Bleeding Diathesis Secondary to a Heparin-Like Anticoagulant in a Patient with Multiple Myeloma — A Case Report and Review of Literature

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Introduction
Multiple myeloma (MM) is a clonal plasma cell disorder that commonly presents with anemia, renal failure, hypercalcemia, and lytic bone lesions.MM also affects the hemostatic system and contributes to thrombosis and bleeding.Hemorrhagic manifestations usually have a multifactorial etiology with thrombocytopenia, dysfibrinogenemia, platelet dysfunction, and acquired coagulation factor deficiencies being commonly reported. 1Rarely, paraproteins with heparin-like anticoagulant (HLAC) activity can also cause bleeding.][4] We report a case of a middle-aged man with relapsed MM who presented with epistaxis and eventually developed a fatal right parietal lobe hemorrhage.The challenges in establishing the diagnosis and management of these rare HLAC are discussed along with a brief review of the literature.

Case Report
A 42-year-old gentleman was diagnosed with MM in January 2019 when he presented with anemia, low back pain, and hypercalcemia.Investigations revealed immunoglobulin G (IgG) lambda monoclonal protein at a concentration of 62 g/L and the bone marrow biopsy showed 80% clonal plasma cells.He was risk stratified as Revised International Staging System (R-ISS) stage II and received eight cycles of triplet induction therapy with bortezomib, lenalidomide, and dexamethasone.He attained a very good partial response but deferred autologous stem cell transplantation.Thereafter, he remained on lenalidomide maintenance for 16 months.The course of disease has been shown in ►Fig. 1.In his present visit, the patient complained of epistaxis, gingival bleed, and oozing at the venepuncture site.
Laboratory investigations at this time, approximately 2 years from the time of initial diagnosis, were suggestive of disease relapse with IgG lambda monoclonal band of 35 g/L and serum free light chain kappa, 1.07 mg/L; lambda, 3310mg/L; the kappa/lambda ratio, 0.0003.The platelet count was normal (183 Â 10 9 /L), but the results of his coagulation tests were deranged (►Table 1).The addition of an equal volume of normal plasma did not correct the elevated activated partial thromboplastin time (aPTT) and thrombin time (TT) indicating the presence of an inhibitor.Plasma levels of factor VIII, IX, and X were normal as was the fibrinogen level (Clauss assay) and D-dimer, ruling out disseminated intravascular coagulation.The addition of protamine sulfate (concentration of 100 µg/mL) to the patient's plasma in a 4:1 ratio normalized the TT.This indicated a possibility of a heparin like mechanism contributing to the derangement.A detailed review of the patient's drug chart did not identify the use of exogenous heparin.Considering this background, it was thought that an endogenous heparin activity attributable to the paraprotein was the causative factor.
Local hemostatic measures and infusion of fresh frozen plasma (15 mL/kg) did not arrest the bleeding.He was treated with a continuous infusion of protamine sulfate (5mg/hour) that led to a slight improvement in his TT in vitro (75 seconds) but did not stop his bleeding manifestations.Given the lack of evidence available for the ideal management of this rare complication, we considered managing the underlying disease aggressively with a quadruplet regimen consisting of daratumumab, carfilzomib, pomalidomide, and dexamethasone.This led to a significant reduction in his bleeding manifestations and further treatment was administered on an outpatient basis.Heparin-Like Anticoagulant in Multiple Myeloma Desai et al.
However, he returned to us 2 weeks later with complaints of epistaxis, gingival bleed, headache, and vomiting, and a right parietal hematoma was seen on a noncontrast computed tomography of the brain.His coagulation parameters were deranged again and there was a significant increase in his lambda light chain (18,600mg/L; ►Fig.2).He underwent six cycles of plasma exchange as a means to reduce his light chain burden but his clinical condition continued to worsen and he developed status epilepticus for which he was intubated.Despite continuing supportive care his hemorrhagic manifestations worsened and he could not be salvaged.

Discussion
Contrary to the more common predisposition to thrombotic complications, patients with MM have been reported to have clinically significant bleeding diathesis ranging from 13 to 36%. 5 The underlying etiology is not identified but thrombocytopenia, platelet function defects, acquired factor VIII and X deficiency, and inhibition of fibrin polymerization are some of the mechanisms proposed. 6,7A rarely reported cause of bleeding is the presence of a circulating HLAC with less than 30 cases being reported to date (►Table 2).
HLAC is usually suspected when patients with monoclonal gammopathies present with hemorrhagic manifestations and an elevated prothrombin time (PT), aPTT, and TT.The aPTT remains prolonged despite mixing studies with normal plasma suggesting the presence of an inhibitor.The correction of TT on the addition of protamine sulfate further supports the diagnosis.
The mechanism by which HLAC causes hemorrhagic manifestations is unclear.It has been hypothesized that the negatively charged, sialic acid-bearing monoclonal immunoglobins bind the heparin-binding domain of antithrombin and cause a similar activation to that caused by exogenous heparin. 8However, Khoory et al proposed that the coagulopathy was not due to a myeloma protein, but a circulating proteoglycan functioning as a cofactor for antithrombin III. 9 The source of this acquired anticoagulant is also debated with neoplastic plasma cells, their paraprotein product, damaged endothelial cells, and soluble CD138 (syndecan) being implicated by various authors. 10Patients with primary amyloidosis also frequently present with clinically significant bleeding and a prolonged TT, suggesting that the HLAC may not always be derived from the myeloma protein. 11f the reported cases, most patients presented with bleeding manifestations at the time of their initial diagnosis.However, our patient had no coagulation abnormalities at the time of diagnosis and developed fatal hemorrhage at the time of disease relapse.Patients most frequently presented with mucocutaneous bleeding, deep-seated hematomas, and bleeding from surgical/biopsy sites. 12The severity of bleeding does not correlate with the disease burden and severe bleeding has been reported in patients with monoclonal gammopathy of underdetermined significance and smoldering multiple myeloma as well. 12Earlier studies did report a high frequency of HLAC in patients with high disease burden like plasma cell leukemia but most contemporary reports show no such association.The impact of HLAC on the prognosis is also not known.Most of the studies have reported deaths due to bleeding and sepsis, rather than the primary disease. 13here is a paucity of data to guide the management of this rare complication and the treatment is usually decided by the degree of bleeding.Given the mechanism of action of this inhibitor, protamine sulfate has been used by many authors with variable success, but the optimal dose and duration of protamine therapy have not been determined. 14,15Studies have also demonstrated an improvement in the coagulation parameters with reduction in the tumor burden and successful treatment with plasma exchange has been reported by Goddard et al. 16,17 To the best of our knowledge, this is the first report on the use of novel agents like monoclonal antibodies for these patients and also the first report from India.Our patient was treated with daratumumab, carfilzomib, pomalidomide, and dexamethasone as a means of rapidly reducing his plasma cell burden.He also underwent plasma exchange with minimal improvement in his laboratory parameters but without any clinical benefit.However, our approach was limited as experimental studies to isolate and characterize the HLAC activity of the paraprotein were not carried out.There is a paucity of literature regarding its mechanism, and treatment is largely supportive.Future research is warranted to better understand the mechanism, source, and optimal management of patients with this dreaded complication.

Conclusion
HLAC is an uncommon cause of bleeding in patients with plasma cell disorders that should be considered in those who present with bleeding diathesis and a prolonged TT.It may manifest at the time of initial presentation or later in the disease course and its severity may not correlate with the disease burden.Heparin-Like Anticoagulant in Multiple Myeloma Desai et al.

Declaration of Patient Consent
Yes.

Table 1
Coagulation studies at the time of onset of bleeding Indian Journal of Medical and Paediatric Oncology © 2023.The Author(s).

Table 2
Summary of coagulation abnormalities, treatment, and outcome of patients with heparin-like anticoagulant-literature review