Causes of Deep Vein Thrombosis (DVT)

Causes of Deep Vein Thrombosis (DVT)

Causes of DVT affect one or more of the 3 components of Virchow’s triad:

Stasis of blood

  • Immobility from
    • e.g. hospital admission or plaster cast
  • Proximal compression of veins from
    • e.g. inguinal lymphadenopathy, ovarian tumour or cervical rib

Hypercoagulable state

  • Acquired
    • Inflammation
      • Following trauma or surgery
      • Post-partum
      • Malignancy
      • Acute inflammatory (e.g. IBD) or infectious illness
    • Organ dysfunction
      • Liver disease
      • Renal failure
      • Nephrotic syndrome
    • Haematological
      • Anti-phospholipid syndrome
      • Hyperviscosity due to leukocytosis (>100), or high levels of IgM or IgA paraprotein
      • Myeloproliferative disorders (polycythaemia rubra vera, essential thrombocythaemia, myelofibrosis)
      • Paroxysmal nocturnal haemoglobinuria
      • ITP and heparin-induced thrombocytopenia (HIT)
    • Drugs
      • Oral contraceptives and hormone replacement therapy
      • Glucocorticoids
      • Thalidomide and its derivatives
  • Congenital
    • Antithrombin deficiency
    • Protein C and Protein S deficiency
    • Prothrombin G20210A
    • Factor V Leiden (activated protein C resistance)
    • Note much inherited risk is due to numerous unidentified polymorphisms in other genes.

Endothelial injury

  • Recreational intravenous drug use
  • Iatrogenic central venous catheters
  • Surgery

Others

  • There are some risk factors, e.g. obesity, which do not clearly affect any of Virchow’s triad
  • Many risk factors e.g. recent surgery affect more than one part of Virchow’s triad
  • To guide clinical management it is helpful to divide risk factors into reversible (e.g. trauma, acute inflammation) and irreversible (e.g inoperable cancer, genetic factors)

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Non-Hodgkin Lymphoma (NHL)

Non-Hodgkin Lymphoma (NHL)

 

  • Non-Hodgkin lymphoma (NHL) is an umbrella term for many cancers deriving from lymphocytes, which predominantly are found in lymphoid tissue (lymph nodes, spleen and mucosa-associated lymphoid tissue a.k.a. MALT).
  • ‘Lymphoproliferative disease’ is often used interchangeably. However, while NHL makes up the majority of lymphoproliferative diseases, this term includes others such as Hodgkin disease, and acute lymphoblastic leukaemia.
  • Lymphadenopathy is the most common clinical syndrome seen in NHL, but sometimes lymph nodes are unaffected, and the disease is only found in bone marrow or in extranodal sites.
  • Leukaemia means the presence of circulating cancerous white blood cells, and implies bone marrow involvement. In some types of NHL, leukaemia is common (e.g. chronic lymphocytic leukaemia), and in many others it is a rarely encountered manifestation.

Types (classification) of Non-Hodgkin Lymphoma

  • According to pathological grade (high grade or low grade)
  • According to cell of origin (B cell or T cell)
  • According to histological features:

Classification of Non-Hodgkin Lymphoma (NHL)

DiagnosisGradeProportion of NHL casesB or T cell
Chronic lymphocytic leukaemiaLow26%B cell
Follicular lymphomaLow12%B cell
Marginal zone lymphomaLow13%B cell
Lymphoplasmacytic lymphoma, a.k.a. Waldenström’s macroglobulinaemiaLow1%B cell
Mantle cell lymphomaVariable3%B cell
Diffuse Large B cell lymphomaHigh31%B cell
Burkitt’s lymphomaHigh1%B cell
T cell lymphoma (various)Variable4%T cell

Epidemiology of non-Hodgkin lymphoma (NHL)

  • Accounts for 5% of all cancers in the UK
  • Incidence of high grade NHL in the UK: 18 per 100,000 per year.
    • It is rising for reasons that are not well understood.
  • 10 year prevalence of low grade NHL in the UK: 106 per 100,000
  • Median age at diagnosis 70 years.

 

Video on the pathophysiology and types of non-Hodgkin lymphoma

Risk factors for non-Hodgkin lymphoma (NHL)

  • In most cases of NHL, no particular risk factors can be identified.
  • A small proportion of NHL is attributable to infection:
    • Untreated HIV infection is associated with high grade NHL
    • H. pylori can cause marginal zone lymphoma, especially affecting gastric MALT.
    • Epstein-Barr virus is associated with various types of NHL, especially post-transplant lymphoproliferative disease (PTLD) seen in recipients of solid organ transplants.
    • Human T cell lymphotropic virus-1 (HTLV-1) is associated with T cell lymphoma
  • Ionising radiation (most commonly due to previous cancer treatment)
  • Some immunosuppressant medication (e.g. ciclosporin)
  • Autoimmune disease (e.g. Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus)
  • Coeliac disease is associated with enteropathy-associated T cell lymphoma (EATL)

Pathogenesis of non-Hodgkin lymphoma (NHL)

  • Many subtypes of lymphoma have characteristic genetic changes, causing overexpression of particular genes which drive proliferation or promote survival. Many involve translocations with genes highly expressed in lymphocytes, such as immunoglobulin heavy chain.
  • Follicular lymphoma is associated with BCL2 overexpression due to a translocation t(14:18) between the BCL2 gene on chr. 18 and the Ig heavy chain chain on chr. 14.
  • Mantle cell lymphoma is associated with t(11:14) between the cyclin D1 gene (chr. 11) and the Ig heavy chain gene (chr. 14), which upregulates cyclin D1 expression.
  • Lymphoplasmacytic lymphoma is associated with Myd88 overexpression due to an activating point mutation.
  • Burkitt lymphoma has a rearrangement which causes overexpression of the oncogene MYC on chr. 8. The most common is t(8:14) between the Ig heavy chain gene on chr. 8, but t(2:8) is also seen, with the kappa light chain gene, as is t(8:22) with the lambda light chain gene.
  • Diffuse large B cell lymphoma is associated with overexpression of BCL6, though there are a number of mechanisms, both isolated mutations and chromosomal rearrangements, underlying this.

Presentations of non-Hodgkin lymphoma (NHL)

  • Due to its anatomical and pathological variety, NHL has a myriad of presentations:
    • Symptoms due to local mass effect
      • Enlarged lymph nodes noted by patient, their family or a healthcare professional
      • Extrinsic compression of structures by lymphadenopathy e.g. biliary obstruction causing jaundice or cholangitis, ureteric obstruction causing hydronephrosis and renal failure, collapse of a lung lobe due to bronchial obstruction
      • Symptomatic splenomegaly (LUQ pain, early satiety, abdominal swelling)
      • Extralymphatic mass effect (e.g. spinal cord compression due to lymphoma in vertebrae or the spinal canal)
      • Rarely, T cell lymphomas affecting the skin present as raised red or purple plaques.
    • Symptoms due to local inflammation
      • Malignant pleural effusion
      • Ascites
      • Malignant meningitis which may cause hydrocephalus
    • Systemic symptoms (‘B symptoms’)
      • Night sweats (drenching)
      • Fever
      • Unintentional weight loss
    • Symptoms due to bone marrow infiltration
      • Anaemia causing shortness of breath or fatigue.
      • Thrombocytopenia causing petechiae, bleeding or bruising.
      • Neutropenia causing recurrent infection
    • Incidental findings
      • Lymphadenopathy or soft tissue deposits identified on scans
      • Raised lymphocyte count
      • Abnormal lymphocytes on blood film
      • Incidental paraprotein on serum electrophoresis
    • Symptoms due to immune system dysfunction
      • Hypogammaglobulinaemia causing recurrent infection
      • High levels of IgM paraprotein causing hyperviscosity
      • Autoimmune haemolytic anaemia or immune thrombocytopenia purpura (ITP)
      • Paraneoplastic neuropathy
      • Amyloidosis
    • Metabolic disturbance
      • Hypercalcaemia (lethargy, dehydration, renal failure)
      • Tumour lysis syndrome (renal failure due to products of high cell turnover, seen in high grade lymphoma)

Patient-focused and slight dated video on overview of NHL

Differential diagnosis of non-Hodgkin lymphoma (NHL)

  • Hodgkin disease
  • Lymphatic metastasis from solid organ malignancy
  • Non-malignant lymphadenopathy
    • Reactive lymphadenopathy, to a lesion (infectious, traumatic or malignant) in the tissues drained by the affected lymph node
    • Associated with connective tissue disease
    • Viral infection (particularly acute Epstein-Barr virus infection, and HIV)
    • Granulomatous disease (Tuberculosis, sarcoidosis)
    • Toxoplasmosis, Cat-scratch disease
    • Castleman’s disease

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Differential diagnosis for lymphoma

Differential diagnosis for lymphoma

Differential diagnosis for lymphoma

Classification of diagnosisDiagnosis
Other malignancyLymphatic metastasis from solid organ malignancy
Non-malignantNon-malignant lymphadenopathy
Non-malignantReactive lymphadenopathy, to a lesion (infectious, traumatic or malignant) in the tissues drained by the affected lymph node
Non-malignantAssociated with connective tissue disease
Non-malignantViral infection (particularly acute Epstein-Barr virus infection, and HIV)
Non-malignantGranulomatous disease (Tuberculosis, sarcoidosis)
Non-malignantToxoplasmosis, Cat-scratch disease
Non-malignantCastleman's disease

 

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