Treatment of venous thrombosis at unusual sites

Opinion statement The literature is filled with randomized controlled trial data to guide most steps in managing patients with deep venous thrombosis of the extremities or pulmonary embolism. Venous thrombosis, however, is not limited to these locations and may involve the cerebral venous sinuses, renal veins, splanchnic veins, and ovarian veins. The causes of these thrombi are often unique to the venous segments involved and typically stem from pathologies of the organs supplied by these veins. Very little randomized controlled trial data exist to guide therapy for these atypical venous thrombi. Treatment should focus on correcting the underlying disease and relieving venous congestion of the involved organ while preserving organ functionality. Although natural history data are limited, recurrence rates for these atypical venous thrombi appear to be relatively low. Indefinite secondary anticoagulant prophylaxis is therefore primarily dictated by the congenital or acquired pathology precipitating the event.     

Venous thrombosis in unusual sites: A practical review for the hematologist

Thrombosis of unusual venous sites encompasses a large part of consultative hematology and is encountered routinely by practicing hematologists. Contrary to the more commonly encountered lower extremity venous thrombosis and common cardiovascular disorders, the various thromboses outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review attempts to outline the most up to date literature on cerebral, retinal, upper extremity, hepatic, portal, splenic, mesenteric, and renal vein thrombosis, focusing on the incidence, pathophysiology, provoking factors, and current recommended treatments for each type of unusual thrombosis to provide a useful and practical review for the hematologist.     

Arterial thrombosis and the role of thrombophilia

Thrombophilia is a prominent risk factor for venous thromboembolism. The role of thrombophilia in determining the risk of arterial thrombotic events is less well defined. In this review, we summarize the existing literature on the relationship between thrombophilic defects and the risk of arterial thrombosis, in particular myocardial infarction and stroke. The six defects reviewed are the factor V Leiden mutation, the prothrombin G20210A mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, and the antiphospholipid syndrome. We observed that substantial evidence supports an association between the presence of the antiphospholipid syndrome and the risk of myocardial infarction, particularly among people in whom the atherosclerotic burden is low. The literature contains no solid evidence to support an important relationship between the other thrombophilic defects reviewed and the risk of arterial thrombosis. We conclude that thrombophilia screening in unselected patient populations with myocardial infarction or ischemic stroke is not justified.     

Recurrent intracardiac thrombosis as an unusual manifestation of inherited thrombophilia

Patients with inherited thrombophilia are at high risk for the development of venous thrombosis that manifests mainly as deep venous thrombosis of the legs and/or pulmonary embolism. We report spontaneous right-sided intracardiac thrombosis in a young man as an unusual manifestation of inherited thrombophilia. The diagnosis of thrombophilia was confirmed by demonstration of the prothrombin-G20210A-mutation in the homozygous state. A second spontaneous intracardiac thrombosis occurred 3 years after discontinuation of oral anticoagulant treatment. This indicates the high risk for recurrence in patients developing intracardiac thrombosis in the absence of an underlying cardiac disease and warrants long-term oral anticoagulant treatment.     

The role of thrombophilia in splanchnic vein thrombosis

In the last few years, the mechanistic role of thrombophilia due to hypercoagulability and of clonal disorders of hemopoiesis such as chromosome Philadelphia-negative chronic myeloproliferative disorders has been increasingly recognized in primary splanchnic vein thrombosis. As in deep venous thrombosis of the lower limbs, the frequent finding of several prothrombotic disorders in the same individual has led to the concept of primary splanchnic vein thrombosis as a multifactorial disease. Significant progress has been made in determining the molecular bases of inherited thrombophilia, and particularly in the identification of molecular markers of clonal disease in the so-called occult or latent myeloproliferative disorders. In this review article, the authors discuss the current knowledge on the role of thrombophilia in extrahepatic portal vein obstruction and in the Budd-Chiari syndrome, two of the most clinically relevant splanchnic vein thromboses.     

Direct oral anticoagulant use in patients with thrombophilia,antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review

Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of venous thromboembolism (VTE). However, the use of DOACs in unusual VTE, including cerebral venous thrombosis (CVT) and splanchnic venous thrombosis (SVT), and in patients with biological thrombophilia including minor thrombophilia (Factor V Leiden and prothrombin G20210A), major innate thrombophilia (protein C and S deficiency, and antithrombin) and major acquired thrombophilia (antiphospholipid syndrome [APS]), remains controversial due to the paucity of available data. There are some reports of DOACs use in the initial treatment or long-term maintenance of patients with either CVT or SVT, but their efficacy remains unclear. The efficacy of DOACs may be suitable in patients with biological minor or major thrombophilia. The use of DOACs for the long-term maintenance of patients with APS is more contentious. Randomized clinical trials, which are currently underway, should offer definitive insight into the efficacy and safety profiles of DOACs in these patient populations.     

Heritable thrombophilia and childhood thrombosis

Thrombotic problems are rare during childhood but are increasingly recognized, particularly in tertiary care paediatric populations, and represent a different spectrum of disorders to those seen in adults. An understanding of the aetiological factors involved in the pathogenesis of these events is important both for prevention and management. A number of inherited prothrombotic defects have been shown to be independent risk factors for thromboembolism in adult studies, and may also contribute to thrombotic events in childhood. Homozygous deficiencies of naturally occurring inhibitors of coagulation are clearly associated with major prothrombotic disorders, often presenting in the perinatal period. The association of other inherited prothrombotic disorders with thrombosis in childhood is less well defined. The prevalence of heritable thrombophilia varies in different clinical settings and the risks associated with individual defects has only been addressed in a small number of studies to date. Additional acquired risk factors are also present in a high percentage of cases and again differ from those seen in adult thrombosis. Further studies are required to assess the risks associated with heritable thrombophilia during infancy and childhood, and to define the place of thrombophilia screening in paediatric practice.     

Maternal thrombophilia and neonatal thrombosis

In neonates and infants, numerous clinical and environmental conditions lead to elevated thrombin generation and subsequent thrombus formation. Genetic prothrombotic defects (protein C, protein S and antithrombin deficiency, mutations of coagulation factor V and factor II, elevated lipoprotein (a)) have been established as risk factors of thromboembolic events in neonates and infants. The interpretation of the laboratory evaluation relies on age-dependent normal reference values. Because appropriate clinical trials are missing in these age groups, treatment recommendations are adapted from small-scale studies in neonates and infants and from guidelines relating to adult patient protocols. Secondary long-term anticoagulation should be administered on an individual basis.     

Sex,thrombosis and inherited thrombophilia

The incidence of venous thromboembolism (VTE) is two-fold higher in women than in men during reproductive age, which is likely explained by the use of hormonal contraceptives and by pregnancy in this phase of life. After adjustment for these factors, men have a two-fold higher risk of developing a first VTE compared with women, which is in line with earlier observations that men have a two-fold higher risk of recurrent VTE. These findings indicate that the intrinsic risk of VTE is higher in men than in women. Hormonal contraceptives increase the risk of VTE and the risk varies per type, dose, and administration route. In women with a high baseline risk of VTE, avoidance of some hormonal contraceptives should be considered, as well as thrombosis prophylaxis during pregnancy. Presence of hereditary thrombophilia increases the risk of a first VTE episode. This review focuses on the differences in risk of VTE between men and women, hormonal risk factors for women, and how these interact with common types of hereditary thrombophilia.     

Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis.

The 20210A prothrombin mutation has recently been associated with an increased risk of venous thrombosis, but the mechanism of the increased thrombotic risk in affected persons has not been elucidated. We report on a thrombophilic family in which the proband presented with cerebral vein thrombosis and homozygosity for the 20210A prothrombin mutation as her only identifiable risk factor for venous thrombosis. Extended genotyping of family members revealed seven other affected, but asymptomatic, first-degree relatives (one A/A homozygote and six G/A heterozygotes). Plasma levels of prothrombin, prothrombin fragments 1 + 2 and thrombin-antithrombin complexes were highest in A/A homozygotes, intermediate in G/A heterozygotes and lowest in those with the G/G homozygous normal genotype, while D-dimer levels were elevated only in A/A homozygotes. Our results suggest that the 20210A prothrombin mutation is associated with activation of coagulation and increased thrombin generation, not only in patients with a past history of thrombosis but also in otherwise healthy asymptomatic persons. In a similar fashion to the homozygous factor V Leiden mutation, patients with the homozygous 20210A prothrombin mutation could be at highest risk of thrombosis, as suggested by our patient who presented with unusual thrombosis.     

Venous thrombosis of the upper extremities

Opinion statement The goals of treating patients with upper-extremity deep vein thrombosis (UEDVT) are to relieve acute symptoms of venous occlusion, prevent pulmonary embolism, reduce the likelihood of recurrent thrombosis, and avoid the development of postphlebitic syndrome. Although the details of management differ, depending on the underlying cause and precipitating factors, anticoagulant therapy should be the first-line treat-ment of choice in all cases. For patients with primary or idiopathic UEDVT (Paget-von Schroetter syndrome), aggressive measures including catheter-directed thrombo-lysis, vascular procedures (eg, balloon angioplasty, stenting, filter), and surgical maneuvers (eg, first rib resection) have been advocated by some surgeons, but none of these high-risk interventions has been evaluated properly in prospective controlled trials. In contrast, for patients with catheter-associated central venous thrombosis (CACVT), or other secondary cases of UEDVT, many clinicians simply withdraw the catheter and avoid anticoagulant therapy. Because well-designed clinical trials are lacking, recommendations about the management of UEDVT are derived from descrip-tive studies and case series. Until further research identifies the natural history and optimum management of UEDVT, it seems reasonable to base treatment on antico-agulant regimens with proven effectiveness in lower-extremity deep vein thrombosis (LEDVT). The use of additional intervention(s) should be reserved for carefully selected patients.     

Prevalence of thrombophilia and catheter-related thrombosis in cystic fibrosis

Venous thrombosis in children and young adults is frequently associated with predisposing conditions and with an indwelling catheter or totally implantable venous access device (TIVAD). These systems are commonly used for the delivery of antibiotic therapy in patients with cystic fibrosis (CF). We reviewed our CF center's history of catheter-related events over 13 years and prospectively investigated the presence of risk factors for thrombosis in 66 children and adults with CF (age, 3-38 years; 32 females). Five thrombotic events had occurred in 4 patients, 2 of whom carried the factor V Leiden mutation. Five asymptomatic patients were diagnosed with heterozygous mutations of the factor V or prothrombin gene. Functional activity of protein C was decreased in 13 subjects, with a correlation to impaired liver function. Protein S activity was abnormal in 20 patients and was related to CF genotype. Anti-phospholipid antibodies (APA) were present in 6 asymptomatic patients. A reinvestigation after 3 years confirmed protein S deficiency in 12 of 14 patients, while most abnormalities for protein C or APA were inconsistent. In conclusion, a thrombophilic state was detected in 53% of patients, and 2 out of 4 subjects with TIVAD-related thrombosis carried a genetic defect. It may thus be helpful to include a hemostatic evaluation in the clinical decision process for or against TIVAD insertion in eligible CF patients.