French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

Anticoagulant activity and pleiotropic effects of heparin.

The recognized therapeutic effect of heparins is an anticoagulant activity (anti-Xa and anti-IIa) acting in an indirect manner (cofactor of antithrombin) but which is carried by only 20% at best of the glycan chains composing any commercial preparation of heparin, whether unfractionated or low molecular weight. However, the effects of glycan chains that participate in the therapeutic but also potentially adverse effects of heparin preparations must also be considered. These specific effects of glycans are potentially different for each commercial preparation of heparins and, in particular, low molecular weight heparins (LMWH) compared with unfractionated heparin (UFH) and LMWH between them. The glycanic nature of heparin is responsible for its very particular pharmacology: exchange with the glycocalyx of cells in particular endothelial. Exchanges which depend on the length and structure of the glycan chains therefore different between UFH and LMWH between the different heparin preparations between them but also according to the state of glycocalyx differently altered according to the underlying diseases and their degree of evolution. If the anticoagulant effects of heparins can potentially be replaced with those of new oral anticoagulants, the glycan effects of heparins cannot be replaced by synthetic non-glycan molecules. This replacement will undoubtedly limit certain risks such as heparin-induced thrombocytopenia (HIT) but other beneficial effects participating to the overall efficacy of heparin (whose relative importance remains to be ascertained), will also disappear: effects on surfaces, anti-inflammatory effects, antineoplastic and anti-metastatic effects, ancillary anticoagulant effects (not dependent on antithrombin), effect on endothelial dysfunction. This review will be focused on all of these related/pleiotropic effects of heparins that are in fact the effects of the glycan nature of heparin. Among the antithrombotic effects not dependent on antithrombin one has been more recently highlighted: the passivation/neutralization of the positively charged fibrils of Netosis, by the negatively charged glycan chains of heparin. This also has clinical implications: in the era of generics and biosimilars where biosimilar heparins begin to appear, it is important to know that accordingly to FDA and EMEA rules: their biosimilarity is judged only on the "classical" anticoagulation effect cofactor of antithrombin (anti-IIa/anti-Xa) but that all glycan effects that are potentially beneficial or potentially deleterious are not taken into consideration in their assessment.

Determinants of aspirin resistance in patients with type 2 diabetes.

BACKGROUND: Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. METHODS: Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. RESULTS: Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. CONCLUSION: Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.

[Involvement of thrombophilia in coronary thrombosis]. / Implication des thrombophilies dans les thrombus coronaires.

This review of thrombophilia and coronary thrombosis takes into account the "classical" thrombophilia commonly found in venous pathology and the conditions under which their research may be useful in certain forms of arterial thrombosis especially coronary thrombosis. In addition to the classical thrombophilia, exceptional thrombophilia are evoked, which are both factors of venous thrombosis but also arterial thrombosis. There are also thrombophilia that are more specific to the arterial system such as - homocystein which is potentially both a thrombosis factor but also an agent of arterial parietal lesion or - serotonin which is a factor of arterial spasm and especially coronary spasm. Finally, under the term thrombophilia, it is possible to include thrombophilic conditions, in particular cancers and inflammatory conditions.

Validation of a live animal model for training in endoscopic hemostasis of upper gastrointestinal bleeding ulcers.

BACKGROUND AND STUDY AIMS: The management of upper gastrointestinal bleeding requires training of the endoscopist. We aimed to validate a live animal model of bleeding ulcers for training in endoscopic hemostasis. MATERIALS AND METHODS: Bleeding ulcers were created by repeated grasp-and-snare gastric mucosectomies in pigs rendered "bleeders" by preadministration of clopidogrel, aspirin, and unfractionated heparin. The feasibility and reproducibility of the model (proportion of bleeding ulcers, number of ulcers per animal, and time needed to produce a bleeding ulcer) were prospectively evaluated in six animals. Ten endoscopic experts assessed the similarity of this pig model to human bleeding ulcers (four-point Likert scale). The training capabilities of the model for hemostatic techniques (needle injection, bipolar electrocoagulation, and hemoclipping) were evaluated in 46 fellows (four-point Likert scale). RESULTS: A total of 53 gastric ulcers were created in 6 animals (8.8 ± 1.5 ulcers/animal). Successful active ulcer bleeding (Forrest Ib) was achieved in 96.2 % of cases. Bleeding was moderate to abundant in 79 % of cases. Ulcerations consistently reached the submucosal layer. The mean (± SD) time taken to create a bleeding ulcer was 3.8 ± 0.6 minutes. Endoscopic experts assessed the realism of the ulcers and bleeding at 3.2 ± 0.7 and 3.6 ± 0.7 respectively on a four-point Likert scale. The training significantly improved the endoscopic skills of the 46 fellows (P < 0.0001) in all hemostatic techniques. CONCLUSIONS: The live porcine model of bleeding ulcers was demonstrated to be realistic, reproducible, feasible, time efficient, and easy to perform. It was favorably assessed as an excellent model for training in endoscopic treatment of bleeding ulcers.

Prothrombin G20210A carriers the genetic mutation and a history of venous thrombosis contributes to thrombin generation independently of factor II plasma levels.

SUMMARY BACKGROUND: The prothrombin (PT) G20210A gene mutation is a common risk factor for venous thrombosis (VT), which is mainly mediated through an increase in factor II (FII) plasma levels. High FII plasma levels may act through an increase in endogenous thrombin potential (ETP) a key step in hemostasis and thrombosis. While FII may be the main contributor to ETP in PT G20210A carriers, the knowledge of other environmental or genetic factors influencing ETP may help to better identify those at risk of VT. AIMS: ETP was determined in 472 non-carriers of PT G20210A (PT-) and in 325 unrelated carriers of PT G20210A (PT+) with (symptomatic n = 158) or without (asymptomatic, n = 167) a history of VT. All PT+ were heterozygous and free of other thrombophilic defects. RESULTS: ETP was higher in asymptomatic PT+ than in PT- (2038 +/- 371 vs. 1616 +/- 267 nmol L(-1) min; P < 0.0001). ETP was significantly higher in symptomatic PT+ than in controls PT+ (2129 +/- 430 vs. 2038 +/- 371 nmol L(-1) min; P = 0.01). Multivariate analyses evidenced the importance of FII and fibrinogen plasma levels in determining ETP. DISCUSSION: After taking these variables into account, a personal history of VT remained associated with ETP in PT+ carriers. Moreover, PTG20210A still contributes to ETP after consideration of FII levels. CONCLUSION: In conclusion, the increase in ETP observed in carriers is not entirely explained by higher FII or fibrinogen plasma levels but also by the history of VT.

[Antiplatelet agents and diabetes mellitus]. / Antiagrégants plaquettaires et diabète.

Diabetes and more specially type 2 diabetes are a major cardiovascular risk factor. The high incidence of cardiovascular thromboischemic events in type 2 diabetic patients is explained by the development of atherothrombotic lesions and by their high rate of recurrence after angioplasty but also by their high thrombogenic potential due to the association of platelet hyperactivity, hypercoagulability and hypofibrinolysis. Platelets are involved at two different levels: their hyperreactiviy but also their lower sensitivity to antiplatelets agents and specially the two main aspirin and clopidogrel. That focuses the interest of the newer antiplatelet agents (prasugrel and ticagrelor) whose efficacy seems to be less affected in the sub-group of diabetics. Besides the increased thrombo-ischemic risk in diabetics: they are also characterized by an increased hemorrhagic risk (global hemorrhagic risk and risk conferred by anti-thrombotic treatments). Sub-group analysis clearly evidenced this increased hemorrhagic risk for aspirin and clopidogrel but seems to be much less for the newer antiplatelet agents (prasugrel and ticagrelor). Specific trials of primary and secondary prevention with these new agent are particularly awaited in the high risk populations specially diabetics.

Effect of the thromboxane prostaglandin receptor antagonist terutroban on arterial thrombogenesis after repeated administration in patients treated for the prevention of ischemic stroke.

BACKGROUND: The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke. METHODS: This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 +/- 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation. RESULTS: Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well TOLERATED. CONCLUSIONS: Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation.

[Monitoring of anticoagulant treatment in patients with cancer]. / Surveillance des traitements anticoagulants chez les patients atteints de cancer.

Venous thromboembolic events are frequent in patients with cancer. Patients on anticoagulant therapy are both at increased risk for subsequent thromboembolic and bleeding events. Whatever the therapeutic option (vitamin K antagonists [VKA] or low-molecular-weight heparin [LMWH]) a clinic and biological monitoring is required. International Normalized Ratio (INR) variability is increased in patients with cancer as compared with patients without cancer and should be maintained in the target range. Anti-Xa activity measurement may be used in LMWH treatments, in order to detect a possible accumulation in any patients; platelet count monitoring is recommended. Interpretation is most often difficult because of numerous possible causes of thrombopenia in the patient with cancer. Anticoagulant clinics are developed in order to help practitioners and participate in the monitoring of anticoagulant treatments in those patients.

Lack of association between ADH3 polymorphism, alcohol intake, risk factors and carotid intima-media thickness.

OBJECTIVE: We assess the relationships between alcohol dehydrogenase 3 (ADH3) polymorphism, alcohol consumption and cardiovascular risk factor levels. METHODS: In a representative population sample from Southwestern France (614 men, 567 women, age 49.7+/-8.5 years), alcohol intake was assessed by questionnaire. RESULTS: Alcohol consumption was significantly related with higher levels of total and HDL cholesterol, triglycerides, apolipoprotein A-I in men and with higher levels of HDL cholesterol in women. Also, an inverse relationship between alcohol consumption and intima-media thickness was found in men. Conversely, in both genders, no differences were found between ADH3 genotypes regarding all cardiovascular risk factors studied and carotid intima-media thickness. Also, in both genders, no significant ADH3xalcohol interaction was found for all variables, and further adjustment on age, body mass index, educational level, smoking status or after excluding subjects on hypolipidemic or antihypertensive drug treatment did not change the results. CONCLUSION: We found no interaction between the ADH3 polymorphism and alcohol intake on cardiovascular risk factor levels and atherosclerotic markers in Southwestern France.

Paracetamol: a haemorrhagic risk factor in patients on warfarin.

AIM: To quantify the effect of paracetamol on the anticoagulant effect of warfarin under normal clinical conditions. PATIENTS AND METHODS: In a prospective double-blind, cross-over, placebo-controlled study, 11 patients on stable warfarin therapy received in random order two 14-day regimens of paracetamol 4 g day(-1) or placebo, with a 14-day or more wash-out period in between, time necessary to fulfil the inclusion criteria. RESULTS: In patients on paracetamol, the mean maximum increase in the International Normalized Ratio (INR) observed was 1.04 +/- 0.55 vs. 0.20 +/- 0.32 in those on placebo (P = 0.003). The mean maximum INR observed was significantly higher with paracetamol than with placebo (3.47 vs. 2.61, P = 0.01). In patients receiving paracetamol, the mean observed INR was significantly increased after 4 days (+ 0.6 +/- 0.6, P < 0.001). CONCLUSION: Paracetamol at 4 g day(-1) induces a significant increase in INR in patients receiving a stable regimen of warfarin, increasing the risk of bleeding associated with warfarin.

Rationale for the use of antifactor Xa in the treatment and prevention of venous and arterial thromboembolic events.

The design and synthesis of new antithrombotic agents have led to numerous recent clinical trials to investigate their efficacy and safety. Analysis of the data from these trials, especially when the results were not totally expected, has provided interesting information, allowing a better understanding of the pathophysiology of thrombosis in various clinical situations. The aim of the present manuscript is to present the hypotheses on thrombogenesis generated by some of these recent clinical trials, notably those investigating the antithrombotic efficacy of a new synthetic and selective factor Xa inhibitor, fondaparinux. The antithrombotic efficacy of fondaparinux was recently investigated in a number of trials in the prevention and treatment of venous and arterial thrombotic disorders. In each case, the concept of the clinical efficacy of a selective factor Xa inhibitor has been proven. These trials have also clarified the implication and mode of action of factor Xa in these various types of thrombotic events. In the light of these trials, we discuss the clinical efficacy of such a selective factor Xa inhibitor, and other specific points such as the apparent lack of dose-dependency of its antithrombotic effect.

Activity of a synthetic hexadecasaccharide (SanOrg123781A) in a pig model of arterial thrombosis.

The activity of SanOrg123781A, a new synthetic antithrombotic drug inhibiting both factor Xa and thrombin through antithrombin (AT), was compared to that of unfractionated heparin (UFH) and of the synthetic pentasaccharide (fondaparinux, SP) in an ex vivo arterial thrombosis model in the pig. Six groups of four pigs were administered intravenously with SanOrg123781A (1, 3, 10 and 30 nmol kg(-1)), UFH (30 nmol kg(-1)) or SP (30 nmol kg(-1)). In this arterial model in which platelet thrombus was formed on a thrombogenic surface under a constant high shear rate, UFH and SP had moderate antithrombotic effects while SanOrg123781A exhibited a strong, dose-dependent inhibitory activity on platelet adhesion and platelet thrombus formation. In contrast to UFH, SanOrg123781A did not modify the activated partial thromboplastin time (aPTT) even at 30 nmol kg(-1), but strongly inhibited thrombin generation. At the same dose, despite a lower antithrombotic activity than SanOrg123781A, UFH significantly affected all the coagulation parameters. Taken together, these results show that SanOrg123781A, due to its potent and selective antifactor Xa and antifactor IIa activities is a promising new antithrombotic agent even in arterial setting.

No alteration in platelet function or coagulation induced by EGb761 in a controlled study.

Some cases of spontaneous bleeding have been reported in patients treated with Ginkgo biloba. A prospective, double-blind, randomized, placebo-controlled study was carried out in 32 young male healthy volunteers to evaluate the effect of three doses of Ginkgo biloba extract (120, 240 and 480 mg/day for 14 days) on hemostasis, coagulation and fibrinolysis. This study did not reveal any alteration of platelet function or coagulation. This suggests that the reported clinical bleeding events in patients receiving Ginkgo biloba extract are not related to pharmacological properties of EGb761.

[Fibrinogen: factor and marker of cardiovascular risk]. / Fibrinogène et risque d'accident cardio-vasculaire.

Most cardiovascular events result from a thrombotic complication in patients with atherosclerosis. Inflammation plays a central role both in the pathogenesis of atherosclerosis and in the development of complications (particularly plaque rupture). Fibrinogen is both a marker of inflammation and a major determinant of thrombosis and hemorrheology. Clinical data corroborate with epidemiological data showing that higher serum fibrinogen level (compared with matched controls) is predictive of both the risk of primary cardiovascular events in the general population and the risk of secondary events among patients. Fibrinogen level, determined by both environmental and genetic factors, is a good example of gene-environment interaction. The rise in fibrinogen level indicative of significantly increased risk is actually very small, lying within the normal range. This explains why epidemiological data cannot be used to establish cardiovascular risk for individual patients in routine practice (excepting very high elevations rarely encountered). To date, fibrinogen is the only compound formally recognized as both a risk factor and a marker of cardiovascular risk. Other compounds, including CRP, von Willebrand factor, and more recently the CD40-CD40 ligand system, have also been shown to play a double role as predictors and markers. These new developments shed new light on fibrinogen as a risk marker/factor for atherothrombotic ischemic events.

Clopidogrel-induced qualitative changes in thrombus formation correlate with stent patency in injured pig cervical arteries.

Thienopyridines (ticlopidine or clopidogrel) alone or in combination with aspirin are now the reference antiplatelet therapy after stent implantation. To better understand the high efficacy and low risk of bleeding with these agents, we tested clopidogrel alone or with aspirin in an acute ex vivo flow chamber model and in a subacute in vivo arterial thrombosis model. Clopidogrel induced a dose-dependent increase in bleeding time (BT), inhibited ADP-induced platelet aggregation and in the flow chamber reduced thrombus size, and changed thrombus structure to broad-based structure composed of nondegranulated loosely attached platelets contrasting with the tight clumps of degranulated platelets seen without clopidogrel. The in vivo model involved angioplasty and stenting at the site of a preinduced arterial lesion and thrombosis in pig carotid arteries. Clopidogrel alone or with aspirin (but not aspirin alone) decreased the number of stented vessels occluded for more than 24 h and conversely reduced the number of occluding thrombus. At 96 h after stenting, 100% and 90% of the arteries were patent with clopidogrel/aspirin and clopidogrel alone, respectively (vs. 67% and 44% with aspirin and saline, respectively). Clopidogrel destabilizes thrombus without complete abolishment of platelet reactivity.

The calcium inhibitor SR33805 reduces intimal formation following injury of the porcine carotid artery.

We studied the effect of SR33805, a calcium channel blocker, in vitro on the proliferation of vascular smooth muscle cells (SMC) stimulated by foetal calf serum, basic fibroblast growth factor and platelet derived growth factor, and in vivo with regard to SMC migration and proliferation which occurred following injury of the porcine carotid artery. The intimal lesion was induced by a silasten collar surgically positioned around the carotid artery and by a stenosis reducing blood flow by 50% for 30 days. Animals received SR33805 (5 mg/kg/day) 8 days before the induction of the lesion and up to 30 days after. In vitro, SR33805 inhibited in a dose-dependent manner growth factor-induced proliferation of SMC (0.20

[The role of thrombotic and hemostatic mechanisms in the initial phases of atherosclerosis]. / Participation des mécanismes de la thrombose et de l'hémostase aux étapes initiales de l'athérosclérose.

The factors of thrombosis (endothelium, haemostasis, coagulation, fibrinolysis) are implicated from the initiating phase of atherosclerotic lesions. Their participation is more established (and studied) in the later phases of intraluminal evolution of atherosclerosis, of thromboembolic complications of the lesions and interventional procedures. The traditional theory of response to physical lesions of the endothelium as an initiating factor of atherosclerotic lesions, which gave platelets an essential role, has been replaced by that linking an early functional lesion of the endothelium and a cellular response by monocytes infiltrating the vessel wall, becoming macrophages. The macrophages participate in changes of the LDL in the wall, ingest the lipids at the same time as the smooth muscle cells which have migrated and proliferated from the media to the intima. The lipid overload, especially with oxidised LDL, is intracellular at first in these foam cells, then extracellular as the cells die. During the early stages, all the tissue factors of activation and development of coagulation are present in the vessel wall and then within the lesion. This intra-cellular coagulation results in the production of thrombi in the tissues and the transformation of fibrinogen to fibrin. These stages precede and participate in cellular proliferation and extracellular lipid deposits. Factors of tissular thrombolysis (the uPA pathway) play a part in cellular immigration and proliferation. It is only at a later stage that the lesion activates intravascular coagulation and fibrinolysis which, in conditions of variable equilibrium, will result in the clinical complications of the atherosclerotic process. All these factors therefore participate firstly in the tissues and then within the lumen, in the progression and complications of atherosclerosis which for these reasons is often called atherothrombotic disease. The comprehension of these mechanisms is essential for the development and interpretation of tests and treatment applied to different stages of the disease, which is all the more complex given that in a given patient at a given time, lesions at different stages are present in the arterial network.

Effects of human recombinant, plasma-derived and porcine von Willebrand factor in pigs with severe von Willebrand disease.

The effects of the infusion of a human recombinant von Willebrand factor (vWF) preparation in pigs homozygous for von Willebrand disease (vWD) were evaluated on serial measurements of von Willebrand factor antigen and activity, FVIII activity, vWF multimer analysis, in-vivo bleeding time and platelet adhesion and thrombus formation on collagen at high shear rates in an ex-vivo model of experimental thrombosis. Plasma-derived human and porcine vWF were used for comparison. Before infusion, the pigs were characterized by undetectable plasma vWF levels, a low level of FVIII, prolonged bleeding time, severely impaired platelet adhesion and thrombus formation. After infusion of the human recombinant vWF, in-vivo recovery of vWF activity ranged from 58% to 82%, depending on the dose infused, and its half-life was longer than for the plasma-derived concentrates. The highest-molecular-weight forms of human recombinant vWF were removed from the circulation gradually. Infusion of the three vWF concentrates produced inconsistent effects on bleeding time and moderate improvement of platelet adhesion and thrombus formation. After infusion, a prolonged increase of FVIII (> 48 h) was observed, suggesting that human recombinant vWF is able to bind and to stabilize porcine factor VIII and that porcine vWD is a good model for studying such interactions.