Page 58 - 2020_08-Haematologica-web

M. Franchini and P.M. Mannucci
described in lymphoproliferative diseases (multiple myeloma, Waldenström’s macroglobulinemia, non- Hodgkin lymphoma, hairy cell leukemia) and solid can- cers.33 In MGUS, the aberrant expression on abnormal plasma cells of the glycoprotein Ib (the principal platelet receptor of vWF) was associated with its selective binding to these cells.34 vWF adsorption onto the cell membranes and subsequent plasma clearance has also been involved in AvWS associated with myeloproliferative neoplasms.35 For example, adsorption on platelets is the mechanism in essential thrombocythemia, with an inverse relationship between platelet count and the plasma defect of HMW multimers.35 In addition, essential thrombocythemia and other myeloproliferative neoplasms may cause the syn- drome through increased plasma vWF proteolysis.
Clinical features
The bleeding diathesis usually occurs rather late in life in persons with no past and family history of bleeding. The main symptoms are mild to moderately severe muco- cutaneous bleeding (ecchymosis, epistaxis, menorrhagia, gastrointestinal tract bleeding), similar to inherited vWD, or excessive bleeding following trauma or surgical proce- dures, particularly when FVIII:C is low. Gastrointestinal bleeding is usually associated with the detection of angiodysplasia. The mechanism of this vascular abnor- mality, which has also been described in inherited type 2 and type 3 vWD, involves the defect of HMW vWF mul- timers, that characterizes all AvWS cases10 with the only exception of those associated with hypothyroidism. According to the ISTH registry,16-18 patients with AvWS associated with lymphoproliferative disorders have more severe bleeding symptoms than those with other underly- ing conditions, even though bleeding-related deaths have seldom been reported. As mentioned above, lymphopro- liferative disorders account for a significant proportion of AvWS cases, ranging from 30% to 48%. A few studies have investigated the association of myeloproliferative neoplasms with AvWS.35-38 Mital et al., in two studies involving 312 consecutive patients with essential throm- bocythemia (n=170) or polycythemia vera (n=142), found prevalences of 20% and 12%, respectively, and they rec- ommend that persons with these disorders and a bleeding tendency should be screened for the presence of an under- lying AvWS.35,36 A high prevalence was also found by Rottenstreich et al.37 in 173 patients with thrombo- cythemia (n=116) or polycythemia (n=57),37 meaning that 55% of those with thrombocythemia and 49% of those with polycythemia had an AvWS. Younger age, higher platelet count and hemoglobin levels, as well as the pres- ence of the JAK2V617F somatic mutation, independently pre-
dicted the syndrome in patients with thrombocythemia but not in polycythemia, the only predictor being a higher platelet count.37 Furthermore, Mital et al.,38 in an investiga- tion of 21 patients with systemic mastocytosis, found a high rate of AvWS accompanied by mild to moderate symptoms of mucocutaneous bleeding (ecchymosis, men- orrhagia, epistaxis).
Diagnosis
In the absence of a family history of bleeding, the diag- nosis of AvWS is usually based on the laboratory tests used to diagnose inherited vWD.39,40 A defect in primary hemostasis is demonstrated by a prolonged skin bleeding time or prolonged closure time with PFA-100.40 Plasma samples usually show normal or mildly decreased vWF:Ag contrasting with a more marked decrease in vWF:RCo and vWF:CB.40 The latter qualitative platelet-related activity assays of vWF are frequently lower than the quantitative vWF:Ag assay, resulting in vWF:RCo/vWF:Ag ratios that are often below 0.7, similar to type 2A vWD.40 When FVIII:C is low, a prolonged APTT is also observed. vWF multimer electrophoresis is warranted to demonstrate the defect of HMW multimers that helps to distinguish AvWS from type 1 vWD.9,10 Measurement of the plasma vWF propeptide, which reflects the degree of vWF biosynthe- sis, is not currently recommended to distinguish inherited vWD from AvWS41,42 because the latter is often character- ized by an accelerated clearance of vWF from the circula- tion but normal synthesis, so that propeptide levels are normal. At variance with acquired hemophilia, autoanti- bodies that inhibit platelet-related vWF activity play a mechanistic role in a minority of AvWS cases.43,44 Nevertheless, because the presence of neutralizing anti- bodies seems to be associated with a more severe bleeding tendency, antibody screening should be performed in all AvWS cases. The most common method used to look for an inhibitory activity against vWF is based upon mixing studies (patient plasma mixed with normal plasma and incubated at 37°C), followed by the measurement of both residual vWF:RCo and vWF:CB.40-44 However, an inhibitor is seldom demonstrated and the antibodies that bind vWF and accelerate its plasma clearance without neutralizing vWF activity cannot be detected with this method. Enzyme-linked immunosorbent assays (ELISA) are an option that has, however, not yet been adequately stan- dardized.45 Overall, diagnosis of AvWS is difficult, and a correct workup should consider all information from both clinical and case history evaluation as well as laboratory results. In particular, the differential diagnosis with milder forms of inherited vWD is important given the difference in therapeutic approach (see below).
Table 1. Conditions associated with the acquired von Willebrand syndrome. Conditions
Cancers
Autoimmune diseases Drug-induced
Other
Hematologic: MGUS, multiple myeloma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, hairy cell leukemia, lymphomas, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia.
Solid: Wilm’s tumor, lung and bladder adenocarcinoma.
Systemic lupus erythematosus, autoimmune thyroid disorders, connective tissue diseases, GvHD. Antibiotics (griseofulvin, ciprofloxacin), anticonvulsants (valproic acid), plasma volume expander (HES).
Cardiovascular disorders (aortic stenosis, congenital cardiac defects, mitral valve prolapse, left ventricular assist
devices), infections (viral, parasitical), uremia, gastrointestinal angiodysplasia, diabetes.
MGUS: monoclonal gammopathy of unknown significance; GvHD: graft-versus-host disease; HES: hydroxyethyl starch.
2034
haematologica | 2020; 105(8)