**3. Sinusoidal obstruction syndrome and transplant associated thrombotic microangiopathy**

The sinusoidal cells, which share many features of ECs, are particularly at risk of toxic injury. Both hepatic sinusoidal obstruction syndrome (SOS) and transplant

#### *Danaparoid Sodium: A Review of Its Use in Hepatic Thrombotic Disorders DOI: http://dx.doi.org/10.5772/intechopen.103851*

associated thrombotic microangiopathy (TA-TMA) are examples of sinusoidal cell and EC injury. Detoxification of chemotherapeutic drugs and other toxins, including pathogen induced endotoxins, is mediated by the hepatic cytochrome P450 complex and any toxic side-products produced are neutralised by the glutathione enzymatic system (GSH). The centrilobular cells of the sinusoids have the least GSH and the lowest oxygen supply thus they are at most risk of toxic injury. If the activity of the P450 and/or GSH is impaired or overwhelmed, e.g. in hepatic disorders and/or the presence of high intensity chemotherapy, then toxic side-products accumulate leading to sinusoidal and EC injury. The resultant disruption of local haemostasis and immune system control result in microvascular thromboses the development of SOS [15] (formerly known as veno occlusive disease or VOD). The injury may extend beyond the sinusoids allowing toxic chemotherapeutic drugs and their side products to access ECs in the general circulation and other organs. If these are already injured by prior total body radiation and/or infections or by graft v host disease (GvHD) following haematogenous stem cell transplantation (HSCT), then further endothelial damage will develop with gradual or sudden emergence of the clinical and pathological picture of TA-TMA. Both SOS and TA-TMA occur most frequently as complications of HSCT as a result of the chemotherapy used to prepare for the transplant, the use of allogeneic in place of autologous transplants and post-transplant use of further chemotherapy and a cocktail of drugs to prevent or control infection, transplant rejection and GvHD. Both SOS and TA-TMA are associated with a high mortality. **Table 1** shows risk factor associated with one or both complications.

Complement cascade proteins also originate in the liver. In health the immunological/anti-inflammatory and haemostatic systems are finely tuned and, because of their cross-talk via various interacting pathways, maintain a finely balanced vascular homeostasis ready to repel 'foreign' invasion and seal damaged vessels to limit blood loss and procoagulant products (including PAI-1, thrombomodulin, vWF and microparticles). However, sinusoidal cell and EC injury related to HSCT injury leads to release of a cocktail of cytokines and mitogens, the so-called 'cytokine storm'. Unregulated complement activation [16–20] ensues and the balance and cross-talk between haemostasis and the immune systems is disturbed. The result is further EC damage with fibrin deposition and thrombi feeding into the pathogenesis of both SOS and TA-TMA.

SOS usually manifests within 21 days but may present late, with thrombocytopenia and signs of portal hypertension due to fibrous obliteration of the sinusoids and central venules. Endothelial injury underlies both disorders but for some [21] this is insufficient to consider SOS as a vascular endothelial syndrome. However, others [22] disagree since TA-TMA, with its mixed endothelial/immune origin is included [21]. Furthermore, immunological involvement in the pathogenesis of SOS is also very likely since injured ECs release cytokines and mitogens and these are capable of complement cascade activation and disruption [23]. These can also activate the coagulation cascade via the intrinsic pathway further increasing thrombin production. Observations that the frequency of SOS increases with the use of mis-matched and unrelated donor cells and is redusced in T-cell depleted HSCT also point to an immunological connection. The overall frequency of SOS development after bone-marrow transplantation (BMT) is about 14% (range 5%–50%), depending upon the chemotherapeutic drug and/or conditioning regimen used for cancer treatment and transplantation, and the clinical diagnostic criteria used [24, 25]. Children appear to be more prone to SOS but the wide range is greatly influenced by diagnostic imprecision, clinical status of the patient at BMT, and the conditions of the transplant, particularly the type of conditioning used. SOS is associated with a 40% mortality but in the presence of organ disfunction this may rise to 80%.


#### **Table 1.**

*Risk factors for SOS and TA-TMA.*

TA-TMA usually presents at any time within the first 3 months of transplantation but may appear up to several years after the HSCT. The overall frequency of TA-TMA is about 5% but up to 76% [26] has been reported (see **Table 1**). Mortality may reach 80% and is related to the number of risk factors present, e.g. the type of cytotoxic agent, particularly methotrexate, cyclophosphamide, etc., used in the conditioning regimens for transplantation, presence of active infection, use of matched unrelated donors, transplant mismatches, presence of GvHD and previous BMT. Survivors may suffer long term morbidity due to chronic organ damage.

Perhaps TA-TMA represents a vascular form of GvHD since it may precede the appearance of GvHD and its frequency increases with the severity of GvHD [21] and they share similarities in pathophysiology [27–29]. These considerations may explain the overlaps and differences between SOS and TA-TMA in their risk factors (see **Table 1**) and their distribution, clinical presentation and sequelae (see **Table 2**). In addition, it may account for their presence together in some patients and the continuing controversy over their diagnostic criteria that confounds early recognition and treatment of both disorders.

It is possible that SOS and TA-TMA are different clinical presentations of the same problem. Their pathogenesis is similar and the resulting sinusoidal and EC injury triggers release of many factors resulting in disruption of both haemostasis and immune systems. In this respect both SOS and TA-TMA are similar to the general group of microangiopathies [22, 30].

