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.

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).

The major ("type 1") thrombophilias are rare. Antithrombin deficiency is present in 0.2% of the general population and 0.5–7.5% of people with venous thrombosis. Protein C deficiency, too, is present in 0.2% of the population, and can be found in 2.5–6% of people with thrombosis. The exact prevalence of protein S deficiency in the population is unknown; it is found 1.3–5% of people with thrombosis.

The minor ("type 2") thrombophilias are much more common. Factor V Leiden is present in 5% of the population of Northern European descent, but much rarer in those of Asian or African extraction. In people with thrombosis, 10% have factor V Leiden. In those who are referred for thrombophilia testing, 30–50% have the defect. The prothrombin mutation occurs at rates of 1–4% in the general population, 5–10% of people with thrombosis, and 15% of people referred for thrombophilia testing. Like factor V Leiden, this abnormality is uncommon in Africans and Asians.

The exact prevalence of antiphospholipid syndrome is not well known, as different studies employ different definitions of the condition. Antiphospholipid antibodies are detected in 24% of those referred to thrombophilia testing.

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.

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)

Hypoprothrombinemia can be the result of a genetic defect, may be acquired as the result of another disease process, or may be an adverse effect of medication. For example, 5-10% of patients with systemic lupus erythematosus exhibit acquired hypoprothrombinemia due to the presence of autoantibodies which bind to prothrombin and remove it from the bloodstream (lupus anticoagulant-hypoprothrombinemia syndrome). The most common viral pathogen that is involved is Adenovirus, with a prevalence of 50% in postviral cases.

Inheritance:

Autosomal recessive condition in which both parents must carry the recessive gene in order to pass the disease on to offspring. If both parents have the autosomal recessive condition, the chance of mutation in offspring increases to 100%. An individual will be considered a carrier if one mutant copy of the gene is inherited, and will not illustrate any symptoms. The disease affects both men and women equally, and overall, is a very uncommon inherited or acquired disorder.

Non-inheritance and other factors:

There are two types of prothrombin deficiencies that occur depending on the mutation:

Type I (true deficiency), includes a missense or nonsense mutation, essentially decreasing prothrombin production. This is associated with bleeding from birth. Here, plasma levels of prothrombin are typically less than 10% of normal levels.

Type II, known as dysprothrombinemia, includes a missense mutation at specific Xa factor cleavage sites and serine protease prothrombin regions. Type II deficiency creates a dysfunctional protein with decreased activity and usually normal or low-normal antigen levels. A vitamin K-dependent clotting factor is seldom seen as a contributor to inherited prothrombin deficiencies, but lack of Vitamin K decreases the synthesis of prothrombin in liver cells.

Acquired underlying causes of this condition include severe liver disease, warfarin overdose, platelet disorders, and disseminated intravascular coagulation (DIC).

It may also be a rare adverse effect to Rocephin.

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

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.

Hypoprothrombinemia is found to present itself as either inherited or acquired, and is a decrease in the synthesis of prothrombin. In the process of inheritance, it marks itself as an autosomal recessive disorder, meaning that both parents must be carriers of the defective gene in order for the disorder to be present in a child. Prothrombin is a glycoprotein that occurs in blood plasma and functions as a precursor to the enzyme, thrombin, which acts to convert fibrinogen into fibrin, therefore, fortifying clots. This clotting process is known as coagulation.

The mechanism specific to prothrombin (factor II) includes the proteolytically cleaving, breakdown of proteins into smaller polypeptides or amino acids, of this coagulation factor in order to form thrombin at the beginning of the cascade, leading to stemming of blood loss. A mutation in factor II would essentially lead to hypoprothrombinemia. The mutation is presented on chromosome 11.

Areas where the disease has been shown to present itself at include the liver, since the glycoprotein is stored in this area.

Acquired cases are results from an isolated factor II deficiency. Specific cases include:

1. Vitamin-K Deficiency: In the liver, vitamin K plays an important role in the synthesis of coagulation factor II. Body's capacity in the storage of vitamin K is typically very low. Vitamin K-dependent coagulation factors have a very short half-life, sometimes leading to a deficiency when a depletion of vitamin K occurs. The liver synthesizes inactive precursor proteins in the absence of vitamin K (liver disease). Vitamin K deficiency leads to impaired clotting of the blood and in some cases, causes internal bleeding without an associated injury.

2. Disseminated Intravascular Coagulation (DIC): Involving abnormal, excessive generation of thrombin and fibrin within the blood. Relative to hypoprothrombinemia, due to increased platelet aggregation and coagulation factor consumption involved in the process.

3. Anticoagulants: Warfarin Overdose: Used as a treatment for prevention of blood clots, however, like most drugs, side effects have been shown to increase risk of excessive bleeding by functioning in the disruption of hepatic synthesis of coagulation factors II, VII, IX, and X. Vitamin K is an antagonist to warfarin drug, reversing its activity, causing it to be less effective in the process of blood clotting. Warfarin intake has been shown to interfere with Vitamin-K metabolism.

Hypercoagulability in pregnancy, particularly due to inheritable thrombophilia, can lead to placental vascular thrombosis. This can in turn lead to complications like early-onset hypertensive disorders of pregnancy, pre-eclampsia and small for gestational age infants (SGA). Among other causes of hypercoagulability, Antiphospholipid syndrome has been associated with adverse pregnancy outcomes including recurrent miscarriage. Deep vein thrombosis has an incidence of one in 1,000 to 2,000 pregnancies in the United States, and is the second most common cause of maternal death in developed countries after bleeding.

Inherited or congenital FX 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 usually do not exhibit the disease, but can pass the gene on to half their offspring. Different genetic mutations have been described.

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

In the acquired form of FX deficiency an insufficient amount of factor X is produced by the liver due to liver disease, vitamin K deficiency, buildup of abnormal proteins in organs (amyloidosis) or certain medications (i.e. warfarin). In amyloidosis FX deficiency develops as FX and other coagulation factors are absorbed by amyloid fibrils.

The amount of fresh frozen plasma required to reverse disseminated intravascular coagulation associated with purpura fulminans may lead to complications of fluid overload and death, especially in neonates, such as transfusion-related acute lung injury. Exposure to multiple plasma donors over time increases the cumulative risk for transfusion-associated viral infection and allergic reaction to donor proteins found in fresh frozen plasma.

Allergic reactions and alloantibody formation are also potential complications, as with any protein replacement therapy.

Concomitant warfarin therapy in subjects with congenital protein C deficiency is associated with an increased risk of warfarin skin necrosis.

Unfractionated heparin, low molecular weight heparin, warfarin (not to be used during pregnancy) and aspirin remain the basis of antithrombotic treatment and prophylaxis both before and during pregnancy.

While the consensus among physicians is the safety of the mother supersedes the safety of the developing fetus, changes in the anticoagulation regimen during pregnancy can be performed to minimize the risks to the developing fetus while maintaining therapeutic levels of anticoagulants in the mother.

The main issue with anticoagulation in pregnancy is that warfarin, the most commonly used anticoagulant in chronic administration, is known to have teratogenic effects on the fetus if administered in early pregnancy. Still, there seems to be no teratogenic effect of warfarin before six weeks of gestation. However, unfractionated heparin and low molecular weight heparin do not cross the placenta.

Factor X deficiency (X as Roman numeral ten) is a bleeding disorder characterized by a lack in the production of factor X (FX), an enzyme protein that causes blood to clot in the coagulation cascade. Produced in the liver FX when activated cleaves prothrombin to generate thrombin in the intrinsic pathway of coagulation. This process is vitamin K dependent and enhanced by activated factor V.

The condition may be inherited or, more commonly, acquired.

Risk factors for developing antiphospholipid syndrome include:

- Primary APS

- genetic marker HLA-DR7

- Secondary APS

- SLE or other autoimmune disorders

- Genetic markers: HLA-B8, HLA-DR2, HLA-DR3

- Race: Blacks, Hispanics, Asians, and Native Americans

There is an additional elevated risk of adrenal gland bleeds leading to Waterhouse–Friderichsen syndrome (Neisseria meningitidis caused primary adrenal insufficiency). This will require adrenal steroid replacement treatment for life.

Several studies have attempted to predict the survival of patients with Budd–Chiari syndrome. In general, nearly 2/3 of patients with Budd–Chiari are alive at 10 years. Important negative prognostic indicators include ascites, encephalopathy, elevated Child-Pugh scores, elevated prothrombin time, and altered serum levels of various substances (sodium, creatinine, albumin, and bilirubin). Survival is also highly dependent on the underlying cause of the Budd–Chiari syndrome. For example, a patient with an underlying myeloproliferative disorder may progress to acute leukemia, independently of Budd–Chiari syndrome.

The risk of VTE is increased in pregnancy by about five times because of a more hypercoagulable state, a likely adaptation against fatal postpartum hemorrhage. Additionally, pregnant women with genetic risk factors are subject to a roughly three to 30 times increased risk for VTE. Preventative treatments for pregnancy-related VTE in hypercoagulable women were suggested by the ACCP. Homozygous carriers of factor V Leiden or prothrombin G20210A with a family history of VTE were suggested for antepartum LMWH and either LMWH or a vitamin K antagonist (VKA) for the six weeks following childbirth. Those with another thrombophilia and a family history but no previous VTE were suggested for watchful waiting during pregnancy and LMWH or—for those without protein C or S deficiency—a VKA. Homozygous carriers of factor V Leiden or prothrombin G20210A with no personal or family history of VTE were suggested for watchful waiting during pregnancy and LMWH or a VKA for six weeks after childbirth. Those with another thrombophilia but no family or personal history of VTE were suggested for watchful waiting only. Warfarin, a common VKA, can cause harm to the fetus and is not used for VTE prevention during pregnancy.

The cause can be found in more than 80% of patients.

- Primary Budd–Chiari syndrome (75%): thrombosis of the hepatic vein

- Hepatic vein thrombosis is associated with the following in decreasing order of frequency:

2. Polycythemia vera

1. Pregnancy

2. Postpartum state

3. Use of oral contraceptives

4. Paroxysmal nocturnal hemoglobinuria

5. Hepatocellular carcinoma

6. Lupus anticoagulants

- Secondary Budd–Chiari syndrome (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)

Budd–Chiari syndrome is also seen in infections such as tuberculosis, congenital venous webs and occasionally in inferior vena caval stenosis.

Often, the patient is known to have a tendency towards thrombosis, although Budd–Chiari syndrome can also be the first symptom of such a tendency. Examples of genetic tendencies include protein C deficiency, protein S deficiency, the Factor V Leiden mutation, hereditary anti-thrombin deficiency and prothrombin mutation G20210A. An important non-genetic risk factor is the use of estrogen-containing (combined) forms of hormonal contraception. Other risk factors include the antiphospholipid syndrome, aspergillosis, Behçet's disease, dacarbazine, pregnancy, and trauma.

Many patients have Budd–Chiari syndrome as a complication of polycythemia vera (myeloproliferative disease of red blood cells). Patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) appear to be especially at risk for Budd–Chiari syndrome, more than other forms of thrombophilia: up to 39% develop venous thromboses and 12% may acquire Budd-Chiari.

A related condition is veno-occlusive disease, which occurs in recipients of bone marrow transplants as a complication of their medication. Although its mechanism is similar, it is not considered a form of Budd–Chiari syndrome.

Other toxicologic causes of veno-occlusive disease include plant & herbal sources of pyrrolizidine alkaloids such as Borage, Boneset, Coltsfoot, T'u-san-chi, Comfrey, Heliotrope (sunflower seeds), Gordolobo, Germander, and Chaparral.

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.

The three factors of Virchow's triad—venous stasis, hypercoagulability, and changes in the endothelial blood vessel lining (such as physical damage or endothelial activation)—contribute to DVT and are used to explain its formation. Other related causes include activation of immune system components, the state of microparticles in the blood, the concentration of oxygen, and possible platelet activation. Various risk factors contribute to DVT, though many at high risk never develop it.

Acquired risk factors include the strong risk factor of older age, which alters blood composition to favor clotting. Other important acquired risk factors include major surgery and trauma, both of which may increase the risk because of tissue factor from outside the vascular system entering the blood. In orthopedic surgery, venous stasis may be temporarily provoked by a cessation of blood flow as part of the procedure. Cancer can grow in and around veins, causing venous stasis, and can also stimulate increased levels of tissue factor. Pregnancy causes blood to favor clotting, and in the postpartum, placental tearing releases substances that favor clotting. Oral contraceptives and hormonal replacement therapy increase the risk through a variety of mechanisms, including altered blood coagulation protein levels and reduced fibrinolysis.

The disease term venous thromboembolism (VTE) includes the development of either DVT or pulmonary embolism (PE). Genetic factors that increase the risk of VTE include deficiencies of three proteins that normally prevent blood from clotting—protein C, protein S, and antithrombin—in addition to non-O blood type and mutations in the factor V and prothrombin genes. Deficiencies in antithrombin, protein C, and protein S are rare but strong, or moderately strong, risk factors. These three thrombophilia increase the risk of VTE by about 10 times. Factor V Leiden, which makes factor V resistant to inactivation by activated protein C, and the genetic variant prothrombin G20210A, which causes increased prothrombin levels, are predominantly expressed in Caucasians. They moderately increase risk for VTE, by three to eight times for factor V Leiden and two to three times for prothrombin G20210A. Having a non-O blood type roughly doubles VTE risk. Non-O blood type is common in all races, making it an important risk factor. Individuals without O blood type have higher blood levels of von Willebrand factor and factor VIII than those with O blood type, increasing the likelihood of clotting.

Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate, whereas thrombophilias and age do not seem to increase risk. In upper-extremity DVT, the most important risk factor is having a central venous catheter, and thoracic outlet syndrome also increases risk.

Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis.

GPS is primarily inherited in an autosomal recessive manner, and the gene that is mutated in GPS has recently been mapped to chromosome 3p and identified as "NBEAL2". "NBEAL2" encodes a protein containing a BEACH domain that is predicted to be involved in vesicular trafficking. It is expressed in platelets and megakaryocytes and is required for the development of platelet alpha-granules. "NBEAL2" expression is also required for the development of thrombocytes in zebrafish.

GPS is characterized by "thrombocytopenia, and abnormally large agranular platelets in peripheral blood smears." The defect in GPS is the failure of megakaryocytes to package secretory proteins into alpha-granules. Patients with the GPS are affected by mild to moderate bleeding tendencies. Usually these are not major bleeds but there has been some life threatening cases. Also Women will tend to have heavy, irregular periods. Myelofibrosis is a condition that usually comes with the Gray Platelet syndrome.

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.

Increased platelet counts can be due to a number of disease processes:

- Essential (primary)

- Essential thrombocytosis (a form of myeloproliferative disease)

- Other myeloproliferative disorders such as chronic myelogenous leukemia, polycythemia vera, myelofibrosis

- Reactive (secondary)

- Inflammation

- Surgery (which leads to an inflammatory state)

- Hyposplenism (decreased breakdown due to decreased function of the spleen)

- Splenectomy

- Asplenia (absence of normal spleen function)

- Iron deficiency anemia or hemorrhage

Over-medication with drugs that treat thrombocytopenia, such as eltrombopag or romiplostim, may also result in thrombocytosis.

Other causes include the following

- Kawasaki disease

- Soft tissue sarcoma

- Osteosarcoma

- Dermatitis (rarely)

- Inflammatory bowel disease

- Rheumatoid arthritis

- Nephritis

- Nephrotic syndrome

- Bacterial diseases, including pneumonia, sepsis, meningitis, urinary tract infections, and septic arthritis.

The vast majority of causes of thrombocytosis are acquired disorders, but in a few cases, they may be congenital, such as thrombocytosis due to congenital asplenia.

Familial Isolated Vitamin E Deficiency is caused by mutations in the gene for a-tocopherol transfer protein.

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