In addition to our wide range of educational resources, the BSH has produced two booklets focusing on helping undergraduate students decide whether to choose Haematology as a career, and to understand the skills and knowledge they will need as a haematologist. 

 

  

 

 

 

 

Our Careers in Haematology booklet discusses the attractions of haematology, the range of conditions that haematologists treat and what makes a good haematologist. 

    

 

    

This curriculum outline acts as a guide both to students and medical schools regarding the extent and depth of knowledge of haematology that would be expected of newly-qualified doctors commencing their first posts.

It is expected that this knowledge will be acquired during both the pre-clinical and the clinical years

 
     
     
     
 

Essential Haematology Day

Our popular Essential Haematology Day took place on the 25 February 2017 at St Thomas', London.

 

     
     

 

 

 

 

Essay Prize 2016

The BSH is very happy to announce the Essay Prize for 2016 - Discuss the Impact of Obesity on the Incidence and Management of Haematological Disorders has been awarded to Prateek Yadav from UCL Medical School, and the prize for the runner up essay to Maria Fala from the University of Cambridge.

 

 

Prateek Yadav - The Impact of Obesity on the Incidence and Management of Haematological Disorders

Introduction

The obesity epidemic is one of the biggest healthcare challenges of our lifetimes. The WHO reports that obesity has more than doubled worldwide since 1980, By 2014 1.9 billion adults were overweight with 600 million of these classified as obese. This accounts for 39% of adults over 18 years of age being overweight worldwide. When looking at child and adolescent populations, it is estimated that 41 million children under 5 years of age are overweight worldwide. Most notably, developing countries and recently developed countries account for a large proportion of these; in 2014 almost half of overweight children under 5 lived in Asia. In addition, the number of overweight children under 5 years of age doubled in the African continent from 1980 to 2014.[1]  Both the rate of rapid development across the world and the increasing proportion of children who are obese indicate that this is not a problem that is going to go away; if anything, the pressures of obesity on our healthcare systems will only increase in the coming years. Furthermore, haematologists must be highly aware of how obesity and the associated metabolic syndromes interact with haematological conditions to provide high quality personalized care for patients. This essay looks at the interplay between obesity and haematological conditions and the impact on patients and our healthcare systems.

 

What drives the pro-coagulable state in obese patients?

Obesity is associated with hypertension, hyperlipidaemia and atherosclerosis, which are all risk factors for clotting events and obese patients are more likely to have difficulties with mobility, causing venous stasis. There are also a multitude of co-existing factors that create the increased clotting risk in the obese, and a plethora of hormonal disturbances and inflammatory reactions putting patients at a higher risk. Adipose tissue is an active endocrine organ, releasing cytokines such as leptin, adiponectin, interleukin-6 and tumour necrosis factor-α (TNF-α) that have subsequent effects on insulin resistance, haemostasis and inflammation. In terms of clotting components, obese patients tend to have higher circulating levels of fibrinogen, von Willebrand factor and plasminogen activator inhibition as well as factors VII and VIII[2]. These increased levels are likely to be produced by alterations in hepatic synthesis via pro-inflammatory cytokines. A single standard deviation increase in fibrinogen, in both men and women, was associated with a 20% increased incidence of primary cardiovascular events when adjusted for age and other risk factors[2].Atherosclerotic disease is also promoted by increased expression of intercellular adhesion molecules such as ICAM -1 which are at higher levels in obese patients[3].

Higher than normal levels of plasminogen activator inhibitor-1 (PAI-1) is regarded as part of the metabolic syndrome of insulin resistance and obesity[4]. High levels of PAI-1 is a risk factor for atherosclerosis and thrombosis, as it is the principle inhibitor of tissue plasminogen activator which in turn has a key role in fibrinolysis.  It has been shown that adipocytes can produce PAI-1, which is a potential mechanism for increased coagulability in obesity and indeed waist circumference and PAI-1 levels correlate strongly. Weight loss in turn reduces PAI-1 levels but does not necessarily reduce fibrinogen levels, providing further evidence that PAI-1 is a key player in the higher clotting risk in the obese [2][5].

The inflammatory markers that are raised in obesity and insulin resistance, including TNF-α and transforming growth factor-β, have been shown to promote PAI-1 production[5]. This can contribute to the already significant production of PAI-1 by adipose tissue. These effects may be further compounded by disturbances in glucocorticoid and insulin levels in these patients, although the causal direction is unclear; there is some evidence to suggest that PAI-1 drives the development of insulin resistance rather than the other way around.

 

The leptin produced by adipose tissue increases thrombogenicity via a variety of potential mechanisms, including increasing platelet aggregation and von Willebrand factor levels [3]. Leptin also enhances calcification of the vasculature, providing targets for thrombogenic processes. The concentration of pro-inflammatory cytokines increases with adiposity; obesity is accompanied by a chronic inflammatory process. IL- 6 can be three times higher in obese patients than slim patients and it is thought to contribute to insulin resistance syndrome. The commonly measured inflammatory marker C reactive protein (CRP) has a strong association with obesity even accounting for age, race and smoking status differences[6]. CRP is independently associated with atherothrombotic risk and is an important direct link between obesity, inflammation and thrombotic risk. Raised CRP induces platelet adhesion to endothelial cells and interestingly, activated platelets convert pentameric CRP to its monomeric form, where it is more likely to capture neutrophils. This evidently makes up part of the atherosclerotic chain of events. Raised CRP levels also inhibit release of tissue-type plasminogen activator, which is important to produce the fibrinolytic substance plasmin, and upregulates release of PAI-1 from endothelial cells. Furthermore, in vitro experiments have shown CRP stimulates blood monocytes to produce tissue factor, which is a key part of the clotting cascade [7].

 

Management of Haemostasis in Obese Patients

Evidence suggests that normal doses of thromboprophylaxis are suboptimal in morbidly obese patients and a trend towards higher doses of thromboprophylaxis may be seen. This is because, despite clinicians currently prescribing weight-adjusted doses for VTE treatment, the doses for thromboprophylaxis are often fixed dosage regimens. This regardless of evidence of a dose-response relationship for VTE prevention and is likely to be due to fears of bleeding risk. It has been shown that high dose thromboprophylaxis with heparin (7500 units TDS) or enoxaparin (40mg BD) nearly halved the incidence of VTE in the morbidly obese when compared to standard doses without increasing bleeding risk [8]. It is important to note that while this study has a very large sample size of 9241 and a good mix of patient settings, it has borderline statistical significance (p=0.050).

The tendency towards higher doses is compounded by the fact that stockings and pneumatic compression has reduced efficacy in the severely obese.  More insight and clarity is needed into the specifics of dosage regimens in the obese for prevention of VTE as there are a large variety of dosages tested in studies. There are other practical considerations to consider, for example enoxaparin is often manufactured in prefilled 40mg syringes which might make it difficult for early adopters of a 0.5mg/kg regimen or similar. It remains to be seen whether dosage regimens for the new direct oral anticoagulant drugs (DOACs) will need to be optimized for patient weight.

Knowledge of the pathways and mechanisms influencing the high risk of clotting events may open more obscure avenues to optimize patient care for prevention. For example, it is useful to note that decreases in PAI-1 activity are noted with ACE-inhibitors and angiotensin receptor blockers, along with diabetes drugs such as metformin and thiaizolidinediones [9]. This could potentially allow doctors to use synergistic drug combinations in comorbid patients in the future. Many patients at thrombotic risk are taking statins which have been shown to reduce CRP levels[7] and in the future anti-inflammatory medications could potentially mitigate the inflammation mediated thrombotic risk in obese patients.

 

Obesity and Transfusion Medicine

A subject of much debate is whether being obese leads to increased numbers of surgical complications and therefore increased requirement for transfusions, or whether higher BMI and circulating volume protects against blood loss. The ‘obesity paradox’ of outcomes is the idea that overweight or obese patients may have better outcomes in certain situations than those who are of normal weight. The relationship between obesity and the need for perioperative transfusions is not clearly identified and much of the evidence is from low powered studies with no uniform definition of obesity across studies. In one recent study of elective procedures, namely total hip and total knee arthroplasties, patients who had an elevated BMI (>30) had decreased rates of blood transfusion (p=0.001). Patients with elevated BMI also lost significantly smaller percentages of blood volume perioperatively[10]. While this example is apt, as arthroplasties are more common in the obese population due to increased risk of osteoarthritis, this is not a generalizable result.

The relationship between obesity and transfusion needs in trauma has not been fully established. It is possible to speculate that an obese patient might lose a lower percentage of their blood volume than a non-obese patient in comparable situations. However, patients who are obese are at higher initial risk of mortality after trauma mostly due to haemorrhagic and hypovolaemic shock[11]. Risk in obese patients is compounded by the difficulty doing other procedures during resuscitation such as intubation and insertion of central venous catheters. A study looking at the frequency of massive transfusion in obese patients, with massive transfusion (MT) defined as 10 units of packed red cells in the first 24 hours, found that obese patients were more likely to need massive transfusion than non-obese patients with an odds ratio of 1.68 (95%CI 0.97 – 2.72), p = 0.07. The p value is relatively large, and the 95% confidence intervals overlap; obese patients had 15%(95%CI: 9-23%) receiving MT, non-obese 10% (95%CI: 8-12%) [11]. Despite the drawbacks to this study it might point to a new direction in transfusion protocol and while scores such as the Trauma Associated Severe Haemorrhage score (TASH) score do not mention BMI or weight, this might be a useful parameter in the future to assess transfusion demands in trauma patients.

Obesity and Benign Haematology

Despite associations with thin children with poor growth, conditions like sickle cell disease and thalassaemia now have drastically improved lifespans and prognoses and to see an obese patient with these conditions is not uncommon. Obesity complicates care as systemic changes in obesity add to the risk already present in these patients. The spectrum of complications that sickle cell anaemia can cause overlap significantly with risk factors obesity brings. Obesity and sickle cell both contribute to risk of stroke, cardiovascular events and vascular disease. In addition, obesity related hypertension combined with sickle cell anaemia can contribute to retinopathy and end-organ damage. It follows that these patients need close monitoring and careful management, and sickle cell patients of normal BMI do have lower admission rates than those with very high or low BMI [12]. However, it was found that BMI has an overall inverse relationship with number of admissions. More research is needed in this area to see how metabolic changes in obesity will affect patients with benign haematological conditions.

Obesity and haematological malignancies

Obesity increases the risk of the haematological malignancies, including leukaemias, lymphomas and myeloma [13]. If the obesity epidemic is not tackled successfully, demands on haemato-oncology services are going to increase in coming years. The distribution of risk is a dose-response relationship; increasing weight leads to increasing risk and vice versa. The meta-analysis of cohort studies found significant association between obesity and risk of developing non-Hodgkin’s lymphoma and myeloma. The evidence for increased risk of the leukaemia generally was significant in 11 out of 15 studies, however stratification into different subtypes was not carried out in most of the studies so specific information on these was not reported [13]. However, a strong association between obesity and promyelocytic leukaemia was found.

 

The mechanism by which obesity increases cancer risk is not fully clear but two major theories are called the ‘inductive’ and ‘selective’ hypotheses. The former relies on inflammatory and metabolic changes in obesity encouraging neoplastic changes, while the latter hypothesizes that the environment obesity produces selects in favour of already present abnormal cells that are dormant. Leptin produced by adipocytes induces cancer progression via the MAPK, PI3K and STAT pathways. In a similar way to the disturbances in haemostasis in obesity, proinflammatory cytokines including TNF-α, IL-2, IL-8 and IL-10 mediate increased cancer risk. Insulin and IGF-1 levels in obese patients is also implicated in cancer risk and mortality, thought to be acting via the AKT/PI3K/mTOR cascade. The fact that metformin reduces cancer incidence and mortality, but drugs that stimulate insulin secretion increase incidence and mortality, emphasizes the importance of insulin and IGF-1 in cancer biology [14].

The presence of a malignancy drastically increases risk of clotting events and may produce a perfect storm in obese patients who are already high risk and much of the mortality and morbidity is accounted for by hypercoagulation[15]. These patients need close attention to prevent VTE, cardiopulmonary events and stroke. There are further complications in that conditions such as type 2 diabetes, with high prevalence in the obese population, can modulate toxicity of cancer therapy regimens. The presence of diabetes significantly increases the risk of cardiotoxicity, from anthracycline treatment in patients with lymphoma, breast cancer and gastric cancer [16]. Chemotherapy regimens may have to be adjusted to prevent adverse effects that are exacerbated by comorbid conditions, especially as cancer prognoses improve.

 

Obesity and Healthcare Funding

It is important to look at the way funding structures across healthcare systems change as the burden of obesity-related problems increases. In the UK, the direct cost to the NHS was estimated at £4.2 billion in 2007, with indirect costs estimates ranging to up to £15.8 billion[17]. When compared to the estimate of cost in 1998, at 469.9 million, it puts into perspective the speed and magnitude of the growth in spending. Future projections of total indirect costs reach as high as £15.8 billion. This will put pressure on all branches of medicine, but haematology is a speciality that could be particularly affected due to the high costs of chemotherapy drugs for haematological malignancies. An instructive example of this is the drug ibrutinib for chronic lymphocytic leukaemia, which was not approved by NICE due to its high cost (£55.000 per patient) until a recent deal where prices were lowered for the NHS [18].  As the obesity burden increases, healthcare providers may be forced to make difficult decisions about funding treatments and more of the financial burden of these expensive treatments may have to be shouldered by organisations such as the Cancer Drugs Fund. This will have a major impact on the range treatments available to haematologists and will affect how funding decisions are made in the future.

 

Conclusion

Obesity brings with it increased risk of VTE, cardiovascular and cerebrovascular events, and increasing obesity rates may change the landscape of thromboprophylaxis of the future. It will also be a strong driving force for innovations in this area, as seen recently with the development of the DOAC drugs. More investigation is needed into the interaction between obesity and benign haematological conditions, and patient management may have to change to account for greater risk. Obesity also increases the incidence of almost all the haematological malignancies and the associated metabolic syndromes may complicate management of cancer. Mechanistically, hormonal imbalances and inflammatory processes influence many of these risk increases and are still fertile areas for more research. The severe financial pressures obesity puts on healthcare services will force providers to make difficult decisions about resource allocation in the future, and may reduce the range of treatments available in the NHS to haematologists in the future.

 

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References

[1]       World Health Organization, “Media centre Obesity and overweight,” January, pp. 1–5, 2015.

[2]       I. Mertens and L. F. Van Gaal, “Obesity, haemostasis and the fibrinolytic system,” Obes. Rev., vol. 3, no. 2, pp. 85–101, 2002.

[3]       L. F. Van Gaal, “Mechanisms linking obesity with cardiovascular disease,” Diabetes, Obes. Metab., vol. 12, no. December, p. 21, 2010.

[4]       I. Juhan-Vague, M. C. Alessi, and P. E. Morange, “Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity.,” Ann. Med., vol. 32 Suppl 1, pp. 78–84, Dec. 2000.

[5]       S. J. Appel, J. S. Harrell, and M. L. Davenport, “Central obesity, the metabolic syndrome, and plasminogen activator inhibitor-1 in young adults,” J Am Acad Nurse Pr., vol. 17, no. 12, pp. 535–541, 2005.

[6]       M. Visser, L. M. Bouter, G. M. McQuillan, M. H. Wener, and T. B. Harris, “Elevated C-reactive protein levels in overweight and obese adults.,” JAMA, vol. 282, no. 22, pp. 2131–5, Dec. 1999.

[7]       W. P. Fay, “Linking inflammation and thrombosis: Role of C-reactive protein.,” World J. Cardiol., vol. 2, no. 11, pp. 365–9, Nov. 2010.

[8]       T.-F. Wang, P. E. Milligan, C. A. Wong, E. N. Deal, M. S. Thoelke, and B. F. Gage, “Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients.,” Thromb. Haemost., vol. 111, no. 1, pp. 88–93, Jan. 2014.

[9]       M. Gnacińska, S. Małgorzewicz, M. Stojek, W. Lysiak-Szydłowska, and K. Sworczak, “Role of adipokines in complications related to obesity. A review.,” Adv. Med. Sci., vol. 54, no. 2, pp. 1–8, 2009.

[10]     N. Frisch, N. M. Wessell, M. Charters, E. Peterson, B. Cann, A. Greenstein, and C. D. Silverton, “Effect of Body Mass Index on Blood Transfusion in Total Hip and Knee Arthroplasty.,” Orthopedics, vol. 39, no. 5, pp. e844-9, 2016.

[11]     A. De Jong, P. Deras, O. Martinez, P. Latry, S. Jaber, X. Capdevila, and J. Charbit, “Relationship between obesity and massive transfusion needs in trauma patients, and validation of TASH score in obese population: A retrospective study on 910 trauma patients,” PLoS One, vol. 11, no. 3, pp. 1–15, 2016.

[12]     M. W. Farooqui, N. Hussain, J. Malik, Y. Rashid, M. Ghouse, and J. Hamdan, “Prevalence of Obesity in Sickle Cell Patients,” Blood, vol. 124, no. 21, 2014.

[13]     M. A. Lichtman, “Obesity and the Risk for a Hematological Malignancy: Leukemia, Lymphoma, or Myeloma,” Oncologist, vol. 15, no. 10, pp. 1083–1101, 2010.

[14]     I. Vucenik and J. P. Stains, “Obesity and cancer risk: Evidence, mechanisms, and recommendations,” Ann. N. Y. Acad. Sci., vol. 1271, no. 1, pp. 37–43, 2012.

[15]     G. J. Caine, P. S. Stonelake, G. Y. H. Lip, and S. T. Kehoe, “The hypercoagulable state of malignancy: pathogenesis and current debate.,” Neoplasia, vol. 4, no. 6, pp. 465–73, 2002.

[16]     A. Gomes, L. Lopes, A. Ferreira, M. Correia, H. Mansinho, and H. Pereira, “The effect of cardiovascular risk factors and cancer type in anthracycline’s cardiotoxicity,” Eur. Hear. J. ( 2016 ) 37 ( Abstr. Suppl. ), 572, vol. 17 (Supple, p. ii269, 2016.

[17]     L. Morgan and D. Monica, “The economic burden of obesity,” Natl. Obes. Obs., no. October, pp. 1–13, 2010.

[18]     “NICE reverses decision on CDF leukaemia drug after price drop | News and features | News | NICE.”

 

 

           

 

 

 

 

 

Maria Fala - Discuss the impact of obesity on the incidence and management of haematological disorders

Obesity is currently one of the main challenges experienced by medicine. The obesity epidemic is constantly spreading, with the worldwide rates more than doubling in the last thirty-five years2. Its consequences are numerous and diverse. Obesity has an impact on all systems of the body, including haematology. It is stratified in terms of the Body Mass Index (BMI), where a value of 20-25 kg/m2 is generally considered to be normal weight, 25-30 kg/m2 is overweight, 30-35 kg/m2 is obese and anything above 35 kg/m2 is superobese2. Haematology is affected by obesity-driven systemic and local changes in the Bone Marrow, many of which are still unknown. This essay will explore these changes, their effect on haematological disorders and their management.

 

Haematological cancers form a large part of the haematological disorders in terms of their prevalence in the human population as well as their morbidity and mortality. Obesity has been found to increase the incidence and worsen the prognosis of many different types of cancers. It is, therefore, not surprising that haematological cancers are also affected by obesity.

 

Adipocytes constitute the most abundant cell type in bone marrow6. They play an important role in the tissue microenvironment within the bone marrow. In obese patients, the number of adipocytes in the bone marrow is increased and their cytokine and lipid profile changes, affecting the neighbouring cells. For example, studies on obese mice have demonstrated that adipocytes release more leptin and inflammatory markers and less adiponectin and anti-inflammatory proteins6. These chemicals activate various signalling cascades and lead to increased genomic instability, impaired DNA repair, tumour progression, local immunosuppression and epigenetic changes, all of which are detrimental for the patient6. For this reason, adipocytes now constitute a potential therapeutic target for several cancers.

 

A cancer that has been found to be affected by obesity is Multiple Myeloma(MM). This is a plasma cell neoplastic tumour which constitutes 10% of haematological cancers6. It is characterised by a clonal expansion of abnormal plasma cells in the bone marrow, osteolytic bone disease, anaemia and renal failure5. It is currently incurable. Risk factors include older age, African ethnicity, family history and Monoclonal Gammopathy of Undetermined Significance (MGUS)6. Obesity has recently been identified as another important risk factor for multiple myeloma, causing an increase in incidence and mortality6. A recent paper suggests that this increased risk is an indirect effect because obesity is, in fact, a risk factor for MGUS, which was found to be twice as common among obese patients compared to non-obese patients3. MGUS is the stage which commonly precedes MM, in which an increase in the secretion of monoclonal immunoglobulin is observed without any accompanying myeloma features such as osteolytic changes5.

 

One of the mechanisms by which obesity is linked to increased risk of cancer is the communication between adipocytes and cancer cells, aiding tumour initiation, growth and metastasis6. In a murine study, the role of adipocytes and the bone marrow microenvironment in tumour growth and progression has been demonstrated. 5T myeloma cells were inoculated in mice whose diet was varied. In mice on a high-fat diet, an increased amount of myeloma-specific IgG2bk para-protein was detected, before myeloma inoculation, suggesting that obese mice were in an obesity-driven MGUS state before tumour inoculation. They developed myeloma after the tumour was inoculated and the tumour burden was reduced once the high fat diet was removed. Collectively, these results suggested that the obese host provided a myeloma-permissive microenvironment for the myeloma cells to grow. Also, obesity did not have a direct effect on tumour growth and survival, but had an important role in enabling the initiation of the tumour5. A possible driver for this change in the microenvironment is Insulin-like Growth Factor 1 (IGF-1) which was raised in obese mice, even before inoculation of the myeloma cells. Therefore, IGF-1 acts as a potent myeloma growth factor. Interleukin-6, on the other hand, commonly raised in cancer, only appeared to be raised in myeloma-bearing mice, suggesting that it is released by myeloma cells6.

 

Conversely, some study results suggest a role of the altered microenvironment in tumour growth and progression. One of the causal mechanisms for this relates to the increased amount of Interleukin-6 (IL-6) in the bone marrow microenvironment. IL-6 leads to activation of the STAT-3 signalling pathway, leading to increased proliferation and reduced apoptosis in monoclonal plasma cells6. Additionally, tumour growth and progression is aided by the obesity-driven changes enabling better cell adhesion and angiogenesis. Better adhesion is correlated with the alpha-4 integrin, whose expression has been shown to increase in obesity6. This offers increased proliferation, survival, migration and drug resistance to the tumour cells, which is why alpha-4 integrin blockers can restore sensitivity of the myeloma cells to bortezomib6. Angiogenesis is enhanced in the obese state via two- to three-fold overexpression of Matrix Metalloproteinase 2 (MMP-2) in obese compared to normal6.

 

Another haematological cancer affected by obesity is Acute Myeloid Leukaemia (AML). This is the most common form of acute leukaemia in adults and is frequently fatal14. Obesity is known to increase both incidence and mortality rates but research is still undergoing to investigate the pathogenesis mechanism. In a study undertaken using murine models, the leukaemia burden was shown to be higher in diet-induced obese mice14. This was associated with higher levels of Fatty Acid Binding Protein 4 (FABP-4) and Interleukin-6 (IL-6) in serum. The Fatty Acid Binding Proteins are cytosolic intracellular receptors that can bind hydrophobic ligands and mediate lipid trafficking in the cell. FABP-4 is a good marker of obesity as it is highly expressed in adipocytes and macrophages of the obese. Upregulation of FABP-4 has been shown to promote tumour growth in AML and this study proposes a mechanism through which this occurs. They have shown that FABP-4 upregulation is correlated with increased amounts of IL-6, which leads to activation of the STAT-3 transcription factor. This transcription factor promotes DNA Methyl Trasferase-1 (DNMT-1) expression, overexpression of which leads to DNA hyper-methylation and silencing of Tumour Suppressor Genes such as p53. Aberrant DNA methylation has already been shown to be involved in AML, which makes the proposed mechanism highly likely14.

 

Non-Hodgkin’s lymphoma is a group of malignant diseases which originate from lymphocytes. The effect of obesity on the risk of non-Hodgkin’s lymphoma was investigated in a meta-analysis study which used the random effects model4. This showed that obesity is associated with a statistically significant increase in the risk of non-Hodgkin’s lymphoma and in particular in the risk of diffuse large B-cell lymphoma. Overweight people were found to have a 7% higher risk and obese patients were found to have a 20% higher risk of developing the disease4.The mechanism through which obesity increases the risk of this cancer is still unclear but several hypotheses exist. Altered immune function and chronic inflammation are risk factors for non-Hodgkin’s lymphoma, therefore this might be the mechanism via which obesity increases the risk of lymphoma. For example, the obesity-driven reduction in adiponectin can lead to such immune changes since adiponectin normally has anti-inflammatory effects and reduces lymphocyte proliferation. In contrast, leptin, whose levels are increased in obesity, enhances monocyte proliferation and hence the release of inflammatory cytokines such as Tumour Necrosis Factor-alpha (TNF-α). Another possible mechanism is related to the resistance to insulin which develops in obesity. As a result, the body produces more insulin which leads to a compensatory hyperinsulinaemia. This leads to elevated levels of IGF-1 which leads to increased cell proliferation and reduced apoptosis. This could also explain why Type II diabetes is also associated with an elevated risk for non-Hodgkin’s lymphoma4.

 

The coagulation and fibrinolytic cascades are very important cascades in haematology, as they determine a major property of the circulating blood, which is its tendency to clot. Obesity has been associated with higher levels of coagulation factors VII, VIII, IX, XII as well as the Von Willebrand Factor (VWF), tissue factor, fibrinogen and plasminogen activator inhibitor-1 and reduced levels of tissue plasminogen activator activity and activated protein C (APC) ratio1,7. As a result of this imbalance, obesity leads to a hypercoagulable state.

 

These coagulation and fibrinolytic factors are affected by obesity via different mechanisms. A study investigating the effects of obesity on the expression of tissue factor, found that compensatory hyperinsulinaemia in obesity might play a role in inducing tissue factor overexpression7. High insulin levels also lead to increased expression of Plasminogen Activator Inhibitor-1 (PAI-1), which also contributes to the hypercoagulable state. Thirdly, hyperinsulinaemia could also be the cause of the reduced Tissue Factor Pathway Inhibitor (TFPI) levels, leading to reduced inhibition of tissue factor activity in the clotting cascade7.

 

Based on the hypercoagulable state, a study has been undertaken to investigate the risk of bleeding in obese patients compared to normal weight patients, hypothesising that the hypercoagulable state would lead to a protection against bleeding in obese. However, even though the number of bleeding events was reduced in normal weight participants compared to underweight, the risk of bleeding in obese was not significantly different to the risk in normal weight participants1.

 

The hypercoagulable state in obesity is very important because it is a risk factor for thromboembolism. A study investigating the combined effect of obesity with other risk factors on the risk of thromboembolism has identified a number of interactions between risk factors15. People with genetic mutations that predispose them to thromboembolic events, have a higher combined risk in obesity compared to the sum of the two individual risks. Also, obesity in combination with oral steroids increases the risk of venous thromboembolism. This is because obesity produces a pro-thrombotic state while oestrogen increases the resistance to activated protein C and further increases the concentration of factors II, VII, VIII and X, thus enhancing the effects of obesity.

 

Haemophilia A is a hereditary X chromosomal recessive haematological disorder which is related to the coagulation cascade10. It is caused by a deficiency or a functional defect in clotting factor VIII, leading to impaired coagulation of blood and bleeding episodes, causing various problems such as limitations in joint range of motion due to haemorrhage in the joint. These episodes are prevented and controlled by intravenous infusion of Clotting Factor Concentrate (CFC). Several studies have been conducted to investigate the effect of the obesity-driven hypercoagulable state on the presentation of Haemophilia A. An increased net CFC usage was observed in obese patients compared to normal BMI patients, but this difference disappeared when adjusting the CFC usage for the patients’ weight10.  No difference was seen in FVIII activity between obese and non-obese patients, which is not surprising as even though obesity leads to overexpression of factor VIII, in Haemophilia patients this would not be possible, or the protein would be non-functional. Plasminogen Activator Inhibitor–1 (PAI-1) has been shown to be increased in in obese patients but led to no reduction in the need for coagulation10. Additionally, for reasons that continue to be unclear, obesity has been found to be associated with further limitations in joint range of motion and further joint mobility loss compared to non-obese patients. More research needs to be undertaken in the effects of obesity on haemophilia, for correct dosing of Clotting Factor Concentrate, according to the patient’s weight, to be determined.

 

The coagulation imbalance is also important to consider when treating patients with anticoagulants. These are needed when thrombus formation is likely and needs to be prevented or treated. However, clinical trials for most of these drugs excluded obese participants. There are many uncertainties regarding dosing in obese patients due to lack of evidence. This is a serious problem, because obesity increases the risk of venous thromboembolism and the duration of inpatient stay. Studies have been undertaken to determine whether the current drug dosing recommendations are appropriate for obese patients6. For venous thromboembolism prophylaxis, fixed doses of enoxaparin, dalteparin or tinzaparin are currently prescribed in the UK. However, this study provides evidence that enoxaparin and tinzaparin dose adjusted for BMI is more effective than the fixed dose6. The pharmacokinetics of each drug depend on its volume of distribution and its clearance, hence the effective dose and its dependence on the patient’s BMI is drug-specific. Therefore, mathematical models need to be applied to predict each drug’s behaviour.

 

Another systemic effect of obesity discovered, is the premature thymic involution that it causes. As a result, T cell generation is compromised and T cell apoptosis is increased leading to reduced thymocyte counts16. Consequently, obesity leads to reduced peripheral naïve T cells, causing impaired immunity and increased susceptibility to persistent infections.

 

Lastly, obesity can affect other haematological disorders such as amyloidosis, a disease involving extracellular deposition of protein fibrils. In amyloidosis AA, the protein fibrils are derived from SAA, an acute phase protein produced by hepatocytes under inflammatory conditions. A study on the effect of obesity on amyloidosis revealed a positive correlation between body weight and degree of amyloidosis, suggesting that obesity can cause enhanced chronic secretion of SAA11.

 

Surgical interventions to treat morbid obesity can also affect haematology. Case reports have suggested that gastric bypass leads to microcytic anaemia due to reduced iron absorption. This is because iron absorption normally occurs in the bypassed duodenum and because iron chelation, that normally occurs when iron moves from the acidic environment to the alkaline duodenum and precipitates as a hydroxide, is impaired13. Gastric bypass surgery also leads to reduced vitamin B12 levels, due to the loss of parietal cells which normally release intrinsic factor enabling vitamin B12 absorption in the distal ileum. Another case report presents the effects of total gastrectomy on haematology8. In this case, the vitamin B12 deficiency led to high homocysteine levels, a risk factor for thrombophilia. Therefore, it might be useful to provide prophylaxis against thrombosis in patients undergoing such interventions.

 

Unfortunately, haematological conditions themselves are also related with obesity. Many debilitating diseases can lead to a sedentary lifestyle which can cause weight gain and obesity. It has been shown that patients suffering from childhood acute lymphoblastic leukaemia, gain excessive weight during and after two years of therapy12. Previously, hypothalamic dysfunction due to cranial irradiation in treatment of the leukaemia was suspected to cause the increased rates of obesity in the survivors. However, a study on the causes of weight gain, has suggested that weight gain occurs even in the absence of cranial irradiation12. Reduced total energy expenditure, mainly due to reduced energy expanded on activity is the main cause of obesity, meaning that measures can be taken to reduce obesity in these patients.

 

To conclude, medicine must face the serious problem of obesity. This is a challenge due to the many diverse effects that obesity has on health but also because of its increasing prevalence. In haematology, obesity constitutes a risk factor and affects progression of many diseases, including cancers, coagulopathies and amyloidosis. Research in this field needs to be continued to find out how to deal with these emerging problems and how current treatments need to be modified to accommodate obese patients. Importantly, preventative measures need to be taken in order to minimise the cases of obesity to avoid its destructive consequences.

 

References:

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