Venous hypercoagulability

I. Problem/Condition.

A wide range of conditions can create a hypercoagulable environment that increases the likelihood of forming clinically significant venous thromboembolism (VTE). Risk increases in the setting of a variety of inherited and acquired conditions collectively referred to as thrombophilias, some of which increase the risk of both venous and arterial clotting.

However, many people who have venous thromboembolism have no identifiable thrombophilia, but remain at risk for further events. There are many other conditions that increase risk for VTE, and there is increasing recognition of the contribution and synergistic effects of transient risk factors such as surgery, medications, and tobacco use, as well as malignancy, chronic diseases, and acute inflammatory states.

Thrombophilias may be hereditary or acquired. The majority of hereditary defects either increase the amount or activity of clotting factors, or decrease the amount or efficacy of clotting factor inhibitors. The most common and problematic acquired thrombophilia is the antiphospholipid antibody syndrome (addressed in a separate chapter), but many other acquired conditions also lead to elevated risk for VTE.

Some thrombophilic defects lead to a greater risk of clotting than others. Deficiency of antithrombin III, quantitative or functional deficiency of protein C or protein S, and the antiphospholipid antibody syndrome (APS) are among the high risk thrombophilias. Lower risk thrombophilias include the Factor V Leiden and Prothrombin 20210 heterozygous gene mutations, which are also among the most commonly inherited abnormalities in individuals of European descent, affecting from 4-8% of the population. Other defects associated with a moderate risk of clotting include abnormally high Factor VIII levels, and hyperhomocysteinemia.

Clotting risk increases markedly when an individual has multiple thrombophilic defects, is homozygous for Factor V Leiden or the Prothrombin 20210 gene mutation, or has a combination of thrombophilic defects and additional risk factors.

II. Diagnostic Approach

A. What is the differential diagnosis for venous hypercoagulability?

The most important initial question for a patient presenting with a new VTE is whether the VTE was provoked or not. Major provoking factors include trauma and surgery. Other triggers include pregnancy, the post-partum period, immobilization, and acute inflammatory states. Certain medications such as oral contraceptives, hormone replacement therapy, and chemotherapy also increase VTE risk. Clots that occur in the setting of transient risk factors are considered “provoked” clots whether the patient has an underlying thrombophilia or not.

For clots that are not clearly provoked, or occur with only mild provocation, the clinician should consider other disease processes that contribute to hypercoagulability. Malignancy is a major risk factor; follow-up studies of large case series indicate that up to 10% of patients who have an initial episode of venous thrombosis will be diagnosed with a malignancy within a year. Other conditions such as inflammatory bowel disease, nephrotic syndrome, sickle cell and sickle trait, other rheumatologic disorders, and to lesser extents chronic diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea, and diabetes also place patients at risk.

Other important hematologic diseases also lead to increased clotting risk, and need to be considered in the differential diagnosis of an idiopathic clot. These include myeloproliferative disorders such as polycythemia vera and essential thrombocythemia, and paroxysmal nocturnal hemoglobinuria (PNH) which is a clonal stem cell disorder. These disorders should be particularly suspected when clots arise in unusual and critical anatomical locations such as the splanchnic veins. It is important to identify these disorders, if present, to provide appropriate therapy in addition to anticoagulation.

The presence of both arterial and venous clots should trigger consideration of a specific differential diagnosis including:

Hyperviscosity syndromes (monoclonal gammopathy, multiple myeloma, Waldenström’s macroglobulinemia)
Antiphospholipid syndrome
Hyperhomocysteinemia
Heparin induced thrombocytopenia and thrombosis (HITT)
Disseminated intravascular coagulation (DIC)
Malignancy
Paradoxical embolism (DVT with patent foramen ovale)
Paroxysmal nocturnal hemoglobinuria (PNH)
Nephrotic syndrome
Inflammatory bowel disease

Rarely, anatomic anomalies may cause VTE. These include May-Thurner syndrome (iliac vein compression) in which the left iliac vein is compressed by the right iliac artery, inferior vena cava atresia, and Paget-Schroetter syndrome in which anatomical abnormalities at the thoracic outlet lead to axillary and subclavian venous thrombosis with strenuous activity of the upper extremities.

B. Describe a diagnostic approach/method to the patient with this problem

Identifying (or testing for) thrombophilia is not recommended in most cases, since the presence of most thrombophilic defects does not influence type or duration of anticoagulation.

For patients presenting with a straightforward venous thromboembolism, immediate laboratory work-up prior to initiation of anticoagulation should include complete blood count (CBC), prothrombin time (PT), and partial thromboplastin time (PTT). Prolonged PTT may be suggestive of antiphospholipid syndrome, although it is neither sensitive nor specific for the disease.

Diagnostic evaluation at the time of presentation with VTE should include careful chart review and review of systems for disease processes noted above, and age-appropriate malignancy screening.

A thorough history should be obtained for any recent provoking factors. For patients with provoked VTE, such as those with major surgery in the past 3 months, thrombophilia testing is not recommended and a time-limited course of anticoagulation should be pursued.

For patients with unprovoked VTE, recurrence risk is higher, approaching 10% over the first year after the initial event and 30% at five years in the absence of extended-duration anticoagulation therapy. Extended duration anticoagulation is generally recommended for these patients provided bleeding risk in not high. Studies have demonstrated no clear difference in recurrence risk for patients with unprovoked VTE who test positive for known thrombophilias versus those who do not.

In general, testing for thrombophilia after unprovoked VTE in all comers is not recommended. However, work-up should be considered in the following situations:

Patients with unprovoked VTE at low bleeding risk who desire to stop anticoagulation, for whom positive thrombophilia testing would change this decision
Patients with recurrent VTE or VTE despite anticoagulation
Patients with unusual or life-threatening clots (e.g., cerebral and splanchnic/pelvic vein clots)
Women in childbearing years
Patients with strong family history of early or recurrent venous thrombosis
Patients with VTE at young age (<50)

1. Historical information important in the diagnosis of this problem.

History pertinent to thrombophilia:

Previous history of blood clots, especially recurrent clots or clots that occur despite therapeutic anticoagulation
Family history of blood clots or thrombophilia
VTE in early adulthood
Recurrent pregnancy complications

History suggestive of other causes of clotting:

Symptoms suggestive of myeloproliferative disorder (pruritus, early satiety, headaches, visual changes) or malignancy (weight loss, anorexia, unexplained pain)
Symptoms or history suggestive of other conditions strongly associated with VTE including inflammatory bowel disease, lupus, and paroxysmal nocturnal hemoglobinuria

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Findings suggestive of thrombophilia:

Evidence of previous clots or persistent clots (i.e., swelling or stasis changes of the lower extremities, varicosities)

Evidence of chronic pulmonary hypertension, a rare consequence of extensive pulmonary emboli

Findings suggestive of other causes of clotting:

Ruddiness or splenomegaly suggests myeloproliferative disorder
Cachexia lymphadenopathy or palpable masses suggest malignancy

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Further testing should by guided by the patient’s history and physical exam, as noted above. When evaluation for laboratory thrombophilia is indicated, testing should be timed correctly to minimize the potential for misleading results, and results should be interpreted with care.

Tests to consider include:

Factor V Leiden mutation
Prothrombin G20210A mutation
Protein S: quantitative and functional assay
Protein C: quantitative and functional assay
Antiphospholipid syndrome:

presence of lupus anticoagulant using 2 separate assays

levels of specific antibodies (beta-2 glycoprotein; anticardiolipin antibodies), as described in depth in antiphospholipid syndrome chapter
Homocysteine level
Antithrombin III quantitative and functional assay

Specific assays may differ, and consultation with a haematologist or discussion with laboratory staff may help ensure that appropriate testing is correctly ordered and performed.

Testing for genetic mutations (Factor V Leiden and the Prothrombin G20210A mutation) may be performed at any time. Results of testing for the other thrombophilias noted above may be affected by presence of acute clot and/or by concomitant anticoagulant use.

Tests that should be avoided during anticoagulant therapy:

Antithrombin III levels may be low during use of unfractionated heparin or low molecular weight heparin (LMWH), but not be reflective of true deficiency.
Protein C and protein S are vitamin K-dependent and may be decreased during warfarin use.
Ideally coagulation based tests for lupus anticoagulant should not be done while patients are on any type of anticoagulation due to possible false positive and false negative results; however, testing for antiphospholipid antibodies are serologic tests and can be done while a patients are anticoagulated.

Tests that are affected during acute thrombosis:

Antithrombin III, protein C, and protein S levels may be decreased.

Other conditions affecting protein C and S levels in particular:

Protein S levels are decreased during pregnancy and are particularly difficult to interpret in pregnant patients.
DIC, acute infection, and liver disease may decrease protein C and S levels.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Negative thrombophilia testing in VTE patients does not indicate the lack of an inherited or acquired clotting abnormality; at this point we are able to test for just a few thrombophilic disorders and there is no doubt there are many more yet to be discovered.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Extensive testing for thrombophilia is expensive and is not routinely indicated for patients presenting with VTE. In general, it should not be performed during hospitalization for acute VTE, but can be pursued if appropriate when the patient has completed an initial course of anticoagulation.

III. Management while the Diagnostic Process is Proceeding

A. Management of Clinical Problem venous hypercoagulability.

Patients presenting with first episodes of venous thrombosis should receive a standard approach to the management of anticoagulation. This may include initiation of parenteral anticoagulation with a heparin while bridging to warfarin therapy, or consideration of a direct acting oral anticoagulant (DOAC), as DOACs have been shown to be equally effective to standard therapy in treatment of acute VTE and in secondary prevention. For patients with malignancy associated VTE, LMWH remains the preferred agent for long-term therapy. Daily blood counts and renal function should be assessed in patients hospitalized with acute VTE, especially those receiving renally metabolized anticoagulation medications.

Duration of anticoagulation therapy depends on presence of provoking factors, bleeding risk, other identified risk factors for further VTE, and patient preferences. For patients with proximal DVT or PE that is provoked by surgery or a nonsurgical transient risk factor, the American College of Chest Physicians (ACCP) and the Anticoagulation Forum recommend a 3-month course of therapeutic anticoagulation. For most patients with unprovoked proximal DVT or PE, provided they are not at high risk for bleeding, consideration should be given to extended duration anticoagulation with periodic re-assessment of risks and benefits. However, for patients at high risk for bleeding with unprovoked VTE a defined 3-month course of anticoagulation is recommended.

Inherited thrombophilia is occasionally identified in the asymptomatic patient without personal history of VTE when a family member is found to harbor laboratory thrombophilia. Testing of unaffected family members of patients with genetic thrombophilias is controversial. These “asymptomatic” patients should be counseled about relative risks of clotting, which will be influenced by the type of thrombophilic defects and other intrinsic physiologic conditions such as age, pregnancy, weight, and underlying diseases. The inherited thrombophilic defects with the highest clotting risk include ATIII, PC and PS deficiency states, and potentially homozygosity or double heterozygosity for Factor V Leiden and Prothrombin 20210 gene mutations. Each patient with known thrombophilia should have a prevention strategy that is appropriate for their level of risk developed with a hematologist /coagulation specialist.

In general, long-term anticoagulation of healthy individuals with thrombophilia who have not had a thrombosis is not recommended.

Basic considerations for all asymptomatic individuals with thrombophilia, and for all patients with a history of VTE, include:

Maintaining normal body weight and healthy lifestyle
Regular exercise and avoidance of periods of excessive inactivity or immobilization
Good hydration
Avoiding or minimizing hormonal (estrogen-based) therapy
Consideration of a prophylaxis plan for high risk periods such as surgeries, pregnancies and the post-partum period, long-haul plane flights, etc.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

The most common side effect of anticoagulation therapy is bleeding risk, and patients should be followed by providers with expertise in anticoagulation management while on these medications.

Burnett, A, Mahan, C, Vazquez, S, Oertel, L. “Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment”. J Thromb Thrombolysis. vol. 41. 2016. pp. 206-232.

Kearon, C, Akl, EA, Ornelas, J, Blaivas, A. “Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report”. Chest. vol. 149. 2016. pp. 315-352.

Moll, S.. “Thrombophilia: clinical-practical aspects”. J Thromb Thrombolysis. vol. 39. 2015. pp. 367-78.

Stevens, SM, Woller, SC, Bauer, KA, Kasthuri, R. “Guidance for the evaluation and treatment of hereditary and acquired thrombophilia”. J Thromb Thrombolysis. vol. 41. 2016. pp. 154-64.

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Venous hypercoagulability