findings.

The initial appearance of purpura fulminans lesions is of well-demarcated erythematous lesions which progress rapidly to develop irregular central areas of blue-black haemorrhagic necrosis. Advancing areas of necrosis are often surrounded by a thin border of erythema that fades into adjacent unaffected skin. Haemorrhage into the necrotic skin causes purpura fulminans lesions to become painful, dark and raised, sometimes with vesicle or blister (bulla) formation.

The distribution of purpura fulminans lesions may be different according to the underlying pathogenesis. Purpura fulminans in severe sepsis typically develops in the distal extremities and progresses proximally or appears as a generalised or diffuse rash affecting the whole body surface. In cases of severe inheritable protein C deficiency, purpura fulminans with disseminated intravascular coagulation manifests within a few hours or days after birth.

The cardinal features of purpura investigations are the same as those of disseminated intravascular coagulation: prolonged plasma clotting times, thrombocytopenia, reduced plasma fibrinogen concentration, increased plasma fibrin-degradation products and occasionally microangiopathic haemolysis.

Heparin enhances ATIII activity and neutralizes "activated serine protease coagulation factors." Patients with ATIII deficiency requiring anticoagulant therapy with heparin will need higher doses of heparin. ATIII binds to thrombin and then forms the thrombin-anti thrombin complex or TAT complex. This is a major natural pathway of anticoagulation. This binding of thrombin to AT is greatly enhanced in the presence of heparin. Heparin does not affect vitamin K metabolism, so giving vitamin K1 (Phytonadione) will not reverse the effects of heparin.

Heparin is used as "bridging" therapy when initiating a patient on warfarin in a hospital setting. It can be used in DVT prophylaxis and treatment, acute coronary syndromes, and ST-segment elevated MI.

Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.

The diagnostic criteria require one clinical event (i.e. thrombosis or pregnancy complication) and two antibody blood tests spaced at least three months apart that confirm the presence of either lupus anticoagulant or anti-β-glycoprotein-I (since β-glycoprotein-I antibodies are a subset of anti-cardiolipin antibodies, an anti-cardiolipin assay can be performed as a less specific proxy).

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as systemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome" (CAPS or Asherson syndrome) and is associated with a high risk of death.

Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.

The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).

Antiphospholipid syndrome can cause arterial or venous blood clots, in any organ system, or pregnancy-related complications. In APS patients, the most common venous event is deep vein thrombosis of the lower extremities, and the most common arterial event is stroke. In pregnant women affected by APS, there is an increased risk of recurrent miscarriage, intrauterine growth restriction, and preterm birth. A frequent cause of such complications is placental infarctions.

In some cases, APS seems to be the leading cause of mental and/or development retardation in the newborn, due to an aPL-induced inhibition of trophoblast differentiation. The antiphospholipid syndrome responsible for most of the miscarriages in later trimesters seen in concomitant systemic lupus erythematosus and pregnancy.

Other common findings, although not part of the APS classification criteria, are low platelet count, heart valve disease, and livedo reticularis. There are also associations between antiphospholipid antibodies and headaches, migraines, and oscillopsia. Some studies have shown the presence of antiphospholipid antibodies in the blood and spinal fluid of patients with psychological symptoms.

Very few patients with primary APS go on to develop SLE.

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome. Nephrotic syndrome, a kidney disorder, causes excessive loss of protein in the urine, hypoalbuminemia, hypercholesterolemia and edema, triggering a hypercoagulable state and increasing chances of clot formation. Other less common causes include hypercoagulable state, cancer, renal transplantation, behcet syndrome, antiphospholipid antibody syndrome or blunt trauma to the back or abdomen. Treatment of RVT mainly focuses on preventing further blood clots in the kidneys and maintaining stable renal function. The use of anticoagulants has become the standard treatment in treating this abnormality. Membranous Glomerulonephritis, the most common cause for nephrotic syndrome in adults, peaks in people ages 40–60 years old and It is twice as likely to occur in men than in women. Since nephrotic syndrome is the most common cause of RVT, people over 40 years old and men are most at risk to develop a renal vein thrombosis.

Common signs and symptoms of DVT include pain or tenderness, swelling, warmth, redness or discoloration, and distention of surface veins, although about half of those with the condition have no symptoms. Signs and symptoms alone are not sufficiently sensitive or specific to make a diagnosis, but when considered in conjunction with known risk factors, can help determine the likelihood of DVT. In most suspected cases, DVT is ruled out after evaluation, and symptoms are more often due to other causes, such as cellulitis, Baker's cyst, musculoskeletal injury, or lymphedema. Other differential diagnoses include hematoma, tumors, venous or arterial aneurysms, and connective tissue disorders.

Phlegmasia cerulea dolens is a very large and dangerous type of DVT. It is characterized by an acute and almost total venous occlusion of the entire extremity outflow, including the iliac and femoral veins. The leg is usually painful, tinged blue in color, and swollen, which may result in venous gangrene.

Aside from the occasional flank or lower back pain caused by a sudden clot in the major veins to the kidneys, RVT produces few symptoms. Some patients may not display any symptoms while other patients may experience bloody urine, decrease in urine output, edema and worsening proteinuria. Usually the diagnoses of RVT is first made when a nephrotic syndrome patient experiences a pulmonary embolism or a sudden decrease in renal function or renal failure. These symptoms may vary in duration since a blood clot can resolve itself, but precautions should be taken to prevent the migration of the clot to other parts of the body. The most severe complication of RVT is a pulmonary embolism, caused by a clot, also called a thrombus, that originates from the renal vein or any other vein in the body and migrates to the pulmonary artery. A pulmonary embolism is a serious condition because; it can damage the lungs due to pulmonary hypertension and cause low blood oxygen, damaging other organs in the body. This condition can cause death if left untreated; about 30% percent of patients who have a pulmonary embolism will die, usually within one hour.

Infants and young children experiencing dehydration induced RVT, may experience dehydration symptoms (dry mouth, low urine output, loss of skin turgidity) as while as vomiting, nausea and fever, and the usual RVT symptoms like flank pain, blood in the urine, anaemia, edema, enlarged kidneys and kidney failure.

Deep vein thrombosis (DVT), is the formation of a blood clot in a deep vein, most commonly the legs. Symptoms may include pain, swelling, redness, or warmth of the affected area. About half of cases have no symptoms. Complications may include pulmonary embolism, as a result of detachment of a clot which travels to the lungs, and post-thrombotic syndrome.

Risk factors include recent surgery, cancer, trauma, lack of movement, obesity, smoking, hormonal birth control, pregnancy and the period following birth, antiphospholipid syndrome, and certain genetic conditions. Genetic factors include deficiencies of antithrombin, protein C, and protein S, and factor V Leiden mutation. The underlying mechanism typically involves some combination of decreased blood flow rate, increased tendency to clot, and injury to the blood vessel wall.

Individuals suspected of having DVT may be assessed using a clinical prediction rule such as the Wells score. A D-dimer test may also be used to assist with excluding the diagnosis or to signal a need for further testing. Diagnosis is most commonly confirmed by ultrasound of the suspected veins. Together, DVT and pulmonary embolism are known as venous thromboembolism (VTE).

Anticoagulation (blood thinners) is the standard treatment. Typical medications include low-molecular-weight heparin, warfarin, or a direct oral anticoagulant. Wearing graduated compression stockings may reduce the risk of post-thrombotic syndrome. Prevention may include early and frequent walking, calf exercises, aspirin, anticoagulants, graduated compression stockings, or intermittent pneumatic compression. The rate of DVTs increases from childhood to old age; in adulthood, about one in 1000 adults are affected per year. About 5% of people are affected by a VTE at some point in time.

Symptoms generally begin around puberty but can occur earlier. These individuals have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract. Some patients describe a sensation of fullness but not pain or itching in the affected area except for those with abdominal swellings who often experience acute abdominal pain. Others experience an intense amount of pain, described as radiating from the bone outward along with intense itching just beneath the skin and intense heat, regardless of the area targeted.

Instances of swelling around the throat or larynx can cause difficulties in breathing should the swelling obstruct airways. This has been known to cause a large number of fatalities in those afflicted with the disorder. Episodes that attack the gastrointestinal tract can cause a number of complications including dehydration from being unable to keep anything down (which, depending on length of the episode, can prove fatal). Symptoms from gI tract swelling including violent vomiting, intense pain from the midsection, dehydration, and intense exhaustion.

Some suffered of HAE suffer from 'wandering' attacks. These attacks will center around an extremity. For example: Should the sufferer's hand swell up, it will go through the normal swelling cycle before 'transferring' to either the connection limb (In this case wrist to forearm) or move to the opposite hand. Sufferers with this symptom may find their episodes last longer, and may find their triggers more difficult to track.

Affected infants present within a few months after birth with failure to thrive and severe folate deficiency manifested as macrocytic anemia and developmental delays. There can be (i) pancytopenia, (ii) diarrhea and/or mucositis and/or (iii) immune deficiency due to T-cell dysfunction and hypoimmunoglobulinemia resulting in pneumonia usually due to Pneumocystis jirovecii. Recently, several infants with the immune deficiency syndrome were described. Untreated, or with inadequate treatment, there are progressive systemic and neurological signs with a spectrum of manifestations including seizures that are often intractable. Females with HFM are fertile and, if folate sufficient during pregnancy, have normal offspring. Subjects that carry one mutated PCFT allele are normal. The genomic and clinical features of HFM were recently reviewed.

Hereditary angioedema (HAE) is disorder that results in recurrent attacks of severe swelling. This most commonly affects the arms, legs, face, intestinal tract, and airway. Itchiness does not typically occur. If the intestinal tract is affected abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction. Attacks, without treatment, typically occur every couple of weeks and last for a few days.

There are three main types of HAE. Type I and II are caused by a mutation in the SERPING1 gene that makes the C1 inhibitor protein while type III is often due to a mutation of the factor XII gene. This results in increased amounts of bradykinin which promotes swelling. The condition may be inherited from a person's parents in an autosomal dominant manner or occur as a new mutation. Triggers of an attack may include minor trauma or stress, but often occurs without any obvious preceding event. Diagnosis of type I and II is based upon measuring C4 and C1-inhibitor levels.

Management involves efforts to prevent attacks and the treatment of attacks if they occur. During an attack supportive care such as intravenous fluids and airway support may be required. The medication C1 esterase inhibitor can be used for both prevention and treatment. Ecallantide and icatibant can be used to treat acute attacks.

This disorder affects approximately one in 50,000 people. The condition is typically first noticed in childhood. Type I and II affected females and males equally. Type III affects females more often than males. When the airway is involved, without treatment, death occurs in about 25%. With treatment outcomes are generally good. The condition was first described in 1888 by William Osler.

Hereditary folate malabsorption (HFM - OMIM #229050) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.

Mutations in the FAH, TAT, or HPD gene cause a decrease in the activity of one of the enzymes in the breakdown of tyrosine.

As a result, tyrosine and its byproducts accumulate to toxic levels, which can cause damage and death to cells in the liver, kidneys, nervous system, and other organs.