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Long-term treatment with warfarin is recommended for patients with atrial fibrillation at risk of stroke and those with recurrent venous thrombosis or prosthetic heart valves. Patient education before commencing warfarin − regarding signs and symptoms of bleeding, the impact of diet, potential drug interactions and the actions to take if a dose is missed − is pivotal to successful use. Scoring systems such as the CHADS2 score are used to determine if patients with atrial fibrillation are suitable for warfarin treatment. To rapidly achieve stable anticoagulation, use an age-adjusted protocol for starting warfarin. Regular monitoring of the anticoagulant effect is required. Evidence suggests that patients who self-monitor using point-of-care testing have better outcomes than other patients.

Catastrophic antiphospholipid syndrome (CAPS) is an unusual complication of antiphospholipid syndrome (APS) occurring in about 1% of patients. If left untreated, mortality can be as high as 50%. Therapy of APS and its complication CAPS is hampered by the lack of validated prospective, controlled, intervention clinical trials, although there is consensus that treatment should include anticoagulation therapy. But there are issues that need to be addressed such as duration and intensity of therapy. The present report describes our experience in 7 patients with CAPS in whom anticoagulation was discontinued after 6 months of therapy. During an average follow-up of 5.5 years, only 2 patients exhibited one episode each of recurrent venous thrombosis, but none of the patients in whom anticoagulation was discontinued experienced recurrent CAPS.

A patient with Glanzmann Thrombasthenia developed recurrent venous thrombosis with a JAK2 positive myeloproliferative neoplasm. This indicates that the platelet aIIbβIII integrin has no role in venous thrombosis. We discuss the other potential mechanisms that are involved. In addition, we describe the successful use of dabigatran in this patient., Glanzmann thrombasthenia does not protect from venous thrombosis in MPN. We hypothesize on other mechanisms of thrombosis in MPN. Dabigatran can be given in a patient with Glanzmann thrombasthenia.

Suspected recurrent venous thromboembolism (VTE) is a common and vexing clinical problem. Confounding the diagnosis of recurrent VTE is a high frequency of residual VTE from prior VTE. The diagnosis of recurrent VTE must be established by comparing current imaging with past imaging to distinguish acute from chronic thrombosis. Next, we must ascertain if non-compliance was the cause of "apparent therapeutic failure" and if non-compliance is at play then re-initiate anticoagulant therapy. Therapeutic failure is relatively uncommon. As such, we must consider underlying causes of therapeutic failures including malignancy and potent thrombophilias. Finally, short term anticoagulant management of therapeutic failures is controversial, and requires further research, but the best current evidence supports a course of full-dose low-molecular-weight heparin (LMWH) (and dose escalated LMWH if failure occurs while on full-dose LMWH).

Activated protein C inactivates factor Va and VIIIa. Deficiency of this natural anticoagulant may result in recurrent venous thrombosis. Performance characteristics of clot-based and chromogenic protein C activity assays are different. The clot-based assay has limitations because of interference with coagulation inhibitors resulting in spuriously increased protein C levels or underestimation because of elevated levels of factor VIII and Factor V-Leiden mutation. The chromogenic assay is not influenced by such interferences but only detects functional defects of protein C that involve the active site rendering it insensitive to rare mutations. To compare two methods, we conducted a retrospective study from January 2015 to June 2017. Our results showed a good correlation between clot-based and chromogenic assay (R = 0.94 and r = 0.88). The study of agreement between the two methods by the Bland-Altman method showed that chromogenic method on an average measures 7.8% more protein C than that of clot-based. The results also showed that the bias between the two methods is significant. The positive trend noted was contributed by the values of less than 20% of protein C. Both clot-based and chromogenic assays had high sensitivity; however, the chromogenic assay showed better specificity (97%) as compared with the clot-based assay (93%). In conclusion, we recommend the chromogenic method as the assay of choice, which is also recommended by the College of American Pathologist Consensus Study over activated partial thromboplastin time-based assay. We have shown here that despite a good correlation between the two techniques, there is a difference as highlighted by the difference plots.

Essentials Factor XI is a potential target for anticoagulation. The association between factor XI and venous thrombosis recurrence was tested in a cohort study. Low factor XI was associated with reduced risk of recurrent venous thrombosis. A sex-and age-adjusted linear association between D-Dimer and factor XI was found. SUMMARY: Background and objectives Low factor XI activity (FXIa) reduces the risk of venous thromboembolism (VTE), and FXI is regarded as a potential target for anticoagulation. Patients/methods We studied the relationship between FXIa and VTE in 851 patients with unprovoked VTE in whom anticoagulation had been stopped. Results Recurrent VTE was recorded in 265 patients. The sex-adjusted and age-adjusted hazard ratio (HR) of recurrence was 0.94 (95% confidence interval [CI] 0.89-0.99) for each decrease of 10 IU dL-1 in FXIa. The HRs of recurrence were 0.73 (95% CI 0.54-0.99) for patients with FXIa below the 34th percentile, and 1.05 (95% CI 0.79-1.39) for patients with FXIa between the 34th and 67th percentiles, as compared with patients with higher FXIa. The probability of recurrence was lower among patients with FXIa below the 34th percentile than in patients with higher FXIa (P = 0.029). At 10 years, the probabilities of recurrence were 31%, 43% and 41% among patients with FXIa below the 34th percentile, with FXIa between the 34th and 67th percentiles, or with higher FXIa, respectively. We found a significant sex-adjusted and age-adjusted linear association between D-dimer levels, measured 3 weeks after anticoagulation, and FXIa. When patients' age and sex are taken into account, a patient with 10 IU dL-1 lower FXIa is expected to have a 2.79% (95% CI 0.95-4.59%) lower D-dimer value (P = 0.003). Conclusions Our findings of a lower thrombosis risk and less pronounced hemostatic system activation among patients with low FXIa is in line with the concept that FXI is a promising target for anticoagulation.

Herein, we report a case of a 27-year-old man with Ebstein's anomaly and a history of unexplained recurrent venous thrombosis despite adequate anticoagulation. After surgical correction of the Ebstein's anomaly, the venous thromboembolic events did not recur. This case demonstrates the possible etiopathogenesis of Ebstein's anomaly in causing recurrent venous thromboembolism, which is likely caused through impedance of venous blood flow.Our objective in presenting this particular case is to highlight the possible association between Ebstein's anomaly and venous thrombosis.

Protein S (PS) deficiency is an inherited thrombophilia associated with an increased risk of venous thromboembolism (VTE). In Japan, unfractionated heparin followed by warfarin has been historically applied for the treatment of VTE. Recent evidence showed that direct oral anticoagulants (DOACs) were non-inferior to standard therapy with warfarin, with significantly less bleeding in patients with VTE. However, it is unknown whether DOACs are effective for the treatment of VTE in patients with thrombophilia, including protein S deficiency, due to lack of evidence. Here, we report a case of recurrent venous thrombosis during edoxaban therapy in a patient with protein S deficiency, which was successfully treated using high-dose apixaban therapy. J.Med. Invest. 66 : 182-184, February, 2019.

Non-cirrhotic and non-malignant splanchnic vein thrombosis (SVT) recognizes Philadelphia-negative myeloproliferative neoplasms (MPN) as the most frequent systemic cause. An overt MPN is diagnosed in 40% of the patients with Budd–Chiari syndrome (BCS). In BCS patients, the MPN molecular hallmark JAK2 V617F is present in up to 80% of those with overt MPN and up to 43% of those without an overt diagnosis according to the WHO criteria. In those latter, the other MPN driver mutations in the JAK2 exon 12, CALR, and MPL genes are infrequent.

Background Several models are available to predict recurrent venous thrombosis (VT) in patients with unprovoked first events. Objectives To validate these prediction models externally. Methods Within the MEGA follow-up study (n = 3750), we externally validated the Vienna and DASH score. These models were validated (a) by using the original study's criteria for patients with unprovoked VT and (b) by using our own criteria for unprovoked VT. In addition, absolute recurrence risks based on individual VT risk factors were calculated. Results The recurrence rate was 5.2 (95% CI, 4.6-5.9) per 100 patient-years in those who had a first unprovoked VT according to our definition. For the Vienna model it was 3.4 per 100 patient-years and for DASH 3.8 per 100 patient-years. The C-statistic was 0.62 for Vienna and 0.65 for DASH. The C-statistic declined to 0.58 for both Vienna and DASH when we used our own definition of "unprovoked VT." Within the provoked group a strong gradient in risk was found dependent on the presence of traditional risk factors or biomarkers in a patient. Conclusions The ability to distinguish patients' recurrence risks is lower than proposed in the original prediction model studies and dependent on the definition that is used for an unprovoked first event. Furthermore, our results suggest that a more-refined risk estimation is possible, also in patients with a provoked first event, who are currently all classified as low risk.

BACKGROUND Inherited thrombophilia represents a prothrombotic disorder that predisposes to thrombosis. METHODS We present a case of a 67-year-old female with a personal and family history of iterative thrombotic events. She was admitted in the Surgical Clinic at the age of 59, presenting the classical symptoms and signs for left lower limb deep vein thrombosis, confirmed by a venous Duplex Ultrasonography. This was the third episode of a venous thrombosis. Under anticoagulant treatment the evolution was good. The patient was advised to test for inherited thrombophilia mutations. RESULTS Four years later, she experienced another episode of thrombosis. The patient tested positive for five of the most frequent mutations found in inherited thrombophilia. CONCLUSIONS Patients with recurrent venous thrombosis and positive family history for thrombotic events must be checked for thrombophilic conditions, inherited or acquired.

The direct oral anticoagulant (DOAC) rivaroxaban, an oral Factor Xa inhibitor, is increasingly used as an alternative to vitamin-K-antagonists (VKAs). Absorption and elimination of DOACs are dependent on the permeability glycoprotein (P-gp) efflux transporter protein system, and DOACs are substrates of the hepatic cytochrome P 450 3A4 (CYP3A4) enzymes. Therefore, drug-interactions may occur when DOACs are administered with drugs affecting the activity of P-gp or CYP3A4 systems. Several antiepileptic drugs like carbamazepine are known to affect P-gp and CYP3A4-activity.A 55-year-old male was admitted because of pain and swelling of his right leg spontaneously since 2 days. He was under a therapy with 20mg rivaroxaban since 4 months because of an unprovoked venous thrombosis of his right leg. He had a history of poliomyelitis at age 6 months, structural epilepsy due to poly-microgyria with complex partial seizures with secondary generalization since age 6 years, why he was treated with carbamazepine (900mg/d). He reported to be highly adherent to his anticoagulant and antiepileptic medication. Anti-Xa activity was20ng/ml according to a rivaroxaban calibrated anti-factor Xa assay. Therapy with rivaroxaban was stopped, and low-molecular-weight heparin, followed by phenprocoumon, was started.The combination of DOACs with carbamazepine, an inducer of P-gp and CYP3A4-activity, should be avoided since the anticoagulant effect is decreased. There is an urgent need to increase our knowledge and physicians' awareness about the potential of drug-drug interactions of DOACs.

Few reports have been published on the correlation between plasma concentrations of rivaroxaban and clinical outcome in patients who have experienced venous thromboembolism. This article describes the case of a 44-year-old woman who experienced deep vein thrombosis during anticoagulation therapy with rivaroxaban, with evidence of repeated low plasma levels of the drug. We postulate that the determination of plasma rivaroxaban anti-Xa activity can be useful in the evaluation of anticoagulation therapy in selected cases. LEARNING POINTS Some patients with deep vein thrombosis do not respond to rivaroxaban therapy. Accurate determination of rivaroxaban plasma concentrations is important in clinical practice. The clinical value of rivaroxaban plasma concentrations might be limited by intra- and inter-individual variations.

Venous thrombosis, which mainly manifests as deep vein thrombosis of the leg or pulmonary embolism, is a major contributor to global disease burden. With a recurrence rate of approximately 25% in 5 years, and a 30-day case fatality rate of 5–10%, identification of predisposing factors for venous thrombosis is imperative. Dozens of risk factors for first venous thrombosis are known today, which can be grouped into three categories: first venous thrombosis ‘provoked by a transient risk factor’, ‘provoked by a persistent risk factor’, or ‘unprovoked’. This chapter comments on how risk factors known today can be classified into these categories, how this classification determines recurrence risk, and how knowledge on predisposing risk factors should be interpreted and integrated for optimal clinical use. The chapter proposes that predisposing factors for venous thrombosis are not the same for each high-risk situation. This is important to consider when one wants to identify high-risk groups in, for example, cancer patients, surgical patients, in patients with a medical illness, or in patients at risk for recurrent venous thrombosis. This way it will be possible to expose only those patients at unacceptably high risk of thrombosis to the risks and burden of anticoagulant treatment. In conclusion, the knowledge on predisposing factors for venous thrombosis is extensive, but the patient will benefit most when this knowledge is properly integrated, depending on the clinical situation.

Background: Genetic risk factors for a first venous thrombosis (VT) seem to have little effect on recurrence risk. Therefore, we aimed specifically to identify novel genetic determinants of recurrent VT. To date, genome-wide association studies are lacking. Methods and Results: We performed a genome-wide association scan in 1279 patients from the MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) follow-up study; 832 patients who remained recurrence free during a median follow-up time of 6.1 years and 447 recurrent VT patients with a median time-to-recurrence of 2.6 years. We analyzed genotype probabilities of ≈8.6 million variants, imputed to the Genome of the Netherlands project reference panel, with a minor allele frequency ≥1% for an association with recurrent VT. One region exceeded genome-wide significance ( P ≤5×10 − 8 ), mapping to the well-known factor V Leiden locus. Conditional association analyses on factor V Leiden did not yield any secondary association signals. We also identified 52 suggestive association signals ( P −5 ) at 17 additional loci. None of these loci were previously implicated in VT risk. Replication analyses for 17 lead variants were performed in 350 patients with recurrent VT and 1866 patients with a single VT event from the MEGA follow-up study, THE-VTE (Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism) study, and LETS (Leiden Thrombophilia Study). We observed an association with recurrence for an intergenic variant at 18q22.1 with an odds ratio of 1.7 (95% confidence interval, 1.2–2.6) per copy of the minor allele. Conclusions: We confirmed the association of factor V Leiden and identified a novel risk locus at 18q22.1 in the first large genetic study on recurrent VT.

Introduction Whether statin use after first venous thrombosis reduces the risk of recurrence is uncertain. Therefore, we aimed to examine the risk of recurrent venous thrombosis in statin users vs non‐users. Methods Patients with a first venous thrombosis were recruited from the MEGA follow‐up study. Information on statin use was obtained by linkage to the Dutch Foundation for Pharmaceutical Statistics register. Linkage was successful in 54% of all patients (n = 2,547). Cox‐regression models with statin‐exposure as a time‐dependent co‐variate were used to estimate hazard ratios (HR) with 95% confidence intervals (CI 95) for recurrence. Results Statin therapy was continued in 153 (6.0%) patients and initiated in 233 (9.1%) patients during a median follow‐up of 5.7 years. There were 367 recurrent venous thrombotic events, of which 32 occurred among statin users. Incident statin use was associated with 22% reduced risk of recurrence after multivariable adjustments (HR 0.78, CI 95: 0.46‐1.31), and 13% reduced risk after propensity score adjustment (HR 0.87, CI 95: 0.52‐1.47). Statin use seemed not to have an effect on recurrence in patients with an unprovoked first event (multivariable HR 1.03, CI 95: 0.54‐1.98), but the statistical power was low due to few events and the results must be interpreted with caution. In general, the risk estimates were slightly attenuated when prevalent users were included in the analyses. Conclusion Our findings suggest that statins may have a modest decreasing effect on the risk of recurrent venous thrombosis. While we took care to minimize bias and confounding, the causality of the association is still unsettled.

Summary: An anterolateral thigh flap was salvaged using 110 medical leeches in the absence of an available vein for reanastomosis. After surgical construction of the flap for full-thickness thoracic wall reconstruction, the patient developed complete venous occlusion. Specifically, the anastomotic vein developed complete occlusion, and the internal jugular vein had a thrombus. In addition, because the lung was posterior to the flap, the angiogenic area of the flap was very small. When the medical leeches were first applied, the flap showed prominent venous congestion. However, the congestion began to resolve by day 6 of leech use, leading to complete survival of the flap.

Statins may be causally associated with a decreased risk of venous thrombosis. If so, this could be a substantive breakthrough since statins do not increase the risk of bleeding and could therefore be used as a safer antithrombotic drug. However, scepticism exists on the observed reduction of venous thrombosis by statins, as it may have been confounded by healthy user effects or other biases. Areas covered: The main focus of this review will be the biases that may have arisen in clinical studies that investigated the relationship between statin use and risk of venous thrombosis. We also discuss the suggested causal association from a pathophysiological perspective. Furthermore, we integrate the knowledge from clinical and pathophysiological studies into a proposal for new study designs that are needed to sufficiently answer the question whether we can, and should, prevent recurrent venous thrombosis with statins. Expert commentary: A drug to prevent recurrent venous thrombosis in patients at risk of bleeding that does not induce bleeding and in which the number needed to treat for the prevention of venous thrombosis is sufficiently high, is a remedy that we should continue to look for, and for which statin therapy might be a suitable candidate.

Background Several autoimmune skin disorders are characterised by an increased risk of thrombosis, with bollous pemphigoid carrying a higher risk than pemphigus vulgaris (PV). We describe the case of a middle aged gentleman who developed recurrent venous thromboembolism despite adequate oral anticoagulation during very active PV that required escalation of treatment to bring the disease under control. Case presentation In May 2014 a 49 year gentleman was admitted for widespread mucocutaneous blistering diagnosed as PV by histology and immunofluorescence. After 6 weeks of treatment with systemic steroids and azathioprine the patient developed pulmonary emboli and started oral anticoagulation with warfarin. In late September, the patient re-presented with a severe flare of PV and a recurrent deep vein thrombosis despite oral anticoagulation within therapeutic range. Warfarin was changed to subcutaneous low molecular heparin in therapeutic dose while treatment for pemphigus was escalated: first azathioprine was switched to mycophenolate mofetil and the steroids dose increased; then due to poor response, intravenous immunoglobulins were given for three courses and finally he received four infusions of Rituximab that induced sustained remission. In April 2015 the dose of mycophenolate was decreased but anticoagulation was continued until the beginning of July 2015 to ensure that decreasing immune suppression did not allow the emergence of another flare with attendant thrombotic risk. Conclusion The case highlights the risk of thrombosis and re-thrombosis in aggressive PV and demands further clinical research in this area to assess the need for thromboprophylaxis in aggressive bollous skin disease.

Modern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, these conclusions have been supported by an increasing number of independent case-control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk.

Post-thrombotic syndrome is an important chronic complication of deep vein thrombosis. This syndrome can be debilitating to patients and has a major economic impact on health care services. The pathophysiology of post-thrombotic syndrome is currently incompletely understood. Because therapeutic options for post-thrombotic syndrome are extremely limited and results are often disappointing, recognizing of the pathophysiology and risk factors of this syndrome is essential to prevent the disabling consequences of this disease. The present paper focuses on risk determinants of post-thrombotic syndrome after deep vein thrombosis. The contribution of recurrent venous thrombosis and inherited thrombophilia to the pathogenesis of this syndrome is reviewed and discussed in details.

Clinicians managing patients with iliofemoral DVT have an important responsibility to the patient. The physician should have an understanding of the natural history of iliofemoral DVT treated with anticoagulation alone and the outcome expected if that same patient were treated with a strategy to remove the thrombus. The patient should be informed of their likelihood of postthrombotic morbidity and their likelihood of recurrence. Of course, recurrent DVT further increases the frequency and severity of postthrombotic morbidity. Numerous observations of patients with iliofemoral DVT treated with anticoagulation have been published. Anticoagulation alone results in over 95% of the patients having ambulatory venous hypertension; 90% develop symptoms of chronic venous insufficiency and ulceration develops in 15% within 5 years. 1 When exercised, 40% develop symptoms of venous claudication. 2 Recurrent venous thrombosis is a powerful risk factor for postthrombotic morbidity. 3 Patients with iliofemoral DVT have a 2.6-fold higher risk of recurrence when treated with conventional anticoagulation than patients with less extensive DVT. 4 It appears that the likelihood of

Livedoid vasculopathy is a rare condition which predominantly affects young women. It is characterized by intense painful purpuric maculae in the legs, ankles and feet, due to thrombosis of the small and medium-sized dermal vessels, in the absence of vasculitis. Livedoid vasculopathy has been frequently associated with hypercoagulable states and antiphospholipid syndrome. We describe a 34-year-old White woman suffering from systemic lupus erythematosus, livedo reticularis, haemolytic anaemia, severe thrombocytopenia and recurrent venous thrombosis who was admitted to the hospital for extremely painful purpuric lesions in her lower limbs. The clinical and histological findings were diagnostic of livedoid vasculopathy. Once the initial sub-therapeutic international normalized ratio levels were corrected, livedoid vasculopathy did not recur. Tests for antiphospholipid antibodies were repeatedly negative. This case, the first reported of livedoid vasculopathy in a patient with seronegative antiphospholipid syndrome and systemic lupus erythematosus, draws attention to livedoid vasculopathy, a thrombotic dermopathy that may be under-diagnosed in patients with antiphospholipid syndrome. Lupus (2010) 19, 1340—1343.

6 members of a family with a tendency to thrombosis and defective fibrinolysis were examined. After stimulation of plasminogen activator release from the vessel wall by local venous occlusion or by submaximal physical exercise, they had a lower plasminogen activator activity in blood than a healthy control group (P less than 0.01). 5 of the examined members suffered from recurrent venous thrombosis. The defect appeared to be autosomal dominant.

SummaryBackground Tall people have an increased risk of a first venous thrombosis. Sedentary lifestyle has been shown to act synergistically with body height, especially during long-haul flights. Objective To estimate the relation between height and risk of a first and recurrent venous thrombosis and a possible additional association with a mobile or an immobile lifestyle. Methods Patients with a first venous thrombosis and control subjects were included between 1999 and 2004 (MEGA case–control study). Patients were followed for recurrence for an average time of 5.1 years (MEGA follow-up study). Odds ratios and hazard ratios (HRs) per increase of 5 cm were calculated compared with a height of 165–170 cm, separately and in combination with (im)mobility. Results In 4464 patients who reported their height, we found an increasing risk of a first and recurrent event with height. For men, a 2.9-fold (95% confidence interval [CI] 1.9–4.4) increased risk for first venous thrombosis was found for those between 195 and 200 cm and a 3.8-fold (95% CI 1.5–9.8) higher risk for those > 200 cm compared with the reference category. For recurrence risk, the HRs were 1.7 (95% CI 0.8–3.3) and 3.7 (95% CI 1.4–10.0), respectively. For women, a 1.5-fold (95% CI 0.7–3.4) and 3-fold (95% CI 0.9–9.4) increased risk was found for those > 185 cm for first and recurrent venous thrombosis, respectively. For the tallest men and women, a slight additionally increased risk was observed for sedentary lifestyle. Conclusions Tall men and women have an increased risk of first and recurrent venous thrombosis, possibly higher in combination with a sedentary lifestyle.

Protein C deficiency is a rare autosomal dominant disorder with a characteristic of hypercoagulation state and recurrent venous thrombosis in clinics. It is one important cause for youth vascular ishcaemic events including cerebral stroke. However, less attention was focused on the disorder of protein C deficiency so that misdiagnosis is very common. Here, we reported two cases of recurrent vascular ischaemic events due to protein C deficiency. They accepted warfarin and fresh frozen plasma respectively and fully recovered. Our report suggest the importance of early recognition of protein C deficiency in youth with recurrent vascular thrombosis and personalized management should be emphasized.

Complications following free tissue transfer have been well established in the literature. Common and rare causes of free flap failure must be addressed by the treating surgeon when microvascular patency is threatened. With the evolution and prevalence of microsurgery, ‘rare’ causes of free flap failure will become increasingly frequent. A high index of suspicion must be established in patients with multiple failed operative interventions. A case of recurrent free flap failure secondary to heparin-induced thrombocytopenia is presented in a patient with a history of squamous cell carcinoma of the floor of the mouth, and a long-standing history of alcohol and tobacco consumption.

Thrombotic complications are a significant cause of morbidity and mortality in cancer patients. Studies in Caucasian populations have shown that up to one-third of such patients test positive to antiphospholipid antibodies. Our aim was to determine the prevalence and serotypes of antiphospholipid antibodies in an unselected group of Asian cancer patients with thrombosis. All patients with cancer-related thrombosis seen in the Department of Hematology-Oncology and Radiation Oncology were enrolled in this study. The study period was from April 2000 to May 2001. Antiphospholipid antibodies tests were performed, namely lupus anticoagulant screen, anti-cardiolipin antibodies (IgG and IgM) and anti-beta-2 glycoprotein I antibodies (B2 GPI) IgG, IgM and IgA. Thirty-three patients were recruited. There were 14 males and 19 females, with an age range of 35-78 years of age. Of those enrolled, there were 25 Chinese, five Malays and three Indians. The patients had several cancer types: 11 (36.7%) patients had adenocarcinoma as the histological cell type. Of the 33 patients, 75.8% had stage IV disease. Arterial thrombosis was seen in eight patients (24.2%), and venous thrombosis occurred in 29 patients (87.9%). Antiphospholipid antibodies were positive in 60.6% of the patients, of which anti-B2GPI IgA antibody was the most prevalent antiphospholipid present (46.9%). The presence of anti-beta-2 glycoprotein I IgA antibody was associated with strokes, extensive and recurrent venous thrombosis, and coincident arterial and venous thrombosis. A high prevalence of antiphospholipid antibodies (60.6%) was found in Asian patients with cancer-related thrombosis. The presence of antiphospholipid antibodies, particularly anti B2GPI IgA, may identify a subset of cancer patients who are at high risk of developingthrombotic complications, and further studies are warranted.

Background— The prediction of recurrent venous thrombosis using individual genetic risk predictors has proven to be challenging. The aim of this study was to assess whether multiple genetic single nucleotide polymorphism (SNP) analysis would predict recurrent venous thrombosis. Methods and Results— Patients with a first venous thrombosis were followed for a recurrent venous thrombosis up to 2009 (MEGA follow-up study), which occurred in 608 out of 4100 patients (2.7%/year). Thirty-one common thrombosis-associated single nucleotide polymorphisms (SNPs) were associated with the risk of recurrence. A genetic risk score (GRS) for each individual was calculated by summing the number of risk-increasing alleles for each of the 31 SNPs and for a simplified model consisting of 5 SNPs: rs6025, rs1799963, rs8176719, rs2066865, and rs2036914. The risk of recurrence associated with the GRS was calculated continuously and after stratification in a low and high score. All individual SNPs were at most mildly associated with recurrence risk. Regarding the 31-SNP GRS, recurrence risk was highest in patients with ≥31 and lowest in patients with Conclusions— Multiple genetic SNP analysis is useful in the prediction of recurrent thrombosis, even more so when combining this model with clinical risk factors.

Venous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral contraception, postmenopausal hormone therapy, pregnancy and the puerperium). In this thesis, we showed that these women are at particularly high risk of venous thrombosis if they have previously experienced an episode of superficial vein thrombosis, or are over the age of 50 years (Chapters 2 and 3). There is no known male counterpart to female reproductive risk factors. Nevertheless, the incidence of venous thrombosis is approximately similar in men and women. In this thesis we established that, once female reproductive risk factors are taken into account, men have an approximately twofold higher risk of both first and recurrent venous thrombosis than women (Chapters 4 and 5). Further to these findings, in Chapter 6, we reviewed the literature on sex-specific risk factors for venous thrombosis. We hypothesized that sex-specific genetic risk factors, an excess in overweight and smoking, or hypercoagulable changes such as microalbuminuria may explain the higher risk of venous thrombosis in men than in women.

SummaryVenous thromboembolism is a chronic and potential fatal disease. Determination of recurrence risk is time-consuming and costly, and sometimes not feasible: many patients carry more than one risk factor, the relevance of some factors with regard to risk of recurrence is unknown, and existence of thus far unknown risk factors must be considered. A laboratory assay that measures multifactorial thrombophilia would be useful to identify patients at risk of thrombosis. The process of thrombin generation is the central event of the hemostatic process. Thrombin generation is increased in patients at risk of thrombosis including those with antithrombin deficiency or those who are taking hormonal contraceptives. Risk of first and recurrent venous thrombosis is higher in patients with increased thrombin generation. Thus, by use of a simple global marker of coagulation stratification of patients according to their risk of thrombosis is possible. Future studies are needed to improve the management of patients with VTE and increased thrombin generation.