Hypercoagulability or thrombophilia is the increased tendency of blood to thrombose. A normal and healthy response to bleeding for maintaining hemostasis involves the formation of a stable clot, and the process is called coagulation. Hypercoagulability describes the pathologic state of exaggerated coagulation or coagulation in the absence of bleeding. Different constituents of the blood interact to create a thrombus. Arterial thrombosis, such as in myocardial infarction and stroke, is different from venous thromboses, such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Pathophysiology and treatment differ for arterial and venous thrombosis, but risk factors overlap. Thromboembolism describes the migration of a local thrombus to distant areas leading to luminal obstruction. Different hypercoagulable states and thrombophilic diseases cause hypercoagulability. As early as 1906 Wasserman et al., described the antiphospholipid syndrome. In 1965 Egeberg et al., discovered antithrombin III deficiency. During the 1980s protein C (Griffin, 1981) and protein S (Comp, 1984) deficiencies were introduced. Dahlbäck discovered activated protein C resistance in 1993, which is commonly caused by the factor V Leiden mutation.
Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thus explaining the inter-individual differences observed in patients with inherited mutations. Genetic factors can now be identified in up to 30% of patients with VTE and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. Other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Acquired factors also influence the coagulation cascade and include surgery, pregnancy, hormonal replacement therapy, contraception, malignancy, inflammation, infection, and heparin-induced thrombocytopenia.
Venous thromboembolism is the second most common cardiovascular disorder following myocardial infarction; it is more frequent than stroke. Its incidence ranges between 1 and 5 in 1000 per year in the general population. The incidence is age dependent with 1 per 100000 per year in children and increases to 1 per 1000 per year in adults and 1/100/year in the elderly. Thomas reported the frequency of thrombophilias with APS, APC resistance, elevated factor VIII as 25 to 28%; protein C deficiency, protein S deficiency, hyperhomocysteinemia and prothrombin mutation as 5 to 10%. Up to 4% of strokes are due to hypercoagulability disorders.
Coagulation is an inherent property of the hematologic system and under healthy conditions, normal blood flow is maintained by the balance between the pro-coagulant and anti-thrombotic factors. A hypercoagulable state and subsequent thromboembolism is a result of overactivity of pro-coagulant factors or a deficiency in anti-coagulants. The interplay of factors is complicated - coagulation activators and inhibitors and their production and degradation (quantitative) and functional properties (qualitative) all influence thrombosis. The triad of hypercoagulability, vascular stasis and vascular trauma as described by Virchow in 1856 still holds and remains the harbinger of vascular thrombosis. Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Stasis behind venous valves contributes to venous thrombosis and red thrombus. Mutations influence coagulation depending on whether they are present in heterozygous or homozygous genotype.
Some Coagulation Disorders include the following:
Antithrombin III (ATIII) deficiency. Antithrombin III binds to heparin on endothelial cells and forms a complex with thrombin (thrombin-antithrombin (TAT) complex) thus inhibiting coagulation. The prevalence may be 1 in 500 in the general population. Its deficiency may present as early age thrombosis (less than 50 years old) and carries the highest risk for thrombotic events among the inherited thrombophilias. Antithrombin is synthesized in the liver but is not vitamin K-dependent. ATIII deficiency can occur as a consequence of reduced synthesis (liver damage) or increased loss (nephrotic syndrome, enteropathy, DIC, sepsis, burn, trauma, microangiopathy, and cardiopulmonary bypass surgery). Qualitative defects of ATIII (type II deficiency) describe mutations which either affect the heparin-binding site (HBS), the reactive site (RS) or result in pleiotropic effects (PE). Homozygous ATIII deficiency is incompatible with life unless affecting the heparin-binding site. Usually these patients present with venous thrombosis and less likely with arterial thrombosis.
Protein C deficiency can present as thrombosis in teenagers. Protein C and S deficiency may be inherited but is also inducable by liver dysfunction, vitamin k antagonists, renal failure, DIC, and active thrombosis. Protein S enhances the effect of activated protein C. Protein S deficiency can be classified as type I (reduced quantity of protein S), type II (low APC activity), and type III (low free protein S due to increased binding to the complement factor C4b). The interaction of protein S with C4, which is an active phase reactant exemplifies the relation of coagulation, inflammation, and autoimmunity.  The half-life of protein C is shorter than the half-life of other vitamin K-dependent coagulation factors, hence the risk of increased coagulation with the initiation of vitamin K antagonists and need for bridging with parenteral heparin (warfarin-induced skin necrosis).
Protein C interacts with thrombomodulin to become activated protein C (APC). APC has anticoagulant, anti-inflammatory, and cytoprotective properties and has been proposed for the treatment of sepsis. The signal cascade leading to APC can become distorted through many acquired or inherited mechanisms leading to APC resistance. Activated protein C inactivates coagulation factors V and VIII. The factor V Leiden mutation is a common cause for APC resistance and the most frequent genetic thrombophilia. The FV Leiden mutation is also suspected of increasing the risk of arterial thrombosis. Other FV mutations include factor V Cambridge and factor V Hong Kong. The most common genetic risk factor for thrombophilia is Factor V Leiden mutation. It increases the risk of thrombosis by enhanced thrombin production.
Prothrombin is the precursor of thrombin, which is factor II. The prothrombin G20210A mutation is the second most common inherited risk factor for thrombosis and leads to increased levels of prothrombin which demonstrates a higher risk for arterial and venous thrombotic events. It is due to a single point mutation. It is seen commonly in Caucasians.
Hyperhomocysteinemia is associated with premature atherosclerosis and thrombosis and caused by defects of the methionine metabolic pathway. Deficiencies of cofactors of this pathway such as vitamin B6, B12, and folate or defects of enzymes such as cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) decrease the efficiency of homocysteine metabolism. Furthermore renal failure, hypothyroidism, and drugs such as methotrexate, phenytoin, and carbamazepine increase homocysteine levels. On the other hand, lowering homocysteine levels has not been shown to reduce thrombotic risk.
Elevated factor VIII (FVIII) increases the risk of thrombosis. African-Americans appear to have higher levels whereas individuals with blood group O tend to have lower levels of FVIII. High levels of this factor also correlate with acute phase reactions, estrogen usage, pregnancy, and after aerobic exercise. A high FVIII level may cause APC resistance not due to FV mutation. In contrast, low levels of FVIII correlate with bleeding in hemophilia A patients.
Dysfibrinolysis includes plasminogen deficiency, dysfibrinogenemia, tissue plasminogen activator (tPA) deficiency, plasminogen activator inhibitor (PAI) increase, and factor XII deficiency, which is involved in plasmin generation. Deficient plasminogen clinically appears similar to protein c deficiency with thrombosis during the teenage years. PAI increase and deficient tPA has an association with diabetes mellitus, inflammatory bowel syndrome and coronary atherosclerosis. In patients with structural or functional changes to fibrinogen (dysfibrinogenemia) thrombosis or bleeding can occur.
The sticky platelet syndrome is an autosomal dominant disease in which platelets coming into contact with epinephrine or adenosine diphosphate (ADP) react to induce hypercoagulability.
The most common acquired thrombophilia is the antiphospholipid syndrome (APS) in which antibodies are directed against natural constituents of cell membranes, the phospholipids. These antiphospholipid antibodies (APLA) occur in 3 to 5% of the population and may cause arterial or venous thrombosis and fetal loss. APLAs being tested for include lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein. Lupus anticoagulant leads to prolongation of coagulation (aPTT) in vitro but thrombosis in vivo. Antiphospholipid antibodies may also occur secondary to other diseases (collagen vascular disease or infections) or drugs (phenytoin and cocaine among others). The most common thrombotic event is deep vein thrombosis. Any patient with stroke and rheumatological disorder should be screened for antiphospholipid antibody syndrome.
Malignancy is the second most common acquired hypercoagulability and leads to a prothrombotic state through the production of procoagulant factors (tissue factor and cancer procoagulant) and the interaction of tumor cells with blood and vascular endothelium. Stasis from tumor compression, paraproteinemia, and cytokine release pose an additional risk. In 85% of cancer patients, cancer procoagulant (CP) is elevated. This enzyme actives factor X thus causing hypercoagulability in cancer patients. Polycythemia vera poses a thrombotic risk in addition to hyperviscosity. Migratory thrombophlebitis as a consequence of visceral malignancy is known as Trousseau syndrome. The interaction of malignancy and coagulation is of interest as not only malignancy favors thrombosis but the hemostatic system influences angiogenesis which support tumor growth and spread. Targeting the hemostatic system might offer treatment options for anticancer therapy.
The extrinsic coagulation pathway trigger is tissue factor (TF) which activates coagulation factor VII. Tissue factor is not expressed under physiologic conditions by endothelial cells but continuously produced by subendothelial (activation of coagulation in case of vessel damage) and malignant cells (association of malignancy and thrombotic events). TF is naturally counteracted by the tissue factor pathway inhibitor (TFPI).
Arterial bypass grafts fail prematurely in smokers. Smoking tobacco contains various toxins. Nicotine results in endothelial cell damage. The release of tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) get reduced. Carbon monoxide increases the permeability of endothelium to lipids thus leading to atheroma formation.
In general, exercise improves the cardiovascular risk profile, but observations of sudden cardiac death in some individuals led investigators to search for causes. Exercise influences coagulation, fibrinolysis, and platelet aggregation. Usually, this is kept in balance but in some individuals, the immediate postexercise period is characterized by a hypercoagulable state with an increase of factor eight (intrinsic pathway activation) and platelet activation. Older individuals carry more cardiovascular risk factors and are less well trained. Thus they are prone to suffer adverse effects from the temporary hypercoagulable state following exercise. In the Tromso study regular, moderate-intensity exercise did not significantly impact the risk for thrombosis.
The onset of arterial thrombosis (myocardial infarction and stroke) follows a circadian pattern being most frequent during the early morning hours. This pattern might be explained by variation in blood pressure and platelet activation. Circadian changes in blood rheology and coagulation factors during the day have also been reported and might undergo influence by the dietary pattern.
Endogenous and exogenous hormones influence coagulation. Oral contraception and hormone replacement therapy are a risk factor for thrombosis and cardiovascular events. Testosterone therapy can influence thrombotic risk through increasing blood pressure, hemoglobin, LDL cholesterol, hyperviscosity, and platelet aggregation.
Through the increase of procoagulants (diverse coagulation factors and the number of platelets) and the decrease of anticoagulants (PAI) in addition to stasis caused by compression of the gravid uterus, pregnancy presents a time of hypercoagulability extending 2 months into the postpartum period. This was under evaluation in the MEGA study and LMWH is being tested to prevent miscarriage in pregnant women with inherited thrombophilias in the ALIFE study. The association of pregnancy complications and thrombophilia is subject to ongoing research.
Heparin is a commonly used anticoagulant. Under certain circumstances, arterial and venous thrombosis concomitantly with thrombocytopenia paradoxically results from prolonged heparin administration, which is called heparin-induced thrombocytopenia (HIT). In type-I HIT platelets show a weak reduction of platelets and have little clinical consequences. This is in contrast to the strong reduction of thrombocytes and serious sequelae of HIT type-II. The conformational change of heparin following heparin binding to platelet factor 4 triggers antibody production to heparin. Subsequently, monocytes become activated and attack the vascular endothelium leading to thrombotic events.
There is an interplay between inflammation and the coagulation system. Inflammation triggers a hypercoagulable state. Endotoxin activates the complement system leading to thrombocytopenia and hypercoagulability. The relation between inflammation and coagulation can be observed clinically in patients with purpura, vasculitis, and septic thromboembolism. Coagulation helps to limit the expansion of infection, and some bacteria use fibrinolytic properties to oppose this response. Autoimmune diseases like systemic lupus erythematosus, immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis, dermatomyositis, inflammatory bowel disease, and Behcet's syndrome increase the risk of thrombotic events. The cytomegaly virus (CMV) has correlations to atherogenesis through a change of the cellular lipid metabolism and leukocyte adherence.
Trauma is another acquired hypercoagulable state. Procoagulant disbalance is more pronounced during the first 24 hours following injury and in women. The onset of respiratory distress syndrome and multiorgan failure following trauma has been associated with elevated tissue factor.
Other conditions associated with a hypercoagulable state include myeloproliferative disorders, multiple myeloma, paroxysmal nocturnal hemoglobinuria, heart failure. The endothelium of the left atrial appendage showed higher expression of tissue factor and plasminogen activator inhibitor compared to the right atrial appendage. This inherent prothrombotic property of the LAA in addition to flow disturbances of atrial fibrillation leads to thromboembolic events.
A detailed history is critical to differentiate between provoked and unprovoked thromboembolism and should include demographics, family history, assessment of risk factors, description of symptoms and followed by a standard physical examination. In up to 70% of patients suffering from VTE, a provoking factor is present. One in three patients reports a positive family history.  Early age thrombosis is defined as thrombotic events occurring in people younger than 40 or 50 years old. Unusual site thrombosis includes cerebral, jugular (i.e., Lemierre syndrome), splanchnic  and portal (i.e., Budd-Chiari ) and upper extremity veins.    Based on history and physical exam, the Wells score guides diagnostic workup in first time venous thromboembolism (VTE).
To diagnose hypercoagulability syndromes, the combination of screening tests, confirmation tests, and risk factors all must merit consideration. The thrombophilia screen includes functional assays for antithrombin III, protein c and s deficiency, PCR for factor V Leiden mutation and prothrombin G2021A mutation, testing for antiphospholipid antibodies and homocysteine level. Additional laboratory investigations include routine coagulation panel, d-dimer, and CBC.
Moll et al. suggest the "4P" approach, which is patient selection, pretest counseling, proper laboratory test interpretation, and provision of education and advice. Additionally, they created a risk of recurrence triangle to decide based on risk assessment, how long it would take to achieve anticoagulation. Not every patient requires testing for thrombophilia. Testing is not advisable during the acute thrombotic event (rather schedule for 3-month follow-up) while being on anticoagulation, and patients with provoked thromboembolism. In cases of unprovoked thromboembolism, guidelines differ, and some suggest starting anticoagulation balancing risks and benefit without specific thrombophilia testing. Testing might be useful to exclude thrombophilia and stop anticoagulation. Testing to guide primary prevention in relatives of asymptomatic VTE patients is not useful. Nevertheless, anticoagulation as primary prevention during exposure to provoking factors merits consideration. Testing should be a two-staged approach or 3 months after finishing anticoagulation. Testing guidelines differ between medical societies. Some authors propose thrombophilia testing in patients with unprovoked or recurrent VTE, VTE in young patients (less than 40 years old), in patients with strong family history, thrombosis in unusual sites (cerebral, mesenteric, hepatic, renal), neonatal purpura fulminans, warfarin-induced skin necrosis, and fetal loss.
In patients with a history that brings up suspicion for APS (female, young age, recurrent VTE or fetal loss) unexplained PTT may prompt investigation for APS which are Enzyme-linked immunosorbent assay (ELISA) testing for antiphospholipid antibodies, the diluted Russell venom viper test (dRVVT) and PTT-LA. The Sapporo criteria combine clinical and laboratory criteria to diagnose APS.
As DVT and PE occur in up to 20% of patients with undetected cancer and unexplained VTE in older patients should prompt work-up for malignancy. Screening for cancer includes routine (history and physical examination, ESR, CBC, liver and kidney function tests, urinalysis, and CXR) or extended investigations (tumor markers, CT of the chest, abdomen, and pelvis, mammography in women more than 40 years old, and prostate ultrasound in men older than 50 years, lower endoscopy, Papanicolaou smear, and fecal occult blood test).
Up to 4% of strokes are due to coagulation disorders. The incidence of stroke in young adults is increasing gradually. In patients with hypercoagulability syndromes, there is an increased risk of venous thrombosis than ischemic stroke. In some instances, venous thrombosis can also give rise to arterial strokes by paradoxical embolism, commonly through patent foramen ovale. So, young adults with stroke and a right to left shunt should be checked for venous thrombosis like deep vein thrombosis by ultrasound of lower extremities. The Homocystinuria and antiphospholipid antibody syndrome associated with arterial strokes. Stroke is the most common arterial event secondary to antiphospholipid antibody syndrome. Any stroke patient younger than 45 should be screened for antiphospholipid antibody syndrome.
The substitution of coagulation factors can achieve causal treatment. ATIII can be substituted in cases of inherited (prophylaxis and treatment of ongoing thrombosis) or acquired deficiency (increased consumption in DIC and sepsis). Fresh frozen plasma (FFP) contains the natural balance of procoagulant and anticoagulant factors.
Antithrombotic treatment decision should be based on a risk-benefit analysis. Tools to evaluate the individual risk of thrombosis include different scores such as HERDOO, VIENNA, and DASH and the different thrombotic potential of thrombophilias (strong vs. weak thrombophilias) needs consideration. On the other side, bleeding risk is assessable through the HAS-BLED, RIETE, OBRI, KUIJER, ACCP, HEMORR2HAGES, and ORBIT scores. The HAS-BLED score performed best to predict bleeding risk in patients with atrial fibrillation and is recommended in guidelines. Treatment duration following VTE divides into three phases: acute (a few days following the event), intermediate (short-term anticoagulation for three months) and chronic (long-term anticoagulation for more than 3 months). Factors such as male gender, age, proximal compared to distal deep vein thrombosis which has a higher thrombotic burden, increased d-dimer, and unprovoked VTE implicate a higher recurrence rate and can trigger extended coagulation. Risk stratification tools for the estimation of VTE recurrence in cancer include the COMPASS-CAT, Ottawa (Louzada) and Khorana scores.
Different anticoagulants and antiplatelets are available to prevent recurrent VTE. They include vitamin K antagonist (VKA), aspirin (as assessed in the WARFASA and ASPIRE trials), rivaroxaban (EINSTEIN trial), dabigatran (RE-MEDY and RE-SONATE trials), and apixaban (AMPLIFY trial). Additional considerations are prudent regarding special populations. The CLOT trial assessed low molecular weight heparin against warfarin in cancer patients. Heparin did not show teratogenicity and is FDA-approved during pregnancy and the postpartum period. Prevention of thrombotic events includes compression stockings and mobility. Rosuvastatin prevents the occurrence of VTE.
For investigation of patients suffering from thrombotic events, it is essential to differentiate provoked and unprovoked thrombosis through history and physical. Thrombotic events are observable under diverse conditions. Therefore a broad differential diagnosis is essential including the more frequent (immobilization, travel) and less frequent entities such as cardiac disease (atrial fibrillation, cardiomyopathy, mitral valve prolapse, prosthetic valves), non-bacterial thrombotic endocarditis (NBTE) and hematologic causes such as disseminated intravascular coagulopathy (DIC) and heparin-induced thrombocytopenia (HIT). Clinical decision aids such as the HIT score can help to evaluate pretest probability and guide diagnostic workup.
Thrombophilia should be a differential diagnosis for vaso-occlusive events. Arterial thrombosis such as osteonecrosis, ischemic stroke and myocardial infarction can be related to thrombophilia. Celik et al. investigated a population of young patients suffering from myocardial infarction. They concluded that the established cardiovascular risk factors but not thrombophilias contributed to myocardial infarction in young patients. Other studies suggest to include thrombophilia in the differential diagnosis of myocardial infarction with non-occlusive coronary arteries (MINOCA). Thrombophilias might also be associated with stroke in young people by venous thromboembolism through a patent foramen ovale.
Deep venous thrombosis has two major complications: pulmonary embolism, which is acute and life-threatening, and postthrombotic syndrome (PTS) with chronic venous ulceration (CVU). In one study more than 40% of patients with CVU had at least one thrombophilia, but the association between thrombophilia and micro- and macrovascular thrombosis leading to PTS and CVU remains unclear. The two main complications are recurrent thrombosis or bleeding as a side effect of treatment. To avoid these individual risk assessment and therapy is necessary. Micro- and macro thrombotic events in pregnancy can not only cause maternal death but can also cause fetal growth restriction, pregnancy loss, preeclampsia, and placental abruption.
When considering hemophilia testing (recurrent thromboembolic events, strong family history, etc.) referral to a hematologist should be considered.
Thomas proposed the mnemonic CALMSHAPES to remember the causes of the hypercoagulable state.
It is essential to exercise prudence on when to test for thrombophilia. Considering the negative implications of a positive test for the individual (anxiety, bleeding risk) and costs should be balanced with the benefit of avoiding adverse effects from thrombotic events or miscarriage through anticoagulation.
Prognostication implicates the question for the risks of recurrent thrombosis or bleeding as a side effect of anticoagulation. Patients with one VTE event have a 30% risk of recurrence in 10 years. Different scoring systems are available to predict the risk of recurrence. Thrombosis carries a high in-hospital mortality and is the second most common cause of death in cancer patients.
A multidisciplinary approach involving nurses and physicians in the evaluation and treatment of these patients results in the best outcomes. [Level V]
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