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. Protein C deficiency is associated with an increased incidence of venous thromboembolism (relative risk 8–10), whereas no association with arterial thrombotic disease has been found.

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.

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

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)

The disease causes an increased risk of bleeding. The most common sites of bleeding are the umbilicus, mucous membranes, gastrointestinal tract, circumcision and venepunctures.

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.

Haemorrhagic disease of the newborn, also known as vitamin K deficiency bleeding (VKDB), is a coagulation disturbance in newborn infants due to vitamin K deficiency. As a consequence of vitamin K deficiency there is an impaired production of coagulation factors II, VII, IX, X, protein C and protein S by the liver, resulting in excessive bleeding (hemorrhage).

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

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.

Activated protein C resistance (APCR) is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). This results in an increased risk of venous thrombosis, which can cause problems with circulation, such as pulmonary embolism.

The disorder can be acquired or inherited, the hereditary form having an autosomal dominant inheritance pattern.

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:

The presentation of hemophilia B is consistent with easy bruising, urinary tract bleed and nosebleeds. Additionally, the affected individual may experience bleeding into their joints.

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.

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".

Defined as those seen in any macrocytic, megaloblastic anemia:

- Anemia: causing fatigue, conjuctival pallor, pale complexion, and in some cases, a mild icterus (yellowing of the eye).

- Glossitis ("shiny tongue"): shiny, glossy tongue.

- Cheilosis (stomatitis): Inflammation of the edges of the lips and the oral mucosa.

- Tabes dorsalis ("subacute combined degeneration of the spinal cord"): This involves the posterior section of the spinal cord and therefore involves proprioception (sense of position), touch, sense of vibration and in severe cases the lateral corticospinal tract, causing spastic paralysis of the limbs.

- Peripheral neuropathy: tingling sensation in the arms and legs.

- Pancytopenia: decreased number of blood cells of all lineages (RBCs, leucocytes, platelets), due to decreased bone marrow production.

- Methylmalonyl CoA-emia: defined as blood having an unusually high concentration of methylmalonyl CoA.

- Peripheral findings such as hypersegmented neutrophils and large RBCs on high field view of the blood smears.

- Laboratory findings indicating increased MCV (Mean Corpuscular Volume), decreased Hgb/Hct (indicating anemia), and decreased value of vitamin B in the blood.

- Proteinuria: protein found in the urine detected by analysis or by dipstick.

- Reversal of all symptoms except neurological symptoms, by IV injection of vitamin B.

- Schilling test indicating no radioactive vitamin B in the urine. (This test has dropped out of favor and should not be tried in patients with any form of renal failure).

Individuals with congenital hypfibringenemia often lack any symptoms are detected by routine lab testing of fibrinogen or when tested for it because close relatives have symptomatic hypofibrinogenmeia. Indeed, studies indicate that, among family members with the identical congenital hypofibrinogenemia mutation, some never exhibit symptoms and those that are symptomatic develop symptoms only as adults.

The following symptoms (signs) are consistent with complement deficiency in general:

Vitamin K deficiency or hypovitaminosis K is a form of avitaminosis resulting from insufficient vitamin K or vitamin K or both.

Symptoms include bruising, petechiae, hematomas, oozing of blood at surgical or puncture sites, stomach pains; risk of massive uncontrolled bleeding; cartilage calcification; and severe malformation of developing bone or deposition of insoluble calcium salts in the walls of arteries. In infants, it can cause some birth defects such as underdeveloped face, nose, bones, and fingers.

Vitamin K is changed to its active form in the liver by the enzyme Vitamin K epoxide reductase. Activated vitamin K is then used to gamma carboxylate (and thus activate) certain enzymes involved in coagulation: Factors II, VII, IX, X, and protein C and protein S. Inability to activate the clotting cascade via these factors leads to the bleeding symptoms mentioned above.

Notably, when one examines the lab values in Vitamin K deficiency [see below] the prothrombin time is elevated, but the partial thromboplastin time is normal or only mildly prolonged. This may seem counterintuitive given that the deficiency leads to decreased activity in factors of both the intrinsic pathway (F-IX) which is monitored by PTT, as well as the extrinsic pathway (F-VII) which is monitored by PT. However, factor VII has the shortest half-life of all the factors carboxylated by vitamin K; therefore, when deficient, it is the PT that rises first, since the activated Factor VII is the first to "disappear." In later stages of deficiency, the other factors (which have longer half lives) are able to "catch up," and the PTT becomes elevated as well.

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.

Individuals with this disorder are usually less symptomatic than patients with other fibrinogen disorders because their fibrinogen levels are generally sufficient to prevent spontaneous bleeding. Those with particularly low blood fibrinogen levels (<0.5 gram/liter) may develop serious bleeding spontaneously and many with the disorder do so following trauma or surgery. Depending on their fibrinogen levels, women with the disorder may also bleed excessively during delivery and the postpartum period; in rare cases, they may have an increased risk of suffering miscarriages. Individuals with the disorder also suffer thrombotic events which may include blockage of large arteries in relatively young patients who have high levels of cardiovascular risk factors. The thrombi which form in these individuals are unstable, tend to embolize, and may therefore lead to thromboembolic events such as pulmonary embolism. Both bleeding and thrombotic events can occur at separate times or even concurrently in the same individual with the disorder.

In terms of the symptoms of Hemophilia A there are internal or external bleeding episodes. Individuals with more severe haemophilia suffer more severe and more frequent bleeding, while others with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.

Prolonged bleeding from a venepuncture or heelprick is another common early sign of haemophilia, these signs may lead to blood tests which indicates haemophilia. In other people, especially those with moderate or mild haemophilia any trauma will lead to the first serious "bleed". Haemophilia leads to a severely increased risk of prolonged bleeding from common injuries, or in severe cases bleeding may be spontaneous and without obvious cause. Bleeding may occur anywhere in the body, superficial bleeding such as those caused by abrasions, or shallow lacerations may be prolonged and the scab may easily be broken up due to the lack of fibrin, which may cause re-bleeding. While superficial bleeding is troublesome, some of the more serious sites of bleeding are:

- Joints

- Muscles

- Digestive tract

- Brain

Muscle and joint haemorrhages - or haemarthrosis - are indicative of haemophilia, while digestive tract and cerebral haemorrhages are also germane to other coagulation disorders.Though typically not life-threatening, joint bleeding is one of the most serious symptoms of haemophilia. Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability. Joint damage is not a result of blood in the capsule but rather the healing process. When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded, this exerts a lot of pain upon the person afflicted with the disease.

Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which arise from spontaneous mutations.

Factor VIII medication may be used to treat and prevent bleeding in people with haemophilia A.

Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one of the complement system proteins. Because there are redundancies in the immune system, many complement disorders are never diagnosed, some studies estimated that less than 10% are identified. "Hypocomplementemia" may be used more generally to refer to decreased complement levels while "secondary complement disorder" means decreased complement levels that are not directly due to a genetic cause but secondary to another medical condition.

Imerslund–Gräsbeck syndrome, is a rare autosomal recessive, familial form of vitamin B deficiency caused by malfunction of the ""Cubam"" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

Vitamin B is an important vitamin needed for bone marrow functioning, the deficit of which causes decreased marrow output and anemia. Vitamin B has two forms, one of which, along with folate, is important in DNA synthesis. Vitamin B is sensitive to acid deformation in the stomach, so a molecule called haptocorrin (R-factor), protects it in the stomach. In the small bowel, a molecule named intrinsic factor (IF), allows vitamin B to be absorbed in the ileum. IGS is caused by a mutation in the receptors located in the terminal portion of ileum. This is a very rare, and unlikely cause of vitamin B deficiency but is a cause nonetheless.