Heterozygous protein C deficiency occurs in 0.14–0.50% of the general population. Based on an estimated carrier rate of 0.2%, a homozygous or compound heterozygous protein C deficiency incidence of 1 per 4 million births could be predicted, although far fewer living patients have been identified. This low prevalence of patients with severe genetic protein C deficiency may be explained by excessive fetal demise, early postnatal deaths before diagnosis, heterogeneity in the cause of low concentrations of protein C among healthy individuals and under-reporting.

The incidence of protein C deficiency in individuals who present with clinical symptoms has been reported to be estimated at 1 in 20,000.

Protein C is vitamin K-dependent. Patients with Protein C deficiency are at an increased risk of developing skin necrosis while on warfarin. Protein C has a short half life (8 hour) compared with other vitamin K-dependent factors and therefore is rapidly depleted with warfarin initiation, resulting in a transient hypercoagulable state.

In terms of the cause of protein S deficiency it can be in "inherited" via autosomal dominance.A mutation in the PROS1 gene triggers the condition. The cytogenetic location of the gene in question is chromosome 3, specifically 3q11.1 Protein S deficiency can also be "acquired" due to vitamin K deficiency, treatment with warfarin, liver disease, and acute thrombosis (antiphospholipid antibodies may also be a cause as well)

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

Purpura fulminans is rare and most commonly occurs in babies and small children but can also be a rare manifestation in adults when it is associated with severe infections. For example, Meningococcal septicaemia is complicated by purpura fulminans in 10–20% of cases among children. Purpura fulminans associated with congenital (inherited) protein C deficiency occurs in 1:500,000–1,000,000 live births.

Newborns are relatively vitamin K deficient for a variety of reasons. They have low vitamin K stores at birth, vitamin K passes the placenta poorly, the levels of vitamin K in breast milk are low and the gut flora has not yet been developed (vitamin K is normally produced by intestinal bacteria).

An estimated 64 percent of patients with venous thromboembolism may have activated protein C resistance.

Precise diagnosis by measuring proteins induced by vitamin k absence (PIVKA).

But this is usually not required.

Activated protein C (with protein S as a cofactor) degrades Factor Va and Factor VIIIa. Activated protein C resistance is the inability of protein C to cleave Factor Va and/or Factor VIIIa, which allows for longer duration of thrombin generation and may lead to a hypercoagulable state. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.

The prevalence of vitamin K deficiency varies by geographic region. For infants in the United States, vitamin K deficiency without bleeding may occur in as many as 50% of infants younger than 5 days old, with the classic hemorrhagic disease occurring in 0.25-1.7% of infants. Therefore, the Committee on Nutrition of the American Academy of Pediatrics recommends that 0.5 to 1.0 mg Vitamin K be administered to all newborns shortly after birth.

Postmenopausal and elderly women in Thailand have high risk of Vitamin K deficiency, compared with the normal value of young, reproductive females.

Current dosage recommendations for Vitamin K may be too low. The deposition of calcium in soft tissues, including arterial walls, is quite common, especially in those suffering from atherosclerosis, suggesting that Vitamin K deficiency is more common than previously thought.

Because colonic bacteria synthesize a significant portion of the Vitamin K required for human needs, individuals with disruptions to or insufficient amounts of these bacteria can be at risk for Vitamin K deficiency. Newborns, as mentioned above, fit into this category, as their colons are frequently not adequately colonized in the first five to seven days of life. (Consumption of the mother's milk can undo this temporary problem.) Another at-risk population comprises those individuals on any sort of long-term antibiotic therapy, as this can diminish the population of normal gut flora.

Due to the rarity of Purpura fulminans and its occurrence in vulnerable patient groups like children research on the condition is very limited and evidence based knowledge is scarce. Currently, there is only one Purpura fulminans related clinical research project, http://www.sapfire-registry.org/, which is registered with clinicaltrials.gov.

Menaquinone (vitamin K), but not phylloquinone (vitamin K), intake is associated with reduced risk of CHD mortality, all-cause mortality and severe aortic calcification.

Since the essential pathology is due to the inability to absorb vitamin B from the bowels, the solution is therefore injection of IV vitamin B. Timing is essential, as some of the side effects of vitamin B deficiency are reversible (such as RBC indices, peripheral RBC smear findings such as hypersegmented neutrophils, or even high levels of methylmalonyl CoA), but some side effects are irreversible as they are of a neurological source (such as tabes dorsalis, and peripheral neuropathy). High suspicion should be exercised when a neonate, or a pediatric patient presents with anemia, proteinuria, sufficient vitamin B dietary intake, and no signs of pernicious anemia.

Haemophilia C is caused by a deficiency of coagulation factor XI and is distinguished from haemophilia A and B by the fact it does not lead to bleeding into the joints. Furthermore, it has autosomal recessive inheritance, since the gene for factor XI is located on chromosome 4 (near the prekallikrein gene); and it is not completely recessive, individuals who are heterozygous also show increased bleeding.

Many mutations exist, and the bleeding risk is not always influenced by the severity of the deficiency. Hemophilia C is developed on occasion in individuals with systemic lupus erythematosus, because of inhibitors to the FXI protein.

Inherited or congenital FVII deficiency is passed on by autosomal recessive inheritance. A person needs to inherit a defective gene from both parents. People who have only one defective gene do not exhibit the disease, but can pass the gene on to half their offspring. Different genetic mutations have been described.

In persons with the congenital FVII deficiency the condition is lifelong. People with this condition should alert other family members may they also have the condition or carry the gene. In the general population the condition affects about 1 in 300,000 to 500,000 people. However, the prevalence may be higher as not all individuals may express the disease and be diagnosed.

In the acquired of FVII deficiency an insufficient amount of factor VII is produced by the liver due to liver disease, vitamin K deficiency, or certain medications (i.e. Coumadin).

This is a rare disease with prevalence about 1 in 200,000 to 1 in 600,000. Studies showed that mutations in "CUBN" or "AMN" clustered particularly in the Scandinavian countries and the Eastern Mediterranean regions. Founder effect, higher clinical awareness to IGS, and

frequent consanguineous marriages all play a role in the higher prevalence of IGS among these populations

Two Dutch studies have followed hemophilia patients for a number of years. Both studies found that viral infections were common in hemophiliacs due to the frequent blood transfusions which put them at risk of getting blood borne infections such as HIV and hepatitis C. In the latest study which followed patients from 1992 to 2001, the male life expectancy was 59 years. If cases with known viral infections were excluded, the life expectancy was 72, close to that of the general population. 26% of the cases died from AIDS and 22% from hepatitis C.

There are several treatments available for factor VII deficiency; they all replace deficient FVII.

1. Recombinant FVIIa concentrate (rFVIIa) is a recombinant treatment that is highly effective and has no risk of fluid overload or viral disease. It may be the optimal therapy.

2. Plasma derived Factor VII concentrate (pdFVII) : This treatment is suitable for surgery but can lead to thrombosis. It is virus attenuated.

3. Prothrombin complex concentrate (PCC) containing factor VII: this treatment is suitable for surgery, but has a risk of thrombosis. It is virus attenuated.

4. Fresh frozen plasma (FFP): This is relatively inexpensive and readily available. While effective this treatment carries a risk of blood-borne viruses and fluid overload.

In terms of the signs/symptoms of haemophilia C, unlike individuals with Haemophilia A and B, people affected by it are not ones to bleed spontaneously. In these cases, haemorrhages tend to happen after a major surgery or injury. However, people affected with haemophilia C might experience symptoms closely related to those of other forms of haemophilia such as the following:

Haemophilia A occurs in approximately 1 in 5,000 males, while the incidence of haemophilia B is 1 in 30,000 in male population, of these, 85% have haemophilia A and 15% have hemophilia B.

The cause of complement deficiency is genetics (though cases of an acquired nature do exist post infection). The majority of complement deficiencies are autosomal recessive, while properdin deficiency could be X-linked inheritance, and finally MBL deficiency can be both.

Haemophilia B (or hemophilia B) is a blood clotting disorder caused by a mutation of the factor IX gene, leading to a deficiency of factor IX. It is the second-most common form of haemophilia, rarer than haemophilia A. Haemophilia B was first recognized as a different kind of haemophilia in 1952. It is sometimes called Christmas disease, named after Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the "British Medical Journal".

Two Dutch studies have followed hemophilia patients for a number of years. Both studies found that viral infections were common in hemophiliacs due to the frequent blood transfusions which put them at risk of getting blood borne infections such as HIV and hepatitis C. In the latest study which followed patients from 1992 to 2001, the male life expectancy was 59 years. If cases with known viral infections were excluded, the life expectancy was 72, close to that of the general population. 26% of the cases died from AIDS and 22% from hepatitis C.

In people without a detectable thrombophilia, the cumulative risk of developing thrombosis by the age of 60 is about 12%. About 60% of people who are deficient in antithrombin will have experienced thrombosis at least once by age 60, as will about 50% of people with protein C deficiency and about a third of those with protein S deficiency. People with activated protein C resistance (usually resulting from factor V Leiden), in contrast, have a slightly raised absolute risk of thrombosis, with 15% having had at least one thrombotic event by the age of sixty. In general, men are more likely than women to experience repeated episodes of venous thrombosis.

People with factor V Leiden are at a relatively low risk of thrombosis, but may develop thrombosis in the presence of an additional risk factor, such as immobilization. Most people with the prothrombin mutation (G20210A) never develop thrombosis.

Warfarin necrosis usually occurs three to five days after drug therapy is begun, and a high initial dose increases the risk of its development. Heparin-induced necrosis can develop both at sites of local injection and - when infused intravenously - in a widespread pattern.

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 warfarin 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.