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.

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.

Control of ovulation-induced hemoperitoneum by oral contraceptives in a patient with congenital hypoprothrombinemia and in another with congenital factor V deficiency.

Hemoperitoneum is a serious and often life-threatening bleeding manifestation. This is particularly true for women who carry congenital bleeding disorders. We describe here a hemoperitoneum occurring in 1 patient with congenital prothrombin deficiency and another with congenital factor V deficiency. Both patients have been followed by us for many years. The patient with prothrombin deficiency underwent laparoscopy but was treated consecutively with whole blood, plasma transfusions and 1,000 units of prothrombin complex concentrates. Response was good and she was then placed on oral contraceptives (OC) which prevented any recurrence. The patient with factor V deficiency presented several episodes of ovulation-related bleeding which required hospitalization and fresh frozen plasma transfusions. On the fifth occasion, the patient had to undergo surgery, and a left oophorectomy was carried out. After this last episode, she was also placed on OC which were very effective in preventing further recurrences. Both patients tolerated the medications very well which, in addition, were able to control menometrorrhagia with a consequent decrease over time in transfusional needs. OC are the treatment of choice in congenital bleeding disorders to control both the menorrhagia and, more importantly, ovulation-related hemoperitoneum.

Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature.

The presence of more than one congenital clotting defect in a given patient is a rare event but not an exceptional one. Combined defects of factor X (FX) are very rare because congenital isolated FX deficiency is by itself very rare. A perusal of personal files and of the literature has yielded 12 families with FX deficiency in which an association with another clotting factor deficiency was found. The associated defects were factor VII (FVII) or factor VIII (FVIII) or factor XII (FXII) deficiency. By far the most frequently associated was with FVII. Two forms of this association were found. In the first form there is casual association of both FVII and FX deficiency in the proband with independent recessive segregation of the two defects in other family members. The second form is because of abnormalities in chromosome 13 (deletions, translocations and so on) involving both FX and FVII genes. These genes are known to be very close and located on the long arm of chromosome 13 at about 13q34. In this form the hereditary pattern is autosomal dominant. Isolated FX deficiency and, more frequently, combined FX + FVII deficiency appear also associated with coagulation-unrelated abnormalities (carotid body tumours, mitral valve prolapse, atrial septal defect, ventricular septal defect, thrombocytopenia absent radius (TAR) syndrome, mental retardation, microcephaly and cleft palate). Diagnosis of a combined clotting defect could be difficult on the basis of global tests. For example, both isolated FX deficiency and combined FX + FVII deficiency yield a prolongation of basal PTT and PT. Only specific assays could allow one to reach the correct diagnosis. In cases of casual association with other defects, it is also important to study family members, as the two defects should segregate independently.

Congenital combined defects of factor VII: a critical review.

Factor VII deficiency is the least rare among uncommon congenital coagulation disorders. The majority of cases are isolated deficiencies. In some cases, FVII deficiency has been found to be associated with the deficiency in another coagulation factor or with non-coagulation-related abnormalities or defects. The evaluation of all published studies on the subject has shown that the FVII defect has been reported in association with FV, FVIII, FIX, FX, FXI and protein C defects. Furthermore, FVII deficiency has been described in association with bilirubin metabolism disorders, mental retardation, microcephaly, epicanthus, cleft palate and persistence of ductus arteriosus. The most interesting association appears to be that with FX. This has been shown to be due to a deletion in part of the long arm of chromosome 13. This arm contains genes coding for both FVII and FX. Interestingly, this combined coagulation defect has been found to be associated with carotid body tumors and several other malformations. Combined defects in blood coagulation often create diagnostic difficulties since results cannot be explained if a single factor deficiency is assumed. For example the combined FVII and FX defect yields a rather peculiar laboratory picture (prolonged prothrombin time and partial thromboplastin time, but normal thrombin time) that could suggest FII or FV or FX single deficiency and not FVII deficiency, indicating the need for specific factor assays whenever data are confusing. Finally, the elevated incidence of mental and skeletal malformations present in these combined defects indicates the need for a careful evaluation of all these patients lest some aspects of the defect are missed.

Arterial and venous thrombosis in patients with von Willebrand's disease: a critical review of the literature.

All patients with von Willebrand's disease (vWD) who showed an arterial or venous thrombosis and were reported in the literature have been evaluated. 11 patients had arterial thrombosis while 19 had venous thrombosis for a total of 30 cases. 9 out the 11 cases with arterial thrombosis had myocardial infarction. Two had cerebral thrombosis. Associated risk factors for arterial thrombosis were available only for three patients who showed, respectively, smoking and dyslipidemia (2 cases) and smoking and intravenous desmopressin infusion (1 case). The majority of patients with venous thrombosis showed DVT with or without PE. Four patients presented with apparently isolated PE. In two instances thrombosis occurred in unusual sites (central retinal vein and portal vein, respectively). Several associated risk factors were present, mainly: infusion of FVIII or FVIII + vWF concentrates in 7 cases; surgery in 8 cases, pregnancy in 1, desmopressin infusion in 1, variable coagulation defects or polymorphisms in 5. More than one of these associated conditions were present in a few patients. The majority of vWD patients who showed thrombotic phenomena were type I patient, but in 6 cases were also type 3. The type of defect was not reported in 6 patients. As a conclusion of this review it seems safe to assume that both arterial and venous thrombosis appear rare in vWD. This is confirmed by the fact that arterial or venous thrombosis appears slightly more frequent in hemophilia A and B.

Myocardial infarction and arterial thrombosis in severe (homozygous) FXII deficiency: no apparent causative relation.

Twenty-one patients (12 female and 9 male) with severe (homozygous) factor XII (FXII) deficiency and 58 (32 female and 26 male) with heterozygous FXII deficiency were observed for an average 16.2 years. No patient with homozygous FXII deficiency experienced myocardial infarction or any other arterial thrombosis. The same was true for heterozygotes. The cases of FXII deficiency and arterial thrombosis reported in the literature were evaluated. In every instance, associated risk factors were present that could justify the arterial thrombosis. Dyslipidemia, hypertension, smoking, and diabetes mellitus were the most frequent findings. The examination of the few papers that dealt with the prevalence of arterial thrombosis in patients with severe FXII deficiency showed that only 1 patient of 61 experienced myocardial infarction. In conclusion, it seems that the role of FXII deficiency in the pathogenesis of arterial thrombosis is minor.

Thrombosis-free surgical procedures in severe (Homozygote) factor XII deficiency: report of four additional cases and literature review.

The outcome of various surgical procedures carried out in patients with severe (homozygote) factor XII deficiency were investigated for the appearance of blood coagulation-related complications with particular emphasis on thrombotic complications. The surgical procedures were total mastectomy, tonsillectomy and adenoidectomy, placement of a hip prosthesis, and double hernia repair. None of the patients slowed any complication. Several other reported cases of surgical procedures carried out in several patients ware found in the literature. Bleeding or thrombotic complications were noted in none of these cases. The surgical procedures in some cases were minor such as adenoidectomy, tonsillectomy, or nasal polyp removal. However several major surgical procedures were carried out in some patients (cholecystectomy, gastrectomy, repair of atrial septal defect, coronary bypass). All patients remained asymptomatic. In some cases whole blood and/or plasma were used as requested by the caring surgeons. In a few patients, the plasma was given prophylactically because of the long partial thromboplastin time. Finally, three patients (two for cardiac surgery and one after hip replacement) received heparin prophylaxis as foreseen by accepted procedures without the undue sequels. These data supply further evidence that factor XII deficiency does not only show any bleeding tendency but also can withstand even major surgical procedures without thrombotic complications.

The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature.

According to our personal experience and to the study of the literature, 11 cases of venous thrombosis have been described as sporadic reports in patients with severe (homozygous) factor XII (FXII) deficiencies. In every cases but 4, associated risk factors were found to be present (pregnancy, post-partum period, surgery, trauma, in dwelling catheter, AT deficiency, heterozygous factor V Leiden, Burger's disease). In some instances more then one condition was present. The four patients for whom no information is supplied, were cases gathered from old and logically incomplete files and therefore the existence of associated risk factors cannot be excluded. The papers which investigated the presence of venous thrombosis in cohorts of patients with homoxygous FXII deficiency demonstrated the occurrence of venous thrombosis in 2 additional cases out of a total of 63 patients investigated. In these latter cases thrombosis occurred during pregnancy. This brings the total number of patients with FXII deficiency who showed a venous thrombosis to 13. Only a few of these patients were investigated for the presence of concomitant congenital prothrombotic conditions. The conclusion of the study seem to suggest that the role played by FXII deficiency in the pathogenesis of venous thrombosis is minor, if any.

Effect of age on oral contraceptive-induced venous thrombosis.

This study was undertaken to investigate the effect of age on oral contraceptive-induced venous thrombosis. All women seen in the University of Padua Department of Medical and Surgical Science who had had two courses of oral contraceptive therapy at different ages were included. A total of 28 subjects met these criteria. Fifteen patients had a congenital or acquired prothrombotic condition, whereas 13 women were normal subjects. The mean age at which thrombosis occurred was 33.3 and 36.3 years for women with or without a prothrombotic condition, respectively. The ages during which the women remained asymptomatic were 23.1 and 23.3 years for women with or without a predisposing defect, respectively. Thrombosis occurred, during the second course of oral contraceptive therapy, after the mean duration of 6.5 cycles or 18.4 cycles in women with or without prothrombotic defects, respectively. During the asymptomatic course, approximately the same number of women took old progestins or third-generation compounds. On the contrary, during the second period, 21 of 28 women took progestins with third-generation compounds. Age seems to plays an important role in oral contraceptive-induced venous thrombosis. In normal women, thrombosis occurred after a greater number of oral contraceptive cycles as compared with the women with prothrombotic defects. Because the majority of women took preparations that contained third-generation progestins during the second course of therapy, concomitant contributing effects of these compounds cannot be excluded.

Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial.

Patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. Apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3-36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, -5.5-10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis.

Atherosclerosis and secondary deep vein thrombosis: a difficult correlation.

The aim of this study was to verify the degree of atherosclerosis in a group of subjects affected by secondary deep vein thrombosis and in a matched control group. Sixty-three patients were studied. Of these, 19 were cases (mean age 62.2 +/- 1.2) and 16 were controls (mean age 59.3 +/- 2.7). Twenty-eight were excluded because they were affected by hyperhomocysteinemia. The arterial tree was examined by means of echo color Doppler, and the intima media thickness and the presence of and degree of plaques bilaterally in the carotid and femoral artery and abdominal aorta were measured with a computerized method. No difference was found in the 2 groups as concerns intima media thickness or plaques in the arterial district explored. Secondary deep vein thrombosis is not a greater risk factor for atherosclerosis.

Association of monoclonal gammopathy and polycythemia vera or essential thrombocythemia: study of a large cohort of patients.

Concomitant cases of monoclonal gammopathies with polycythemia vera (PV) and essential thrombocythemia (ET) have been described. We report our experience in a large cohort of patients with ET and PV and the occurrence of M protein in such a population. Retrospective evaluation of clinical and laboratory records of 164 patients with PV and 218 with ET was performed, and 500 subjects matched for sex and age were used as controls. The patients were divided into group A (younger than 55 years), group B (55-70 years), and group C (over 70 years), and the presence of M protein was sought at the time of diagnosis and later during follow-up. M protein was found in 14 patients with myeloproliferative disorders (MPDs), representing 3.6% of patients both with ET and PV, and in 10 subjects of the control group (2%). M protein was detected in 2.1% of MPD patients of group A, in 4.8% of group B, and in 5.7% of group C and in 1.6% of controls of group A, 2.7% of group B, and 2% of group C. No significant statistical difference was observed. The occurrence of M protein in PV and ET does not seem to differ from that observed in the control group. A more relevant increase in the incidence of M protein in MPDs than in the controls was observed by dividing patients and controls by age. However, no statistical significant difference was documented.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia.

BACKGROUND: As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. PATIENTS AND METHODS: We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT. RESULTS: No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03). CONCLUSIONS: Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.

Lack of multimer organization of von Willebrand factor in an acquired von Willebrand syndrome.

We report a case of acquired von Willebrand syndrome (AVWS) in a 20-year-old-woman with systemic lupus erythematosus, in whom severe bleeding complications followed kidney biopsy. Coagulation studies demonstrated undetectable levels of ristocetin-induced platelet aggregation (RIPA), von Willebrand factor antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), associated with significantly prolonged bleeding time; unlike type 3 von Willebrand disease (VWD), platelet VWF was reduced but not undetectable. The plasma VWF multimer pattern was characterized by the presence of only two bands, one of low molecular weight (MW) running as the protomer of plasma VWF in normals, the other of abnormally high MW without detectable intermediate multimers; this pattern resembles that of VWF present in endothelial cells. A search for an anti-VWF antibody demonstrated the presence of an inhibitor at high titre. This anti-VWF antibody did not interfere in the interaction of VWF with platelet glycoprotein (GP) Ib through the A1 domain, and did not react with the A2 domain of VWF; instead, it seemed to modify the relative representation of high and low MW VWF multimers released by normal human umbilical vein endothelial cells (HUVEC). After Azathioprine and corticosteroid treatment, the anti-VWF antibody disappeared and the patient's haemostatic profile normalized, except for the platelet VWF content which still remained decreased. We suggest that the anti-VWF antibody present in the AVWS described compromised both circulating VWF levels and their multimeric organization, inducing the maintenance of the multimer structure that VWF normally has before or in the early phase after secretion from endothelial cells.

Hepatosplenic gammadelta T-cell lymphoma presenting with immune-mediated thrombocytopenia and hemolytic anemia (Evans' syndrome).

We describe an unusual case of hepatosplenic T-cell lymphoma in a 61-year-old man who presented with fever, hepatosplenomegaly, anemia, and thrombocytopenia. A spleen biopsy was consistent with T-cell lymphoma. Cytogenetic studies did not reveal chromosome abnormalities. Using the polymerase chain reaction approach, clonality of the T-cell receptor gamma-chain gene rearrangement could be demonstrated, while Southern blot analysis disclosed only a germline configuration of the T-cell receptor beta chain genes. Of interest, an immune-mediated mechanism was demonstrated and was most likely responsible for erythrocyte and platelet destruction; this is, therefore, the first report of gamma T-cell lymphoma in association with Evans' syndrome. Initial steroid treatment was efficacious in limiting autoimmunity but constitutional symptoms did not subside. Chemotherapy (MACOP-B) was successful in obtaining complete clinical remission. Finally, thrombocytopenia in gammadelta T-cell lymphoma patients should be routinely evaluated for platelet autoantibodies.

Idiopathic deep vein thrombosis and subsequent cancer: suggestions for a patient-oriented and practical approach.

The relationship between an idiopathic deep vein thrombosis and a cancer is well established. It is not clear yet whether all patients with an idiopathic deep vein thrombosis should be thoroughly investigated for an occult cancer or only some. As a matter of fact, once a physician is faced with a patient who has an idiopathic deep vein thrombosis, three approaches are possible, mainly: 1) a wait and see approach; 2) a limited investigation: and 3) an extensive or invasive investigation. No sure criteria for the selection of the patients who should be extensively investigated are available. Suggestions have been made in this regard. Negative family or personal history for thrombosis, advanced age, deep vein thrombosis of upper limbs, existence of silent deep vein thrombosis in contralateral leg, tendency to relapse and/or to migrate, constitutional symptoms, or smoking may represent important clues that may justify an extensive study. This patient-oriented approach is mainly based on the experience of the caring physician.

Early transfusion of factor VIII/von Willebrand factor concentrates seems to be effective in the treatment of gastrointestinal bleeding in patients with von Willebrand type III disease.

The association between gastrointestinal angiodysplasia and von Willebrand disease was reported 30 years ago. The clinical course of patients with von Willebrand disease and angiodysplasia is characterized by numerous admissions to hospital for gastrointestinal bleeding necessitating transfusion with packed red cells, factor VIII and plasma. The management of these patients is problematic. Numerous treatments for the gastrointestinal bleeding have been proposed: surgery, electrocoagulation, laser photocoagulation, sclerotherapy, arteriography with embolization, immunoglobulins, oestrogens, and octreotide, but no treatment modality has been successful in all cases. We report a 66-year-old-female with small bowel angiodysplasia and von Willebrand type III disease in whom prompt administration of factor VIII/vWF concentrates was effective. Education of patients to recognize minimal gastrointestinal bleeding manifestations, periodical clinical visits and early infusion of factor VIII/vWF seems to be fundamental for the success of this therapy. A longer follow-up and the study of other patients are needed to confirm our observation.