Haemostatic changes in urogenital schistosomiasis haematobium: a case-control study in Gabonese schoolchildren.

In many tropical areas schistosomiasis is a major health problem causing hepatosplenic, intestinal or urogenital complaints. Hepatosplenic schistosomiasis mansoni is also characterized by blood coagulation abnormalities. Liver pathology plays a role in the development of haemostatic changes and the parasitic infection may directly affect coagulation. However, these contributing factors cannot be studied separately in hepatosplenic schistosomiasis infections. This pilot study provides insight in haemostatic changes in urinary schistosomiasis by studying coagulation parameters in schistosomiasis haematobium-infected Gabonese schoolchildren. Selection on urinary schistosomiasis patients without hepatosplenic complaints allows for the investigation of the direct effects of the parasite on haemostasis. Levels of von Willebrand Factor (VWF) antigen, active VWF and osteoprotegerin were elevated, indicating inflammation-mediated endothelial activation. In contrast to hepatosplenic schistosomiasis, thrombin-antithrombin complex and D-dimer levels were not affected. Despite its small sample size, this study clearly indicates that Schistosoma haematobium directly alters the activation status of the endothelium, without initiation of coagulation.

Agonist-induced platelet reactivity correlates with bleeding in haemato-oncological patients.

BACKGROUND AND OBJECTIVE: Prophylactic platelet transfusions are administered to prevent bleeding in haemato-oncological patients. However, bleeding still occurs, despite these transfusions. This practice is costly and not without risk. Better predictors of bleeding are needed, and flow cytometric evaluation of platelet function might aid the clinician in identifying patients at risk of bleeding. This evaluation can be performed within the hour and is not hampered by low platelet count. Our objective was to assess a possible correlation between bleeding and platelet function in thrombocytopenic haemato-oncological patients. MATERIALS AND METHODS: Inclusion was possible for admitted haemato-oncology patients aged 18 years and above. Furthermore, an expected need for platelet transfusions was necessary. Bleeding was graded according to the WHO bleeding scale. Platelet reactivity to stimulation by either adenosine diphosphate (ADP), cross-linked collagen-related peptide (CRP-xL), PAR1- or PAR4-activating peptide (AP) was measured using flow cytometry. RESULTS: A total of 114 evaluations were available from 21 consecutive patients. Platelet reactivity in response to stimulation by all four studied agonists was inversely correlated with significant bleeding. Odds ratios (OR) for bleeding were 0·28 for every unit increase in median fluorescence intensity (MFI) [95% confidence interval (CI) 0·11-0·73] for ADP; 0·59 [0·40-0·87] for CRP-xL; 0·59 [0·37-0·94] for PAR1-AP; and 0·43 [0·23-0·79] for PAR4-AP. The platelet count was not correlated with bleeding (OR 0·99 [0·96-1·02]). CONCLUSION: Agonist-induced platelet reactivity was significantly correlated to bleeding. Platelet function testing could provide a basis for a personalized transfusion regimen, in which platelet transfusions are limited to those at risk of bleeding.

High On-Treatment Platelet Reactivity in Peripheral Arterial Disease: A Pilot Study to Find the Optimal Test and Cut Off Values.

OBJECTIVE: Restenosis and stent thrombosis after endovascular intervention in patients with peripheral arterial disease (PAD) can potentially be tackled by more intensive antiplatelet therapy, such as dual antiplatelet therapy (DAPT) consisting of aspirin and P2Y12 inhibitor. Despite clopidogrel treatment, some patients still display high platelet reactivity (HCPR). Tailored antiplatelet therapy, based on platelet reactivity testing, might overcome HCPR. However, more data are warranted regarding the proportion of patients with HCPR in the PAD population, different platelet reactivity tests, their correlation, and the optimal timing for these tests as a stepping stone for a future trial investigating the potential benefit of tailored antiplatelet therapy in PAD patients. METHODS: Thirty patients on DAPT after percutaneous transluminal angioplasty underwent platelet reactivity testing by VerifyNow, vasodilator-stimulated phosphoprotein (VASP) and platelet activation assay, and CYP2C19-polymorphism testing. RESULTS: The proportion of patients with HCPR measured by VerifyNow varied between 43.3% and 83.3%, depending on the cut off values used. Testing within 24 hours of initiation of DAPT gave a higher proportion of HCPR than testing after more than 24 hours. According to DNA testing, 14.8% were CYP2C19*2 homozygote, 22.2% heterozygote, and 63% CYP2C19*2 negative. VASP assay revealed 24% HCPR. The highest HCPR rate was found with a VerifyNow cut off of less than 40% inhibition, whereas the lowest HCPR rate was found with the VASP assay. There was a low correlation between the tests. CONCLUSION: HCPR is present in PAD patients and research on HCPR is needed in this population; timing of tests is relevant and standardisation of tests is needed. The optimal conditions for platelet function testing should be determined.

Perioperative platelet reactivity over time in patients undergoing vascular surgery: An observational pilot study.

BACKGROUND: Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity. AIMS: To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel. METHODS: Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers. RESULTS: Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers. CONCLUSION: In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.

Pathophysiology of thrombotic APS: where do we stand?

The antiphospholipid syndrome (APS) is diagnosed when patients with thrombotic complications or foetal losses have elevated levels of antiphospholipid antibodies in their plasmas. The term APS is confusing, because the pathogenic auto-antibodies are not directed against phospholipids but towards a plasma protein, ß(2)-glycoprotein I. For many years the reason why auto-antibodies against ß(2)-glycoprotein I were pro-thrombotic was unclear, because man and mice deficient in ß(2)-glycoprotein I do not express a clear phenotype. Animal models in which passive transfer of patient antibodies into mice resulted in an increased thrombotic response have provided novel insights in the importance of this protein in the pathology of APS.

Antiphospholipid antibodies and the protein C pathway.

Haemostasis is a delicate balance between procoagulant and anticoagulant processes. In the human body usually anticoagulant mechanisms prevail over procoagulant mechanisms, thereby preventing a prothrombotic state. The antiphospholipid syndrome is an example in which this balance is shifted to a more prothrombotic state due to the presence of antiphospholipid antibodies. One of the most extensively proposed pathogenic mechanisms within the antiphospholipid syndrome is the inhibition of protein C by antiphospholipid antibodies. Antiphospholipid antibodies have been described to have different actions on the protein C pathway, for example decreasing protein C and/or S plasma levels, inducing increased resistance against activated protein C and lowering thrombin levels (resulting in an impaired protein C activation). This review briefly discusses the actions of protein C in human body but mainly focuses on the effects of antiphospholipid antibodies on the protein C pathway that have been described in literature.

The role of LRP8 (ApoER2') in the pathophysiology of the antiphospholipid syndrome.

One of the greatest enigmas in thrombosis research is the observation that one can diagnose a person with a thrombotic risk with a prolongation of the clotting time. Our textbooks have taught us that prolongation of clotting correlates with a tendency to bleed. To confuse our textbook knowledge further, the same patients often have a prolonged bleeding time, a diagnostic test to detect a dysfunction in primary haemostasis. In this paper we critically review the literature that tries to explain the contradiction that exists between in-vitro diagnostic tests and the observed clinical manifestations and discuss our current opinion on how antiphospholipid antibodies can disturb the haemostatic balance.

Antiphospholipid syndrome. Current insights into laboratory diagnosis and pathophysiology.

The antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL) in the plasma of patients with vascular thrombosis, recurrent complications of pregnancy, or both (1, 2). The presence of aPL in plasma of patients can be detected with either a prolongation of phospholipid dependent coagulation tests (lupus anticoagulant, LAC), or with solid phase immune assays against the protein beta2-glycoprotein I (beta2-GPI) or the phospholipid cardiolipin (anti-beta2-GPI antibody ELISA and anti-cardiolipin antibody ELISA, respectively) (3). For a long time there was a lot of confusion on who had the syndrome and who not. To solve this dispute, an international consensus meeting was organized in Sapporo in 1999 to formulate classification criteria for patients with the antiphospholipid syndrome (4). These criteria have been updated in 2004 at another international consensus meeting in Sydney (5). The classification criteria were defined for scientific purposes and were aimed to be used as inclusion criteria in patient related studies. They were specifically not defined for diagnostic purposes. However, current practice is that these criteria are used as a diagnostic tool. This is very unfortunate because the specificity of the different aPL assays to detect the clinical manifestations that characterize APS are disputable. One of the aims of defining the criteria was to initiate studies to determine the value of the different anti-phospholipid antibody assays to serve as biomarker for the risk of thrombosis and pregnancy morbidity. The recent progress made on this important topic will be discussed.

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

INTRODUCTION: The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS. METHODS: Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written. RESULTS: Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre. CONCLUSION: This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

Validation of flow cytometric analysis of platelet function in patients with a suspected platelet function defect.

Essentials The diagnosis of mild platelet function disorders (PFDs) is challenging. Validation of flow cytometric testing in patients with suspected PFDs is required. Flow cytometry has added value to light transmission aggregometry (LTA) in diagnosis of PFDs. There is fair agreement in diagnosing PFDs between LTA and flow cytometry. SUMMARY: Background Light transmission aggregometry (LTA) is the most commonly used test for the diagnosis of platelet function disorders (PFDs), but has moderate sensitivity for mild PFDs. Flow cytometry has been recommended for additional diagnostics of PFDs but is not yet standardized as a diagnostic test. We developed a standardized protocol for flow cytometric analysis of platelet function that measures fibrinogen binding and P-selectin expression as platelet activation markers in response to agonist stimulation. Objectives To determine the additional value of flow cytometric platelet function testing to standard LTA screening in a cross-sectional cohort of patients with a suspected PFD. Methods Platelet function was assessed with flow cytometry and LTA in 107 patients suspected of a PFD in whom von Willebrand disease and coagulation factor deficiencies were excluded. Both tests were compared in terms of agreement and discriminative ability for diagnosing patients with PFDs. Results Out of 107 patients, 51 patients had an elevated bleeding score; 62.7% of the patients had abnormal platelet function measured with flow cytometry and 54.2% of the patients were abnormal based on LTA. There was fair agreement between LTA and flow cytometry (κ = 0.32). The discriminative ability of flow cytometric analysis in patients with an elevated bleeding score was good (AUC 0.82, 0.74-0.90), but moderate for LTA (AUC 0.70, 0.60-0.80). Both tests combined had a better discriminative ability (AUC 0.87, 0.80-0.94). Conclusion Flow cytometric analysis of platelet function has added value in diagnostics of PFDs in patients with unexplained bleeding tendency.

High prevalence of reduced thrombin generation and/or decreased platelet response in women with unexplained heavy menstrual bleeding.

INTRODUCTION: Heavy menstrual bleeding (HMB) is a condition that affects 20%-30% of women of reproductive age. HMB has a multifactorial pathophysiology, which is incompletely understood. HMB symptoms are very common in patients with established haemostasis defects, likewise, women with heavy menstrual bleeding have a higher prevalence of impaired Von Willebrand factor (VWF) levels and function, thrombocytopenia, impaired platelet function and impaired coagulation. The aim of this study was to quantify the prevalence of impaired platelet function, impaired coagulation and reduced VWF activity in patients with HMB. METHODS: We have used thrombin generation (TG), a flow cytometry-based platelet function test and a flow cytometry-based VWF function test to study haemostasis in 58 women (median age: 48.4 years, range 40-60 years) with HMB. In addition, we determined VWF antigen levels and VWF ristocetin co-factor activity in platelet-poor plasma. Reference ranges of platelet function were measured in whole blood of 123 healthy volunteers, while reference ranges of TG were determined in platelet-poor plasma (PPP) of 126 healthy volunteers. RESULTS: Fourteen (24%) patients with HMB had impaired platelet function and 17 (29.3%) patients had impaired coagulation. Five patients (8.6%) had both impaired platelet function and impaired coagulation. Only 2 (3.4%) patients had an impaired VWF function or levels; one of them was in combination with impaired coagulation. CONCLUSION: Our approach in women with HMB using a high precision platelet function test in combination with thrombin generation showed impaired coagulation or impaired platelet function in more than 40% of the patients.

Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2'.

BACKGROUND: The major antigen implicated in the antiphospholipid syndrome is beta2-glycoprotein I (beta2GPI). Dimerized beta2GPI binds to apolipoprotein E receptor 2' (apoER2') on platelets and increases platelet adhesion to collagen under conditions of flow. AIM: To investigate whether the interaction between dimerized beta2GPI and platelets is sufficiently strong to resist shear stresses. METHODS: We studied the interaction of platelets with immobilized dimerized beta2GPI under conditions of flow, and further analyzed the interaction using surface plasmon resonance and solid phase immunoassays. RESULTS: We found that dimerized beta2GPI supports platelet adhesion and aggregate formation under venous flow conditions. Adhesion of platelets to dimerized beta2GPI was completely inhibited by the addition of soluble forms of both apoER2' and GPIbalpha, and the addition of receptor-associated protein and the removal of GPIbalpha from the platelet surface. GPIbalpha co-precipitated with apoER2', suggesting the presence of complexes between GPIbalpha and apoER2' on platelet membranes. The interaction between GPIbalpha and dimeric beta2GPI was of intermediate affinity (Kd = 180 nM) and Zn2+, but not Ca2+-dependent. Deletion of domain V from dimeric beta2GPI strongly reduced its binding to both GPIbalpha and apoER2'. Antibodies that inhibit the binding of thrombin to GPIbalpha inhibited platelet adhesion to dimeric beta2GPI completely, while antibodies blocking the binding of von Willebrand factor to GPIbalpha had no effect. Dimeric beta2GPI showed reduced binding to low-sulfated GPIbalpha compared to the fully sulfated form. CONCLUSION: We show that platelets adhere to dimeric beta2GPI under both arterial and venous shear stresses. Platelets adhere via two receptors: GPIbalpha and apoER2'. These receptors are present in a complex on the platelet surface.

Platelets express three different splice variants of ApoER2 that are all involved in signaling.

BACKGROUND: beta2-Glycoprotein I is the most relevant antigen in antiphospholipid syndrome. We have shown that binding of dimerized beta2-GPI to platelets via ApoER2' sensitizes platelets for second activating stimuli. OBJECTIVE: Determine the region of ApoER2 involved in the binding of dimeric beta2-GPI. METHODS: Cultured human megakaryocytes (MK) and three different human megakaryocytic cell lines were used for mRNA isolation to clone and express recombinant soluble platelet ApoER2. Domain deletion mutants of ApoER2 were constructed to identify the binding site for dimeric beta2-GPI. The presence of ApoER2 splice variants in platelets was demonstrated by immuno-blotting. RESULTS: Three different mRNA splice variants were isolated from all four types of megakaryocytic cells used. Sequence analysis identified the splice variants: (i) shApoER2Delta5 lacking low-density lipoprotein (LDL) binding domains 4, 5 and 6; (ii) shApoER2Delta4-5 lacking LDL binding domains 3, 4, 5, 6 and (iii) shApoER2Delta3-4-5 lacking LDL binding domains 3, 4, 5, 6 and 7. The presence of three splice variants of ApoER2 on platelets was confirmed by immuno-blotting, with ApoER2Delta4-5 being the most abundantly expressed splice variant. Upon stimulation with dimeric beta2-GPI, all three splice variants were translocated to the cytosol; however, ApoER2Delta4-5 translocation was most prominent. Dimeric beta2-GPI binds platelet ApoER2 variants via LDL-binding domain 1. CONCLUSIONS: Three different ApoER2 mRNA splice variants were isolated from MK and platelets express all three splice variants. All splice variants were shown to be functional by translocation upon stimulation with dimeric beta2-GPI. All three splice variants express LDL-binding domain 1.

[Platelet function tests: tailored antiplatelet therapy for vascular patients?] / Bloedplaatjesfunctietesten.

- Platelet aggregation inhibitors, also known as antiplatelet therapy (APT), are prescribed for the prevention of secondary cardiovascular events (CVE) after endovascular revascularization procedures.- Platelet aggregation inhibitors are not equally effective in all patients. The phenomenon of high residual platelet reactivity despite APT is called 'high on-treatment platelet reactivity' (HTPR); it bears an increased risk of secondary CVE.- Platelet function tests (PFT) can be used to diagnose HTPR. There are various tests available; of those, light transmission aggregometry (LTA) is considered the gold standard. Some tests are only suitable for determining the effect of a certain category of APT.- Research into the usefulness of PFTs to optimise treatment with APT has not yet produced an unambiguous conclusion.- Currently there is not yet an indication for routine use of PFT in clinical practice. However, for the treatment of certain categories of patients with thromboembolic disease - such as those with renal failure or a history of kidney transplant - PFT can be considered.

Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state.

Essentials The role of von Willebrand Factor (VWF) in the pathophysiology of sickle cell disease is unclear. We assessed markers of VWF during admission for vaso-occlusive crisis (VOC) and steady state. VWF reactivity was higher during VOC and was associated with inflammation and neutrophil activation. Hyper-adhesive VWF may promote VOC in sickle cell disease. SUMMARY: Background Endothelial activation plays a central role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), facilitating adhesive interactions with circulating blood cells. Upon activation, various adhesive molecules are expressed, including von Willebrand factor (VWF). Increased VWF levels have been observed in patients with SCD during steady state. However, the role of VWF in the pathogenesis of SCD vaso-occlusion is unclear. Objectives To longitudinally assess the quantity and reactivity of VWF and its regulating protease ADAMTS-13 during vaso-occlusive crisis (VOC). Methods In this observational study, we obtained sequential blood samples in adult SCD patients during VOC. Results VWF reactivity was significantly higher during VOC (active VWF, VWF glycoprotein Ib-binding activity, and high molecular weight multimers), whereas platelet count and levels of ADAMTS-13 antigen and ADAMTS-13 activity were concomitantly lower than during steady state. Levels of VWF antigen, VWF propeptide (VWF:pp) and ADAMTS-13 specific activity did not change during VOC. VWF reactivity correlated strongly with markers of inflammation and neutrophil activation, and was inversely correlated with the platelet count. In patients who developed acute chest syndrome, levels of VWF, VWF:pp and active, hyperadhesive VWF were significantly higher, whereas ADAMTS-13 activity was lower, than in patients without this complication. Conclusions We provide the first evidence that VOC in SCD is associated with increased reactivity of VWF, without a pronounced ADAMTS-13 deficiency. This hyper-reactivity may be explained by resistance of VWF to proteolysis, secondary to processes such as inflammation and oxidative stress. Hyperadhesive VWF, scavenging blood cells in the microcirculation, may thereby amplify and sustain VOC in SCD.

Interaction of beta2-glycoprotein I with members of the low density lipoprotein receptor family.

The antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies that recognize beta2-glycoprotein I (beta2GPI) bound to phospholipids. We have previously demonstrated that dimerization of beta2GPI by autoantibodies induces platelet activation, involving the platelet receptor apolipoprotein E receptor 2' (apoER2') a receptor belonging to the low-density lipoprotein receptor (LDL-R) family. Here, we show that dimeric beta2GPI, but not monomeric beta2GPI, interacts with four other LDL-R family members: the LDL-R related protein (LRP), megalin, the LDL-R and the very-low density lipoprotein receptor (VLDL-R). Interaction between dimeric beta2GPI and LDL-R, apoER2' and VLDL-R was best described with a one-site binding model (half-maximal binding; approximately 20 nm for apoER2' and VLDL-R and approximately 300 nm for LDL-R), whereas the interaction between dimeric beta2GPI and LRP or megalin was best described with a two-site binding model, representing a high- (approximately 3 nm) and a low-affinity site (approximately 0.2 microm). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of beta2GPI, which is known to disrupt the phospholipid binding site of beta2GPI. Also deletion of domain I or II left the interaction with the receptors unaffected. Deletion of domain V, however, significantly decreased the affinity for the receptors. In conclusion, our data show that dimeric beta2GPI can interact with different LDL-R family members. This interaction is dependent on a binding site within domain V of beta2GPI, which does not overlap with the phospholipid-binding site within domain V.

Decreased plasma levels of activated factor VII in patients with deep vein thrombosis.

BACKGROUND: The initiating trigger in the development of deep vein thrombosis (DVT) remains unidentified. It has been suggested that tissue factor (TF)-bearing microparticles play a key role, which indicates a role for the TF pathway in the initiation of DVT. OBJECTIVE: To assess the role of the TF pathway in the initiation of venous thrombosis, we measured plasma levels of factor VII and VIIa in patients with acute DVT and in controls. METHODS: We included 148 patients diagnosed with acute DVT and 179 controls in this study. Antigen levels of FVII and FVIIa were measured by using assays recently developed in our laboratory. RESULTS: Median FVII levels in patients were 109.8% (interquartile range [IQR] 86.0-153.2) compared with 102.2% (IQR 76.1-141.7) in controls. Individuals with FVII levels in the upper quartile had a 1.6-fold increased risk for the presence of a DVT (odds ratio 1.6, 95% confidence interval 0.8-3.1). Median FVIIa levels in patients were 50.2 ng mL(-1) (IQR 25.2-86.1) compared with 96.6 ng mL(-1) (69.9-168.9) in controls. Individuals with FVIIa levels in the lowest quartile had a > 5-fold increased risk for the presence of a DVT (odds ratio 5.5, 95% confidence interval 2.8-10.6). Both risks did not change substantially after adjustment for potential confounders. CONCLUSION: Decreased plasma levels of FVIIa in patients with deep vein thrombosis may indicate ongoing consumption of FVIIa and suggest a contributory role for TF in venous thrombus formation.

[Withdrawing the use of acetylsalicyclic acid prior to an operation usually not necessary]. / Staken van gebruik van acetylsalicylzuur vóór een operatie meestal niet nodig.

Acetylsalicylic acid (aspirin) induces an irreversible inactivation of cyclo-oxygenase in blood platelets which lasts for the entire period that the platelets remain in the circulatory system, 7 to 10 days. In order to prevent excessive bleeding, patients presenting for surgery are asked to stop using aspirin 10 days before the procedure. Some studies have found that aspirin causes increased peri-operative blood loss, whilst other studies have found that it does not. All effect studies found in Medline (January 1966-May 2002) on surgery and bleeding complications due to aspirin were analysed. The studies available were assessed for methodological quality and the results were summarised in an evidence table. No clinically relevant bleeding complications were reported for cardiovascular, vascular and orthopaedic surgery and epidural anaesthesia. Most studies reported an increase in clinically non-relevant bleeding induced by aspirin. The literature contains too little information on cataract surgery, dermatological surgery, gynaecological and abdominal surgery, ENT and dental surgery, urological surgery, lung biopsy and endoscopic biopsy. In those types of surgery in which even a minor bleeding leads to severe complications, e.g. neurosurgery, aspirin should be withdrawn 5-10 days in advance. Also in patients with coagulation disorders, aspirin should be withdrawn prior to the operation. There is no scientific evidence for the withdrawal of aspirin in all patients, 5-10 days prior to surgery. Indeed for heart patients in particular, the continued use of aspirin is recommended.

Recent developments in our understanding of the antiphospholipid syndrome.

The antiphospholipid syndrome is an autoimmune disease that manifests clinically as recurrent thrombotic complications or foetal losses and serologically with elevated levels of antiphospholipid antibodies in the plasmas of these patients. The term 'antiphospholipid syndrome' is confusing, because the auto-antibodies are not directed against phospholipids but towards a plasma protein, ß(2) -glycoprotein I. For many years, the reason why auto-antibodies against ß(2) -glycoprotein I were pro-thrombotic was unclear, because ß(2) -glycoprotein I seems to be an obsolete protein in our circulation. Human and mice deficient in this protein do not express a clear phenotype. Recent studies on the structure and function of ß(2) -glycoprotein I have provided novel insights into the importance of this protein in physiology and its role in the pathology of the antiphospholipid syndrome.