Thrombosis in stem cell transplantation

Abstract

Hemostatic changes and thrombotic events are frequent in patients undergoing stem cell transplantation. Arterial and venous thromboses are major causes of morbidity and mortality. Thrombotic complications can be classified into four groups including: catheter-related thrombosis, venous thromboembolic (VTE) events, sinusoidal obstructive syndrome (SOS)/veno-occlusive disease, and transplant-associated thrombotic microangiopathy (TAM). The incidence of catheter-related thrombosis is 8–20% in patients undergoing autologous hematopoietic stem cell transplantation (HSCT), and the incidence is low in syngeneic and allogeneic transplant patients. Venous duplex Doppler ultrasound, venogram, and computed tomography scan are required to visualize the venous thrombus. The treatment should be aimed at the prevention of pulmonary embolism, the avoidance of thrombus extension, and the preservation of catheter patency. Patients undergoing HSCT may have risk factors for VTE including underlying malignancy, traumatic brain injury, prolonged hospitalization, administration of conditioning regimens, and central venous catheters. Important risk factors are presence of history of VTE and graft-versus-host disease. One-year incidence of symptomatic VTE is 3·7%. SOS, also known as veno-occlusive disease, is a serious liver disease, seen in approximately 50–60% of HSCT patients. The mortality rate from the severe form of SOS is 84·3% and majority of the patients have multi-organ failure. The frequency is quite low after autologous transplantation. Risk factors for SOS include pre-existing hepatic damage, previous high-dose chemotherapy and abdominal irradiation, female gender and donor-recipient human leukocyte antigen disparity. Cyclophosphamide and busulphan are the most common agents with the highest incidence and fatal SOS. Histopathologic features of SOS include dilatation of sinusoids, necrosis of perivenular hepatocytes, and obstruction of small intrahepatic central venules by microthrombi and fibrin deposition. Signs of SOS usually occur within first 30 days after HSCT including hyperbilirubinemia, hepatomegaly, ascites, and weight gain. Symptoms of liver failure, including encephalopathy, coagulopathy, and renal failure will appear in severe form. A hepatic venous pressure gradient above 10 mmHg is highly specific for SOS. Early use of defibrotide has been shown to be effective in the treatment of high-risk SOS. TAM is a distinct, infrequent, and significant life-threatening complication of HSCT. TAM is seen in the range of 0·5–76% and was reported to be 10–25% in patients undergoing allogeneic HSCT with a mortality rate around 50%. It can also be seen after autologous HSCT and mainly affects the glomerular capillaries. There has been no standard therapy for TAM. Few case series reported good response to rituximab and high-dose corticosteroids were used with limited success. Trials with complement inhibitors such as eculizumab are currently underway.

Keywords:

• Thrombosis
• Stem cell transplantation
• Sinusoidal obstructive syndrome
• Transplant-associated thrombotic microangiopathy

Introduction

Hematopoietic stem cell transplantation (HSCT) has been developed as curative therapy for many malignant and non-malignant diseases. The indications of stem cell transplantation are continuously being revised as new treatment strategies are defined. In spite of significant progress in donor selection, histocompatibility typing, conditioning regimens, sources of hematopoietic stem cells, graft-versus-host disease (GVHD), and peri- and post-transplant care, patients undergoing stem cell transplantation still develop infectious, immunologic, and hemostatic complications.1^–3

Transplant-related or unrelated long-term morbidity after allogeneic stem cell transplantation has to be seriously considered and evaluated. Use of central venous catheters, immunosuppressive agents, infections, GVHD, and underlying disease are all important risk factors for post-transplant complications. Although allo-HSCT is a curative treatment for several hematologic disorders, it is hampered by treatment-related complications.

Hemostatic changes are observed and thrombotic events are frequent in patients undergoing stem cell transplantation.1^–5 Arterial and venous thromboses are major causes of morbidity and mortality.1^–4

Thrombotic Complications

Thromboembolic events can be seen during the transplant and early post-transplant period. These complications can be classified into four groups:

1. catheter-related thrombosis;

2. venous thromboembolic (VTE) events;

3. sinusoidal obstructive syndrome (SOS)/veno-occlusive disease (VOD);

4. transplant-associated thrombotic microangiopathy (TAM).

Catheter-related thrombosis

Central venous access has been the standard practice for chemotherapy and therapeutic interventions. Indwelling access devices are being used for wide variety of purposes including administration of chemotherapeutics, fluids, nutritional support, medications, hematopoietic cell collection, plasmapheresis, and stem cell reinfusions.6

Long-term central venous access devices are prone to catheter tip malposition, kinking, and thrombosis. Inability to withdraw from a catheter may be due to development of a fibrin sheath which can occur in 50–80% of the catheters, and does not always lead to catheter occlusion. If catheter-related venous thrombosis occurs, patient presents with unilateral arm swelling, pain, and collateral veins.3,6

The incidence of catheter-related thrombosis is 8–20% in patients undergoing autologous stem cell transplantation, and the incidence is low in syngeneic and allogeneic transplant patients. Venous duplex Doppler ultrasound, venogram, and computed tomography scan are required to visualize the venous thrombus in the lumen. When the patient develops catheter-related venous thrombosis, the treatment should be aimed at the prevention of pulmonary embolism, avoidance of thrombus extension, and preservation of catheter patency.

Patients should be given low molecular weight heparin for 1 week to 10 days followed by warfarin. Catheter can remain in place if it is needed and symptoms improve. There is no evidence for routine use of coumarin or low molecular weight heparin for prophylaxis of catheter-related venous thrombosis.³3,6

VTE

VTE can be seen after HSCT.6 Patients undergoing HSCT may have risk factors for VTE including underlying malignancy, total body irradiation (TBI), prolonged hospitalization, administration of conditioning regimens, and central venous catheters. Important risk factors are presence of history of VTE and GVHD. A retrospective analysis reported by Gonsalves et al. in 2008 involving 589 patients undergoing autologous (382) or allogeneic (207) HSCT in a single center at Canada, showed a total 1-year incidence of symptomatic VTE of 3·7% and among all the 589 patients, seven patients (1·2%) developed symptomatic non-catheter-related VTE during post-transplant period after HSCT (four patients pulmonary embolism and three patients deep vein thrombosis).7 In this study, all VTE events developed after hematopoietic recovery. Another study reported by Pihusch et al. in 2002 showed increased rates of VTE and pulmonary embolism in allogeneic HSCT patients, and increased rates of VTE in the group with chronic GVHD. Although VTE and related events appear to have a high incidence and a risk in patients during the post-HSCT period, reduced-intensity regimens being employed in out-patient settings may decrease the rate of these complications.

SOS

This disorder has also been called ‘VOD’, but recently McDonald in Seattle named it as SOS. VOD does not correctly represent the disease because obstruction of hepatic venules is not always required for signs and symptoms.8 SOS is a serious liver disease, seen in approximately 50–60% of HSCT patients. Its incidence varies depending on the diagnostic criteria, conditioning regimens as well as type of transplants.8 Recent comprehensive review published by Coppell et al. analyzed 135 studies performed between 1979 and October 2007, and reported the overall mean incidence of SOS/VOD of 13·7%.9 The mean incidence of SOS was significantly lower between 1979 and 1994 compared to the period of 1994–2007. In pediatric patients, the incidence of VOD/SOS ranges from 27 to 40%.10,11 The mortality rate from severe form of SOS was 84·3% and majority of the patients had multi-organ failure. The frequency of SOS is quite low after autologous transplantation.

Risk factors for SOS/VOD include pre-existing hepatic damage, previous high-dose chemotherapy, previous abdominal irradiation, female gender and donor-recipient human leukocyte antigen (HLA) disparity. The most important risk factor is the conditioning regimen which may contain more liver damaging agents, the dose of TBI, and the patient’s underlying liver disease.8,9 Cyclophosphamide and busulphan are the most common agents with the highest incidence and fatal SOS. In patients receiving cyclophosphamide and TBI, a synergistic effect of both therapeutic options may cause endothelial cell injury in the sinusoids. Acute myelogenous leukemia patients treated with high-dose gemtuzumab ozogamicin (humanized anti-CD33 conjugated to calicheamicin, Myelotarg) were also reported to be a risk for SOS.8

SOS can be diagnosed with a histologic sample obtained through transdermal or transjugular liver biopsy and hepatic venous pressure measurement. Histopathologic features of SOS include dilatation of sinusoids, necrosis of perivenular hepatocytes, obstruction of small intrahepatic central venules by microthrombi and fibrin deposition, hepatic congestion, and signs of portal hypertension in the absence of inflammatory infiltrates. In the later stage of SOS, there is extensive collagen deposition in sinusoids and venules with obstruction of venular lumens.8,9 Obstruction of sinusoids and hemorrhage occurs at zone 3 of liver acinus which is rich in cytochrome P-450 and serves as the main enzymatic system for the biodegradation and clearance of the chemotherapeutic agents used in conditioning regimens. Transforming-growth factor beta-1 released from activated platelets was shown to induce an increased endothelial cell plasminogen activator inhibitor-1 and tissue factor secretion which were considered to cause sinusoidal fibrosis and occlusion.12 Recent studies show no correlation between the coagulation parameters suggesting that SOS may be an ‘epiphenomenon’ due to centrilobular damage.

Signs of SOS usually occur within first 30 days after HSCT. Clinical signs and symptoms include hyperbilirubinemia, hepatomegaly, ascites, and weight gain. Insidious weight gain is typically the first sign of hepatic SOS. If it progresses, more severe symptoms of liver failure, including encephalopathy, coagulopathy, and renal failure will be present.8,9

Clinical course of SOS can be mild, moderate, and severe. The staging criteria of SOS are shown in Table 1. A poor prognosis correlates with high serum aspartate transaminase and alanine transaminase, portal vein thrombosis, kidney failure, and hypoxia. In HSCT patients, a hepatic venous pressure gradient above 10 mmHg is highly specific for SOS.8

Table 1. Staging of SOS

Mild: resolved without intervention

Moderate: requires treatment

1. Bilirubin >6 mg per 100 ml

2. Glutamate pyruvate transaminase <5 N

3. Weight gain >5%

4. Ascites

Severe: progression to multi-organ failure (stage 3)

1. Respiratory failure (O2 saturation <90%)

2. Hepato-renal syndrome

3. Encephalopathy

4. Severe renal failure (creatinine > ×2)

5. Bilirubin >20 mg per 100 ml

Treatment of SOS includes supportive care with sodium and water balance, diuretics, and relief of ascites with paracentesis which may cause spontaneous recovery in two-thirds of the patients. In severe cases with multi-organ failure, hemodialysis and mechanical ventilation can be used, when needed.8,9 Although there is no efficient therapy for SOS, some measures such as corticosteroids, recombinant-human tissue plasminogen activator, human anti-thrombin concentrate, I.V. N-acetylcysteine, and transhepatic shunts were tried without a definitive success and cannot serve as a treatment option.8,9,13

Early use of defibrotide has been shown to be effective in the treatment of high-risk SOS. To date, mechanism of action of defibrotide is not well defined. In a randomized, multi-center phase-II dose-finding study reported by Richardson et al., adult and pediatric patients received either lower-dose (25 μg/kg/day, n = 75) or higher-dose (40 μg/kg/day, n = 74) intravenous defibrotide.14 Overall complete response was 46% and 100-day post-HSCT survival rate was 42%. No significant difference was observed between two dose levels and 25 μg/kg/day was chosen for phase III trials in severe VOD/SOS.14 Defibrotide appears to have an efficacy in the early treatment of severe SOS but placebo-controlled and randomized clinical trials are needed.

We conducted a retrospective analysis of two randomized clinical trials to determine the effect of intravenous immunoglobulin infusions on the development and severity of VOD/SOS in HLA-identical sibling (n = 414), mismatched or unrelated (n = 178), or autologous or syngeneic (n = 41) HSCT patients. We concluded from the controlled trials of 633 patients that the administration of intravenous immunoglobulin did not influence the development or severity of VOD/SOS.15

TAM

TAM is a distinct, infrequent, and significant life-threatening complication of HSCT. TAM is seen in the range of 0·5–76%. In retrospective studies, prevalence of TAM was reported to be 10–25% in patients undergoing allogeneic transplantation with a mortality rate around 50%.16 The disease can also be seen after autologous HSCT. TAM has some similarities to thrombotic thrombocytopenic purpura such as presence of thrombocytopenia, kidney failure, neurologic manifestations, hyperbilirubinemia, elevation of lactate dehydrogenase and microangiopathic changes.16,17 In contrast, TAM is not caused by ADAMST13 deficiency and plasma exchange for thrombotic thrombocytopenic purpura does not improve the clinical picture.

TAM mainly affects the glomerular capillaries. Renal pathology shows thickened capillary walls, occlusion of vascular lumens, fibrin deposition, and endothelial separation with expansion of subendothelial zone. Endothelial cell damage appears to be the inciting event which then leads to thrombotic processes and fibrin deposition in the microcirculation. Although the exact pathogenesis of TAM has not been elucidated, complement system, cytokines presence of GVHD, fungal or viral infections, unrelated or HLA-mismatched donor grafts, female sex, and use of cyclosporine or mTOR inhibitors (sirolimus) are all considered as potential adverse causative factors in the microvascular pathology.16,17 There are no good biomarkers for the diagnosis and monitoring of TAM.

TAM usually develops within 100 days after HSCT and mostly affects the kidneys. But there have been few papers reporting involvement of gastrointestinal system and lungs. Clinical features include hypertension, proteinuria, and kidney failure.17

Validation of proposed consensus criteria for the diagnosis of TAM has been reported by Cho et al. as shown in Table 2.18

Table 2. Consensus criteria for the diagnosis of transplant-associated thrombotic microangiopathy, validated by Cho et al.18

All criteria must be present for the diagnosis:

1. Schistocytes >2% per high-power field in peripheral blood

2. Thrombocytopenia (<50·000/mm^3 or >50% decrease in platelet count)

3. Increase in lactate dehydrogenase

4. Decrease in hemoglobin

5. Decrease in haptoglobin

6. Negative Coombs test

7. No coagulopathy

There has been no standard therapy for TAM. Few case series reported good response to rituximab (anti-CD20) and high-dose corticosteroids were used with limited success.17 Trials with complement inhibitors such as eculizumab are currently underway. In TAM, significant renal dysfunction leading to chronic kidney disease and fatal outcome still remains as most critical issues.