Elsevier

Blood Reviews

Volume 26, Issue 4, July 2012, Pages 175-181
Blood Reviews

REVIEW
Recurrent venous thromboembolism while on anticoagulant therapy

https://doi.org/10.1016/j.blre.2012.04.002Get rights and content

Abstract

There has been immense progress in the management of venous thromboembolism in recent years with increased awareness and adequate thromboprophylaxis proving successful in reducing the morbidity and mortality associated with this condition. One of the commonest complications of an initial venous thrombosis is the development of recurrent thrombosis. Unlike in the case of the first clot, the diagnosis and management of the recurrent episode remain a difficult issue. Even more challenging is the clinical situation where a new thrombus develops while the patient is being treated with anticoagulant medication for a previous clot. The clinical approach and management of these patients are complex, and require understanding of the differences in thrombus development in the different clinical circumstances.

Introduction

Recurrent venous thromboembolism (VTE) is a frequent problem in patients who sustained a first episode of VTE with a reported prevalence of up to 50% at 10 years in those who had no precipitating factors compared with 23% in those who had associated risk factors.1 Recent attempts to formulate prediction markers for recurrent venous thrombosis including D-dimer testing after discontinuation of anticoagulation, and endogenous thrombin potential still await widespread acceptance.[2], [3] In this context, the clinical situation of a new clot developing while being treated with anticoagulant agents presents an even more difficult challenge. The exact incidence for recurrent VTE while on anticoagulation is not well-known. This may be as a result of difficulties in formulating study designs due to multiple etiologies, the lack of standardized diagnostic strategies, high mortality rates in such patients or simply due to under-reporting of negative outcomes.

Thrombus formation is a complex process. It involves various cellular and fluid components including the platelets, vascular endothelium, von Willebrand factor and coagulation factors working in orchestrated fashion to seal a traumatic wound and prevent blood loss. Since unchecked activation of any of these components can be a risk factor for thrombus formation, it is easy to understand why the routine anticoagulant agents may not be appropriate in every new episode of clot. Also the activation of the clotting system in the circulation in the absence of endothelial damage may require different strategies to inhibit further thrombus formation. Finally, the expression of tissue factor on leukocytes can lead to clots which are not prevented by conventional oral anticoagulants.

Section snippets

Diagnosis of recurrent VTE

One of the most difficult issues with respect to recurrent VTE, especially lower limb deep vein thrombosis (DVT), is the accurate diagnosis of a new thrombus in the same anatomical distribution. Since anticoagulant treatments are intended to prevent thrombus extension and embolization and not directly lyse the thrombus, incomplete resolution of the thrombus can result, which can lead to two clinical problems; post-thrombotic syndrome (PTS) and/or persistent thrombus. Both these conditions can

Causes of recurrent VTE on anticoagulation

The causes of recurrent VTE on therapeutic anticoagulation can be arbitrarily divided into those which are present in the initial stages of treatment and those which develop after a period of adequate therapeutic anticoagulation (Fig. 2). Each of these clinical situations is further discussed. The clinical approach to a patient with recurrent VTE after the anticoagulation has been discontinued is summarized in excellent reviews and is not further elaborated.[2], [17]

Under-anticoagulation

Therapeutic ranges for the currently available, well-established, anticoagulant medications (heparin and warfarin) have been formulated after robust studies have proven their clinical efficacy. Maximizing the time spent in therapeutic range is imperative for optimal outcomes with these agents. Despite this, several studies have shown that patients in the community spend on average only 40–60% of their time in therapeutic range while on warfarin anticoagulation.[18], [19] Although these studies

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an increasingly recognized drug-induced thrombocytopenia caused by platelet-activating antibodies that recognize complexes of platelet factor 4 bound to heparin.26 It is observed more often with UFH but can also develop rarely with LMWH. HIT presents an interesting paradox where a patient develops a new thrombus despite being on adequate anticoagulation. Thrombotic complications with HIT can affect any vascular bed but is noted most often at sites of

Malignancy-related thrombosis

Cancer patients are at a very high risk for recurrent VTE. In prospective cohort study of cancer patients, recurrent thrombosis was noted in approximately 20% of cases compared with 6.8% in those without cancer.33 This increased risk of recurrent VTE is highest in the first few months after malignancy is diagnosed and while receiving chemotherapy.34 It has been suggested that the best strategy to prevent a cancer-related clot recurrence is by preventing the first clot. Different measures

Antiphospholipid syndrome

Several authors have reported on the risk of recurrent thrombosis in patients with antiphospholipid syndrome while being treated with anticoagulation. Three retrospective studies demonstrated that patients with antiphospholipid antibodies have a high risk (50–70%) of recurrent thrombosis while receiving moderate-intensity warfarin (target INR of 2–3 compared with 3–4).[44], [45], [46] These studies contained a higher number of patients with secondary antiphospholipid syndrome probably

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition which can present with protean manifestations, but classically a triad of hemolysis, thrombosis and aplastic anemia.64 It results from genetic mutations which result in failure to synthesize two regulators of the complement pathway, CD55 and CD59. PNH is associated with a markedly increased risk of thrombosis, predominantly in the venous circulation.65 Thrombosis, commonest cause of death in this condition, can occur in atypical

Vasculitis

VTE was only recently identified as a possible manifestation of antineutrophil cytoplasmic antibody-associated vasculitis with an incidence varying from 1.8 to 6.7 events/100 person years.[73], [74], [75] Thrombosis in these cases is usually related to the degree of inflammation suggesting a role for the latter in the pathophysiology of the former. Inflammation-coagulation cross-talk is an increasingly examined concept with several clinical scenarios providing supportive evidence to the many

Other considerations

Other rare conditions have been associated with thrombosis while receiving anticoagulation but these diseases have not been studied in detail from the recurrent thrombosis point of view.

Disturbances to venous circulation can be a cause of recurrent thrombosis especially once the anticoagulation has been discontinued and rarely while continuing to be on these agents since the anatomical defect in the inferior venacava or other big venous sites are not “corrected” by the anticoagulation. Inferior

Conclusion

Recurrent VTE while being treated with anticoagulation can present as a difficult management issue. A good understanding of the mechanisms leading to thrombosis in the different circumstances would help in identifying the most appropriate therapeutic strategy in each of these cases.

Practice points

  • •

    Diagnosis of recurrent venous thrombosis can be difficult.

  • •

    The commonest cause of recurrent thrombosis while on therapy with anticoagulants is under-anticoagulation.

  • •

    In an individual who develops a new thrombus while on adequate treatment with anticoagulant agents, an occult malignancy or antiphospholipid syndrome should be high on the list of suspicion.

  • •

    Vasculitis is a condition where recurrent thrombosis would require additional therapies like immunosuppressive agents for thrombus prevention.

  • •

Research agenda

  • •

    Prospective studies involving multiple disciplines should be considered to identify the best method/methods to diagnose recurrent venous thromboembolism.

  • •

    More studies are required to understand the incidence of under-anticoagulation with low molecular weight heparins especially in relation to under-dosing to weight.

  • •

    Further exploration of non-anticoagulant properties of heparin and its derivatives may help in widening the use of these agents in other clinical settings.

  • •

    Although several postulates

Conflicts of interest

There are no potential conflicts of interest on behalf of the author. There have been no funding sources in relation to the preparation of this manuscript either.

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