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This paper reviews the current evidence on the pathogenesis, clinical manifestations, diagnosis and management of cancer-associated non-bacterial thrombotic endocarditis (NBTE). NBTE is an underdiagnosed condition characterized by sterile valvular vegetations composed of platelets and fibrin which are susceptible to systemic embolization. Cancer is a leading cause of NBTE and should be excluded in NBTE cases without a clear etiology. Malignancies most frequently associated with NBTE are mucin-releasing adenocarcinomas of the lung, ovary, biliary system, pancreas, breast and stomach. NBTE carries a high risk of arterial thromboembolism, while cardiac valvular dysfunction is much less frequent. NBTE appears to be an important underdiagnosed cause of cancer-associated embolic stroke of undetermined source. Characteristics associated with cancer-associated NBTE include elevated D-dimer, visceral infarcts, cerebral infarcts in multiple vascular territories, transcranial doppler microembolic signals, disseminated cancer and adenocarcinoma histology. Transesophageal echocardiography is the diagnostic test of choice, and all suspected cases should be evaluated for the presence of elevated D-dimers and disseminated intravascular coagulation. Long-term anticoagulation with low molecular weight heparin should be strongly considered, and surgical intervention is usually not needed. Underlying cancer must be diagnosed swiftly (if previously undiagnosed) and anti-cancer treatment should be initiated as soon as possible. The paucity of data regarding all aspects of NBTE, and the severe clinical consequences of untreated NBTE, are an urgent call for future research.

Background Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented. Objective This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice. Methods A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included. Results A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction. Conclusion Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events., Highlights • Patients on direct oral anticoagulants (DOACs) can encounter drug interactions. • Drug interactions can alter the amount of DOAC in a patient's system. • Research on DOAC interactions is currently limited and larger studies are required. • Health providers should continue to be cautious with potential DOAC interactions.

Despite a breadth of data on the management of cancer-associated thrombosis, all the studies informing clinical guidelines excluded patients receiving palliative care. Patients with advanced cancer have a higher rate of recurrent venous thromboembolism (VTE) and bleeding, making them one of the most challenging populations to treat. The dearth of population-specific research leaves clinicians with few options but to extrapolate data from clinical trials conducted on a healthier population. Recent observational studies have challenged the utility of doing this, suggesting the natural history of VTE in the advanced cancer patient may differ to our first beliefs and that a less aggressive approach to anticoagulation is warranted particularly near the end of life. This paper highlights what we know so far.

Recently, in a previous paper [1], we have described the antithrombin and antithrombotic activity of a novel fucansulfate extracted from brown algae and patented in the USA in 1999 [2]. The reason why such a fucansulfate was developed and patented is because it is free of the problems (such as bovine spongiform encephalitis, BSE) that antithrombotic and anticoagulant polysaccharides of animal origin might have [1]. In the present paper, we give the evidence that our novel fucansulfate, when given by subcutaneous route, has a better absorption than calcium heparin, as far as activated partial thromboplastin time (APTT) is concerned.

Patients with cancer have increased risks of venous and arterial thromboembolism and/or atrial fibrillation, for which anticoagulation is commonly used. For these indications, three main types of anticoagulants are recommended or used: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and vitamin K antagonists (VKAs), all have different advantages and disadvantages. Drug-drug interactions (DDIs) with anticoagulation are often cautioned against by major guidelines, but evidence remains scarce regarding the best management approach for specific drug combinations, particularly with DOACs. Significant DDIs might affect the efficacy and safety of anticoagulants and/or anticancer therapies as well as other interfering medications, and more studies are needed. This paper will review the available evidence and guidelines on DDIs with anticoagulants, focusing on the cancer population whenever possible, and propose directions for future research.

The Fontan procedure has transformed the lives of children born with single-ventricle physiology, previously deemed inoperable. Worldwide, there are an increasing number of children with Fontan circulation, with the potential for survival into adulthood. Due to the abnormal circulation, Fontan patients have an increased risk of thromboembolic (TE) events, with up to 25% of events leading to death. Despite the importance of preventing TE events in this patient population, there is currently no clinical consensus on the optimal monitoring, thromboprophylaxis therapies, and treatment of these events. This paper reviews the available literature regarding anticoagulation in the pediatric and adult Fontan population, including the mechanisms for thrombosis and current antithrombotic therapies.

Placenta-mediated pregnancy complications, such as pre-eclampsia, placental abruption, birth of a small-for-gestational age infant and late pregnancy loss, are common and carry significant morbidity and mortality. The etiology of placenta-mediated pregnancy complications is likely multifactorial and may include abnormal coagulation activation of the maternal-fetal interface. The use of antepartum low-molecular-weight heparin (LMWH) prophylaxis to prevent recurrent placenta-mediated pregnancy complications has become common practice despite limited and conflicting evidence to support its use. This paper reviews the evidence, including recently published data from an individual patient level meta-analysis, which challenges the role of LMWH in preventing recurrent placenta-mediated pregnancy complications. Incorporating this recent evidence, we recommend against the use of LMWH to prevent recurrent placenta-mediated pregnancy complications in women with and without inherited thrombophilia.

The relationship between cancer and thrombosis is a complex one with the haemostatic system and mechanisms of cancer growth and metastasis inextricably linked. The possibility that antithrombotics may confer a survival benefit on cancer patients has been considered for over sixty years, over which time a growing body of evidence has suggested that drugs such as low molecular weight heparins may inhibit cancer growth and metastasis through a myriad of mechanisms. Much of the trial data suggesting a survival benefit has been obtained through secondary subgroup analyses in highly heterogeneous populations. To date no sufficiently powered studies have been undertaken which support the routine use of LMWH to improve survival in cancer patients. This paper will review the current evidence around the topic to identify where we currently stand in this exciting yet challenging field.

Introduction Deep vein thrombosis (DVT) is one of the common complications of orthopedic surgery. Low molecular weight heparin (LMWH) is a usually used agent for DVT, but it would increase the risk of bleeding. LRRFIP1 has been shown to play an important role in the formation of thrombosis. Therefore, we investigated the effect of LRRFIP1 shRNA lentivirus on DVT in mice. Materials and Methods Lentiviral Vectors carrying LRRFIP1 shRNA were constructed and transfected into cultured mouse bone marrow cells (BMCs). Male ICR mice were irradiated with a single dose of 9.5 Gy and then were injected with different agents through the tail vein. Stasis venous thrombosis was induced by inferior vena cava (IVC) ligation. Mice were sacrificed on the 1st, 3rd and 7th day post operation and the thrombi were removed, blotted the excess blood on it with filter paper and immediately weighed. P-selectin and d-Dimer were determined by enzyme-linked immunosorbent assay (ELISA). Results LRRFIP1 shRNA significantly suppressed the expression of LRRFIP1 in the thrombi. In contrast, low molecular weight heparin (LMWH) and negative shRNA exhibited little effect on the expression of LRRFIP1. LRRFIP1 shRNA, LMWH and negative shRNA inhibited the thrombus formation in vivo significantly. The plasma P-selectin and d-Dimer levels were significantly increased after IVC ligation. LRRFIP1 shRNA significantly decreased the plasma P-selectin and d-Dimer levels. However, LMWH and negative shRNA showed little effects on the levels of plasma P-selectin and d-Dimer. Conclusion LRRFIP1 shRNA might represent a promising prevention strategy for DVT.

Whilst the term cancer associated thrombosis (CAT) offers an overarching term for all thrombotic events encountered during the cancer journey, the reality is that this is a far too simplistic reflection of a complex multifactorial process occurring within a heterogeneous population. The management of CAT needs to consider factors beyond the thrombus itself: patients must be treated as individuals within the context of their own cancer journey and their preferences for different treatment options. The breath of pathological, pharmacological and psychosocial variants means it is highly unlikely that one treatment regime will be appropriate for all patients. It is inevitable that regimes may need to be modified and anticoagulant agents changed according to clinical and patient preference needs. There is strong evidence supporting the use of low molecular weight heparin first line in the treatment of acute CAT. The evidence for warfarin and the direct acting oral anticoagulants is not as strong but, as oral agents, may be preferred by some patients. This paper shall identify the various treatment options available, factors which will influence the decision making process and when it is justifiable to treat patients differently to the established protocol.

Background Lenalidomide in combination to steroid therapy, including high-dose dexamethasone (RD), low-dose dexamethasone (Rd) or triple therapy of melphalan, prednisolone, lenalidomide (MPR), has shown to be an effective and well-tolerated treatment for patients with newly diagnosed multiple myeloma (NDMM) and relapsed refractory multiple myeloma (RRMM). Lenalidomide is associated with an increased risk of venous thromboembolism, and studies have consistently demonstrated the need for venous thromboembolism (VTE) prophylaxis in patients receiving these combinations. However, the optimal approach to thromboprophylaxis has not yet been established. Objective In this systematic review we sought to compare the efficacy of aspirin (ASA) or low molecular weight heparin (LMWH) in the prevention of VTE in patients with myeloma using lenalidomide- based therapy. Methods A systematic literature search strategy was used to identify potential studies on MEDLINE, EMBASE, and CENTRAL using an OVID interface. The methodological quality of the selected cohort studies was assessed according to Newcastle-Ottawa Quality Assessment Scale, and risk of bias of randomised controlled trials (RCTs) was assessed according to risk of bias assessment tool from the Cochrane Handbook. The primary outcome measure was the incidence rate of VTE while using ASA or LMWH. Results Out of 247 studies, 6 met our inclusion criteria with a total of 1126 participants including a total of 5 phase III RCTs, and one retrospective study. Overall, all studies show high quality: In 4 of the 5 RCTs type of randomization was clearly reported, outcome assessment was blinded, and withdrawal rates were reported, and the remaining RCT was an abstract. In 4 RCTs the intervention and comparator arms were related to anti-myeloma treatment regimens. Pooled data of studies of NDMM treated with lenalidomide based regimen with ASA prophylaxis show a VTE rate of 98 of 915 (10.7%) [95% CI: 8.86-12.88] (Table1). In NDMM and RRMM patients treated with lenalidomide, VTE rate on LMWH prophylaxis was 3 of 211 (1.4%) [95% CI: 0.48-4.09] (Table2). The relative risk (RR) of VTE in patients receiving ASA compared to LMWH was 7.5 (95% CI: 2.41-23.53, p =0.0005). Overall, the rate of VTE was 1.4 (95% CI: 1.14 - 1.69) per 100 patient-cycles of anti-myeloma treatment. A subgroup analysis on patient using ASA showed a similar risk of 1.5 (95% CI: 1.24 - 1.84).The incidence of VTE in those using ASA while on RD was 52 of 195 (26.6%) [95% CI: 20.9-33.2], while VTE rate in those receiving Rd was 27 of 262 (10.3%) [95% CI: 7.18-14.58] demonstrating a statistically significant higher risk for patients on RD [RR=2.5 (95% CI: 1.68- 3.96), p Conclusion The study showed that the most frequent thromboprophylaxis of choice for patients with myeloma on lenalidomide-based therapy is ASA. However, ASA may not confer appropriate protection against VTE, especially in patients using high dose dexamethasone. On the other hand, the risk of VTE in patients receiving MPR and ASA was low and ASA may be a safe option for these patients. More studies comparing the safety of ASA to other anticoagulants such as LMWH or direct oral anticoagulants are warranted. Table 1. Rate of VTE using ASA in NDMM with different lenalidomide based regimens. Rx: treatment; 95% CI: 95% confidence interval. Study Design Rx N VTE rate: N (%) 95% CI Zonder, 2010 Rajkumar, 2010 Phase III RCT RD 195 52 (26.6) 20.9-33.2 Larocca, 2011 Rajkumar, 2010 Phase III RCT Rd 262 27 (10.3) 7.18-14.58 Palumbo, 2012 Stewart, 2014 Phase III RCT MPR 458 19 (4.1) 2.67-6.38 Total 915 98 (10.7) 8.86-12.88 Table 2. Rate of VTE using LMWH in myeloma patients (NDMM or RRMM) on lenalidomide-based regimen. 95% CI: 95% confidence interval. Paper Design Induction Setting N VTE rate: N (%) 95% CI Klein, 2008 Retrospective cohort RD RRMM 45 1(2.2) 0.39-11.57 Larocca, 2011 Phase III RCT Rd NDMM 166 2(1.2) 0.33-4.28 Total 211 3(1.4) 0.48-4.09 Disclosures Louzada: pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion; Celegene: Consultancy, Other: advisory board and expert opinion.

Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to "usual intensity" anticoagulation; recent evidence suggests that most such patients are adequately treated with "usual therapy". After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most "experts" recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.

With the availability of efficient and safe clotting factor replacement therapy, elective total joint arthroplasty is increasingly performed in subjects with haemophilia suffering from chronic haemophilic arthropathy. Little has been published addressing the prevalence and the specific risk factors of thromboembolic complications and the role of thromboembolic prophylaxis in this specific population. While the risk of thrombosis in hemophilic patients following hip or knee arthroplasty is considered to be low and probably mitigated by the clotting factor deficiency, cases have been reported of pulmonary embolism and deep vein thrombosis in hemophilic patients. Although most guidelines advocate thromboembolic prophylaxis in the general population undergoing major orthopaedic surgery, no such standard of care is in place for hemophilic patients. This paper discusses the scope of the problem of venous thromboembolism in patients with haemophilia undergoing major orthopaedic surgery and reviews the published approaches to the use of prophylactic anticoagulation in this setting.

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.

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Cancer-associated thrombosis is a major cause of morbidity and mortality. Although anticoagulation remains the mainstay for prevention and treatment of thrombosis, current anticoagulants are problematic in cancer patients. Parenteral anticoagulants, such as heparin or low-molecular heparin, require daily subcutaneous injection, whereas warfarin requires coagulation monitoring and frequent dose adjustments. Idrabiotaparinux, a reversible long-acting pentasaccharide, and new oral anticoagulants, such as dabigatran etexilate, rivaroxaban and apixaban, have been designed to replace warfarin for extended prevention or treatment of VTE. Clinical trials with these agents have yielded promising results, and dabigatran etexilate and rivaroxaban are already licensed in many countries for thromboprophylaxis after elective hip or knee replacement surgery. In the coming years, these drugs are likely to replace warfarin for most indications. This paper addresses their potential role for prevention and treatment of cancer-related thrombosis.

Bleeding is the most common complication of anticoagulant therapy. Despite the frequency of its occurrence, little evidence is available to guide the care of anticoagulated patients with, or at high risk of, bleeding. This article attempts, using a case based format, to describe common clinical scenarios encountered by clinicians who manage anticoagulated patients and who are bleeding. The paper is "case based" and narrative since there is little evidence to guide practice in this area.

In principle, the answer to this question is obvious: "as long as the risk of continued therapy is outweighed by the benefit." In practice, determining an individual patient's risk of recurrent venous thromboembolism (VTE) without warfarin or other vitamin K antagonists is difficult. However, there are many factors (both intrinsic and environmental) that can alter the risk of VTE recurrence. This paper will discuss evidence and considerations (including the issue of bleeding risk) that may be relevant to decisions about duration of anticoagulant therapy for patients with VTE.

Background This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard “Clinical laboratory testing and in vitro medical devices — Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy”. The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin. Methods The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard. Results Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias − 0.19 to 0.18 INR; > 97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity. Conclusion The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007.

Introduction Enoxaparin is the current anticoagulant of choice for neonatal thrombosis. Present neonatal treatment guidelines of 1.5 mg/kg every 12 hours (q12 h) are extrapolated primarily from an earlier study with 9 infants less than 2 months of age. More recent studies indicate an increased dose requirement for neonates. Materials and methods Relevant data from articles and abstracts were identified by searching MEDLINE and pediatric and hematology conference proceedings. Results Publications between 1996 and 2007 included 8 papers, 4 abstracts and 1 review article with primary research documenting enoxaparin use in 240 neonates. The mean maintenance dose of enoxaparin ranged from 1.48 to 2.27 mg/kg q12 h for all infants, but was higher for preterm neonates at 1.9-2.27 mg/kg q12 h. The efficacy of enoxaparin, causing either complete or partial resolution was between 59 and 100%. Minor side effects were common and adverse events (major bleeding) occurred in 12 patients (0-19%). Conclusions Increased experience with enoxaparin use in neonates in the past decade has indicated higher doses to achieve accepted target anti-factor Xa values. The long-term use of indwelling catheters (Insuflon catheter) for enoxaparin administration may need to be reevaluated in ELBW infants. Suggested starting doses of enoxaparin are 1.7 mg/kg q12 h for term neonates and 2.0 mg/kg q12 h for preterm neonates if there is no considerable bleeding risk. However, further prospective studies are needed to validate an increased initial dose of enoxaparin.

The aim of this paper is to review the thrombogram and its use for phenotyping the haemostatic system. The thrombogram can be readily obtained through Calibrated Automated Thrombography (CAT), using a commercially available fluorometer, dedicated software (Thrombinoscope (R)) and a calibrator. Here we explore the possibility to use platelet-rich plasma (PRP) triggered with a low amount of recombinant human tissue factor (similar to 0.5 pM) and also explore the function of the protein C system by adding activated protein C (APC) or soluble recombinant thrombomodulin (TM). Examples are shown: inherited antithrombin (AT) and protein C deficiencies, and antiphospholipid antibodies. (c) 2004 Elsevier Ltd. All rights reserved.

Antithrombin (AT) high affinity of unfractionated heparin (UFH) resides in a specific pentasaccharide sequence. Heparin also regulates complement activity on the classical and the alternative pathways. Most experimental pieces of evidence accumulated show that these important activities reside in different segments of the heparin molecule. We demonstrated in previous papers that a low ionic strength and the presence of calcium ions are essential to detect specific interactions between glycosaminoglycans and proteins. Then these very strict conditions were used, and we demonstrated that the first protein complex of the human complement cascade recognizes in the UFH a fraction with very high anticoagulant activity. After isolation from the precipitate of the interaction, this fraction of heparin also contained the pentasaccharide sequence responsible for the great affinity with AT: in fact, it was strongly bound to a resin of AT agarose, and to detach it, an ionic strength of 0.6 M sodium chloride was required. In this way, the heparin regions responsible for the anticoagulant activity and also for the effects over the complement system were identified on the same short segment of the heparin molecule, which includes the active fraction of the glycosaminoglycan. The differences with early results could be explained by our experimental conditions of low ionic strength and the presence of calcium ions used for the interaction of the protein and the glycosaminoglycan.

In many countries, low molecular weight heparins (LMWHs) have replaced unfractionated heparin (UH) for prevention and treatment of venous thromboembolism. The present paper reviews the possible advantages of LMWHs over UH. In spite of their lower molecular weight distribution, LMWHs are functionally more heterogeneous than UH. Their anti-Xa/anti-IIa ratio varies significantly, and the injection of the same dose generates different anti-Xa activities and activated partial thromboplastin time (APTT) prolongations. Their pharmacodynamic properties account for their more convenient use in comparison with UH; however, there is a risk of accumulation in case of renal insufficiency. Even if they are less anticoagulant on the basis of the APTT prolongation, they are not less prohemorrhagic than UH. LMWHs are probably less immunogenic and probably induce less osteoporosis. Several meta-analyses published between 1992 and 1999 indicate that LMWHs are as efficient as UH in preventing postoperative deep vein thrombosis (DVT) in general surgery and more efficient than UH in preventing DVT in orthopedic surgery and treating established DVT.

This paper describes the first human study with aprosulate, a new chemically synthesized anticoagulant with a defined molecular structure and a molecular weight of 2388. Twelve healthy male volunteers received subcutaneous injections of placebo on the first day followed by ascending doses of aprosulate in the range of 0.25 mg/kg to 2.0 mg/kg body weight on alternate days. Anticoagulant, pharmacokinetic and safety parameters were assessed for 48 hours after each injection. The activated partial thromboplastin time and the Heptest showed a dose-dependent increase for up to ten hours after each application. A trend towards prolongation of the bleeding time was indicated with higher doses. In general, the tolerance was good. Plasma transaminase concentrations were raised in some volunteers but returned spontaneously to normal during or after the study.

In previous papers, we have described the preparation and heparin-like properties of insoluble modified polystyrene resins. We now report results about the interactions of several coagulation factors with some of these materials. Most of the non-activated factors are neither adsorbed nor modified, except factor V and prekallikrein. In contrast thrombin, antithrombin III and factor Xa adsorb on the surface of such insoluble polymers. Thrombin can be desorbed by addition of a polycationic compound. The inactivation of thrombin or factor Xa by antithrombin is catalysed by the presence in the mixture of these insoluble materials as it is with soluble heparin. The initial velocity of these reactions is second order for both types of catalysis-homogeneous or heterogeneous - as previously reported for soluble heparin. In the case of these insoluble materials, the inhibition of protease by antiprotease seems to be accelerated when complexes are formed between the polymer and the proteins.