Isolated pulmonary embolism - a specific clinical entity?

Pulmonary embolism in classical meaning is a complication of deep vein thrombosis (usually in the leg veins), developing after a part of the thrombus dislodged and got wedged in pulmonary arteries. However, in half of the patients with pulmonary embolism, deep vein thrombosis is not found. One potential explanation is a different, less common location of the thrombus or previous complete embolization of the whole thrombotic mass. Another possibility is pulmonary artery thrombosis in situ, which is a specific clinical entity associated with some typical risk factors. It develops in the place of vascular injury, as a consequence of hypoxia, inflammatory changes, endothelial dysfunction and injury. Pulmonary artery thrombosis in situ can be a complication after lung resection, radiation therapy, chest trauma, in the patients with Behçet´s disease, sickle cell anemia, chronic obstructive pulmonary disease, tuberculosis or covid pneumonia. Pulmonary artery thrombosis in situ may differ from classical pulmonary embolism in prognosis as well as in therapeutic approach.

Liver status and outcomes in patients without previous known liver disease receiving anticoagulant therapy for venous thromboembolism.

The association between elevated liver enzymes or FIB-4 (fibrosis index 4) and outcome in patients with venous thromboembolism (VTE) has not been evaluated. Data from patients in RIETE (Registro Informatizado Enfermedad TromboEmbólica) were used to assess the association between elevated liver enzymes or FIB-4 levels and the rates of major bleeding or death in apparent liver disease-free patients with acute VTE under anticoagulation therapy. A total of 6206 patients with acute VTE and without liver disease were included. Of them, 92 patients had major bleeding and 168 died under anticoagulation therapy. On multivariable analysis, patients with elevated liver enzymes were at increased mortality risk (HR: 1.58; 95% CI: 1.10-2.28), while those with FIB-4 levels > 2.67 points were at increased risk for major bleeding (HR: 1.69; 95% CI: 1.04-2.74). Evaluation of liver enzymes and FIB-4 index at baseline in liver disease-free patients with VTE may provide additional information on the risk for major bleeding or death during anticoagulation.

Prevalence of cancer in patients with superficial vein thrombosis and its clinical importance.

OBJECTIVE: The objective of the present study was to evaluate the prevalence of cancer in patients with superficial vein thrombosis (SVT) of the legs. Moreover, we evaluated the potential determinants of SVT complications by comparing a subgroup with isolated SVT and a subgroup of SVT complicated by concurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) with respect to the presence of cancer and other clinical and laboratory characteristics. METHODS: The present single-center, retrospective study of prospectively collected data was conducted in a tertiary care setting. We included patients who had been treated in the thrombosis clinic from 2006 to 2018 for symptomatic SVT of the legs, either isolated SVT or SVT complicated by concurrent DVT/PE. We evaluated the prevalence and type of malignancy (diagnosed ≤12 months before SVT and/or ongoing therapy), demographics, and clinical and laboratory characteristics of the patients. For statistical evaluation, we used the Student t test, Kruskal-Wallis test, Fisher exact two-sided test, and logistic regression. RESULTS: Of 276 patients with SVT (mean age, 58.9 ± 14.7 years; 60.9% women), 191 had had isolated SVT and 85 had had SVT complicated by concurrent DVT/PE. The prevalence of malignancy was 8.7% in the whole group (mainly breast and urinary tract cancer), including 4.2% of those with isolated SVT and 18.8% of those with SVT and concurrent DVT/PE (P < .001). Between the two subgroups, no significant differences were present in the duration of leg symptoms, family or personal history of SVT and/or DVT, SVT location, and smoking. In logistic regression, several factors were significantly associated with the concurrent presence of DVT/PE: age (odds ratio [OR], 1.024; 95% confidence interval [CI], 1.004-1.044), female gender (OR, 0.545; 95% CI, 0.309-0.960), varicose vein SVT (OR, 0.42; 95% CI, 0.194-0.902), thrombophilia (OR, 1.939; 95% CI, 1.089-3.454), and cancer (OR, 4.727; 95% CI, 1.814-12.316). CONCLUSIONS: The prevalence of malignancy in the patients with SVT was 8.7%. Age, thrombophilia, male gender, nonvaricose vein SVT, and cancer were significantly associated with the presence of concurrent DVT/PE. Cancer was the strongest determinant of concurrent DVT/PE.

Coagulopathy associated with COVID-19.

Infection with a new type of coronavirus surprised with the diversity of its clinical symptoms. The disease may be asymptomatic, with only mild symptoms in the form of olfactory loss, general weakness or flu-like symptoms. However, in some patients, COVID-19 infection can be severe, with hypercoagulation being a common finding, with vascular endothelial damage and the consequent risk of venous and arterial thrombotic complications. Coa-gulopathy subsequently significantly worsens the prognosis of patients and increases overall mortality. Recently, a new term has been introduced to indicate the presence of activated hemostasis in SARS-CoV-2 infection - coagulopathy associated with COVID-19 (CAC). The current global pandemic of COVID-19 has triggered intensive research on the disease, which has clarified a number of findings about the infection, but we still have many unanswered questions, especially regarding possible treatment.

Anticoagulation therapy in cancer associated thromboembolism - new studies, new guidelines.

Low molecular weight heparin (LMWH) has become a standard of treatment of cancer-associated thromboembolism (CAT). Until recently, direct oral anticoagulants (DOAC) have not had data about efficacy and safety in cancer patients. However, in the last two years, four randomized open-label studies comparing DOAC and LMWH in the treatment of CAT have been published. The first one was a large trial with edoxaban, followed by two smaller studies with rivaroxaban and apixaban, and, recently, by another large trial with apixaban. There are some differences among the studies concerning design, inclusion and exclusion criteria, length of treatment. In summary, DOAC are associated with a trend to the reduction of the risk of recurrence of venous thromboembolism; however, this is at the expense of some increase in bleeding risk. This risk is differential; the prevailing site of bleeding is the upper part of gastrointestinal tract, and, to a lesser extent, genitourinary tract. The updated guidelines for the treatment of CAT suggest DOAC as an alternative, however with careful consideration of the risk of bleeding and the risk of drug interactions. So far, the guidelines have mentioned edoxaban and rivaroxaban. With emerging evidence, apixaban is expected to play a role as well.

Heparin-induced thrombocytopenia treated with fondaparinux: single center experience.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced, immune-mediated thrombocytopenia. It is associated with significant morbidity and mortality. Anticoagulation with heparin must be stopped immediately and replaced by some suggested alternative - lepirudin, danaparoid or argatroban. Fondaparinux has been also successfully used in HIT. METHODS: We present a cohort of 10 patients diagnosed with HIT and treated in a university hospital in a period of four years. Diagnosis was based on Keeling´s scoring system, screening immunologic test for HIT (STic EXPERT® HIT) and sandwich ELISA (detection of IgG/heparin-PF4 antibodies). While other alternative anticoagulants are not readily available in our hospital, we used fondaparinux in all cases. RESULTS: From 2014 to 2018, eight males and two females (mean age 67 years, range 46-86 years) were diagnosed with HIT in our hospital. This complication developed in 9 cases after low-molecular-weight heparin and in one after heparin flushes in hemodialysis. A drop-in platelet count developed in all patients, thrombotic complications in 7 and skin necrosis in 2 cases. Fondaparinux was used in all patients, including two cases with severe renal impairment, the dose was chosen individually. We observed complete platelet recovery in all cases. One patient died because of advanced malignancy, others did not have any complication. In 6 cases we switched to oral anticoagulation after platelet recovery. CONCLUSIONS: In our group of 10 HIT patients fondaparinux was shown to be both safe and effective, even in those with severe renal impairment. Additional studies are warranted to confirm this observation.

Venous thromboembolism in young adults: Findings from the RIETE registry.

BACKGROUND: Little is known on the clinical characteristics, risk factors and outcomes during anticoagulation in young patients with acute venous thromboembolism (VTE). METHODS: We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the clinical characteristics, risk factors and outcomes during anticoagulation in VTE patients aged 10-24 years. Data were separately analyzed according to initial presentation and gender. RESULTS: Of 76,719 patients with VTE, 1571 (2.0%) were aged 10-24 years. Of these, 989 (63%) were women and 669 (43%) presented with pulmonary embolism (PE). Most women were using estrogens (680, 69%) or were pregnant (101, 10%), while 59% of men had unprovoked VTE. Women were more likely to present with PE (48% vs. 34%). The majority (87%) of PE patients had Sat O2 levels ≥90% at baseline. The vast majority (97%) of PE patients were at low risk according to the PESI score, many (90%) at very low risk. During the course of anticoagulation (median, 192 days), 40 patients had VTE recurrences, 17 had major bleeding and 10 died (3 died of PE). Women had as many VTE recurrences as major bleeds (15 vs. 14 events), while men had many more VTE recurrences than major bleeding (25 vs. 3 events). CONCLUSIONS: VTE is associated with low risk of short-term mortality in young adults. Noticeable gender differences exist in the risk factor profile and the risk of VTE recurrences and major bleeding in the course of anticoagulation.

The Prevalence of Concomitant Deep Vein Thrombosis, Symptomatic or Asymptomatic, Proximal or Distal, in Patients With Symptomatic Pulmonary Embolism.

Patients with pulmonary embolism (PE) may have symptomatic or asymptomatic concomitant deep vein thrombosis (DVT). The reported prevalence of PE-associated DVT is variable, and thus, the utility of routine testing is controversial. The aim of our study was to analyze the prevalence of DVT and the factors associated with proximal DVT/whole-leg DVT in patients with symptomatic PE. In 428 consecutive patients (mean age: 59 ± 16.4 years; 52.3% men), we performed clinical examination and complete bilateral compression ultrasound and ascertained medical history and risk factors for DVT/PE. χ2 and t tests were used. Deep vein thrombosis was found in 70.6%; proximal DVT in 49.5%. Sensitivity/specificity of DVT symptoms was 42.7%/93.7% for whole-leg DVT and 47.6%/83.3% for proximal DVT. Male gender significantly prevailed among those with whole-leg DVT and with proximal DVT (58.9% and 61.8%). Active malignancy was significantly more frequent in the patients with proximal DVT than without proximal DVT (10.4% vs 3.7%). In conclusion, the prevalence of PE-associated DVT is quite high but clinical diagnosis is unreliable. In our group, male gender and active malignancy were significantly associated with the presence of concomitant proximal DVT.

Anticoagulant therapy for venous thromboembolism in patients with inflammatory bowel disease.

BACKGROUND: There is lack of evidence to guide the type, intensity, and the duration of anticoagulation following venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Registro Informatizado Enfermedad Trombo Embólica (RIETE) is an ongoing, multicenter, observational registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We used the RIETE database to compare the rate of VTE recurrences and major bleeding during the course of anticoagulation in noncancer patients with or without IBD. RESULTS: As of October 2014, 41 927 patients without active cancer have been recruited in RIETE. Of these, 265 (0.63%) had IBD and 85 (32%) had the VTE during an acute flare. The duration of anticoagulation was similar in patients with VTE during an acute flare (8.3±8.8 months), in remission (9.4±11.5 months), or without IBD (10.0±12.8 months). The rate of VTE recurrences [7.25, 95% confidence interval (CI): 1.46-21.2; 8.84, 95% CI: 3.23-19.2; and 5.85, 95% CI: 5.46-6.26 per 100 patient-years, respectively] and major bleeding (7.25, 95% CI: 1.46-21.2; 2.95, 95% CI: 0.33-10.6; and 4.79, 95% CI: 4.44-5.15, respectively) were similar in all three subgroups. Propensity score matching analysis confirmed the absence of differences in the rate of VTE recurrences (rate ratio: 1.16, 95% CI: 0.54-2.47) or major bleeding (rate ratio: 0.84, 95% CI: 0.31-2.23) between patients with or without IBD. CONCLUSION: Therapeutic anticoagulation for patients with IBD and VTE is as safe and effective as for those with VTE without IBD.

Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females With Oral Contraceptives Use.

Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception.

[Two perspectives on venous thromboembolism in oncology]. / Dva pohlady na venózny tromboembolizmus u onkologických pacientov.

An increased risk of venous thromboembolism (VTE) in patients with malignancy compared with the current population is determined by risk factors including the use of anticancer treatments, in particular some hormonal drugs, cytostatics, vascular endothelial growth factor (VEGF) inhibitors and epidermal receptor growth factor (EGFR) inhibitors, immunomodulators, and erythropoietins. The population of cancer patients is divided into a group of individuals with a history of malignant disease in complete remission and patients with active (locally advanced or metastatic) malignant disease in terms of approach to VTE. Venous thromboembolism negatively influences the prognosis of a patient with malignancy. Cancer associated VTE is associated with higher risk of recurrence as well as higher risk of bleeding during anticoagulation. For initial and long-term treatment, low molecular weight heparin should be preferred, for a minimum of 3-6 months. Some subgroups deserve a special approach - patients with thrombocytopenia, renal insufficiency, and patients with recurrent VTE despite anticoagulation. The treatment of an incidental pulmonary embolism is another controversial issue. The approach to a patient with cancer associated VTE should be individualized and should take into account patient´s overall prognosis and risk/benefit ratio of treatment.Key words: anticoagulation treatment - cancer - risk factors - venous thromboembolism.

Thrombophilia testing results in patients with a first venous thromboembolic event: should the selection criteria for testing be revisited?

BACKGROUND: After the first episode of venous thromboembolism (VTE), the guidelines recommend selective thrombophilia testing and suggest not to test the patients older than 40 years with a provoked event and all patients above 60. METHODS: We compared thrombophilia workup results in 544 patients, meeting or not meeting the selection criteria. Homozygous factor V Leiden or prothrombin gene mutation, natural anticoagulant deficiencies, antiphospholipid syndrome or combination of ≥2 disorders were considered a strong thrombophilia. RESULTS: Thrombophilia was detected in 28.5% and strong thrombophilia in 6.6% of patients. In the subgroup aged 40-60 years, in men with unprovoked cases the prevalence of thrombophilia was 35.7% and that of strong thrombophilia 12.5%; in provoked cases it was 19.5% and 4.9%, respectively. In women aged 40-60 with unprovoked events, thrombophilia was found in 18.8%, in cases provoked solely by estrogens or pregnancy in 40.9%, and in those with another trigger in 9.1%. Comparing the patients above and under 60, thrombophilia was detected in 27.6% and 29.2%, respectively (P=0.67) and strong thrombophilia in 9.1% and 4.7%, respectively (P=0.041). Factors significantly associated with positive thrombophilia testing were family history of VTE (including superficial vein thrombosis) - OR 1.80; 95% CI 1.71-2.77 and proximal location of deep vein thrombosis - OR 1.94; 95% CI 1.25-3.02. CONCLUSIONS: Of VTE patients not meeting selection criteria for testing, the prevalence of thrombophilia and even strong thrombophilia was high in those older than 60 years. Selection criteria for testing should be respected but in some cases an individual approach might be considered.

A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the lower limbs.

BACKGROUND: No prior studies have identified which patients with deep vein thrombosis in the lower limbs are at a low risk for adverse events within the first week of therapy. METHODS: We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to identify patients at low risk for the composite outcome of pulmonary embolism, major bleeding, or death within the first week. We built a prognostic score and compared it with the decision to treat patients at home. RESULTS: As of December 2013, 15,280 outpatients with deep vein thrombosis had been enrolled. Overall, 5164 patients (34%) were treated at home. Of these, 12 (0.23%) had pulmonary embolism, 8 (0.15%) bled, and 4 (0.08%) died. On multivariable analysis, chronic heart failure, recent immobility, recent bleeding, cancer, renal insufficiency, and abnormal platelet count independently predicted the risk for the composite outcome. Among 11,430 patients (75%) considered to be at low risk, 15 (0.13%) suffered pulmonary embolism, 22 (0.19%) bled, and 8 (0.07%) died. The C-statistic was 0.61 (95% confidence interval [CI], 0.57-0.65) for the decision to treat patients at home and 0.76 (95% CI, 0.72-0.79) for the score (P = .003). Net reclassification improvement was 41% (P < .001). Integrated discrimination improvement was 0.034 for the score and 0.015 for the clinical decision (P < .001). CONCLUSIONS: Using 6 easily available variables, we identified outpatients with deep vein thrombosis at low risk for adverse events within the first week. These data may help to safely treat more patients at home. This score, however, should be validated.

[Variability of the deep femoral venous system]. / Variabilita hlubokých zil stehna.

Deep venous system is known for its extreme variability but in anatomy it receives only marginal interest. Although a few previous anatomical studies have already pointed out the fact of a significant discrepancy between the autopsy findings and the literary description, it has not had any particular output so far. Our findings confirmed the deep femoral vein to be an alternative collateral vein connecting the popliteal with the femoral vein.

Two cases of congenital dysfibrinogenemia associated with thrombosis - Fibrinogen Praha III and Fibrinogen Plzen.

Congenital dysfibrinogenemia is a rare disease characterised by inherited abnormality in the fibrinogen molecule, resulting in functional defects. Two patients, a 26-year-old woman and a 61-year-old man, both with history of thrombotic events, had abnormal coagulation test results. DNA sequencing showed the heterozygous gamma Y363N mutation (Fibrinogen Praha III) and the heterozygous Aalpha N106D mutation (Fibrinogen Plzen), respectively. Fibrin polymerisation, after addition of either thrombin or reptilase, showed remarkably delayed polymerisation in both cases. Fibrinolysis experiments showed slower tPA initiated lysis of clots. SDS-PAGE did not show any difference between normal and Praha III and Plzen fibrinogens. Both mutations had a significant effect on platelet aggregation. In the presence of either ADP or TRAP, both mutations caused the decrease of platelet aggregation. SEM revealed abnormal clot morphology, with a large number of free ends and narrower fibres of both fibrin Praha III and Plzen. Praha III mutation was situated in the polymerisation pocket "a". The replacement of the bulky aromatic side chain of tyrosine by the polar uncharged small side chain of asparagine may lead to a conformational change, possibly altering the conformation of the polymerisation pocket. The Plzen mutation is situated in the coiled-coil connector and this replacement of polar uncharged asparagine residue by polar acidic aspartate changes the alpha-helical conformation of the coiled-coil connector; and may destabilise hydrogen bonds in its neighborhood. Although both mutations are situated in different regions of the molecule, both mutations have a very similar effect on fibrinogen functions and both are connected with thromboses.

Portal and mesenteric vein thromboses in a patient with prothrombin G20210 mutation, elevated lipoprotein (a), and high factor VIII.

A 65-year-old man was examined for abdominal pain. Portal and mesenteric vein thromboses were described by ultrasound and computed tomography. No local cause was found. The patient had a positive history of venous thromboembolism. Thrombophilia workup revealed prothrombin G20210A mutation (heterozygous), C677T mutation of methylenetetrahydrofolate reductase gene (homozygous), elevated level of lipoprotein (a), and high level of coagulation factor VIII. Anticoagulation was started and planned for a long-term duration. The etiology of portal vein thrombosis is often multifactorial, with various combinations of systemic factors (inherited or acquired prothrombotic conditions) and local precipitating factors (inflammation, injury to the portal venous system, cancer of the abdominal organs, cirrhosis). The reported prevalence of hypercoagulable states in patients with portal vein thrombosis has been very heterogeneous so far. Some authors support a role of the prothrombin G20210A mutation. In the reported patient, this mutation was revealed in a combination with other hypercoagulable states.

Percutaneous coronary intervention in a patient with immune thrombocytopenia purpura.

The appropriate regimen of platelet inhibitors that should be used in patients with immune thrombocytopenia purpura (ITP; formerly called idiopathic thrombocytopenic purpura) who are undergoing percutaneous coronary intervention is unclear. We report the case of a patient with ITP who underwent two separate coronary interventions. The first involved the use of aspirin and a cutting balloon to treat obstructive disease of the left circumflex. When the patient presented with restenosis, he received eptifibatide, clopidogrel, and an intracoronary stent. He is currently 16 months removed from his second procedure and remains physically active without any anginal symptoms. Percutaneous revascularization in patients with ITP remains a challenge and this therapeutic approach, while ultimately successful in the patient, requires further validation.