How to prevent VTE in patients with hematological tumors?

Author: Blue whale Xiaohu This article is the author's permission NMT Medical publish, please do not reprint without authorization.

Cancer patients have disorders of the body's hemostatic system, and are people at high risk of thrombosis and bleeding complications.

The estimated annual incidence of venous thromboembolism (VTE) in the cancer population is 0.
5%, and the general population is 0.
1% [1].

In the past, it was thought that thrombotic complications were more common in patients with solid tumors, while hematological system tumors were more common in bleeding and decompensated diffuse intravascular coagulation (DIC).

Recent studies have shown that the incidence of VTE in patients with hematological tumors is similar to that of patients with solid tumors at high risk of thrombosis.

In addition, special attention should be paid to the situation of VTE in patients receiving allogeneic hematopoietic stem cell transplantation.

This article will focus on the incidence of VTE in hematological malignancies, and give practical strategies for the prevention and management of VTE in patients with hematological malignancies.

Risk factors for VTE in hematological tumors 01 Leukemia In patients with acute lymphoblastic leukemia (ALL) [2], older age, comorbidities and the use of L-asparaginase in central venous catheters can increase the risk of VTE.

Asparaginase prevents the growth of leukemia cells by depleting asparagine, and it can also cause thrombotic complications due to the destruction of clotting proteins.

In patients with acute myeloid leukemia (AML), indicators reflecting DIC: fibrinogen, D-dimer, α-2 antiplasmin, antithrombin, prothrombin time and platelet count can effectively predict VTE event.

Patients with chronic myeloid leukemia (CML) [3] using tyrosine kinase inhibitors, especially ponatinib, may increase arteriovenous vascular events.

Large sample studies have shown that compared with imatinib, the use of a new generation of tyrosine kinase inhibitors (dasatinib, nilotinib, prnatinib) is associated with a statistically significant increase in the risk of vascular occlusion events.

02 Lymphoma In a cohort of 422 new lymphoma cases followed up for more than 2 years, the incidence of VTE (deep vein thrombosis [DVT] and pulmonary embolism [PE]) was 17.
1% [4].

Factors associated with VTE include women, high hemoglobin, high serum creatinine, and receiving chemotherapy with doxorubicin or methotrexate.

In a Danish database study [5], the incidence of VTE at 1 and 2 years in all lymphoma patients was 2.
9% and 3.
5%, respectively, with the highest incidence in the first 6 months after diagnosis.

Patients with aggressive lymphoma have a higher incidence of VTE than indolent lymphoma.

Table 1 Summary of the incidence of VTE in hematological malignancies 03 Multiple myeloma immunomodulators (IMiD) have become the standard treatment for MM, and the use of thalidomide and lenalidomide is associated with a significant increase in the risk of VTE.

The incidence of VTE in patients with MM using immunomodulators is about 1% to 6%, but the risk may increase significantly when combined with dexamethasone or anthracyclines [6].

The mechanisms leading to increased thrombotic events include increasing plasma factor VIII and von Willebrand factor levels, inducing protein C resistance, and reducing soluble thrombomodulin.

The guidelines require that thrombosis prevention be mandatory in these patients.

04 Hematopoietic stem cell transplantation Auto-SCT is still a treatment method for patients with MM and relapsed or refractory lymphoma.

Similar to high-intensity chemotherapy, patients receiving auto-SCT will have a lower platelet count within 1 to 3 weeks after stem cell transfusion, and platelet recovery will be slow thereafter.

These patients are still at risk of VTE despite the presence of thrombocytopenia due to reduced physical strength and mobility, central venous catheter insertion, and other reasons.

Studies conducted in autologous stem cell transplant recipients [7] have shown that the incidence of VTE is about 4%, and the use of thalidomide is associated with an increased risk of VTE.

Unlike auto-SCT, patients receiving allogeneic hematopoietic stem cell transplantation are at risk of graft-versus-host disease (GVHD) and hepatic vein occlusive disease, both of which are related to vascular destruction and prolonged systemic inflammation.
VTE in patients with GVHD The risk increases.

Prevention and treatment of VTE01 VTE prevention in patients with hematological malignancies Figure 1 summarizes the factors that should be considered when determining the prevention of thrombosis in patients with hematological malignancies.

In addition to the type of malignant tumor, comorbidities (such as obesity or previous VTE), chemotherapy regimens, and platelet count, the use of central venous catheters increases the risk of VTE.

Most guidelines do not advocate the use of routine thrombosis prevention in cancer patients with indwelling catheters [8].

For the treatment of catheter-related VTE, it is generally recommended to use anticoagulants for at least 3 months or throughout the entire catheter indwelling period.

If symptoms such as limb edema disappear shortly after starting anticoagulation, the catheter can be used for chemotherapy at the same time.

NCCN guidelines [9] point out that platelet counts below 50×109/L are a relative contraindication for VTE prevention.
Acute leukemia patients receiving chemotherapy and hematopoietic stem cell transplant patients often suffer from severe thrombocytopenia, so the possibility of receiving preventive treatment is small .                                              Figure 1 Factors supporting/not supporting the prevention of thrombosis in patients with hematological tumors[8]* DIC score according to ISTH guidelines: platelet count (> 100×109/L = 0 points; <100 = 1; <50 = 2), fibrin Related markers increased (for example, soluble fibrin monomer/FDP, no increase=0; ↑↑=2; ↑↑↑=3), PT prolonged (<3 s=0; 3~6 s=1;> 6 s=2), fibrinogen (> 1.
0 g/L = 0; <1.
0 g/L = 1) **According to Khorana score, platelet count ≥350 × 109/L, hemoglobin <100 g/L and white blood cell count >11 × 109/L is the potential risk of cancer VTE Figure 2 Flow chart of VTE prevention in hematological malignancies [8] Other VTE risk factors include previous history of VTE, known thrombosis tendency, BMI >35 kg/m2, female hormones Treated, hospitalized and bedridden patients; contraindications for VTE prevention include platelets <(25-50)×109/L, untreated central nervous system (CNS) disease, massive bleeding in the last 2 to 4 weeks, and active gastrointestinal tract disease.

02Treatment of hematological malignancies after VTE VTE treatment of patients with hematological malignancies is more complicated than solid tumors.

Most existing guidelines assume that thrombocytopenia is related to the toxicity associated with radiotherapy and chemotherapy.

In hematological malignancies, patients may also have thrombocytopenia due to bone marrow infiltration, treatment-related, hematopoietic stem cell transplantation pretreatment and ablation, and immune-mediated thrombocytopenia.

However, in practice, the existing guidelines can still be used as a rough tool to manage acute VTE in patients with hematological malignancies who are at risk of bleeding (due to thrombocytopenia or other reasons, such as disease site or concomitant GVHD).

According to the recommendations of ASCO [10] and NCCN [11], the overall risk of bleeding and VTE recurrence of low-molecular-weight heparin (LMWH) in cancer patients is lower than that of warfarin.

The NCCN guidelines [11] further pointed out that for patients who refuse to use LMWH or have clear indications that they cannot use LMWH, the new oral anticoagulants apixaban and rivaroxaban are acceptable alternatives.

The following methods are recommended to treat VTE in patients with hematological malignancies: patients with acute VTE with platelet count ≥50×109/L: full-dose anticoagulation therapy; full-dose anticoagulation therapy combined with platelet transfusion, the goal is 2 Platelet count >50×109/L within ~4 weeks; For patients with acute proximal lower extremity VTE and high risk of bleeding, unable to accept platelet transfusion or platelet transfusion ineffective, consider placing an inferior vena cava filter; for non-acute VTE Patients: When the platelet count is 25-50×109/L, reduce the anticoagulation treatment to half or even prevent the dose; when the platelet count is less than 25×109/L, stop the anticoagulation treatment completely.

Table 2 Strategies for the prevention and treatment of VTE related to hematological malignancies based on platelet count [14] a tinzaparin: 4500 IU/d; dalteparin: 5000 IU/d; enoxaparin: 4000 IU/d; b tinzaparin : 175 IU/kg/d for 6 months; dalteparin: 200 IU/d in the first month and 150 IU/d in the next 5 months; enoxaparin: 100 IU, bid; cASA (aspirin): 80- 100 mg/d References 1.
Falanga A, Marchetti M, Russo L.
Venous thromboembolism in the hematologic malignancies.
Curr Opin Oncol.
2012;24(6):702-10.
2.
Libourel EJ, Klerk CPW, van Norden Y, de Maat MPM, Kruip MJ, Sonneveld P, et al.
Disseminated intravascular coagulation at diagnosis is a strong predictor for thrombosis in acute myeloid leukemia.
Blood 2016;128:1854–61.
3.
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al.
Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients.
Leuk Res 2016;48:84–91.
4.
Zhou X, Teegala S, Huen A, Ji Y, Fayad L, Hagemeister FB, et al.
Incidence and risk factors of venous thromboembolic events in lymphoma.
Am J Med 2010;123:935–41.
5.
Lund JL, Ostgard LS, Prandoni P, Sorensen HT, de Nully Brown P.
Incidence, determinants and the transient impact of cancer treatments on venous thromboembolism risk among lymphoma patients in Denmark.
Thromb Res 2015;136:917–23.
6.
Boyle EM, Fouquet G, Manier S, Gauthier J, Noel MP, Borie C, et al.
Immunomodulator drug-based therapy in myeloma and the occurrence of thrombosis.
Expert Rev Hematol 2012;5:617–26.
7.
Zahid MF, Murad MH, Litzow MR, Hogan WJ, Patnaik MS, Khorana A, et al.
Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis .
Ann Hematol 2016;95:1457–64.
8.
Kekre N, Connors JM.
Venous thromboembolism incidence in hematologic malignancies.
Blood Rev.
2019;33:24-32.
9.
Streiff MB,Bockenstedt PL, Cataland SR, Chesney C, Eby C, Fanikos J, et al.
Venous thromboembolic disease.
J Natl Compr Canc Netw 2013;11:1402–29.
10.
Lyman GH, Bohlke K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, et al.
Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014.
J Clin Oncoln, 2015;33:654–6.
11.
Kearon C, Akl EA, Ornelas J, Blaivas A , Jimenez D, Bounameaux H, et al.
nAntithrombotic therapy for VTE disease.
Chest.
149:315–52.
12.
Samuelson Bannow BT, Lee A, Khorana AA, Zwicker JI, Noble S, Ay C, et al.
Management of cancer- associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH.
J Thromb Haemost 2018; 16(6):1246–9.
13.
Mantha S, Miao Y, Wills J, Parameswaran R, Soff GA.
Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study.
J Thromb Thrombolysis 2017;43:514–8.
14.
Annibali O, Napolitano M, Avvisati G, Siragusa S.
Incidence of venous thromboembolism and use of anticoagulation in hematological malignancies: Critical review of the literature.
Crit Rev Oncol Hematol.
2018;124:41-50.
Stamp "read the original text", we make progress together