Maria T. DeSancho

Bleeding and thrombotic complications in critically ill patients with cancer

Alterations in hemostasis are common in patients with cancer admitted to the ICU. Depending on the underlying disease and specific hemostatic abnormality, the patient with cancer may develop bleeding, thrombosis, or both, such as DIC. Bleeding complications usually result from abnormalities in platelets or deficiency of coagulation factors and require specific blood or coagulation factor replacement. Similarly, critically ill patients with cancer are predisposed to thrombotic complications such as DVT, PE, and central vein thrombosis, the last as a result of the widespread use of long-term indwelling catheter devices. Advances in diagnostic imaging and the availability of newer and more potent anticoagulant agents have facilitated the care of these patients greatly. Ultimately, it is hoped that a thorough understanding of the various disturbances in hemostasis, innovative treatment approaches, and implementation of preventive strategies in patients with cancer will lead to decreased morbidity and improved survival rates of critically ill patients with cancer in the ICU.

The effects of Eculizumab on the pathology of malignant atrophic papulosis

BackgroundDegos disease is a frequently fatal and incurable occlusive vasculopathy most commonly affecting the skin, gastrointestinal tract and brain. Vascular C5b-9 deposition and a type I interferon (IFN) rich microenvironment are held to be pathogenetically important in the evolution of the vascular changes. We recently discovered the use of eculizumab as a salvage drug in the treatment of near fatal Malignant atrophic papulosis (MAP). The effects of eculizumab on the pathology of MAP are explored.MethodsArchival skin and gastrointestinal biopsy material was procured over a 2.5-year period before and after eculizumab therapy in our index case. Routine light microscopy and immunohistochemical assessment for C3d, C4d, C5b-9, MxA and caspase 3 were examined. Direct immunofluorescent studies were also conducted on select biopsy material.ResultsThe patient had received eculizumab as a emergent life saving measure and following rapid improvement he continued with biweekly infusions for 4 years. Although improved he continues to have signs and symptoms of persistent abdominal disease. Pre-Eculizumab biopsies showed an active thrombotic microangiopathy associated with a high type I interferon signature and extensive vascular deposits of C5b-9 in skin and gastrointestinal biopsies. Endothelial cell apoptosis as revealed by Caspase 3 expression was noted. Inflammation comprising lymphocytes and macrophages along with mesenchymal mucin was observed as well. Post-eculizumab biopsies did not show active luminal thrombosis but only chronic sequelae of prior episodes of vascular injury. There was no discernible caspase 3 expression. After 12 months of therapy, C5b-9 was no longer detectable in tissue. The high type I IFN signature and inflammation along with mucin deposition was not altered by the drug. In addition, there was little effect of the drug on the occlusive fibrointimal arteriopathy which appears to be one characterized by extensive myofibroblastic expansion of the intima potentially as revealed by staining for smooth muscle actin without immunoreactivity for desmin and myogenin.ConclusionsComplement activation and enhanced endothelial cell apoptosis play an important role in the thrombotic complications of MAP. However, the larger vessel proliferative intimal changes appear to be independent of complement activation and may be on the basis of other upstream mechanisms. Monitoring C5b-9 deposition in tissue is likely not of great value in assessing treatment response to eculizumab given the persistence of C5b-9 in tissue for several months despite clinically effective C5 blocking therapy. A more integrated approach addressing upstream and downstream pathways in addition to those attributable to complement activation are critical for the successful treatment of MAP. Eculizumab may be used as salvage therapy in critically ill patients with thrombotic microangiopathy.

ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia - study protocol for a randomized controlled trial

BackgroundA large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome.Methods/DesignRandomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone.Study population: pregnant women of less than 7 weeks’ gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both.Setting: multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate.Intervention: LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone.Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations.Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions.DiscussionAfter an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study.The study website can be accessed via www.ALIFE2study.org.Trial registrationThe ALIFE2 study was registered on 19 March 2012 under registration number NTR3361

Thrombophilia and the risk of thromboembolic events in women on oral contraceptives and hormone replacement therapy.

Thrombophilia contributes to the risk of thrombosis in women using female hormones. The objective of the present study was to evaluate the prevalence of thrombophilia in women with thromboembolic events (TEEs) using oral contraceptives or hormone replacement therapy (HRT) and assess the contribution of a family history and the duration of hormone use in predicting thrombosis. A retrospective analysis was performed of the case records of women who developed a TEE while on oral contraceptives or HRT and were referred for thrombophilia evaluation over a 4-year period. Among 85 women who developed a TEE while on oral contraceptives or HRT, 65 had at least one additional thrombophilia risk factor. Of the 85 cases, 23 tested positive for more than two thrombophilias, 16 had factor V Leiden, five had the prothrombin gene G20210A polymorphism, 26 had antiphospholipid antibodies, 10 had elevated homocysteine, four had protein C deficiency, and seven had protein S deficiency. There were 64 TEE: 16 pulmonary emboli, 17 cerebrovascular events, 11 intra-abdominal thromboses, 13 deep venous thromboses, five cases of superficial thrombophlebitis, and two retinal vein thromboses. Of the 65 women, 37% had a positive family history of thrombosis. Approximately half of the women had been taking oral contraceptives or HRT for more than 1 year. There is a high prevalence of thrombophilia in women who developed a TEE while using oral contraceptives or HRT for more than 1 year. Family and personal history of thrombosis should be carefully evaluated in all women before initiating or continuing oral contraceptives or HRT, and a positive history may warrant a thrombophilia screening.

Hematological issues in critically ill patients with cancer.

Patients with solid and hematologic malignancies presenting with major bleeding or thrombotic complications, potentially life-ending events in a cancer patients clinical course, usually require admission to an intensive care unit (ICU), making their diagnosis and management even more important for the intensivist. Given the significant advances in the diagnosis and treatment of almost all types of cancers in recent years, the intensivist is likely to encounter an ever-increasing number of cancer patients in the ICU setting with these complications. Abnormal hemostasis can occur as a consequence of both the pathology and treatment of cancer. Because cancer can have multiple effects on hemostatic equilibrium, treatment of these complications can be more complex than in the general population. This article reviews the physiology of coagulation and fibrinolysis, with special attention to those aspects that are most frequently altered in the setting of malignancy. The pathophysiology of bleeding and thrombotic complications specific to critically ill cancer patients are then detailed, and the diagnostic and therapeutic strategies are discussed. Special emphasis is placed on new cancer medications that have an effect on hemostasis, and on novel clotting and anticoagulant agents that are available to the intensivist for the management of these patients.

Risk Factors and Treatment Strategies in Patients With Retinal Vascular Occlusions.

Retinal vein occlusion (RVO) and retinal artery occlusion (RAO) cause significant visual impairment. The role of thrombophilia and cardiovascular testing is uncertain, and optimal treatment strategies have not been determined. We reviewed medical records of 39 patients with RVO and RAO (23 women and 16 men). Thrombophilia and cardiovascular evaluations were performed and outcomes were reviewed. In all, 24 (61.5%) patients had at least 1 thrombophilia. Elevated factor VIII levels were found in RVO (n = 5) but not in RAO. There are no other significant differences in thrombophilias in RVO compared to those in RAO. Most patients had hypertension(41.2% RAO and 55% RVO) and hyperlipidemia (35.5% RAO and 81.8% RVO). In all, 4 women were using oral contraceptives, 2 were pregnant or postpartum. Follow-up data was available for 28 patients (13 RAO, 15 RVO). Nineteen were treated with aspirin, four with warfarin, and one with low molecular weight heparin. Eight patients reported improvement in vision at time of follow-up (5 RAO, 3 RVO). Multiple risk factors are associated with RVO and RAO, and a complete assessment should include thrombophilia and cardiovascular studies.

Lingual thrombosis in a woman with antiphospholipid syndrome

A 28-year-old woman, 34 weeks pregnant, with previously diagnosed antiphospholipid syndrome, presents with vesicular tongue lesions treated as herpes outbreak and new onset of preeclampsia. Tongue biopsy preformed postpartum after induction of labor for preeclampsia reveals tongue infarction.

Recombinant Human Antithrombin in Pregnant Patients with Hereditary Antithrombin Deficiency: Integrated Analysis of Clinical Data.

OBJECTIVES The purpose of this analysis was to evaluate the use of recombinant human antithrombin (rhAT) in preventing venous thromboembolism (VTE) in pregnant patients with hereditary AT deficiency (HATD). STUDY DESIGN Data from two clinical trials were pooled. Dosing of rhAT was based on body weight and baseline AT activity, started up to 24 hours before scheduled induction or cesarean delivery, or at the onset of labor. RESULTS A total of 21 pregnant HATD patients were enrolled. Mean rhAT therapy duration was 4.3 days and dose was 245.1 IU/kg/day. All patients achieved target mean AT activity (80-120% of normal) during rhAT therapy. There were no confirmed VTEs during rhAT treatment or within 7 ( ± 1) days after dosing. Two VTE events (one deep vein thrombosis and one pulmonary embolism) occurred 11 and 14 days after discontinuation of rhAT, in patients managed with prophylactic doses of heparin or low-molecular-weight heparin following delivery. CONCLUSION rhAT was safe and effective in pregnant HATD patients when administered during the peripartum period, the period of highest VTE risk and a time when anticoagulation therapy is normally withheld. Pregnant HATD patients may benefit from therapeutic, rather than prophylactic, doses of anticoagulation after delivery to protect against postpartum VTE.

Risk factors for clinical manifestations in carriers of Factor V Leiden and prothrombin gene mutations.

Carriers of Factor V Leiden and prothrombin G20210A gene mutations have an increased risk of developing thromboembolic events and adverse outcomes of pregnancy. The objective of the present study was to identify risk factors which may predispose carriers of Factor V Leiden and/or prothrombin G20210A gene mutations to develop thromboembolic events and adverse outcomes of pregnancy. A retrospective case–control study of 217 carriers of Factor V Leiden and/or prothrombin G20210A gene mutations at two tertiary centers between January 2000 and December 2006. Symptomatic carriers (cases) were compared with asymptomatic carriers (controls) for the following risk factors: environmental, cardiovascular, family history of thrombosis, and presence of other thrombophilias. For female carriers, we included the use of female hormones, pregnancy, and the postpartum period. Of the 217 carriers, there were 155 (71%) cases and 62 (29%) controls. Of the 155 cases, 90 (58%) had venous thrombosis and 26 (17%) arterial thrombosis. Among the 123 symptomatic female carriers, 55 (45%) had recurrent pregnancy losses and nine (7%) other adverse outcomes of pregnancy. The postoperative state and the presence of antiphospholipid antibodies were risk factors for thromboembolic events and adverse outcomes of pregnancy in 10 (6%) and 22 (13%) cases, respectively. The presence of antiphospholipid antibodies in symptomatic carriers increased the risk of developing thromboembolic events 4.4-fold. The postoperative state and the presence of antiphospholipid antibodies were significant risk factors for thromboembolic events and adverse outcomes of pregnancy among Factor V Leiden and/or prothrombin G20210A gene mutation carriers. Testing for the presence of antiphospholipid antibodies may be warranted in Factor V Leiden and/or prothrombin G20210A gene mutation carriers who develop these adverse clinical manifestations.

Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses

BACKGROUND Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study. METHODS The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. CONCLUSION The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE.