The diagnosis for deficiency of protein S can be done via reviewing family history of condition and genetic testing, as well as the following:

- Protein S antigen test

- Coagulation test (prothrombin time test)

- Thrombotic disease investigation

- Factor V Leiden test

Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any Caucasian patient below the age of 45, or in any person with a family history of venous thrombosis.

There are a few different methods by which this condition can be diagnosed. Most laboratories screen 'at risk' patients with either a snake venom (e.g. dilute Russell's viper venom time) based test or an aPTT based test. In both methods, the time it takes for blood to clot is decreased in the presence of the factor V Leiden mutation. This is done by running two tests simultaneously; one test is run in the presence of activated protein C (APC) and the other, in the absence. A ratio is determined based on the two tests and the results signify to the laboratory whether APC is working or not.

There is also a genetic test that can be done for this disorder. The mutation (a 1691G→A substitution) removes a cleavage site of the restriction endonuclease "MnlI", so PCR, treatment with "MnlI", and then DNA electrophoresis will give a diagnosis. Other PCR based assays such as iPLEX can also identify zygosity and frequency of the variant.

In terms of treatment for protein S deficiency the following are consistent with the "management" (and administration of) individuals with this condition ( it should be noted that the prognosis for "inherited" homozygotes is usually in line with a higher incidence of thrombosis for the affected individual):

Studies have found that about 5 percent of Caucasians in North America have factor V Leiden. The condition is less common in Latin Americans and African-Americans and is extremely rare in people of Asian descent.

Up to 30 percent of patients who present with deep vein thrombosis (DVT) or pulmonary embolism have this condition. The risk of developing a clot in a blood vessel depends on whether a person inherits one or two copies of the factor V Leiden mutation. Inheriting one copy of the mutation from a parent (heterozygous) increases by fourfold to eightfold the chance of developing a clot. People who inherit two copies of the mutation (homozygous), one from each parent, may have up to 80 times the usual risk of developing this type of blood clot. Considering that the risk of developing an abnormal blood clot averages about 1 in 1,000 per year in the general population, the presence of one copy of the factor V Leiden mutation increases that risk to between 4 in 1,000 to 8 in 1,000. Having two copies of the mutation may raise the risk as high as 80 in 1,000. It is unclear whether these individuals are at increased risk for "recurrent" venous thrombosis. While only 1 percent of people with factor V Leiden have two copies of the defective gene, these homozygous individuals have a more severe clinical condition. The presence of acquired risk factors for venous thrombosis—including smoking, use of estrogen-containing (combined) forms of hormonal contraception, and recent surgery—further increase the chance that an individual with the factor V Leiden mutation will develop DVT.

Women with factor V Leiden have a substantially increased risk of clotting in pregnancy (and on estrogen-containing birth control pills or hormone replacement) in the form of deep vein thrombosis and pulmonary embolism. They also may have a small increased risk of preeclampsia, may have a small increased risk of low birth weight babies, may have a small increased risk of miscarriage and stillbirth due to either clotting in the placenta, umbilical cord, or the fetus (fetal clotting may depend on whether the baby has inherited the gene) or influences the clotting system may have on placental development. Note that many of these women go through one or more pregnancies with no difficulties, while others may repeatedly have pregnancy complications, and still others may develop clots within weeks of becoming pregnant.

The diagnosis of hypofibrinogenemia is indicated in individuals who have low levels (<1.5 gram/liter) of plasma fibrinogen as determined by both immunological (e.g. immunoelectrophoresis and (i.e. able to be clotted) methods. The ratio of immunological to functional fibrinogen masses should be ~1.0 as assayed with partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests. These tests are used to distinguish hypofibrinogenemia from hypodysfibrinogenemia, a typically more severe disorder in which plasma fibrinogen levels are low and this fibrinogen includes at least in part dysfunctional fibrinogen. Immunological/functional fibrinogen ratios for the plasma of individuals with hypodysfibrinogenemia for all the cited tests are usually <0.7. Where available, further analyses are recommended; these include analyses of the fibrinogen genes and protein chains for mutations and specialized studies of individuals in vitro induced blood clots for stability and susceptibility to lyses.

The diagnosis of fibrin storage disease requires liver biopsy and the finding of immunologically detectable fibrinogen inclusion bodies in hepatocytes.

Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease.

There are divergent views as to whether everyone with an unprovoked episode of thrombosis should be investigated for thrombophilia. Even those with a form of thrombophilia may not necessarily be at risk of further thrombosis, while recurrent thrombosis is more likely in those who have had previous thrombosis even in those who have no detectable thrombophilic abnormalities. Recurrent thromboembolism, or thrombosis in unusual sites (e.g. the hepatic vein in Budd-Chiari syndrome), is a generally accepted indication for screening. It is more likely to be cost-effective in people with a strong personal or family history of thrombosis. In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventative treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests. Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious trigger. For example, if the thrombosis is due to immobilization after recent orthopedic surgery, it is regarded as "provoked" by the immobilization and the surgery and it is less likely that investigations will yield clinically important results.

When venous thromboembolism occurs when a patient is experiencing transient major risk factors such as prolonged immobility, surgery, or trauma, testing for thrombophilia is not appropriate because the outcome of the test would not change a patient's indicated treatment. In 2013, the American Society of Hematology, as part of recommendations in the Choosing Wisely campaign, cautioned against overuse of thrombophilia screening; false positive results of testing would lead to people inappropriately being labeled as having thrombophilia, and being treated with anticoagulants without clinical need

In the United Kingdom, professional guidelines give specific indications for thrombophilia testing. It is recommended that testing be done only after appropriate counseling, and hence the investigations are usually not performed at the time when thrombosis is diagnosed but at a later time. In particular situations, such as retinal vein thrombosis, testing is discouraged altogether because thrombophilia is not regarded as a major risk factor. In other rare conditions generally linked with hypercoagulability, such as cerebral venous thrombosis and portal vein thrombosis, there is insufficient data to state for certain whether thrombophilia screening is helpful, and decisions on thrombophilia screening in these conditions are therefore not regarded as evidence-based. If cost-effectiveness (quality-adjusted life years in return for expenditure) is taken as a guide, it is generally unclear whether thrombophilia investigations justify the often high cost, unless the testing is restricted to selected situations.

Recurrent miscarriage is an indication for thrombophilia screening, particularly antiphospholipid antibodies (anti-cardiolipin IgG and IgM, as well as lupus anticoagulant), factor V Leiden and prothrombin mutation, activated protein C resistance and a general assessment of coagulation through an investigation known as thromboelastography.

Women who are planning to use oral contraceptives do not benefit from routine screening for thrombophilias, as the absolute risk of thrombotic events is low. If either the woman or a first-degree relative has suffered from thrombosis, the risk of developing thrombosis is increased. Screening this selected group may be beneficial, but even when negative may still indicate residual risk. Professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening.

Thrombophilia screening in people with arterial thrombosis is generally regarded unrewarding and is generally discouraged, except possibly for unusually young patients (especially when precipitated by smoking or use of estrogen-containing hormonal contraceptives) and those in whom revascularization, such as coronary arterial bypass, fails because of rapid occlusion of the graft.

Blood tests are neede to differentiate FVII deficiency from other bleeding disorders. Typical is a discordance between the prolonged prothrombin time (PT) and normal levels for the activated partial thromboplastin time (APTT). FVII levels are <10IU/dl in homozygous individuals, and between 20-60 in heterozygous carriers. The FCVII: C assay supports the diagnosis.

The FVII gene (F7) is found on chromosome 13q34. Heterogeneous mutations have been described in FVII deficient patients.

Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications. In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth. Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for prophylaxis therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.

There are two main types of protein C assays, activity and antigen (immunoassays). Commercially available activity assays are based on chromogenic assays that use activation by snake venom in an activating reagent, or clotting and enzyme-linked immunosorbant assays. Repeated testing for protein C functional activity allows differentiation between transient and congenital deficiency of protein C.

Initially, a protein C activity (functional) assay can be performed, and if the result is low, a protein C antigen assay can be considered to determine the deficiency subtype (Type I or Type II). In type I deficiencies, normally functioning protein C molecules are made in reduced quantity. In type II deficiencies normal amounts of dysfunctional protein C are synthesized.

Antigen assays are immunoassays designed to measure the quantity of protein C regardless of its function. Type I deficiencies are therefore characterized by a decrease in both activity and antigen protein C assays whereas type II deficiencies exhibit normal protein C antigen levels with decreased activity levels.

The human protein C gene (PROC) comprises 9 exons, and protein C deficiency has been linked to over 160 mutations to date. Therefore, DNA testing for protein C deficiency is generally not available outside of specialized research laboratories.

Manifestation of purpura fulminans as it is usually associated with reduced protein C plasma concentrations of <5 mg IU/dL. The normal concentration of plasma protein C is 70 nM (4 µg/mL) with a half live of approximately 8 hours. Healthy term neonates, however, have lower (and more variable) physiological levels of protein C (ranging between 15-55 IU/dL) than older children or adults, and these concentrations progressively increase throughout the first 6 months of life. Protein C levels may be <10 IU/dL in preterm or twin neonates or those with respiratory distress without manifesting either purpura fulminans or disseminated intravascular coagulation.

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.

The diagnosis for hemophilia B can be done via the following tests/methods:

- Coagulation screening test

- Bleeding scores

- Coagulation factor assays

Recommended treatment of asymptomatic congenital hypofibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as indicated by the personal history of the afflicted individual and family members. Where possible, determination of the exact mutation causing the disorder and the propensity of this mutation type to develop these complications may be helpful. Individuals with fibrinogen levels >1.0 gram/liter typically do not develop bleeding or thrombosis episodes. Individuals with fibrinogen levels of 0.5-1.0 grams/liter require fibrinogen supplementation preferably with a plasma-derived fibrinogen concentrate to maintain fibrinogen levels of >1 gram/liter prior to major surgery. Individuals with fibrinogen levels of 1 to 2 gram/liter at the end of pregnancy and during the postpartum period; b) > 1 gram/liter prior to major surgery; c) > 0.5 to 1 gram/liter during the first two trimesters of pregnancy; and d) >0.5 gram/liter prior to minor surgery. Tranexamic acid may be used in place of fibrinogen supplementation as prophylactic treatment prior to minor surgery and to treat minor bleeding episodes.

The differential diagnosis for this inherited condition is the following: hemophilia A, factor XI deficiency, von Willebrand disease, fibrinogen disorders and Bernard-Soulier syndrome

Two of the most common differential diagnoses are haemophilia B which is a deficiency in Factor IX and von Willebrand Disease which is a deficiency in von Willebrand factor (needed for the proper functioning of Factor VIII), haemophilia C is also a possible, differential diagnosis.

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.

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

The diagnosis of hemophilia A may be suspected as coagulation testing reveals an increased PTT in the context of a normal PT and bleeding time. PTT tests are the first blood test done when haemophilia is indicated. However, the diagnosis is made in the presence of very low levels of Factor VIII. A family history is frequently present, although not essential. Recently, genetic testing has been made available to determine an individual's risk of attaining or passing on hemophilia. Diagnosis of haemophilia A also includes a severity level which can range from mild to severe based on the amount of active and functioning factor VIII detected in the blood. Factor VIII levels do not typically change throughout an individual's life. Severe haemophilia A is the most common form occurring in the majority of affected people. Individuals with mild haemophilia often experience few or no bleeding episodes except in the case of serious trauma (i.e. tooth extraction, or surgery).

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.

Tests for thrombophilia include complete blood count (with examination of the blood film), prothrombin time, partial thromboplastin time, thrombodynamics test, thrombin time and reptilase time, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein 1 antibody, activated protein C resistance, fibrinogen tests, factor V Leiden and prothrombin mutation, and basal homocysteine levels. Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation.

For hereditary cases, the patient must have at least 2 abnormal tests plus family history.

Antiphospholipid syndrome is tested for in the laboratory using both liquid phase coagulation assays (lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).

Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Presence of genetic thrombophilia may determine the need for anticoagulation therapy. Thus genetic thrombophilia screening can consist of:

- Further studies for factor V Leiden variant and the prothrombin G20210A mutation, factor VIII levels, MTHFR mutation.

- Levels of protein C, free and total protein S, factor VIII, antithrombin, plasminogen, tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)

The testing of antibodies to the possible individual targets of aPL such as β glycoprotein 1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.

The diagnosis of haemophilia C (factor XI deficiency) is centered on prolonged activated partial thromboplastin time.One will find that the factor XI has decreased in the individuals body.In terms of differential diagnosis one must consider:factor VIII deficiency, lupus anticoagulant and heparin contamination.

Anti-cardiolipin antibodies can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of βglycoprotein 1 dependent anticardiolipin antibodies (ACA).

A low platelet count and positivity for antibodies against β-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.

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.

In terms of hemophilia C medication cyklokapron is often used for both treatment after an incident of bleeding and as a preventative measure to avoid excessive bleeding during oral surgery.

Treatment is usually not necessary, except in relation to operations, leading to many of those having the condition not being aware of it. In these cases, fresh frozen plasma or recombinant factor XI may be used, but only if necessary.

The afflicted may often suffer nosebleeds, while females can experience unusual menstrual bleeding which can be avoided by taking birth control such as: IUDs and oral or injected contraceptives to increase coagulation ability by adjusting hormones to levels similar to pregnancy.