Same Syndrome, Different Causes and Treatment: Path to Diagnosis and Management of Two Interesting Cases of Acquired von Willebrand Syndrome

von Willebrand disease (VWD) is considered the most common inherited bleeding disorder with a population prevalence of 0.6 to 1.3%.[1] [2] [3] Affected patients have a personal and family history of mucocutaneous hemorrhage and abnormal bleeding after surgery or trauma. These clinical features, in combination with evidence of quantitative and/or qualitative defects of von Willebrand factor (VWF), are considered diagnostic for the disease. VWF is a multimeric glycoprotein synthesized by endothelial cells and megakaryocytes that promotes platelet adhesion and aggregation and acts as a carrier for factor VIII protecting it from rapid degradation.[4] Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with clinical and laboratory features similar to congenital VWD but without personal and family history of bleeding. Moreover, unlike acquired hemophilia, which is attributable to neutralizing autoantibodies against coagulation factors, several different mechanisms linked to underlying diseases are involved in AVWS.[3] If VWF is normally synthesized, one of four pathogenetic mechanisms might be involved: (1) specific autoantibodies that inactive VWF; (2) nonspecific antibodies that form circulating immune complexes with VWF, with these then rapidly cleared by Fc-R bearing cells; (3) absorption of VWF into surface of neoplastic cells via an aberrant or a constitutive expression of glycoprotein Ib (GpIb)/IX; (4) increased proteolytic degradation of high molecular weight VWF multimers under conditions of shear stress or by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) enzyme. Often, more than one pathogenetic mechanism coexists.[5]

AVWS may occur secondarily to lymphomyeloproliferative disorders, solid tumors, congenital or acquired cardiac defects, immunologic disorders, angiodysplasia, infectious diseases, and drug therapy such as ciprofloxacin or valproic acid.[3] [5] Among AVWS associated with lymphoproliferative neoplasms, monoclonal gammopathy of undetermined significance (MGUS) represents the largest group.[6] [7]

Whenever possible, therapy of AVWS should address the underlying disorder. Suggested additional treatments are antifibrinolytics, desmopressin, VWF-containing concentrates, intravenous immunoglobulins (IVIG), plasmapheresis.[8] Desmopressin or VWF containing concentrates typically result in short-lived improvements of VWF. IVIG is particularly indicated in autoimmune and lymphoproliferative disorders. Plasmapheresis can be used in AVWS patients with IgM paraproteins to deplete autoantibodies and paraproteins of any immunoglobulin class, as IVIG is not effective in AVWS patients with MGUS of the IgM class.[9] [10] [11] [12]

We report two interesting cases of AVWS diagnosed by clinical symptoms and laboratory tests that required two different therapeutic approaches.

Case 1. A 74-year-old man with a massive throat hematoma that occurred after a thyroid biopsy for a multinodular euthyroid goiter, in absence of previous bleeding episodes. He was previously treated with brachytherapy for prostate cancer. The blood count revealed a leukocyte count of 8.04 × 10⁹/L (reference values [RV]: 4.00–10.00), a hemoglobin of 92 g/L (RV: 110–138), and a platelet count of 196 × 10⁹/L (RV: 140–400). First-line coagulation screening showed a prolongation of prothrombin time ratio of 1.30 (RV: 0.80–1.20), international normalized ratio (INR) of 1.31 (RV: 0.80–1.20), activated partial thromboplastin time (aPTT) ratio of 1.45 (RV: 0.80–1.20), and a fibrinogen level of 9.9 g/L (RV: 1.5–4.0). One-stage clotting factor activities of FII, FV, FVII, FVIII, FIX, FX, FXI, FXII were assayed with Sysmex CS-5100 (Siemens Healthcare Diagnostic, Erlangen, Germany) and Siemens reagents; all measured factors were normal except a low FVIII activity of 25.6% (RV: 60–152%) associated with decreased VWF antigen (VWF:Ag) and platelet GPIb binding activity using mutated recombinant GPIb (VWF:GPIbM; Siemens Innovance assay), respectively, of 18% (RV: 63–166) and 7% (RV: 51–175). VWF:Ag and VWF:GPIbM were performed with Sysmex CS-5100 using immunoturbidimetric assays. The blood smear evaluation showed red blood cells rouleaux and a few plasma cells ([Fig. 1A]) suggestive of an immunoproliferative disorder. A serum protein electrophoresis ([Table 1]) revealed a protein spike in gamma region of 4.4 g/L. The free light chains assay showed K/L ratio of 1.76 (RV: 0.31–1.56) and immunofixation confirmed the presence of a monoclonal IgG-k ([Fig. 1B]). In the case reported, coagulation tests together with the evaluation of the peripheral blood smear allowed us to hypothesize the underlying trigger condition and adopt a prompt therapy. A total of 1 g/kg IVIG dose per day was administered for 2 days. Ten days after, VWF:GPIbM, VWF:Ag, and FVIII normalized to value of 224, 183, and 204.8%, respectively. As otherwise also reported in literature,[11] [12] subsequent follow-up showed VWF:GPIbM, VWF Ag, and FVIII values progressively decreasing from day 30, being 19, 24, and 40.5%, respectively, at day 40 and 8, 12, and 16.8% at day 76. The patient is currently being followed for the immunolymphoproliferative disease.

Fig. 1 Case 1 (A) Blood smear shows red blood cells rouleaux and a few plasma cells; (B) Serum protein electrophoresis. Case 2 (C) Blood smear shows red blood cells rouleaux; (D) Serum protein electrophoresis.

Table 1 Summary table of parameters of serum electrophoresis and result of immunofixation

	Case 1	Case 2	RV	MU
Total serum proteins	64	100	60–80	g/L
Albumin	46.4	26.8	55.8–66.1	%
Alpha-1-globulins	7.9	3.1	2.9–4.9	%
Alpha-2-globulins	15.5	5.5	7.1–11.8	%
Beta-1-globulins	5.6	2.3	4.7–7.2	%
Beta-2-globulins	6.3	56.1	3.2–6.5	%
Gamma-globulins	18.3	6.2	1.10-2.4	%
MP	IgG kappa	IgM kappa	–	–

Abbreviations: MP, monoclonal protein; MU, measurement units; RV, reference values.

Case 2. An 83-year-old man with episodes of epistaxis occurring within 1 month, in absence of previous bleeding events. In this case, suspicion of an interfering agent arose from an instrumental prozone alarm in the bilirubin dosage, which resulted elevated without signs of jaundice.

The blood count revealed a leukocyte count of 4.93 × 10⁹/L (RV: 4.00–10.00), a hemoglobin of 73 g/L (RV: 110–138), and a platelet count of 239 × 10⁹/L (RV: 140–400). The blood smear evaluation showed red blood cells rouleaux ([Fig. 1C]). A serum protein electrophoresis revealed a protein spike in beta1 region of 50.0 g/L and the immunofixation confirmed the presence of a monoclonal IgM-k ([Table 1] and [Fig. 1D]).

First-line coagulation screening showed an INR of 1.13 (RV: 0.80–1.20), a prolonged aPTT ratio of 1.44 (RV: 0.80–1.20), and a fibrinogen level of 2.5 g/L (RV: 1.5–4.0). One-stage clotting factor FVIII, FIX, FXI, FXII activities assayed with Sysmex CS-5100 were normal except for a low FVIII activity of 17.5% (RV: 60–152) associated with decreased VWF:Ag and VWF:GPIbM, respectively, of 13% (RV: 63–166) and 17% (RV: 51–175). A diagnosis of AVWS was made due to the presence of an IgM paraprotein. The patient was then referred to the hematologist and Waldenstrom macroglobulinemia was diagnosed.

Since the hemoglobin value was controlled with transfusions, plasmapheresis was not performed and chemotherapy for Waldenstrom was started at day 15.

At day 90 after chemotherapy, VWF:Ag and VWF:GPIbM were, respectively, of 122 and 149%.

To summarize, AVWS is often underdiagnosed and sometimes misdiagnosed.[3] The simultaneous presence of bleeding symptoms not previously reported, and the reduction of VWF and FVIII should raise suspicion of an AVWS. Researching the underlying pathology allows initiation of correct therapy with a consequent rapid resolution of the symptoms. However, long-term resolution of AVWS requires resolve of the primary disorder.

Publication History

Article published online:
28 August 2023

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