[Thrombophilia, preeclampsia and other pregnancy complications]. / Trombofilija, preeklampsija i ostale komplikacije trudnoce.

The aim of this paper is to present the latest developments in therapy and prophylaxis of deep vein thrombosis and other pregnancy complications in women with inherited or acquired thrombophilia and in women with mechanical heart valves. The data presented in the paper have been extracted from the Current Contents database. It is well known that the hypercoagulable state in pregnant women, caused either by the physiological changes of pregnancy or by inherited thrombophilia, increases the risk of venous thromboembolism (VTE), pulmonary embolism (PE), preeclampsia, recurrent early and late fetal loss, intrauterine growth retardation (IUGR), placental abruption, and other less probable complications of pregnancy and its outcome. In women with mechanical heart valves, the risk of systemic embolism is also seen to increase during pregnancy. According to data analyzed, positive antiphospholipid antibodies (APLA) as well as anticardiolipin antibody and lupus anticoagulant (nonspecific inhibitor) positivity, homozygosity and heterozygosity for factor V Leiden mutation and heterozygosity for the prothrombin G20210A variant, MTHFR C677T variant homozygosity and hyperhomocysteinemia are in strong association with pregnancy complications and severe pregnancy outcome. The strongest association for late fetal loss was seen in women with protein S deficiency. In order to reduce such risks, anticoagulation therapy is administered throughout pregnancy. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy and pregnancy complications include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contraindicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early pregnancy is uncertain. LMWH and UFH are quite safe and efficacious when properly selected, dosed and monitored. The efficacy and safety of LMWH have been demonstrated in the prevention and treatment of VTE in pregnancy. LMWH in association with aspirin administered throughout pregnancy have been shown to be associated with a lower risk of complications in women with APLA syndrome. Women at a high risk of preeclampsia are recommended to use low-dose aspirin throughout pregnancy. When there is a history of preeclampsia, the administration of anticoagulation therapy is not recommended as a prophylaxis in subsequent pregnancies, as the risk appears to be already decreased as compared with previous pregnancy. LMWH has probable advantages over UFH for the incidence of side effects. In pregnant women with mechanical heart valves, anticoagulant therapy during pregnancy should include assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism, and decision should also be strongly influenced by the patient's preferences. If the risk of thromboembolism in patients with mechanical heart valves is considered very high, and efficacy or safety of prophylaxis with UFH or LMWH is not satisfactory (older-generation prosthesis in the mitral position or history of thromboembolism), administration of vitamin K antagonists throughout pregnancy is recommended with replacement by UFH or LMWH close to delivery. It should be considered that limited effectiveness of UFH or LMWH in patients with mechanical heart valves might be due to inadequate dosing. The necessity of anticoagulation therapy in women with inherited or acquired thrombophilia is biologically plausible; nevertheless, optimum management in such cases remains unknown.

[Inflammatory indicators in patients after surgery of the large intestine]. / Upalni pokazatelji u bolesnika nakon operacija debelog crijeva.

BACKGROUND AND AIMS: Despite recent advances in surgical techniques and intensive care management, infectious complications and sepsis remain significant problem after abdominal surgery. Therefore, inflammatory parameters were looked for that could help achieve an early and more reliable diagnosis of postoperative infections. C-reactive protein (CRP) is a nonspecific inflammatory mediator which is significantly increased postoperatively, regardless of the type of operation and the presence or absence of complications. Procalcitonin (PCT), the prohormone of calcitonin, referred to as a marker of sepsis, is increased significantly in severe bacterial and fungal infections. Quantitative PCT measurements in surgical patients have shown that postoperative PCT concentrations depend on the type and extent of surgery. PCT increased most after major abdominal surgery, although PCT concentrations were significantly higher in patients with complications compared to patients with uneventful postoperative course. The aim of the study was to determine PCT concentrations with a rapid semiquantitative PCT-Q test in the early postoperative period after colon surgery and to investigate its potential use in the diagnosis of infectious complications compared to CRP. METHODS: Thirty-eight adult patients undergoing elective surgery of the intestine were followed up. None of the patients had clinical or laboratory signs of infection preoperatively. Leukocytes, CRP and PCT were determined preoperatively and on postoperative days 1-3 and 5. PCT was measured with the B. R. A. H. M. S PCT-Q semiquantitative test. CRP and PCT measurements in 30 patients with normal recovery were statistically analyzed. RESULTS: CRP was significantly elevated postoperatively in all patients at the 4 time points with maximum values on postoperative day 2. There was no difference in CRP values between patients with and without complications. Although PCT concentration was increased in 15 of 30 patients with normal recovery, only mild increase (>0.5-2 ng/L) was recorded in 13, and moderate increase (>2-10 ng/L) in only two patients. PCT increase was most frequently found on postoperative day 1 or 2, and more rarely on postoperative day 3. The number of patients with elevated PCT was significantly higher (8 of 8 patients) in the group with complications, which included postoperative infections in 7 of 8 patients, than in the group without complications. CONCLUSION: In the early postoperative period after major abdominal surgery, CRP is invariably increased and cannot help in recognizing infectious complications. In our study, which included a relatively small number of patients after colon surgery, PCT >2 ng/mL, as measured with semiquantitative PCT-Q test on postoperative days 1-5, or >0.5 ng/ml after postoperative day 3, was rarely recorded in patients with normal postoperative course. We conclude that PCT-Q test can be helpful in the early diagnosis of infectious complications after abdominal surgery.

Correlation of perforating vein incompetence with extent of great saphenous insufficiency: cross sectional study.

AIM: To explore the correlation between perforating vein incompetence and the extent of great saphenous vein insufficiency according to Hach. METHODS: Duplex ultrasound was used to determine the number of incompetent perforators and diameter of perforating veins, and the level of great saphenous vein reflux and the presence or absence of deep reflux in 118 lower limbs (59 patients). There were 19 limbs with no clinical evidence of venous disease (CEAP - clinical, etiological, anatomical, pathological grade 0), 16 limbs with telangiectasias only (CEAP grade 1), 36 limbs with varicose veins (CEAP 2), 26 limbs with edema (CEAP 3), and 21 limb affected with lipodermatosclerosis but not ulcer (CEAP 4). RESULTS: Both the number of incompetent perforators and the average diameter of duplex detectable perforators per limb correlated significantly with the extent of great saphenous vein insufficiency (Pearson correlation coefficients were 0.55 and 0.44, respectively; P<0.001 for both). The number of incompetent perforators and the average diameter of perforators per limb were significantly higher with the deteriorating CEAP grade (Kruskal-Wallis H test; P<0.001). The mean number of incompetent perforators per limb did not differ significantly in the absence or presence of deep reflux (0.8-/+1.26 vs 1.3-/+1.6, t test, P=0.172), the average diameter of perforators per limb was higher in the presence of deep reflux (2.4-/+2 mm vs 3.7-/+1.1 mm, t test, P=0.023). CONCLUSION: The extent of great saphenous vein insufficiency correlated with an increase in the number and the diameter of perforators. The perforators' association with deep venous reflux was much poorer. Clinical presentation worsened with the deteriorating duplex signs of perforators' incompetence.

Thrombus size is associated with etiology of deep venous thrombosis--a cross-sectional study.

The aim of this study was to evaluate the impact of risk factors for deep vein thrombosis (DVT) on thrombus sizes in lower extremities. The size and extent of thrombus was scored according to International Consensus Committee for venous disease classification. After the diagnosis of DVT was established and its size scored, predominant risk factors for DVT in each patient were identified (malignant disease, thrombophilia, postoperative state, hormonal therapy, heredity, limb trauma, immobilization, others and unknown risk factors). The average thrombus score was 6 (95% CI 5.47-6.53). The analysis of thrombus size indicated that the largest thrombi were found in patients with malignancy. Their average score was 8.5 (95% CI 7-10) and was significantly higher than in patients with other risk factors for deep vein thrombosis. There was no significant correlation between numbers of days from the onset of symptoms to the moment of DVT diagnosis and thrombus score (r = -0.08, p = 0.38). Age was very slightly correlated to thrombus size (r = 0.19; p = 0.046), while the gender did not have significant impact on thrombus score (p = 0.074). The conclusion of our study was that etiology of thrombosis and particularly malignant diseases has the largest impact on venous thrombus size.

[Coagulation tests in septic surgical patients]. / Koagulacijski testovi u sepsi kirurskih bolesnika: kohortna studija.

AIM: To determine whether sequential change in coagulation parameters such as activated partial thromboplastin time (aPTT), prothrombin time (PT), platelets count and fibrinogen level may predict the outcome of patients in sepsis. STUDY DESIGN: Cohort longitudinal study. PATIENTS AND METHODS: Patients with positive two or more clinical criteria for sepsis were eligible for the study. Thirty patients were included, 24 male and 6 female. Eight patients survived, while 22 deceased. Median age of survivors was 66 years (range 23-77), and in non-survivors it was 69 years (range 48-79), p=0.37. In 9 patients malignancy was an underlying disease. APACHE II score was calculated at admittance, median value for survivors was 10 (range 7-15) and for non-survivors it was 26 (range 6-35), p=0.001. Calculated MODS score at the time blood cultures was 2 (range 0-9) for survivor and 6.5 (range 2-13) for non-survivors, p=0.007. Blood cultures were taken at the onset of sepsis, and in 29 patients they were positive. Coagulation parameters were measured at admittance, at the onset of sepsis and 48 hours after the introduction of the specific antimicrobial therapy. RESULTS: Analysis of variance for repeated measurements between survivors and non-survivors has shown that there were no differences in values of coagulation parameters. The only significant difference between these groups of patients was APACHE II and MODS score. In 7 patients with severe thrombocytopenia (<33,000 x 10(9)/L) as a result of irreversible septic shock a clinically visible bleeding was present in only one patient. DISCUSSION: Disseminated intravascular coagulation (DIC) is a clinical-pathological syndrome in which wide-spread intravascular coagulation is induced by procoagulants that are introduced or produced in the blood circulation and overcome the natural anticoagulant mechanisms. DIC causes tissue ischemia from occlusive microthrombi as well as bleeding from both the consumption of platelets and coagulation factors and the anticoagulant effect of products of secondary fibrinolysis. In sepsis, tissue factor which is the most common trigger of DIC can be generated and expressed on membranes of monocytes and endothelial cells during the systemic inflammatory response syndrome (SIRS). The wide-spread generation of thrombi in sepsis induces deposition of fibrin which leads to vessels obstruction and consumption of substantial amounts of haemostatic factors i.e. platelets, fibrinogen, factors V, VIII and others, protein C and antithrombin III (AT III). Intravascular thrombi trigger secretion of tissue plasmin activator (tPA) from endothelial cells which sets of compensatory thrombolysis which may reopen the occluded blood vessels. But byproducts of thrombolysis such as fibrin/fibrinogen degradation products may enhance bleeding by interfering with platelet aggregation, fibrin polymerization and thrombin activity. The typical feature of sepsis is depression of three powerful anticoagulant systems: protein C pathway, AT III pathway and tissue pathway factor inhibitor (TPFI). This sequence of events led us to hypothesize that alterations in coagulation parameters such as PT, aPTT, fibrinogen, platelets count may predict the outcome of disease, as it is well documented that the development of DIC confers prognosis of sepsis. The failure to distinguish survivors from non-survivors by the alteration in the coagulation parameters in this study may be due to a relatively low sample size or to the clinical necessity of an attending physician to substitute the deficient blood or coagulation product. CONCLUSION: The coagulation parameters PT, aPTT, platelet count and fibrinogen level can not serve as predictors of outcome in patients with sepsis. Further studies including more discerning coagulation parameters: AT III, D-dimer, soluble fibrin monomer, thrombin/antithrombin complex, plasmin/antiplasmin complex, fibrinopeptid A, fibrinopeptid B are necessary to evaluate whether these procoagulant and anticoagulant factors may help in predicting outcome and severity of sepsis.

[Therapy and prevention of deep venous thrombosis and pulmonary embolism in gynecology and obstetrics]. / Terapija i profilaksa duboke venske tromboze i plucne embolije u ginekologiji i opstetriciji.

AIM: The aim of this paper is to present the latest developments in therapy and prophylaxis of deep vein thrombosis in gynecology and obstetrics. DATA EXTRACTION: The data presented in the paper have been extracted from the Current Contents database. In the introduction, the coagulation cascade is described, and certain coagulation abnormalities caused by deficiency or decreased activity of coagulation factors are highlighted. The most prominent signs of deep vein thrombosis in pregnant women are swelling and tenderness of the affected leg, sometimes accompanied with fever and leucocytosis. In pelvic thrombosis, swelling of the leg is often absent and such a condition may be mistaken for other abdominal emergencies. The diagnostic algorithm for deep vein thrombosis starts with the clinical Wells criteria. To confirm the diagnosis it is necessary to visualize the thrombus by one of the imaging methods. The value of D-dimer is limited by its low positive predictive value, particularly in pregnant women. Low weight molecular heparin's have lately almost replaced standard heparin in the treatment of the deep vein thrombosis in pregnant women for providing advantages of subcutaneous application, no need of laboratory control of coagulation parameters, lower risk of bleeding, and lower incidence of osteoporosis and heparin-induced thrombocytopenia. We list the recommendations of the American College of Chest Physicians published in 1991, which stratify pregnant women with deep vein thrombosis according to their medical history and laboratory parameters. We have specified the proposed approach according to: history of deep vein thrombosis due to transient risk factors; previous idiopathic deep vein thrombosis without anticoagulant therapy; previous deep vein thrombosis with thrombophylia; previous idiopathic deep vein thrombosis on anticoagulant therapy; laboratory-proven thrombophilia with no history of deep vein thrombosis; and recurrent deep vein thrombosis. Pregnant women with artificial heart valves may undergo one of three proposed treatments. Long preoperative hospitalization, prolonged operative procedures, extensive injuries of blood vein vessels on radical procedures, frequently present accompanying malignant disease or previous irradiation therapy and postoperative bed-ridden period after major gynecologic procedures increase the risk of perioperative development of deep vein thrombosis. It is necessary to appraise this risk, classify patients in one of the four groups, and administer appropriate measures. Patients at a low risk of developing thromboembolic incidents are those younger than 40, undergoing procedures lasting less than 30 minutes and without other risk factors. The risk is moderate in patients aged 40-60 without other risk factors, or those aged under 40 having malignancy have high risk. Patients at a very high risk are those with a history of deep vein thrombosis, thrombophilia or pelvic exenteration. In the last decade there has been a great advancement in the diagnostics and treatment of deep vein thrombosis. The discovery of genetic disorders predisposing the patient to the development of a thromboembolic incident (thrombophilia) has changed our position concerning the duration of anticoagulant therapy, and nowadays it can last from several months to a lifetime regimen, depending on the underlying mechanism causing the incident. A significant improvement in therapy has occurred with the introduction of low molecular weight heparins in clinical practice. Their therapeutic value is equal to standard heparin, and their advantages include easier dosage and less nursing time as well as in a lower incidence of side effects such as haemorrhage. For these reasons, low molecular weight heparin has almost completely replaced standard heparin in the western world.

Treatment of deep vein thrombosis with oral anticoagulants in patients with malignancy: prospective cohort study.

AIM: To assess the outcome of deep vein thrombosis in patients with malignancy after 6 months of oral anticoagulant therapy, and to compare it with international normalized ratio (INR). METHOD: Thirty-one patients with malignancy (13 with hematological and 18 with solid tumors) and deep vein thrombosis (29 leg thrombosis and 2 upper extremity thrombosis) were included into a prospective cohort study that lasted from March 2000 until May 2001. The presence of malignant tumors was histologically proved and documented, and deep vein thrombosis was proved by ultrasound or venography. Patients were treated with heparin during the acute phase, and with oral anticoagulant therapy during further 6 months. INRs and ultrasound examination performed during the acute event were repeated one month and 6 months afterwards for the needs of analysis. RESULTS: Twenty-four patients concluded the study. Clot resolution was achieved in 13 patients after 6 months of therapy. The patients with INR>2 (n=10) had better clot resolution than those with INR<2 (n=3); p=0.012. There was no statistically significant difference in the outcome of thrombosis with regard to the INR level after a month of therapy (p=0.555). Three patients experienced bleeding, one patient had recurrent thrombosis, and two patients suffered pulmonary embolism. CONCLUSION: Appropriate anticoagulation during 6 months after the acute deep vein thrombosis enhances the rate of the complete clot resolution. The INR values can be used as predictive of complete recovery from the thrombosis. Complications are comparable with those reported for patients without malignancy.

[Ultrasonography in acute pelvic pain]. / Ultrazvucna obrada akutne boli u maloj zdjelici.

Acute pelvic pain may be the manifestation of various gynecologic and non-gynecologic disorders from less alarming rupture of the follicular cyst to life threatening conditions such as rupture of ectopic pregnancy or perforation of inflamed appendix. In order to construct an algorithm for differential diagnosis we divide acute pelvic pain into gynecologic and non-gynecologic etiology, which is than subdivided into gastrointestinal and urinary causes. Appendicitis is the most common surgical emergency and should always be considered in differential diagnosis if appendix has not been removed. Apart of clinical examination and laboratory tests, an ultrasound examination is sensitive up to 90% and specific up to 95% if graded compression technique is used. Still it is user-depended and requires considerable experience in order to perform it reliably. Meckel's diverticulitis, acute terminal ileitis, mesenteric lymphadenitis and functional bowel disease are conditions that should be differentiated from other causes of low abdominal pain by clinical presentation, laboratory and imaging tests. Dilatation of renal pelvis and ureter are typical signs of obstructive uropathy and may be efficiently detected by ultrasound. Additional thinning of renal parenchyma suggests long-term obstructive uropathy. Ruptured ectopic pregnancy, salpingitis and hemorrhagic ovarian cysts are three most commonly diagnosed gynecologic conditions presenting as an acute abdomen. Degenerating leiomyomas and adnexal torsion occur less frequently. For better systematization, gynecologic causes of acute pelvic pain could be divided into conditions with negative pregnancy test and conditions with positive pregnancy test. Pelvic inflammatory disease may be ultrasonically presented with numerous signs such as thickening of the tubal wall, incomplete septa within the dilated tube, demonstration of hyperechoic mural nodules, free fluid in the "cul-de-sac" etc. Color Doppler ultrasound contributes to more accurate diagnosis of this entity since it enables differentiation between acute and chronic stages based on analysis of the vascular resistance. Hemorrhagic ovarian cysts may be presented by variety of ultrasound findings since intracystic echoes depend upon the quality and quantity of the blood clots. Color Doppler investigation demonstrates moderate to low vascular resistance typical of luteal flow. Leiomyomas undergoing degenerative changes are another cause of acute pelvic pain commonly present in patients of reproductive age. Color flow detects regularly separated vessels at the periphery of the leiomyoma, which exhibit moderate vascular resistance. Although the classic symptom of endometriosis is chronic pelvic pain, in some patients acute pelvic pain does occur. Most of these patients demonstrate an endometrioma or "chocolate" cyst containing diffuse carpet-like echoes. Sometimes, solid components may indicate even ovarian malignancy, but if color Doppler ultrasound is applied it is less likely to obtain false positive results. One should be aware that pericystic and/or hillar type of ovarian endometrioma vascularization facilitate correct recognition of this entity. Pelvic congestion syndrome is another condition that can cause an attack of acute pelvic pain. It is usually consequence of dilatation of venous plexuses, arteries or both systems. By switching color Doppler gynecologist can differentiate pelvic congestion syndrome from multilocular cysts, pelvic inflammatory disease or adenomyosis. Ovarian vein thrombosis is a potentially fatal disorder occurring most often in the early postpartal period. Hypercoagulability, infection and stasis are main etiologic factors, and transvaginal color Doppler ultrasound is an excellent diagnostic tool to diagnose it. Acute pelvic pain may occur even in normal intrauterine pregnancy. This may be explained by hormonal changes, rapid growth of the uterus and increased blood flow. Ultrasound is mandatory for distinguishing normal intrauterine pregnancy from threatened or spontaneous abortion, ectopic pregnancy and other complications that may occur in patients with positive pregnancy test. Incomplete abortion is visualized as thickened and irregular endometrial echo with certain amount of intracavitary fluid. If applied, color Doppler ultrasound reveals low vascular resistance signals in richly perfused intracavitary area. Transvaginal sonography has high sensitivity and specificity in visualization of uterine and adnexal signs of ectopic pregnancy. Color Doppler examination may aid in detection of the peritrophoblastic flow. Furthermore, it facilitates detection of ectopic living embryo, tubal ring or unspecific adnexal tumor. Corpus luteum cysts and leiomyomas are another cause of pelvic pain during pregnancy, which can be correctly diagnosed by ultrasound. Detection of uterine dehiscence and rupture in patients with history of prior surgical intervention on uterine wall relies exclusively on correct ultrasound diagnosis. In patients with placental abruption sonographer detects hypoechoic complex representing either retroplacental hematoma, subchorionic hematoma or subamniotic hemorrhage. In closing, ultrasound has already become important and easily available tool which can efficiently recognize patients with possibly threatening conditions of different origins.