The management of thrombosis in pregnancy: role of low-molecular-weight heparin

Fatal pulmonary embolism remains the most common cause of mortality among pregnant women in many Western countries. The physiological changes of pregnancy produce a hypercoagulable state that increases the risk of venous thromboembolism (VTE). Women with inherited or acquired thrombophilias are at particularly high risk of VTE during pregnancy, and thromboprophylaxis may be advisable in some cases. Thrombophilia is also associated with complications of pregnancy, including fetal loss, pre-eclampsia, intra-uterine growth restriction, and placental abruption. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy, and pregnancy complications, include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contra-indicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early and late pregnancy is uncertain. The efficacy and safety of LMWHs have been demonstrated for the prevention and treatment of VTE in pregnancy. These agents are increasingly being used in place of UFH, which is associated with a higher incidence of side effects compared with LMWH, in addition to the need for regular laboratory monitoring. Evidence is also emerging to support the use of LMWH in the prevention of recurrent fetal loss, although further trials are needed to explore the role of LMWHs in this indication and in the prevention of other complications of pregnancy.     

Preeclampsia and pregnancy loss in women with a history of venous thromboembolism and prophylactic low-molecular-weight heparin (LMWH) during pregnancy

Limited data are available regarding complications of pregnancy and pregnancy outcome under prophylaxis with low-molecular-weight heparin (LMWH) in women with a history of thromboembolism (TE). We retrospectively evaluated pregnancy complications in a cohort of 80 women. All had a history of TE (76 venous, two arterial and two venous and arterial) and received prophylactic LMWH during 86 pregnancies. The rate of preeclampsia and stillbirth in these women was compared to that of a control group of 313 women without a history of TE and LMWH. Prophylaxis was started at a median of 10 weeks of gestation and usually continued until six weeks post partum. In 94% of the cases the outcome of pregnancy was favourable with a live birth. Four pregnancies (4.7%) ended in miscarriage. Two (2.3%) pregnancies were complicated by a thromboembolic event (one deep leg vein thrombosis and PRIND, respectively). One patient developed HELLP-syndrome. Severe preeclampsia occurred in three (3.8%) and stillbirth in one (1.3%) of the patients (n = 80), whereas this was the case in four (1.3%, odds ratio 3.01; 95% confidence interval (CI) 0.66-13.73, p = 0.15) and 10 (3.2%, OR = 0.38; 95% CI 0.05-3.04, p = 0.72) control women. Mean birth weight and standard deviation of infants was 3,160 +/- 930 g in patients and 3,300 +/- 540 g in controls (p = 0.11). We conclude that a favourable pregnancy outcome in women with a history of thromboembolism who use prophylactic LMWH during pregnancy can be expected. There was a trend towards a higher risk of preeclampsia, and these women should be carefully monitored for this complication.     

The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis

Objective:

To compare the efficacy and safety of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in the treatment of patients with cerebral venous sinus thrombosis (CVST), and to provide an appropriate treatment option in these patients.

Method:

This is a randomized double blind clinical trial conducted between December 2013 and December 2014. The subjects were selected among patients referred to Neurology Department, Imam Reza Hospital; affiliated to Kermanshah University of Medical Sciences, Kermanshah, Iran. Fifty-two cases of CVST were included in this study and randomly divided into 2 groups. Twenty-six cases received LMWH and the other 26 cases received UFH. The primary outcomes include hospital mortality rate and neurologic deficits as assessed by the National Institutes of Health Stroke Scale (NIHSS). The secondary end point was disability as measured by the Modified Rankin Scale (MRS).

Results:

We observed the rate of mortality and neurological deficits and disability based on NIHSS, and the MRS did not differ between the 2 groups.

Conclusion:

The efficacy of LMWH and UFH in reduction of neurologic deficit and functional disability in patients with CVST are similar.Cerebral venous sinus thrombosis (CVST) is an uncommon stroke that, unlike arterial stroke, occurs mostly in adolescent and young children.1,2 The outcome of patients with CVST is variable from complete recovery to persistent neurological damage.3 Regardless of the fact that most patients have a complete or partial recovery, 10% are observe to have persistent neurological damage by 12 months of follow-up.3 According to information from clinical trials and observational studies, anticoagulation is advised as safe and effective treatment for cerebral venous thrombosis.3-5 Anticoagulants can also prevent pulmonary embolism, which makes sinus thrombosis is highly complicated.4-7 However, there is no agreement on what type of heparin to use: low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH).7,8 The advantage of using UFH is that it acts rapidly due to inhibition of IIa factor, and its effects are reversible by administering protamine sulfate; however, binding to plasma proteins, platelet (platelet factor 4), macrophages, and endothelial cells limit its bioavailability and account for the highly variable anticoagulant response and requires dose adjustments based on activated partial-thromboplastin time values.8,9 The clinical benefits of LMWH comprise higher bioavailability more predictable pharmacokinetic profile, dose-dependent plasma levels, a longer half-life, the lower risk of bleeding and immune-mediated thrombocytopenia and heparin-induced osteoporosis.8,9 Because of these clinical advantages, LMWHs have gradually replaced UFH for most indications. Several clinical trials, in patients with deep venous thrombosis and pulmonary embolism indicates that LMWH is as effective as UFH and associated with the fewest hemorrhagic complications.8,10 There are already limited data directly comparing LMWH with UFH in CVST patients. It is critical for the clinician to understand which drugs are most effective and associated with the fewest adverse events. The aim of this study was to compare the efficacy and safety of these 2 types of heparins in the treatment of patients with CVST to provide an appropriate treatment option in such patients.     

Cerebral venous sinus thrombosis with cerebral hemorrhage during early pregnancy

Cerebral venous sinus thrombosis (CVST) rarely induces cerebral hemorrhage, and CVST with cerebral hemorrhage during early pregnancy is extremely rare. Upon literature review, we are able to find only one case of CVST with cerebral hemorrhage in early pregnancy. In this paper, we report another case of a 27-year-old patient who developed CVST with cerebral hemorrhage in her fifth week of pregnancy. Although the optimal treatment for this infrequent condition remains controversial, we adopted anticoagulation as the first choice of treatment and obtained favorable results.Cerebral venous sinus thrombosis (CVST) accounts for 0.5-1.0% of all strokes.1 During late pregnancy and puerperium, CVST is an uncommon but important cause of stroke.2 Hemorrhagic infarction can occur in the acute stage of CVST. However, CVST with cerebral hemorrhage is extremely rare in early pregnancy. Upon literature review, we are able to find only one case of CVST resulting in cerebral hemorrhage in early pregnancy.3 Here, we present another case of CVST with cerebral hemorrhage in early pregnancy, the patient received a favorable outcome by use of anticoagulation therapy. Our objective in presenting this particular case is to discuss its diagnosis, and treatment, and review the related literature.     

Long-term therapy with low-molecular-weight heparin in cancer patients with venous thromboembolism

Long-term therapy with low-molecular-weight heparin (LMWH) is the treatment of choice for cancer patients with venous thromboembolism (VTE). However, the ideal doses of LMWH have not been thoroughly studied. We used the RIETE Registry data to assess the influence of the daily LMWH dosage on outcome during the first three months after VTE. We used propensity score-matching to compare patients who received <150 vs. those receiving ≥150 UI/kg/day LMWH. Up to July 2010, 3,222 cancer patients with VTE received long-term therapy with fixed doses of LMWH. Of these, 1,472 (46%) received <150 IU/kg/day (mean, 112 ± 28), and 1,750 received ≥150 IU/kg/day (mean, 184 ± 32). Results of the propensity score matching involved 1269 matched pairs. During follow-up, the incidence of pulmonary embolism (PE) recurrences was similar (1.2% vs. 1.9%), but patients receiving <150 IU/kg/day LMWH had a lower incidence of fatal PE than those treated with ≥150 IU/kg/day (0.2% vs. 1.0%; p=0.004). Multivariate analysis confirmed that patients receiving <150 IU/kg/day LMWH had a lower risk for fatal PE (odds ratio [OR]: 0.2; 95% confidence interval [CI]: 0.06-0.8) and for major bleeding (OR: 0.6; 95% CI: 0.3-1.0) than those treated with ≥150 IU/kg/day. In real life, one in every two cancer patients with VTE received lower doses of LMWH than those used in randomised trials, with large variations from patient to patient. Unexpectedly, patients treated with <150 IU/kg/day LMWH had fewer fatal PE cases and fewer major bleeding events than those receiving ≥150 IU/kg/day LMWH. This finding, however, should be validated in prospective clinical trials.     

Treatment of venous thromboembolism during pregnancy

BackgroundAcute VTE occurs with an incidence of 1–2/1,000 during pregnancy and is associated with an acute mortality of 1–2%. However, data on VTE treatment during pregnancy are sparse: Even though 50 cases occur daily in the EU and US, a recent review identified only 174 cases in the literature.Acute treatmentStandard treatment is LMWH at therapeutic doses or APTT-adjusted UFH. LMWH is at least as safe and effective as UFH in non-pregnant patients. In pregnancy, LMWH is the preferred option, because it offers better bioavailability, fewer injections, superior safety regarding HIT and osteoporosis.Long-term treatmentVKA are contraindicated because of teratogenicity and thus heparin is used for secondary prevention. Since UFH requires therapeutic doses throughout pregnancy, carrying the risk of osteoporosis, LMWH is the drug of choice. In a recent review most patients were treated initially with LMWH, predominately with twice daily injections. Recurrent VTE occurred in 1.2%, bleeding in 1.7%, with no HIT. Whether the long-term dose of LMWH can be reduced remains unresolved: Intermediate dose LMWH has been used effectively in cancer patients, who — like pregnant women — continue to have a high pro-thrombotic burden after the initial phase.ConclusionEven though acute VTE is not uncommon and represents a life-threatening event during pregnancy, data are sparse, and prospective trial data are needed to answer open questions concerning treatment modalities. Nevertheless, it is evident that LMWH is the preferred option for treatment of VTE during pregnancy.     

Prevention of deep vein thrombosis by low-molecular-weight heparin and dihydroergotamine in patients undergoing total hip replacement.

In 110 high-risk patients undergoing total hip replacement the antithrombotic efficacy and safety of a single daily injection of 1500 aPTT-U low-molecular-weight heparin plus 0.5 mg dihydroergotamine (Embolex) was, in a double-blind study, compared with a twice daily administration of 5000 IU of the heparin-dihydroergotamine combination Heparin-Dihydergot. Deep vein thrombosis diagnosed with phlebography occurred in 9.6% in the Embolex-group and in 25% in the Heparin-Dihydergot-group. Intra- and postoperative blood loss and blood replacement were similar in both groups. Therefore, and on account of the single daily administration, Embolex offers at least the advantage of improved compliance of the patients and reduced workload of the nursing staff.     

Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis

Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-α₂-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.     

Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo

Treatment of deep venous thrombosis with low molecular weight heparin (LMWH-Novo, Logiparin) was carried out with two different doses of Logiparin, 75 XaI U/kg b.w. twice daily and 150 XaI U/kg b.w. once daily subcutaneously for 5 days. Simultaneously warfarin was given from the first day of heparin treatment. Mean age of the twenty patients was 65 years and one third was females. No serious side effects, hematomas, pulmonary emboli or signs of recurrent thrombosis occurred during treatment with either dose regime. Venografic assessment with Marder scoring one week after initiation of Logiparin treatment showed a slight not significant improvement apparent in 40 % of the patients. The activities of F-IIaI and F-XaI in the blood plasma were found to increase after injection of Logiparin. These two parameters seem to be the most suitable for monitoring the effect during treatment. For future studies on the therapeutic effect of Logiparin in deep venous thrombosis a single dose of 150 to 200 F-XaI activity per 24 hours seems to be most suitable.     

Fixed-dose,body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis

Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.     

Cerebral venous thrombosis associated with oligodendroglioma and pregnancy

Until now, cerebral venous sinus thrombosis (CVST) was principally an autopsy diagnosis; however, with the introduction of MRI and angiography, as well as enhanced clinical attentiveness, it is now reliably diagnosed during life. Herein, we describe a case of CVST accompanied by oligodendroglioma and pregnancy. In our patient, the following factors contributed to the formation of CVST: First, the pregnancy state, which is a known risk factor for developing venous thrombosis; and secondly, the oligodendroglioma could have changed the architecture of adjacent sinus (right lateral sinus) and provocation of the development of clot in the sinus.     

Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis

BACKGROUND AND PURPOSE: Treatment of cerebral sinus thrombosis with heparin is controversial. We conducted a double-blind, placebo-controlled multicenter trial to examine whether anticoagulant treatment improves outcome in patients with sinus thrombosis. METHODS: Patients were randomized between body weight-adjusted subcutaneous nadroparin (180 anti-factor Xa units/kg per 24 hours) and matching placebo for 3 weeks (double-blind part of trial), followed by 3 months of oral anticoagulants for patients allocated nadroparin (open part). Patients with cerebral hemorrhage caused by sinus thrombosis were also included. RESULTS: Sixty patients were enrolled, and none were lost to follow-up. In 1 patient the diagnosis proved wrong after randomization. After 3 weeks, 6 of 30 patients (20%) in the nadroparin group and 7 of 29 patients (24%) in the placebo group had a poor outcome, defined as death or Barthel Index score of <15 (risk difference, -4%; 95% CI, -25 to 17%; NS). After 12 weeks, 4 of 30 patients (13%) in the nadroparin group and 6 of 29 (21%) in the placebo group had a poor outcome, defined as death or Oxford Handicap Score of >/=3 (risk difference, -7%; 95% CI, -26% to 12%; NS). There were no new symptomatic cerebral hemorrhages. One patient in the nadroparin group had a major gastrointestinal hemorrhage, and 1 patient in the placebo group died from clinically suspected pulmonary embolism. CONCLUSIONS: Patients with cerebral sinus thrombosis treated with anticoagulants (low-molecular-weight heparin followed by oral anticoagulation) had a favorable outcome more often than controls, but the difference was not statistically significant. Anticoagulation proved to be safe, even in patients with cerebral hemorrhage.     

Cost-effectiveness of low-molecular-weight heparin for secondary prophylaxis of cancer-related venous thromboembolism

Although extended secondary prophylaxis with low-molecular-weight heparin was recently shown to be more effective than warfarin for cancer-related venous thromboembolism, its cost-effectiveness compared to traditional prophylaxis with warfarin is uncertain. We built a decision analytic model to evaluate the clinical and economic outcomes of a 6-month course of low-molecular-weight heparin or warfarin therapy in 65-year-old patients with cancer-related venous thromboembolism. We used probability estimates and utilities reported in the literature and published cost data. Using a US societal perspective, we compared strategies based on quality-adjusted life-years (QALYs) and lifetime costs. The incremental cost-effectiveness ratio of low-molecular-weight heparin compared with warfarin was 149,865 dollars/QALY. Low-molecular-weight heparin yielded a quality-adjusted life expectancy of 1.097 QALYs at the cost of 15,329 dollars. Overall, 46% (7108 dollars) of the total costs associated with low-molecular-weight heparin were attributable to pharmacy costs. Although the low-molecular-weigh heparin strategy achieved a higher incremental quality-adjusted life expectancy than the warfarin strategy (difference of 0.051 QALYs), this clinical benefit was offset by a substantial cost increment of 7,609 dollars. Cost-effectiveness results were sensitive to variation of the early mortality risks associated with low-molecular-weight heparin and warfarin and the pharmacy costs for low-molecular-weight heparin. Based on the best available evidence, secondary prophylaxis with low-molecular-weight heparin is more effective than warfarin for cancer-related venous thromboembolism. However, because of the substantial pharmacy costs of extended low-molecular-weight heparin prophylaxis in the US, this treatment is relatively expensive compared with warfarin.     

Treatment and prophylaxis of venous thromboembolism during pregnancy

The treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in pregnant patients is challenging for several reasons. Coumarins can cause embryopathy and other adverse effects in the fetus. Although unfractionated heparin and low-molecular-weight heparins, the cornerstones of initial therapy, are safe for the fetus, they can have significant maternal side effects, including osteoporosis and thrombocytopenia. Because they must be given parenterally, long-term administration is inconvenient. Further, although low-molecular-weight heparins probably cause less maternal osteoporosis and thrombocytopenia than unfractionated heparin, the appropriate dosing regimens for prevention and treatment of thrombosis during pregnancy have not been established. In addition, there is a paucity of reliable information on the incidence of venous thromboembolism and the risk of recurrent thrombosis during pregnancy. This paper briefly reviews the areas of controversy and provides recommendations for the treatment and prophylaxis of acute deep vein thrombosis and pulmonary embolism in pregnant patients.     

Proteomics of microparticles after deep venous thrombosis

Background

Microparticles (MP) are submicron size membrane vesicles released from activated cells that are associated with thrombosis and inflammation. MP present diverse biological expressions that may be linked to a unique subset of proteins derived from their origin cells.

Methods

To identify these proteins, plasma samples were taken from 9 patients with deep venous thrombosis (DVT) documented by duplex ultrasound, 9 with leg pain but negative for DVT by duplex, and 6 healthy controls without a history of thrombosis, for fold variation. MP were extracted from platelet-poor plasma, digested separately with trypsin and tagged using iTRAQ reagents. The digests were subjected to 2-D LC separation followed by MALDI tandem mass spectrometry. Peak lists were generated and searched against all human sequences. For protein identification, a minimum of two peptides at 95% confidence was required. Later, iTRAQ ratios were generated comparing relative protein levels of DVT patients to baseline. The proteomic analysis was performed twice for each blood sample. Proteins were considered elevated or depressed if the iTRAQ ratio (R) deviated by 20% change from normal and a p-value less than 0.05.

Results

Two proteins (Galectin-3 Binding Protein, [Gal3BP], R = 1.76 and Alpha-2 macroglobulin [A2M] R = 1.57) were differentially expressed on DVT patients. Nine proteins were depleted including fibrinogen beta and gamma chain precursors (R = 0.65).

Conclusions

These proteins influence thrombosis through inflammation, cell shedding, inhibition of fibrinolysis and hemostatic plug formation. Further studies are needed to confirm the mechanistic role of these proteins in the pathogenesis of venous thrombosis in humans.