Giulia Berti de Marinis

Rare and unusual bleeding manifestations in congenital bleeding disorders: an annotated review.

Epistaxis, superficial and deep hematomas, hemarthrosis, gastrointestinal bleeding, hematuria represent the most frequent hemorrhagic events in congenital coagulation disorders. Occasionally, bleeding manifestations occur in unusual sites or are peculiar. A clotting defect may alter the clinical aspect of skin conditions or infections (hemorrhagic scabies or varicella). Hemobilia may occur as a complication of transjugular liver biopsy in hemophilia or Bernard-Soulier syndrome. Hemarthrosis of small joints of feet and hands occur in patients with hemophilia treated with protease inhibitors. Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies. Spleen fracture with consequent hemoperitoneum has been reported in patients with fibrinogen deficiency. Rectus muscle sheath hematoma may occur in patients with factor VII (FVII)or FX deficiency. Acute or subacute intestinal obstruction may be caused by intramural wall hematomas in hemophilia and von Willebrand (vW)-disease. Physicians should always keep in mind that a congenital hemorrhagic disorder may cause bleeding in any tissue of the body and therefore alter the normal clinical features of a given disease.

Recombinant FVIIa concentrate-associated thrombotic events in congenital bleeding disorders other than hemophilias

Abstract Recombinant FVIIa concentrate has been originally used in the treatment of hemophilia patients with inhibitors. Recently, its use has been expanded to a variety of off-label indications. Thrombosis is the most important side effect. This may occur especially in off-label use but also in hemophiliacs with inhibitors. The present study investigated the occurrence of thrombosis in congenital bleeding disorders other than hemophilias as gathered from personal files and from the literature. Fifteen patients (seven FVII deficiency, one fibrinogen defect, four FXI deficiency, one von Willebrand disease, and two Glanzmanns Thrombasthenia) have been evaluated. Thrombosis was arterial in eight instances, venous in six, whereas in one case the type of thrombosis was unspecified. In eight cases, associated risk factors were present. Two patients with FXI deficiency had inhibitors. Dosage was variable. There was at least one fatality but in five cases evolution was not reported. The remaining patients recovered with variable sequels.

Presence of anti-ADAMTS13 antibodies in obesity

Eur J Clin Invest 2012; 42 (11): 1197–1204

Discrepant ratios of arterial vs. venous thrombosis in hemophilias A and B as compared to FVII deficiency.

The occurrence of a thrombotic event in congenital bleeding disorders has drawn considerable attention in recent years. Both patients with hemophilia and patients with von Willebrand disease and even those with rare coagulation disorders have been shown to present occasional thrombotic events. Little is known on the comparative prevalence of arterial vs. venous thrombosis in these patients.

Worldwide diffusion of FVII Arg304Gln coagulation defect (FVII Padua)

FVII Padua is a Type 2 defect owing to an Arg304Gln substitution in exon 8. The defect was originally discovered in an isolated valley in northeastern Italy. Subsequently, it was described in several other countries of the Mediterranean basin and Middle East. Recently, several proven or suspected cases have been described among Afro‐Americans in the USA. This study has demonstrated the existence of at least a two‐founder effect for this FVII abnormality, Mediterranean countries, and USA Afro‐Americans. Patients are usually asymptomatic or only paucisymptomatic. The defect is characterized by low FVII activity when rabbit brain thromboplastins are used in the assay system. On the contrary, FVII levels are normal when ox‐brain thromboplastins are used. FVII antigen is always normal.

Discrepant ratios of arterial versus venous thrombosis in hemophilia A as compared with hemophilia B

The occurrence of thrombosis in patients with congenital bleeding disorders represents an exceptional event. Hemophilia A and hemophilia B patients have been showed to present both arterial and venous thrombosis (85 cases of arterial thrombosis and 34 cases of venous thrombosis). The great majority of arterial thrombosis are myocardial infarction or other acute coronary syndromes, whereas the majority of venous thrombosis are deep vein thrombosis and/or pulmonary embolisms. However there are discrepancies in the proportion of arterial and venous thrombosis seen in hemophilia A versus hemophilia B. The ratio of arterial versus venous thrombosis in hemophilia A is 3.72 whereas that for hemophilia B is 1.12. This indicates that arterial thrombosis is more frequent in hemophilia A as compared to hemophilia B and the opposite is true for venous thrombosis. The potential significance of this discrepancy is discussed.

Arterial and Venous Thromboses in Patients With Idiopathic (Immunological) Thrombocytopenia A Possible Contributing Role of Cortisone-Induced Hypercoagulable State

Immunological thrombocytopenias, as other forms of thrombocytopenia, are associated with bleeding. Occasionally, these patients manifest thrombotic events. A total of at least 29 patients were reported to have had either arterial (20 cases) or venous (9 cases) thrombosis while platelet count was less than 50 × 103/μL. The most frequent clinical manifestation was a myocardial infarction. Thrombosis occurred in the large majority of patients during prednisone therapy. Patients receiving cortisone or patients with Cushing syndrome show a hypercoagulable state characterized by elevated factor VIII levels, decreased fibrinolysis, and abnormal von Willebrand factor multimers composition. The same is probably true for prednisone-treated patients with thrombocytopenia. However, the 2 conditions are not identical since prednisone is a mainly glycoactive compound, whereas cortisol produced in excess in Cushing syndrome is mainly mineraloactive. The presence of large, young, hyperactive platelets may also play a role. Prednisone-treated patients with thrombocytopenia have to be considered as potentially thrombophilic.

Myocardial infarction in two cousins heterozygous for ASN41HIS autosomal dominant variant of Bernard–Soulier syndrome

Bernard–Soulier Syndrome is characterized by thrombocytopenia with large platelets and defective aggregation to ristocetin. The bleeding tendency is variable but may be severe. The syndrome is due to genetic defects of the GPIb-V-IX complex and it has been maintained to be protective from thrombotic events. Here we present the first two cases of documented M.I. in two cousins, heterozygous for the Arg41His mutation which is responsible for a dominant form of Bernard–Soulier Syndrome. In one of the two patients an aneurysm of the aorta was also present. The patients had a mild bleeding tendency which was severely aggravated by treatment with antiplatelet drugs. These clinical observations are in contrast with experimental studies which demonstrate that Bernard–Soulier-like strains of mice show a decreased thrombus generation in several experimental settings.

Defective ADAMTS13 synthesis as a possible consequence of NASH in an obese patient with recurrent thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare and devastating hematologic disorder frequently associated with multiple organ failure and sometimes death. This syndrome is mainly associated with severe deficiency of ADAMTS13, a disintegrin and metalloprotease with thrombospondin (TSP)‐1 repeats, cleaving high molecular weight von Willebrand Factor (ULVWF) multimers. Decreased plasma ADAMTS13 activity results in the accumulation of ULVWF multimers with consequent platelet activation. Recently, obesity has been considered as a potential independent risk factor for TTP, but the reason of this association is still unknown.

Weight loss reduces anti-ADAMTS13 autoantibodies and improves inflammatory and coagulative parameters in obese patients.

Obese patients have been described at increased risk of thrombotic thrombocytopenic purpura, a disease caused by anti-ADAMTS13 autoantibodies. ADAMTS13 has a structure homology with the adipokine thrombospondin-1. We previously demonstrated an increased presence of anti-ADAMTS13 antibodies in obese patients. We aimed to study the changes induced by weight loss after bariatric surgery on some inflammatory and coagulative parameters and their link with anti-ADAMTS13 autoantibodies. We studied 100 obese patients before and after weight loss induced by bariatric surgery and 79 lean volunteers as controls. We measured anthropometric, metabolic and inflammatory parameters, thrombospondin-1, ADAMTS13 activity, anti-ADAMTS13 autoantibodies, Von Willebrand factor. At baseline, 13 % of patients was positive for anti-ADAMTS13 autoantibodies, while all controls were negative. Thrombospondin-1 levels were higher in obese subjects with than without antibodies, with a positive correlation between the two parameters. In multiple logistic regression analysis only thrombospondin-1 levels predicted positivity for anti-ADAMTS13 antibodies. After weight loss both anti-ADAMTS13 antibodies and thrombospondin-1 reduced significantly. Weight loss in obesity improves the inflammatory and coagulative profile, and in particular anti-ADAMTS13 autoantibodies, ADAMTS13 activity and thrombospondin-1.