Fabiana Tezza

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

Summary.  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.

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.

Arterial thrombosis in young women after ovarian stimulation: case report and review of the literature

Both venous and arterial thrombosis have been described in women after ovarian stimulation and/or hyperstimulation for infertility management. The ratio between venous and arterial thrombosis in this condition is about 2 or 3 to 1, contrary to what seen during pregnancy or oral contraception where it is 5 or 10 to 1. An accurate perusal of the literature and of personal files has yielded 34 cases of arterial thrombosis after assisted reproductive technologies (ART) which entailed ovarian stimulation. There were 15 cases of ischemic strokes; 7 cases of carotid and/or vertebral artery occlusion; 6 of aorta and peripheral vessel thrombosis, 2 of mesenteric artery occlusion, 3 with myocardial infarction and 2 with intracardiac thrombosis. Associated risk factors were as follow: smoking in 4 women; antiphospholipid antibodies in 2; decrease in protein S in 1. Furthermore, polycystic ovaries were present in two women. Ovarian hyperstimulation was obtained with several protocols which included human chorionic gonadotropin (HCG) in all but a few instances. Age of women varied between 22 and 41 with an average of 32. Nineteen women were pregnant at the time of thrombosis. Only seven of these 19 pregnancies were brought to term with fetal survival. Abortion was spontaneous in 5 cases and therapeutic in the additional 7. There were two maternal fatalities.

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.

Toxicity and side effects of hydroxyurea used for primary thrombocythemia

Over the last 20 years a vast array of data has been accumulated on the efficacy of hydroxyurea (HU) in patients with Philadelphia-negative myeloproliferative disorders (MPD). However, several side effects have been described as well. Besides many anecdotal reports, no evaluation of their prevalence and type exists in large series of treated patients. We report here the side effects of HU in a retrospective, single institution, cohort study of 152 patients suffering from MPD with thrombocytosis (median follow-up 8.13 years). In 6.5% of patients drug failure was registered. Unwanted side-effects (five symptomatic macrocytic anemia, two fever reactions, two allergic reactions, four cases each of leg painful ulcers, three acute leukemia or myelodysplasia) induced to withdraw therapy in 16 patients. Three cases of nail pigmentation were observed. In our experience, HU showed to be an effective and safe drug in most patients with MPD. Prompt recognition of side effects, which have been mostly minor and rapidly subsiding on drug withdrawal, is in any case crucial to avoid more severe complications.

Heparin-Induced Thrombocytopenia in Patients with Philadelphia-Negative Myeloproliferative Disorders and Unusual Splanchnic or Cerebral Vein Thrombosis

Background: Philadelphia-negative myeloproliferative disorders (Ph-MPD) are common causes of unusual splanchnic or cerebral vein thrombosis, which is treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Heparin-induced thrombocytopenia (HIT) is a dangerous potential complication of this therapy, but it has rarely been reported in Ph-MPD. Patients and Methods: We retrospectively reviewed clinical records of 29 patients with Ph-MPD who have been treated with UFH or LMWH for unusual splanchnic or cerebral vein thrombosis (3 cerebral sinus, 6 portal and 20 hepatic vein). The goal of the study was to determine the occurrence of new thrombotic events during heparin therapy secondary to HIT (HITT). Results: During heparin therapy, 5 out of the 29 patients (17%) developed a new thrombotic episode (pulmonary embolism) with a high clinical probability of HIT based on the 4 T’s score even though not all the patients developed ‘true’ thrombocytopenia. A diagnosis of HIT was established in 2 patients (6.8%) through the presence of heparin-related antibodies. Conclusions: Ph-MPD patients on heparin warrant careful monitoring and HIT has to be suspected whenever platelet counts drop or a new thrombosis is detectable.

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

Summary.  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.

Leg ulcers in elderly on hydroxyurea: a single center experience in Ph− myeloproliferative disorders and review of literature

Hydroxyurea (HU) is effective in controlling thrombocytosis while reducing the risk of thrombosis in essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). However, HU may carry more or less severe side-effects. Rare cases of patients with painful leg ulcers have been published. We report our experience on such a side-effect in a large cohort of patients with ET and PV treated with HU and review the literature on the topic. Five (4%) out of our 124 patients (69 ET, 51 PV, 4 MF; 49 males, 75 females; mean age at diagnosis 59.1±11.8 years) treated with HU developed painful leg ulcers. Sixty-one other patients affected with Ph− myeloproliferative disorders (Ph− MPD) developing HU-related painful leg ulcers are described in the English literature. All our five patients were women and developed leg ulcers over the age of 75. Sixty-five percent of all described cases are women; 59% were over 65 years of age and 45% over 70. Most cases received over 1 gr HU per day for at least 1 year. The pathogenesis of HU-induced skin ulcers remains elusive. Treatment is difficult and requires prompt cessation of HU therapy.

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.

JAK2V617F mutation is common in old patients with polycythemia vera and essential thrombocythemia

Background: JAK2V617F mutation occurs in 90% of polycythemia vera (PV) and in 50% of essential thrombocythemia (ET) patients. Materials and methods: 253 consecutive patients affected by myeloproliferative disorders (MPD, 121 PV, 132 ET) were evaluated and stratified in 4 age groups: 18–39, 40–59, 60–75 and over 75 years (>75). The JAK2V617F mutation was searched and its allele burden was evaluated. Results: The percentage of mutated patients increased progressively with age mainly in patients >75 (p=0.0015 vs 18–39, p=0.0021 vs 40–59 and p=0.012 vs 60–75). We also found a progressive increase in allele burden with age (R2=0.042). Thrombotic events were more common in patients carrying the mutation in comparison with wild type (WT) (p=0.006, coefficient risk 1.94). No differences in the percentage of patients carrying the JAK2V617F mutation were found, in spite of different follow-up durations (<5 yrs, 5–10 yrs, 10–15 yrs, >15 yrs). The JAK2V617F allele burden was similar in patients with (57±31%) and without (45±26%) long-term hydroxyurea treatment. Conclusions: JAK2V617F mutation is more common in old than in young patients with MPD. Older patients have an higher allele burden.