Correction to: New clotting disorders that cast new light on blood coagulation and may play a role in clinical practice.

The original version of the article unfortunately contained few errors.

Heparin, coumarin, protein C, antithrombin, fibrinolysis and other clotting related resistances: old and new concepts in blood coagulation.

The concept of resistance in blood coagulation has become important. In the past it was limited to the resistance shown by some patients to heparin, coumarin or aspirin. Subsequently, it was demonstrated that a mutation in a single clotting factor, FV, showed resistance to activated protein C. Since activated protein C is supposed to downregulate aFV and aFVIII, their persistence in the circulation gives origin to a hypercoagulable state. Recently antithrombin resistance has been defined. Several prothrombin abnormalities (dysprothrombinemias) have been shown to be resistant to the action of antithrombin. This is associated with the occurrence of a trombophilic state. Prothrombin may therefore be associated like FV with both a bleeding condition (prothrombin deficiency) and a thrombophilic state (some dysprothrombinemias). Finally, thrombomodulin resistance has been defined in liver cirrhosis. These patients often show an increased ratio between FVIII levels and protein C. This imbalance may be partly responsible for the frequent presence of portal vein thrombosis seen in these patients. All these studies have greatly increased the complexity of the clotting mechanisms and interactions. They have cast light on clinical events which had remained unknown or ill-defined.

New clotting disorders that cast new light on blood coagulation and may play a role in clinical practice.

Recently several variants of clotting factors have shown a peculiar behavior so that they appear as new defects. The factors involved are FII, FV and FIX. Prothrombin deficiency is usually associated with bleeding. Recently a few prothrombin abnormalities involving Arg396 mutations, have been demonstrated to show antithrombin resistance with the consequent appearance of a thrombophilic state and venous thromboses in young age. The same is true for an abnormal FIX (FIX Padua). The thrombotic manifestations in the latter condition are also venous. The abnormal FIX (FIX Padua) is characterized by a great increase in FIX activity whereas FIX antigen is only slightly increased. The condition is due to an Arg338Lys mutation. The increased intrinsic clotting activity of this abnormal FIX is being investigated as a useful therapeutic approach in homophile B patients. Another new clotting disorder is represented by two abnormal FV (FV East Texas and FV Amsterdam). These are characterized by a deletion of part of the B domain of FV resulting in a "short" FV. The condition is characterized by a mild bleeding tendency due to high levels of Tissue Factor pathway inhibitor. The "short" factor V is in fact resistant to the action of Tissue Factor pathway inhibitor which is sharply increased in these patients. These new clotting entities have again demonstrated that the study of patients who show a tendency to venous thrombosis or a mild bleeding condition that cannot be explained on the basis of our current concepts of blood coagulation, may represent "new" coagulation disorders. All persons interested in thrombotic or hemorrhagic disorders should be informed about these new clinical and laboratory conditions.

Drug-Induced Thrombophilic or Prothrombotic States: An Underestimated Clinical Problem That Involves Both Legal and Illegal Compounds.

Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.

Prethrombotic, prothrombotic, thrombophilic states, hypercoagulable state, thrombophilia etc.: semantics should be respected even in medical papers.

The study of prothrombotic or thrombophilic states have drawn considerable attention during the past two decades. This was the result of the increasing number of thrombotic events, both arterial and venous reported all over the world but especially in the developed countries. This wealth of studies and papers have not always respected the semantical significance of the various terms used, namely prethrombotic state, hypercoagulable state, thrombophilic or prothrombotic state, thrombophilia, susceptibility to thrombosis and procoagulant state. This review is an attempt to adhere to a correct Semantic format in order to avoid confusion and misinterpretations. This is of fundamental importance in order to avoid the wrong attribution of a thrombosis to a hypercoagulable or a prethrombotic state.

Congenital factor XI and factor VII deficiencies assure an apparent opposite protection against arterial or venous thrombosis: An intriguing observation.

OBJECTIVE: To investigate the prevalence and type of thrombotic events reported in patients with congenital factor XI (FXI) or factor VII (FVII) deficiency. PATIENTS AND METHODS: Data on all patients with congenital FXI or FVII deficiency and a thrombotic event were gathered by means of a time unlimited PubMed search carried out in June 2014 and in February 2015. Appropriate keywords including the medical subject headings were used in both instances. Side tables were also consulted and cross-checking of the references was carried out to avoid omissions. The thrombosis event had to be proven by objective methods. RESULTS: Forty-three patients with FXI deficiency had arterial thrombosis and only eight had venous thrombosis. On the contrary, only five patients with FVII deficiency had arterial thrombosis whereas 31 patients had venous thrombosis. The arterial/venous ratios were 5.37 and 0.17 for FXI or FVII, respectively. CONCLUSIONS: Arterial thrombosis is frequent in FXI deficiency whereas venous thrombosis is rare. The reverse is true for FVII deficiency. The significance of these findings is discussed especially in view of the recent use of synthetic anti-FXI compounds in the prophylaxis of post-orthopedic surgery of venous thrombosis complications.

Congenital FVII deficiency and pulmonary embolism: a critical appraisal of all reported cases.

Fourteen patients with congenital factor VII (FVII) deficiency were reported to have had pulmonary embolism. All patients were type 2 defects with variably low activity but normal or near-normal antigen. Concomitant deep vein thrombosis was present in 7 instances. The majority of patients had no or only a mild bleeding tendency. Associated prothrombotic risk factors were present in 11 patients (old age, surgery, substitution therapy with prothrombin complex, plasma-derived or activated FVII concentrates). Pulmonary embolism was usually moderate or severe. In 2 cases, it was fatal. Only 4 patients were studied by means of molecular biology techniques. The Arg304Gln mutation was found in 5 of the 8 alleles. Heparin and Coumadin together with adequate substitution therapy were carried out in 5 patients with satisfactory results. The FVII deficiency does not grant a sure protection from venous thromboembolism.

First measurement of kaonic helium-3 X-rays.

The first observation of the kaonic (3)He 3d→2p transition was made, using slow K- mesons stopped in a gaseous (3)He target. The kaonic atom X-rays were detected with large-area silicon drift detectors using the timing information of the K+K- pairs of ϕ-meson decays produced by the DAΦNE e+e- collider. The strong interaction shift of the kaonic (3)He 2p state was determined to be -2±2(stat)±4(syst) eV.

Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation.

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

Limits on light-speed anisotropies from Compton scattering of high-energy electrons.

The possibility of anisotropies in the speed of light relative to the limiting speed of electrons is considered. The absence of sidereal variations in the energy of Compton-edge photons at the European Synchrotron Radiation Facility's GRAAL facility constrains such anisotropies representing the first nonthreshold collision-kinematics study of Lorentz violation. When interpreted within the minimal standard-model extension, this result yields the two-sided limit of 1.6×10(-14) at 95% confidence level on a combination of the parity-violating photon and electron coefficients (κ(o+))(YZ), (κ(o+))(ZX), c(TX), and c(TY). This new constraint provides an improvement over previous bounds by 1 order of magnitude.

Thrombotic events in patients with congenital prekallikrein deficiency: a critical evaluation of all reported cases.

The occurrence of thrombotic events in patients with congenital bleeding conditions has received considerable attention in recent years. The same is true for asymptomatic defects of factors of the contact phase of blood coagulation, mainly FXII. Anecdotal reports on thrombosis in patients with prekallikrein deficiency have occasionally been reported. These involved both arterial and venous thrombosis. The purpose of the present article is to analyze the stories and the clinical pictures of all 75 cases of prekallikrein deficiency published so far. Among these patients were 9 with thrombosis, 6 arterial (myocardial infarction and ischemic stroke) and 3 venous (deep vein thrombosis with or without pulmonary embolism). In 6 cases acquired thrombosis risk factors were present; in 2 cases no associated risk factors were present and in 1 case no information was supplied in this regard. One patient who presented both a stroke and a pulmonary embolism had a fatal outcome. The article clearly indicates that prekallikrein deficiency does not protect from thrombosis in spite of the severe in vitro coagulation defect.

Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature.

The occasional occurrence of thrombosis in patients with congenital bleeding disorders has received considerable attention during the past decade. Myocardial infarction, ischemic strokes and venous thromboembolism have been reported in hemophilia A or B patients, in von Willebrand disease and, also, in rare coagulation disorders, especially in factor VII (FVII) deficiency. To explain the relatively high frequency of thrombotic phenomena, mainly venous, seen in the last condition, it was speculated that a special form or variant of FVII deficiency could exist. The presence of associated prothrombotic risk factors has been occasionally reported to be present in these patients but the matter has never been duly evaluated and emphasized. The purpose of the present paper was to evaluate if the clinical setting in which thrombosis appeared in these patients could explain the occurrence of the thrombosis. All reported cases of thrombosis seen in patients with FVII deficiency have been analyzed and the presence of associated risk factors recorded. Out of a population of 33 documented cases, the presence of prothrombotic risk factors was reported in 30 instances. In two of the remaining cases, no mention is made about associated risk factors. In the last case they were explicitly excluded. The critical evaluation of the literature suggests that the occurrence of thrombosis in FVII deficiency may be due to common prothrombotic risk factors. As a consequence it may be only stated that FVII deficiency does not protect from thrombosis.

Hemospermia in patients with congenital coagulation disorders: a study of three cases.

Hemospermia is usually a symptom of urological relevance, however it may have also a medical and hematological significance and has been reported in congenital or acquired bleeding disorders. Because of this symptom's negative psychological impact on the patient, it is likely that the condition is underplayed and therefore underdiagnosed. During the years 1967-2003 we had the opportunity to see 3 patients with hemospermia on a congenital bleeding disorder: a patient with hemophilia A, another with prothrombin deficiency and finally a patient with von Willebrand disease type I. All patients were heterosexual. In all instances the course was benign since it required administration of substitution therapy on only 2 occasions. Rest and abstinence from sexual activity appeared to be helpful. The first patient had other signs and symptoms compatible with the diagnosis of urethritis due to Escherichia coli and he underwent a course of antibiotic therapy. The other 2 cases appeared to be idiopathic since no associated condition was found. Urinary cytology, rectal examination, prostate sonography and prostate-specific antigen were normal in all cases. The rarity of hemospermia in congenital bleeding disorders remains unexplained, although the strong perineal and sphincter muscles may exercise a compressive hemostatic effect which could prevent or reduce bleeding.

Simultaneous photoproduction of eta and pi0 mesons on the proton.

The analysis of the gammap-->etapi(0)p reaction has been performed using data from the GRAAL experiment. The total and differential cross sections and the beam asymmetry have been obtained from threshold up to 1.5 GeV of beam energy. The two resonances S11(1535) and Delta(1700) are expected to be excited in the intermediate states of this reaction. The results are used to test predictions based on the assumption that both resonances are dynamically generated from the meson-baryon interaction provided by chiral Lagrangians. The term involving the Delta(1700) excitation, followed by the decay into etaDelta(1232), is found to be dominant.

Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature.

Myocardial infarction and other arterial occlusions are considered to be rare in hemophilia A. However, a systematic study of the subject has never been attempted. All case reports of myocardial infarction or other arterial occlusions have been now gathered and properly evaluated from a cardiological point of view. Thirty-six patients with myocardial infarction and 6 patients with documented cerebrovascular event were retrieved from the literature. The age of the patients varied between 7 and 79 years, with a mean of 44 years. In 16 cases, the arterial occlusion occurred in men <40 years of age. The majority of myocardial infarctions (MIs) were anterolateral (12 cases). Posterior-inferior MI was present in 6 cases whereas it was of the non-Q type in 4 patients. It was multiple in 6 cases, and in the remaining patients the type of infarction could not be determined. In 26 cases, the thrombotic event (22 myocardial infarctions and 4 ischemic cerebrovascular accidents) occurred during or after the infusion of factor VIII concentrates and, more frequently, after prothrombin complex concentrates (activated or non-activated ones) or recombinant factor VIIa preparations. In 3 cases, the vascular complication occurred after intravenous desmopressin administration. MI was fatal in 7 instances. After the event, signs and symptoms of heart failure were seen as sequels in 7 patients. One patient had to undergo cardiac transplant 5 months after the MI. No death occurred after ischemic cerebrovascular accidents. Since not all hemophilia patients develop inhibitors and therefore are not usually treated with activated concentrates, this series of patients is somewhat biased and does not allow general conclusions. The high prevalence of MI and other arterial complications which occurred after transfusion therapy, usually in patients with inhibitors, clearly indicates the need for a careful evaluation of the appropriate therapeutic approach in each single patient.

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review.

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.

Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemaophilia B: a critical evaluation of reported cases.

Myocardial infarction and other arterial thrombosis are commonly maintained to be rare in hemophilia patients. This, in general, seems true but the occurrence of a thrombotic event in hemophilia B is not exceptional. A thorough search of the literature has yielded 13 patients with myocardial infarction and 1 patient with a cerebrovascular accident. There were three fatalities. In five cases MI occurred after infusion of Prothrombin Complex Concentrates. In three additional patients the event occurred after infusion of plasma, Feiba or cryoprecipitate supernatant. Four patients had an antero-lateral infarction. Two had a non-Q infarction and one each showed a multiple or a posterior-inferior form. Several therapeutic coronary procedures (GABG and PTCA) were carried out in hemophilia B patients without undue complication providing adequate level of FIX were maintained. Heparin prophilaxis was used in all patients but one. The analysis of the literature indicates that (1) MI may occur in hemophilia B patients and (2) that invasive coronary artery therapeutic procedures may be carried out without complications.

Comparable levels of activity and antigen in factor XII deficiency: a study of 21 homozygotes and 58 heterozygotes.

Results of coagulation studies on 21 homozygote patients with factor XII (FXII) deficiency revealed that all of them had no cross-reacting material (CRM) in their plasma. The 58 heterozygotes had in every instance an antigen level comparable to that of clotting activity namely, approximately 50% of normal. An analysis of all pertinent literature also showed that the presence of CRM is very rare in FXII deficiency. CRM is present in approximately 5% of homozygote patients. More precisely, seven of 145 patients. Only in one case, the antigen level was normal (FXII Washington). This prevalence appears lower than that observed for another contact phase factor (prekallikrein). The significance of blood abnormal forms of FXII has not been completely clarified yet. Their study appears useful in the attempt of clarifying the structure-function relation of factor XII.