Приобретение гепариновых антикоагулянтов, связанных с множественной миеломой: three доклады и обзор литературы.

Introduction

Multiple myeloma (MM) is a malignant hematologic disorder characterized by clonal plasma cell proliferation [ 1 ]. While common presentations include bone lesions, anemia, and renal impairment, coagulation abnormalities are also well-recognized complications. These disturbances can manifest as bleeding or thrombosis and arise from diverse mechanisms, including acquired coagulation factor deficiencies, platelet dysfunction, and direct interference from monoclonal immunoglobulins [ 1 – 3 ]. Among these, acquired heparin-like anticoagulants (HLA)—an extremely rare but serious complication—can lead to profound prolongation of thrombin time (TT) and significant bleeding risk, necessitating prompt diagnosis and management [ 3 , 4 ]. Since the initial description by Khoory et al. in 1980 of circulating heparan sulfate proteoglycan anticoagulant in plasma cell disorders [ 5 ], acquired HLA has been recognized as a rare but serious cause of bleeding in MM patients.

However, clinical awareness of HLA in MM remains limited, and its diagnosis is often delayed due to nonspecific presentation and a lack of routine screening. Herein, we report three cases of MM associated with HLA, all presenting with extreme TT prolongation and active bleeding. Through a review of the clinical and laboratory features, diagnostic approach, and treatment outcomes of these cases, this study aims to enhance recognition and guide the effective management of this rare coagulopathy.

Cases presentations

Case 1

A 63-year-old female was admitted on March 5, 2022, with a six-month history of dizziness and fatigue. Laboratory investigations revealed anemia (Hb 48 g/L), thrombocytopenia (Plt 110 × 10⁹/L), and elevated IgG levels (153 g/L). Coagulation studies showed markedly prolonged thrombin time (TT) that was unmeasurable (“FAILED”), with normal prothrombin time (PT) and mildly prolonged activated partial thromboplastin time (APTT). Bone marrow aspiration demonstrated 17% plasma cells (11.5% mature and 5.5% immature), and serum immunofixation confirmed IgGλ monoclonal gammopathy. A diagnosis of multiple myeloma (IgGλ type, DS stage IIIB, ISS stage III) was established.

Diagnosis of multiple myeloma was established based on CRAB-SLiM criteria: Serum IgG elevation > 30 g/L (153 g/L), Lit bone lesions on imaging, Marrow plasma cells > 10% (17%), Anemia (Hb 48 g/L), Bone disease (lytic lesions). Calcium elevation and Renal impairment were absent. Systemic AL amyloidosis was excluded based on absence of proteinuria (urine protein < 0.15 g/24 h), and normal cardiac biomarkers (NT-proBNP 180 pg/mL, cTnI 0.02 ng/mL). And bone marrow biopsy showed no amyloid deposition on Congo red staining.

The patient initially achieved complete remission following four cycles of bortezomib-lenalidomide-dexamethasone (VRd) and plasma exchange. However, she discontinued treatment due to adverse effects and was lost to follow-up.

On September 26, 2025, MM relapsed, and she presented with spontaneous gingival bleeding. According to ISTH bleeding classification, the patient had Grade 2 bleeding (mucosal bleeding requiring medical intervention). Physical examination showed pallor, oral mucosal bleeding, and scattered petechiae. Coagulation tests again revealed extreme prolongation of TT (> 540 s), with normal PT and mildly prolonged APTT. Factor assays were within normal limits, and lupus anticoagulant was negative. There was no history of heparin exposure. A protamine correction test was positive, confirming the presence of heparin-like anticoagulants (HLA).

The patient underwent two sessions of therapeutic plasma exchange (TPE, 1.5 plasma volumes each) and resumed VRd therapy. Protamine sulfate was not administered therapeutically. Bleeding was controlled through plasma exchange and normalization of TT. No thromboprophylaxis was administered due to active bleeding and extreme coagulopathy. No thrombotic events occurred during HLA positivity.

After the first TPE, IgG decreased to 98.8 g/L and TT normalized to 34 s, with cessation of mucosal bleeding. Following the second session, IgG further dropped to 34 g/L and TT returned to 16.2 s. The bleeding episode did not delay myeloma treatment; VRd therapy was resumed promptly after the first plasma exchange. At completion of 4 cycles of VRd (April 2026), coagulation parameters were: TT 15.8 s, PT 11.5 s, APTT 32.4 s, Fib 3.8 g/L.

Case 2

A 57-year-old male was admitted on September 17, 2025, with a two-month history of low back pain following trauma, melena for 20 days, and newly identified plasmacytosis. Imaging revealed multiple osteolytic lesions and pathologic fractures. Bone marrow biopsy showed 37.5% plasma cells. IgG was elevated to 105 g/L. SLiM-CRAB criteria: Serum IgG > 30 g/L (105 g/L), Lit bone lesions with pathologic fractures, Marrow plasma cells 37.5%, Anemia (Hb 73 g/L), Bone disease. Calcium elevation and Renal impairment were absent at presentation. And AL amyloidosis was excluded by absence of proteinuria, normal cardiac function (NT-proBNP 220 pg/mL), and negative Congo red staining of bone marrow biopsy.

Coagulation studies showed unmeasurable TT (> 540 s), with normal PT and mildly prolonged APTT. Fibrinogen was 2.25 g/L, and factor assays were mildly reduced but within functional ranges. Lupus anticoagulant was negative, and there was no heparin exposure. The protamine correction test was positive, confirming HLA. The patient experienced Grade 3 bleeding (gastrointestinal bleeding requiring transfusion and hospitalization) according to ISTH classification.

The patient was treated with two sessions of TPE and started on VRd regimen. Protamine sulfate was not administered therapeutically. Bleeding was controlled through plasma exchange and normalization of TT. No thromboprophylaxis was administered due to active gastrointestinal bleeding and coagulopathy. No thrombotic events occurred.

Gastrointestinal bleeding was managed with somatostatin and omeprazole. VRd therapy was initiated after the first plasma exchange without delay. The gastrointestinal bleeding required 4 units of packed red blood cells transfusion but did not postpone anti-myeloma treatment.

After the second TPE, IgG decreased to 71.4 g/L and TT normalized to 16.8 s, with resolution of bleeding. After 2 cycles of VRd (November 2025), coagulation normalized: TT 14.2 s, PT 11.8 s, APTT 30.5 s, Fib 3.5 g/L.

Case 3

A 56-year-old male was admitted on October 3, 2019, with anorexia, fatigue, and elevated serum creatinine. He had a history of cerebral infarction and was on antiplatelet and antihypertensive agents. Physical examination showed pallor and petechiae on both lower limbs. Laboratory tests revealed renal impairment (creatinine 1.44 mg/dL [127.3 µmol/L]), anemia (Hb 99 g/L), thrombocytopenia (Plt 86 × 10⁹/L), and hyperglobulinemia (globulin 91.8 g/L), and elevated IgG levels (81.4 g/L). Coagulation tests showed unmeasurable PT, APTT, and TT. Immunofixation confirmed IgGκ monoclonal protein. Bone marrow examination showed 73% plasma cells (52% immature), consistent with multiple myeloma (IgGκ type, R-ISS stage III).

SLiM-CRAB criteria: Serum IgG elevation (81.4 g/L), Lit bone lesions, Marrow plasma cells 73%, Calcium elevation (corrected Ca 2.8 mmol/L), Renal impairment (creatinine 127.3 µmol/L), Anemia (Hb 99 g/L). All CRAB features except bone pain were present. Although the patient had renal impairment, AL amyloidosis was excluded by absence of monoclonal light chain in urine immunofixation, and negative Congo red staining of renal and bone marrow biopsies.

The patient presented with Grade 2 bleeding (cutaneous petechiae and mucosal bleeding) according to ISTH classification. Fibrinogen antigen level was measured by immunonephelometry and was 0.69 g/L (reference range 2.0–4.0 g/L), confirming hypofibrinogenemia rather than dysfibrinogenemia (functional/antigen ratio: 1.06).

The patient received initial supportive care with fresh frozen plasma transfusions (15 mL/kg) every 48 h for 2 weeks to stabilize coagulation parameters. Subsequently, bortezomib-cyclophosphamide-dexamethasone (BCD) regimen was initiated. After 2 cycles, M-protein decreased to 15 g/L and TT improved to 45 s. The regimen was then switched to lenalidomide-dexamethasone (RD) due to peripheral neuropathy. After 4 cycles of RD, M-protein became undetectable. Bortezomib was reintroduced in combination with RD (BRD) for consolidation. Throughout treatment, intermittent plasma transfusions were given when TT exceeded 60 s or bleeding occurred.

The initial coagulopathy required adjustment of chemotherapy timing; BCD regimen was started after partial correction of coagulation parameters with plasma transfusions. Protamine sulfate was not used. Management was focused on plasma transfusions and chemotherapy. No thromboprophylaxis was administered during the acute phase due to generalized coagulopathy and bleeding risk. Low-dose aspirin was resumed after coagulation parameters normalized in February 2020. No thrombotic events occurred during HLA positivity.

During follow-up, M-protein decreased to undetectable levels, and renal function improved. Coagulation parameters normalized (TT 16.5 s) by February 2020, with no further bleeding episodes. By February 2020 (after 6 cycles of combination therapy), coagulation parameters normalized: TT 16.5 s, PT 12.1 s, APTT 34.2 s, Fib 2.9 g/L.

Laboratory characteristics and coagulation-related tests

All three patients exhibited extreme prolongation of TT (> 540 s) without prior heparin exposure. PT and APTT were normal in the first two cases and markedly prolonged in the third. Mixing studies were performed by mixing patient plasma with normal pooled plasma (1:1 and 1:4 ratios). In all three cases, the prolonged TT did not correct with normal plasma (TT remained > 540 s), confirming the presence of an inhibitor rather than a factor deficiency.

Coagulation factor activities were measured using one-stage clotting assays performed on the ACL TOP 750 LAS Coagulation Instrument (Instrumentation Laboratory Company, MA, USA). Factor VIII, IX, XI, and XII were assayed using APTT-based methods, while Factor II, V, VII, and X were assayed using PT-based methods using commercial reagents. And the antithrombin (AT) activity was measured using a chromogenic substrate method. Coagulation factor activities were variably preserved (Table 1 ).

The protamine sulfate correction test was performed as follows: Five equal aliquots (100 µL each) were taken from the patient plasma and mixed with equal volumes (10 µL) of protamine sulfate at graded concentrations to achieve final protamine concentrations of 0, 0.125, 0.25, 0.5, and 1.0 mg/mL, respectively. Thrombin time (TT) was measured immediately after mixing. This protocol was adapted from Tefferi et al. [ 6 ] with minor modifications for our laboratory conditions. Normalization of TT at higher protamine concentrations confirmed the presence of heparin-like anticoagulant activity. In all cases, TT normalized at higher protamine concentrations, confirming the presence of HLA (Table 2 ).

Discussion

Multiple myeloma is a malignant plasma cell disorder often accompanied by complex hemostatic abnormalities, which may manifest as either hemorrhagic or thrombotic tendencies. These abnormalities arise from a variety of mechanisms, including acquired coagulation factor deficiencies, platelet dysfunction, hyperviscosity, endothelial injury, and direct interference of the monoclonal immunoglobulin (M-protein) with the coagulation cascade [ 2 – 8 ]. Among these, acquired circulating heparin-like anticoagulants represent an extremely rare but potentially life-threatening cause of bleeding in MM patients [ 4 , 8 ].

HLA are endogenous glycosaminoglycans with anticoagulant properties similar to those of heparin. They potentiate the action of antithrombin, leading to accelerated inhibition of thrombin and other serine proteases in the coagulation pathway [ 4 ]. This results in a marked prolongation of thrombin time, often with normal or near-normal PT and APTT, as observed in two of our three cases. The third case exhibited prolongation of all three parameters, which may be attributed to concurrent hypofibrinogenemia or other coagulopathies. The diagnosis of HLA is supported by a positive protamine sulfate correction test, which neutralizes heparin-like activity and normalizes TT [ 4 , 6 , 8 ]. In all three of our patients, the test confirmed the presence of HLA, enabling timely diagnosis and intervention.

The pathogenesis of HLA in MM remains incompletely understood. It has been proposed that M-proteins may either directly exhibit heparin-like activity or stimulate mast cells to release endogenous heparinoids [ 4 , 5 ]. Alternatively, abnormal immunoglobulin may interfere with fibrin polymerization or bind to thrombin, impairing its function [ 9 , 10 ]. Saadalla et al. [ 4 ] provided crucial mechanistic insights by demonstrating that sialic acid-bearing paraproteins (particularly those with terminal sialic acid residues on N-glycans) are implicated in heparin-like coagulopathy. Their structural analysis revealed that negatively charged sialic acid moieties on the M-protein surface may mimic the anticoagulant properties of heparin by interacting with antithrombin and accelerating thrombin inhibition. Whether similar sialic acid modifications exist on the IgG paraproteins in our three cases remains to be verified through glycomic analysis, but the elevated IgG levels (81.4–137.9 g/L) and positive protamine correction tests support this potential mechanism.

In the present series, all patients presented with severe bleeding—oral mucosal, gastrointestinal, or cutaneous—accompanied by TT > 540 s. Despite normal levels of most coagulation factors and negative lupus anticoagulant, the bleeding risk was substantial. This underscores the importance of suspecting HLA in MM patients with isolated or disproportionate TT prolongation and active bleeding, even in the absence of heparin exposure.

Management of HLA-associated bleeding involves two key strategies: rapid neutralization of the anticoagulant effect and control of the underlying plasma cell disorder [ 8 ]. Plasma exchange effectively removes circulating M-protein and HLA, as demonstrated by the prompt normalization of TT and cessation of bleeding in our first two cases. Concurrent initiation of antimyeloma therapy—such as bortezomib-based regimens—is critical to suppress M-protein production and prevent recurrence [ 1 ]. In the third patient, who also had renal impairment and generalized coagulopathy, combination chemotherapy with supportive plasma transfusions and anticoagulant adjustment also led to hematologic and coagulative recovery.

A review of the literature since 1970 reveals only sporadic reports of MM associated with HLA, highlighting the rarity of this condition [ 3 ]. Consistent with our findings, most reported cases showed rapid response to plasma exchange and chemotherapy, reinforcing the efficacy of this combined approach [ 8 ]. Notably, the use of protamine sulfate as a diagnostic and even therapeutic agent (in acute settings) deserves wider recognition.

It is also important to distinguish HLA from other acquired coagulopathies in MM (Table 3 ), such as acquired von Willebrand syndrome (AVWS) [ 7 , 11 ], acquired factor X deficiency [ 3 , 12 ], or acquired hypofibrinogenemia and dysfibrinogenemia [ 13 , 14 ]. The characteristic pattern of TT prolongation with normal coagulation factor activities and positive protamine sulfate correction reliably differentiates HLA from these entities [ 4 – 6 , 8 ].

In conclusion, although rare, HLA should be considered in MM patients presenting with unexplained TT prolongation and hemorrhage. A high index of suspicion and prompt performance of the protamine correction test are essential for diagnosis. Early intervention with plasma exchange and targeted antimyeloma therapy can rapidly reverse the coagulopathy, control bleeding, and improve outcomes. Further studies are needed to elucidate the molecular mechanisms underlying HLA production and to optimize treatment protocols for this uncommon but serious complication.

Acknowledgements

Not applicable.

Author contributions

YW: study design and concept, writing and revising the manuscript; MZ: protamine sulfate correction test, writing a draft of the manuscript; FZ: protamine sulfate correction test; YG: clinical diagnosis and treatment; XZ: clinical diagnosis and treatment. All authors reviewed the manuscript.

Funding

This work was supported by Hebei Province Medical Applicable Technology Tracking Project (GZ2024020).

Data availability

The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Second Hospital of Hebei Medical University. All patients were informed about the experimental nature of this study and gave their consent to participation.

Consent for publication

Consent for publication have been obtained from the patients.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yan Wang and Mingqian Zhang contributed equally to this work.

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Associated Data

Data Availability Statement

The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.