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.

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.

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.

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.

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

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):

A pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. Such tests include:

- chorionic villus sampling (CVS) – a small sample of the placenta is removed from the womb and tested for the haemophilia gene, usually during weeks 11-14 of pregnancy

- amniocentesis – a sample of amniotic fluid is taken for testing, usually during weeks 15-20 of pregnancy

There's a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care.

Genetic testing and counselling are available to help determine the risk of passing the condition onto a child. This may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia.

The variant causes elevated plasma prothrombin levels (hyperprothrombinemia), possibly due to increased pre-mRNA stability. Prothrombin is the precursor to thrombin, which plays a key role in causing blood to clot (blood coagulation). G20210A can thus contribute to a state of hypercoagulability, but not particularly with arterial thrombosis. A 2006 meta-analysis showed only a 1.3-fold increased risk for coronary disease.

It confers a 2- to 3-fold higher risk of VTE. Deficiencies in the anticoagulants Protein C and Protein S give a higher risk (5- to 10-fold). Behind non-O blood type and factor V Leiden, prothrombin G20210A is one of the most common genetic risk factors for VTE. It was realized in 1996 that a particular change in the genetic code causes the body to make too much of the prothrombin protein. By having too much prothrombin, it increases the chances the blood clotting. Individuals who carry the condition have the prothrombin mutation which can be inherited by offspring.

Having the prothrombin mutation increases the risk of developing a DVT (Deep vein thrombosis), known as a blood clot in the deep veins, often but not always in the legs. DVTs are threatening as they can damage the veins throughout the body, causing pain and swelling, and sometimes leading to disability.

Most variety of people who have this prothrombin gene mutation do not require any treatment but need to be cautious throughout periods when the possibility of getting a blood clot may be enlarged (e.g. after surgery, during long flights etc.); occasionally people with the mutation may need to go on blood thinning medication to decrease the risk of developing blood clots. As there is no cure for the mutation, studies throughout the world are becoming conversant, emitting various medications in order to decrease risk factors.

Heterozygous carriers who take combined birth control pills are at a 15-fold increased risk of VTE, while carriers also heterozygous with factor V Leiden have an approximate 20-fold higher risk. In a recommendation statement on VTE, genetic testing for G20210A in adults that developed unprovoked VTE was disadvised, as was testing in asymptomatic family members related to G20210A carriers who developed VTE. In those who develop VTE, the results of thrombophilia tests (wherein the variant can be detected) rarely play a role in the length of treatment.

Because prothrombin is also known as factor II, the mutation is also sometimes referred to as the factor II mutation or simply the prothrombin mutation; in either case, the names may appear with or without the accompanying G20210A location specifier (unhelpfully, since prothrombin mutations other than G20210A are known).

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.

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.

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

In general, the indications for anticoagulation during pregnancy are the same as the general population. This includes (but is not limited to) a recent history of deep venous thrombosis (DVT) or pulmonary embolism, a metallic prosthetic heart valve, and atrial fibrillation in the setting of structural heart disease.

In addition to these indications, anticoagulation may be of benefit in individuals with lupus erythematosus, individuals who have a history of DVT or PE associated with a previous pregnancy, and even with individuals with a history of coagulation factor deficiencies and DVT not associated with a previous pregnancy.

In pregnant women with a history of recurrent miscarriage, anticoagulation seems to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage.

D-dimers are a fibrin degradation product, and an elevated level can result from plasmin dissolving a clot—or other conditions. Hospitalized patients often have elevated levels for multiple reasons. When individuals are at a high-probability of having DVT, diagnostic imaging is preferred to a D-dimer test. For those with a low or moderate probability of DVT, a D-dimer level might be obtained, which excludes a diagnosis if results are normal. An elevated level requires further investigation with diagnostic imaging to confirm or exclude the diagnosis.

For a suspected first leg DVT in a low-probability situation, the American College of Chest Physicians recommends testing either D-dimer levels with moderate or high sensitivity or compression ultrasound of the proximal veins. These options are suggested over whole-leg ultrasound, and D-dimer testing is the suggested preference overall. The UK National Institute for Health and Care Excellence (NICE) recommends D-dimer testing prior to proximal vein ultrasound.

For a suspected first leg DVT in a moderate-probability scenario, a high-sensitivity D-dimer is suggested as a recommended option over ultrasound imaging, with both whole-leg and compression ultrasound possible. The NICE guideline uses a two-point Wells score and does not refer to a moderate probability group.

The first element of treatment is usually to discontinue the offending drug, although there have been reports describing how the eruption evolved little after it had established in spite of continuing the medication. Vitamin K1 can be used to reverse the effects of warfarin, and heparin or its low molecular weight heparin (LMWH) can be used in an attempt to prevent further clotting. None of these suggested therapies have been studied in clinical trials.

Heparin and LMWH act by a different mechanism than warfarin, so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis (this is called 'bridging').

Based on the assumption that low levels of protein C are involved in the underlying mechanism, common treatments in this setting include fresh frozen plasma or pure activated protein C.

Since the clot-promoting effects of starting administration of 4-hydroxycoumarins are transitory, patients with protein C deficiency or previous warfarin necrosis can still be restarted on these drugs if appropriate measures are taken. These include gradual increase starting from low doses and supplemental administration of protein C (pure or from fresh frozen plasma).

The necrotic skin areas are treated as in other conditions, sometimes healing spontaneously with or without scarring, sometimes going on to require surgical debridement or skin grafting.

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.

When Budd–Chiari syndrome is suspected, measurements are made of liver enzyme levels and other organ markers (creatinine, urea, electrolytes, LDH).

Budd–Chiari syndrome is most commonly diagnosed using ultrasound studies of the abdomen and retrograde angiography. Ultrasound may show obliteration of hepatic veins, thrombosis or stenosis, spiderweb vessels, large collateral vessels, or a hyperechoic cord replacing a normal vein. Computed tomography (CT) or magnetic resonance imaging (MRI) is sometimes employed although these methods are generally not as sensitive. Liver biopsy is nonspecific but sometimes necessary to differentiate between Budd–Chiari syndrome and other causes of hepatomegaly and ascites, such as galactosemia or Reye's syndrome.

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.

Prevention of DVT and other types of venous thrombosis may be required if certain predisposing risk factors are present. One example from Sweden is based on the point system below, where points are summed to give the appropriate prophylaxis regimen.

After adding any risk factors together, a total of one point or less indicates no preventive action is needed. A total of two points indicates short-term prophylaxis, e.g. with LMWH, may be used in temporary risk factors, as well as administering prophylactic treatment seven days postpartum, starting a couple of hours after birth. A total of 3 points increases the necessary duration of "post partum" prophylaxis to six weeks.

A risk score of four points or higher means prophylaxis in the "ante partum" period is needed, as well as at least six weeks "post partum". A previous distal DVT indicates a minimum of 12 weeks (three months) of therapeutic anticoagulation therapy. A previous proximal DVT or pulmonary embolism requires a minimum of 26 weeks (6.5 months) of therapy If the therapy duration reaches delivery time, the remaining duration may be given after delivery, possibly extending the minimum of six weeks of "post partum" therapy. In a very high risk, high-dose "ante partum" prophylaxis should be continued at least 12 weeks after delivery.

Women with antiphospholipid syndrome should have an additional low-dose prophylactic treatment of aspirin.

The diagnosis for thrombophlebitis is primarily based on the appearance of the affected area. Frequent checks of the pulse, blood pressure, and temperature may be required. If the cause is not readily identifiable, tests may be performed to determine the cause, including the following:

- Doppler ultrasound

- Extremity arteriography

- Blood coagulation studies (Blood clotting tests)

The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease.

In terms of treatment/management, bleeding events can be controlled by platelet transfusion.

Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury. In the event of an individual with mucosal bleeding tranexamic acid can be given.

The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing antiplatelet antibodies

Critics of the diagnosis complain that case evidence is spotty and lacking controlled clinical studies.