MALT lymphoma

  • 8% of NHL
  • Most MALT lymphomas are gastric of which 95% are associated with H. pylori
  • May occur in
    • Stomach
    • Orbit
    • Gut
    • Lung
    • Thyroid
    • Salivary gland
    • Skin and soft tissues
    • Bladder
    • Kidney
    • CNS
  • Diagnosis is given by infiltration of CD5- monoclonal B cells on histopathology
  • May transform to diffuse large B cell lymphoma

Genetics

  • Two main forms
    • t(11;18)
      • Usually not gastric (H. pylori related MALT lymphomas do not show t(11:18))
      • t(11:18) > of NF-κB activation > cell survival
      • Genetically stable and do not progress to diffuse large B cell lymphoma
    • Multiple sites of instability including trisomies 3, 7, 12, and 18
      • Often acuire BCL6 mutations > aggresive lymphoma

Clinical Picture

  • Rare in children
  • B symptoms in 20%
  • Localised to organ in 40%
  • Organ and LN group in 30%
  • Associations with
    • Sjoegren’s
    • Hashimoto’s
    • H. pylori gastritis
    • C. psittaci conjunctivitis
    • Borrelia skin infections

Workup

  • Labs
    • FBC
    • LFT
    • Uric acid
    • Calcium
    • QEPP
    • Serum β2-microglobulin
  • Imaging
    • CXR
    • CT abdo / pelvis / chest
  • Bone marrow biopsy

Treatment

  • Eradication of H. pylori = 80% of cases will resolve
  • Chlorambucil
  • Combinations with rituximab

Prognosis

  • 75% 5-year survival
  • 90% 5-year survival with low IPI score
  • 40% 5-year survival with high IPI score

Von Willebrand’s Disease

Von is pronounced with an F. Please always remember this.

Numbers

  • Most common bleeding disorder
  • Prevalence of 1% of which 10% are symptomatic

Physiology

  • vWF has 2 main fucntions
    • Adhesion molecule connecting platelet to subendothelium (dependent on large multimers)
    • Binding protein of FVIII, allowing prolongation of FVIII half life (not dependent on large multimers)
  • Inheritance of vWF is autosomal but disease state modulated by many factors
    • E.g. type O blood patients have vWF levels approximately half of type AB

Classification

  • Type 1 (80%)
    • Decreased vWF levels
    • Decreased vWF activity
    • Decreased FVIII levels
  • Type 2
    • vWF level much higher than vWF activity
    • 2A
      • Increased susceptibility to cleavage by ADAMTS13 > loss of multimers
    • 2B
      • Gain of function mutations > increased unprovoked platelet-vWF binding > clearance of complex by reticuloendothelial system > loss of multimers + reduced platelet count
    • 2M
      • Mutations > molecule dysfunction not affecting multimer structure
    • 2N
      • ‘Autosomal haemophilia’
      • Mutations preventing FVIII binding > short half life of FVIII > markedly decreased FVIII
  • Type 3
    • Near zero vWF and FVIII levels <10%
  • Acquired vWD
    • Rare
    • Most commonly from underlying lymphoproliferative disorders
      • MGUS
      • MM
        Waldenstroem’s
    • Aortic valve disease
      • Heyde’s syndrome (AS + GIT bleeding = partly due to change in vWF from shear stress across AS > increased serum protease susceptibility > type 2 disease; partly also due to angiodysplasia of the GIT)

Clinical presentation

  • Platelet like bleeding
    • Mucosal bleedin
    • Postoperative bleeding less common
    • Very uncommon in infancy
    • Commonly presents as bruising or epistaxis in childhood
    • Menorrhagia very common presentation
    • Dental extractions / tonsils
  • Severe cases may resemble haemophilia
    • Joint symptoms etc.

Labs

  • FBC
  • Coags
  • vWF level
  • vWF activity
    • Ristocetin cofactor
    • Collagen-binding activity
  • FVIII levels

Management

  • Type 1
    • DDAVP
      • Promotes release of vWF and FVIII form endothelial storage
      • IV (peak at 30 min) or IN (peak at 2 hours)
      • Test response in lab
      • Good responders (X2 raise in levels) can use it for operative prophylaxis
      • Causes hyponatremia from decreased free water loss > fluid restrict
  • Type 2A / 2M
    • May respond to DDAVP
  • Type 2 / 3
    • vWF replacement
    • vWF/FVIII concentrate
    • Cryopercipitate at a pinch
  • All
    • Tranexamic acid
      • Either alone or as adjunct
      • Contraindicated in urinary tract bleeding (clot > obstruction)

 

The Acquired Haemolytic Anaemias

Classification

  • Intracorpuscular defects
    • Congenital
      • Haemoglobinopathies
      • Enzymopathies
      • Membrane-cytoskeletal defects
    • Acquired
      • Paroxysmal nocturnal haemaglobinuria
  • Extracorpuscular defects
    • Congenital
      • Familial haemolytic uremic syndrome
    • Acquired
      • Microangioathic (mechanical lysis)
      • Toxins
      • Drugs
      • Infection
      • Autoimmune

General Presentation

  • Jaundice
  • Discoloration of urine may occur (common misconception that only obstructive jaundice causes urine discoloration)
  • Enlarged spleen
  • Enlarged liver
  • Skeletal changes in severe congenital forms due to bone marrow overactivity

General Labs

  • Elevated uncojugated bilirubin
  • Increased urine and stool urobilinogen
  • Raised serum AST
  • Haemoglobinuria implies intravascular haemolysis
  • Raised LDH
  • Reduced haptoglobin
  • Increased reticulocytes

Mechanical Destruction

  • Causes intravascular haemolysis > haemoglobinuria
  • Two common situations
    • March haemoglobinuria (marathon runners)
    • Microangipathic haemolytic anaemia (heart valves)

Toxins

  • A few examples
    • Hyperbaric oxygen
    • Nitrates
    • Cisplatin
    • Dapsone
    • Lead (causes basophilic stippling = phenocopy of P5N deficiency implies enzymatic inactivation)
  • Mechanisms
    • Direct chemical action
    • Drug acts as hapten > antibody production > RBC are caught in the crossfire
    • Trigger of antibody against RBC antigen > direct effects on RBC (eg methyldopa)
    • Venom

Infection

  • Malaria
  • E. coli O157:H7
  • C. perfringens
  • Many others

Autoimmune Haemolytic Anaemia

  • Most common course in non-malarial areas
  • Pathophysiology
    • Antibody against red cell antigen
    • Destruction by two mechanisms
      • Fc portion of antibody recognised by Fc receptor on macrophages > phagocytosis > destruction is apleen, liver and marrow > extravascular haemolysis
      • Antigen-antibody complex activate complement > MAC > intravascular haemolysis
  • Presentation
    • Hb can drop dramatically
    • Jaundice
    • Splenomegaly
    • Associations with SLE = full autoimmune screen important when AIHA first diagnosed
    • AIHA + thrombocytopaenia = Evan’s syndrome
  • Labs
    • Antoglobulin test = Coombs
  • Management
    • Transfusion
      • Problem if antibody involved is non-specific (all X-matched blood is incompatible)
      • Transfusion of incompatible blood may be correct (blood cells will be destroyed but no more than the patient’s own blood cells)
    • Steroids
    • Splenectomy or rituximab as second line
    • Azathioprine, cyclophosphamide, cyclosporin, IVIG all third line

Paroxysmal Cold Haemoglobinuria

  • Rare form of AIHA in children
  • Viral infection trigger
  • Usually self-limiting
  • Involvement of the Donath-Landsteiner antibody
    • Binds to cells only at low temperature
    • Causes lysis in the presence of complement when at body temperature
  • Recovery with supportive therapy is the usual outcome

Cold Agglutinin Disease

  • Fom of AIHA that usually affects the elderly
  • AB reacts with RBCs poorly at body temperature and storngly at lower temperatures
  • AB is uaually IgM with anti-I (present almost universally on RBCs)
  • AB produced by epanded clone of B lymphocytes > think monoclona gammopathy
  • The AB is IgM and there is a relation to Waldenström macroglobulinemia
  • Therefore CAD should be considered as a form of WM, a low grade B cell lymphoma that is unmasked early by the specific properties of the AB
  • Treat with rituximab, azathioprine or cyclophosphamide
  • Splenectomy and prednisolone are ineffective

Paroxysmal Nocturnal Haemoglobolinuria 

  • Pathophysiology
    • RBC intrinsic vulnerability to activated protein C
      • Activation by alternate pathway (hence intravascular haemolysis)
      • Activation by antigen-antibody complex (why PNH can get dramatically worse with concurrent infection)
  • Presentation
    • Classically
      • Intravascular haemolytic
      • Pancytopaenia
      • Venous thrombosis
    • PNH may turn into aplastic anaemia or may develop in patient who previously had AA
    • PNH may also turn to AML
  • Labs
    • High MCV from reticulocytosis
    • LDH commonly >1,000
    • Haptoglobins commonly undetectable
    • Haemoglobinuria may vary dramatically from hour to hour
    • Bone marrow
      • Prominent erythroid hyperplasia
      • Dyserythropoietic features
      • May become hypocellular or aplastic
    • Flow cytometry for CD59-, CD55- (those CDs protect against activated protein C) is diagnostic
  • Treatment
    • Supportive care
      • Transfusion
      • Folic acid
      • Iron
    • Eculizumab (inhibits complement activation)
    • Allogeneic bone marrow transplantation
    • Anticoagulation on those who have had
      • Venous thrombosis
      • Any other genetic prothrombotic state
  • No evidence for long-term steroids

 

 

 

The Inherited Haemolytic Anaemias

Classification

  • Intracorpuscular defects
    • Congenital
      • Haemoglobinopathies
      • Enzymopathies
      • Membrane-cytoskeletal defects
    • Acquired
      • Paroxysmal nocturnal haemaglobinuria
  • Extracorpuscular defects
    • Congenital
      • Familial haemolytic uremic syndrome
    • Acquired
      • Microangioathic (mechanical lysis)
      • Toxins
      • Drugs
      • Infection
      • Autoimmune

General Presentation

  • Jaundice
  • Discoloration of urine may occur (common misconception that only obstructive jaundice causes urine discoloration)
  • Enlarged spleen
  • Enlarged liver
  • Skeletal changes in severe congenital forms due to bone marrow overactivity

General Labs

  • Elevated uncojugated bilirubin
  • Increased urine and stool urobilinogen
  • Raised serum AST
  • Haemoglobinuria implies intravascular haemolysis
  • Raised LDH
  • Reduced haptoglobin
  • Increased reticulocytes

Membrane-cytoskeletal defects

Hereditary spherocytosis

  • Pathology
    • Term given to range of mutations that affect the cytoskeleton
    • Abnormalities of the membrane cytoskeleton > structural weakness > increased susceptibility to lysis
    • Clasically autosomal dominant but severe forms may be autosomal rcessive
    • Spleen has dual role in pathophysiology
      • Site of major destruction
      • Passage of cells through spleen results in more spherocytic cells
  • Presentation
    • Broad spectrum of presentation from mild to severe due to range of underlying genetic lesion
    • Jaundice, enlarged spleen, gallstones
    • Normocytic anaemia with spherocytes on film
    • Increased MCHC (almost pathognomonic)
    • Family history
    • Pink test – test for osmotic fragility
    • Molecular studies
  • Treatment
    • Consider splenectomy (used to be dogma but this is changing)

Hereditary Elliptocytosis

  • Much the same as HS
  • Heterogenous as in HS
  • Elliptocytes give the diagnosis
  • No correlation between elliptocytes and severity of disease
  • Southeast Asia ovalocytosis is an asymptomatic form in malaria endemic regions

Disorders of Cation Transport

  • Rare autosomal dominant disases
  • Increased intracellular Na with associated K loss
  • Pseudohyperkalemia on blood test
  • May be associated with water gain > overhydration > low MCHC > linear central pallor > stomatocytosis
  • May also be associated with dehydrated cells > high MCHC > more rigid > xerocytosis
  • Splenectomy is contraindicated as it is followed by thromboembolic complications

Enzyme abnormalities

Disorders of the Glycolytic Pathway

  • Pyruvate kinase deficiency
    • Persistent neonatal jaundice with very high reticulocytosis
    • Severity of anaemia varies
    • Due to a metabolic block in the last step of glycolysis
    • Compensation occurs as the block leads to an increase to 2,3 DPG which enhance oxygen delivery to tissues by shifting the oxygen saturation curve
    • Treatment is supportive
    • Folic acid supplementation
    • Splenectomy may be of use
  • Other glycolytic enzyme diseases
    • Even more rare than PKD
    • Usually present as severe neonatal jaundice
    • Systemic manifestations include CNS deficits (sometimes severe retardation) and/or neuromuscular lesions
    • Diagnosis is by specilaised molecular testing

Disorders of Redox Metabolism

  • G6PD Deficiency
    • X-linked
    • G6PD crucial in redox metabolism of aeroic cells
    • Only source of NADPH in RBCs, therefore crucial for oxidative stress defence
    • Confers relative protection against P. falciparum
    • Most patients asymptomatic for life
    • May present as neonatal jaundice
    • May develop acute haemolytic anaemia
      • Triggers include fava beans, drugs and infections
      • Typical presentation of malaise, weakness, abdominal and/or lumbar pain followed by jaundice and haemoglobulinuria hours to days later
      • Film shows anisocytosis, polychromasia, spherocytes
      • Bizzare poikilocytes characteristic
        • Hemighosts
        • Blister cells
        • Heinz
      • Quantitative G6PD tessting
    • A subset may develop chronic nonspherocytic haemolytic anaemia – anaemia, jaundice, gallstones
    • Treatment is avoidance and supportive
  • Pyrimidine 5′-nucleotidase (P5N) deficiency
    • Defieincy of enzyme in nucleotide catabolism
    • Causing basophilic stippling
    • Rare but thiird most common enzyme defect
    • Anaemia is of variable severity and may benefit from splenectomy

Atypical Haemolytic Uremic Syndrome (AHUS)

  • Mutations in genes coding complement regulatory proteins
    • CFH / CD46 / MCP / CF1 / C3 / CFB / Thrombomodulin
  • Redundancy in complements = disease only manifests when body is stressed
  • Triad of
    • Microangiopathic haemaolytic anaemia
    • Thrombocytopaenia
    • Acute renal failure
  • Severe disase – 15% acute mortality and 50% progression to ESRD
  • Treat with plasma exchange

 

 

 

 

 

 

The Myeloid Neoplastic Disorders

Nomenclature

  • There are a lot of historical naming problems with the myeloid disorders; this is confusing
  • Broadly speaking, there are 3 major categories of disorders
    • Acute myeloid leukemias – accumulation of myeloid blasts in the marrow suppresses normal haematopoiesis
    • Myelodysplastic syndromes – defective differentiation of of myeloid progenitor cells leads to cytopaenias
    • Myloproliferative disorders – increased production of 1 or more cell lines

Acute Myeloid Leukemia

  • Pathology
    • Immature myeloid blast cells in marrow
    • Replacement of marrow leads to aneamia, thrombocytopaenia and neutropaenia
    • Defined as at least 20% myeloid blasts in bone marrow or specific chromosomal rearrangements
  • Aetiology
    • Genetics – associations with Down’s, Fanconi anaemia, Bloom, atatxia-telangiectasia etc.
    • Radiation
    • Chemical exposure – benzene, herbi/pesticides, ethylene oxide, paint
    • Drugs – alkylating agents (e.g. cisplatin), topoisomerase II inhibitors (e.g. doxorubicin, etoposide)
    • No known viral association
  • Classification
    • Complex
    • WHO classification has superseded the French-American-British system (primary difference is 20% blast cutoff versus 30% cutoff)
    • Acute promyelocytic leukaemia is a variant where a chimeric retinoic acid receptor-alpha (RARA) causes a differentiation block
  • Presentation
    • Systemic – fatigue, fever, weight loss
    • Hepatosplenomegaly
    • Lymphadenopathy
    • Bleeding
    • Recurrent infections
  • Labs
    • Haematological picture
      • Normocytic, normochromic anaemia usually present
      • Leukocyte counts can be low, high or normal
      • Neutrophils may show abnormal lobulation, deficient granulation, and impaired migration / phagocytosis
      • Most platelet counts are <100,000/ul and show both morphological and functional abnormalities
      • Auer rods are not always present but are pathognomonic
    • Elevated serum uric acid may be present and may precipitate acute urate nephropathy
    • Assessment of global organ function prior to treatment
  • Treatment
    • Chemotherapy
      • Induction: Cytarabine + anthracycline
      • Postremission: intensive chemo + autologous/allogenic HSC transplant
    • Supportive care
      • Transfusions
      • Early and aggressive use of broad-spectrum antibiotics for fever
      • Caspofungin / voriconazole / liposomal amphotericin B if persistent fever despite Abx
      • Prophylactic antiinfectives may be considered (e.g. quinolone + azole)
      • Prophylactic antiviral if history/serology of HSV or VZV
      • Treatment of elevated uric acid with rasburicase / allopurinol
      • G-CSF and GM-CSF reduce time to neutrophil recovery but fail to improve survival in RCTs
    • Acute promyelocytic leukemia
      • Induction of differentiation by tretinoin
        • May cause the APL differentiation syndrome of fever, fluid retention, SOB, CP, effusions and hypoxemia
        • Syndrome due to adhesion of newly differentiated neoplastic cells to pulmonary vascular endotheloum
        • Treat with glucocorticoids / cytotoxics
  • Prognosis
    • AML – 60% have complete remission but 5 year disease free rate is around 20%
    • APML – 80% cure rate

 

Myelodysplastic Syndrome

  • Pathology
    • A group of diseases where abnormal clonal stem cells have defects in maturation which results in ineffective haematopoiesis
    • In MDS, a neoplastic multipotent stem cell that is capable of differentiation but does so poorly replaces the bone marrow
    • The bone marrow shows myeloid blasts occupying <20% of the marrow
  • Causes
    • Idiopathic
    • Genetic – Down’s
    • Strongest environmental associations are radiation, benzene and drugs
  • Presentation
    • Picture dominated by symptoms related to anaemia
    • 20% have splenomegaly
    • Fever and weight loss indicate a myeloproliferative disorder
    • Consitutional syndromes may provide clues
      • Short stature, abnormal thumbs – Fanconi anaemia
      • Cutaneous warts – GATA2 deficiency
  • Labs
    • Anaemia usually present
    • Neutropaenia or thrombocytopaenia variable present, isolated neutropaenia / thrombocytopaenia is unusual
    • WBC is normally normal or low
  • Bone marrow
    • Usually normal but may be hypo or hypercellular
    • Erythroid – ringed sideroblasts
    • Granulocytic – hypogranulation, hyposegmentation, increased myeloblasts
    • Megakaryocytes – reduced or disorganised nuclei
  • Treatment
    • HSC transplantation offers cure
    • 3 year survival is 50%

The Myeloproliferative Disorders

  • Pathology
    • The myeloproliferative disorders are united by the presence of constitutively activated tyrosine kinases or other signalling pathway abnormalities that drive growth independent of growth factor regulation resulting in
      • Increased proliferation in the marrow
      • Extramedullary haemtopoiesis
      • Variable progression to an exhausted phase of marrow fibrosis
      • Variable progression into an acute leukemia

Chronic myelogenous leukemia /CML

  • Chimeric BCR-ABL tyrosine kinase (the Philadelphia chromosome)
    • Preferential proliferation of granulocytic and megakaryocytic precursors
    • Release of immature granulocytic forms from marrow to blood
  • The marrow is hypercellular
  • The main presentation is splenomegaly and systemic symptoms
  • Thrombotic / vasocclusive from severe leuko/thrombocytosis may occur
  • Bleeding diathesis findings may be present
  • Natural history is a slow progression followed by an accelerated phase terminating in a blast crisis picture resembling acute leukemia
  • Treatment is with TK inhibitors (e.g. imatinib) and allogenic stem cell transplant as second line in most cases

Polycythaemia rubra vera

  • Activating point mutations in JAK2
  • Increased marrow panmyelosis but the clinical picture is dominated by polycythaemia
  • Presentation
    • Plethorria and cyanosis
    • Increased major bleeding and thrombosis
    • Pruritus
    • Hyperuricemia
  • Treatment
    • Phlebotomy to reduce RBC count and for maintenance
    • No role for anticoagulation unless thrombosis has happened
    • Allopourinol if chemotherapy is considered
    • Anagrelide for thrombocytosis is preferred over hydroxurea as less marrow toxicity
    • Antihistamines / antidepressants for pruitus
    • Aspirin use for thrombosis prophlaxis is unproven

Essential thrombocytosis

  • Difficult to distinguish from reactive thrombocytosis
  • Workup
    • 50% have JAK 2 V617F mutation
    • CALR and MPL mutations are less common but might be helpful
  • Clinical presentation
    • Paradoxical bleeding due to acquired von Willebrand disease
    • May cause thrombosis
    • Usually incidental finding
    • Commonly co-existing with PRV (in which case JAK 2 V617F mutation does not differentiate the two)
  • Therapy
    • Generally no therapy required as no difference in mortality
    • Use of radioactive phosphorus / alkylating agents / hydroxyurea increase acute leukemia risk with no proven beenfit
    • Aspirin may be used for platelet symptoms
    • Choices for platelet reduction include anagrelide, IFN-alpha or hydroxyurea
    • Aspirin and hydroxurea for TIA symptoms (hydroxyurea is also a NO donor)
    • If above 1 million, acquired vWD occurs, in which case prophylactic ε-aminocaproic acid may be used and aspirin avoided

Primary myelofibrosis 

  • PMF is a disorder characterised by
    • Marrow fibrosis
    • Extramedullary haematopoiesis
    • Splenomegaly
  • There is no identified clonal marker
  • THe nonspecific markers JAK2 V617F and MPL may be present in patients but do not differentiate it from PRV or ET
  • The degree of myelofibrosis and extramedullary haematopoiesis are unrelated
  • Presentation
    • Night sweats, fatigue and weight loss are common, unlike in the other myeloproliferative disorders
  • Labs
    • Blood smear – features of extramedullary haematopoiesis
      • Teardrop red cells
      • Nucleated red cells
      • Myelocytes and promyelocytes
      • Myeloblasts
    • Mild hepatomegaly
    • Isolated lympadenopathy is more indicative or another diagnosis
    • LDH and ALP elevated
    • Marrow usually inaspirable
    • Marrow biopsy
      • Hyeprecellular marrow with trilineage hyperplasia
      • Increased numbers of clustered megakaryocytes with dysplastic nuclei
  • Treatment/Prognosis
    • 10% transform to acute leukemia
    • Survival is reduced compared to PRV or ET
    • No specific therapy
    • Splenectomy to prevent cachexia from impaired alimentation
    • Allopurinol from increased uric acid
    • GLucocorticoids +/- thalidomide for symptom control
    • Allogenic bone marrow transplant may be curative
    • Emerging role for JAK2 inhibitors

 

 

Disorders of the Basement Membrane

General Points

  • GBM disorder primarily associated with collagen IV
  • The collagen IV family is composed of 6 chains (α1 – α6)
  • Glomerular and tubular basement membrane, lung, cochlea, eye and testis are α3.α4.α5 (IV) collagen (more resistant to proteases)
  • Skin, smooth muscle, esophagus and Bowman capsules are α5.α5.α6 (IV) collagen

Anti-GBM disease

  • When haemoptysis is present, it is called Goodpasture’s syndrome
  • Pathology
    • The provoking epitope is the quartenary structure of the α3 NC1 domain of collagen IV
    • Epitopes are normally sequestered but can be exposed by smoking, infection, oxidants or solvents
    • Biopsy shows focal or segmental necorsis which combines with with capillary destruction by cellular proliferation leads to crescent formation
    • Concomitant interstitial nephritis and tubular atrophy
  • Epidemiology
    • Goodpastures has two peaks – males in their 20s and females in their 60s
    • Haemoptysis largely associated with smokers
  • Diagnosis
    • Biopsy – staining for IgG (or rarely, IgA) anti-α3 NC1 confirms diagnosis ( anti-α1 NC1 seen in paraneoplastic syndromes, tests that use whole GBM as target will confuse the two)
    • 10-15% will have ANCA against MPO
  • Prognostication
    • Worse out come if >50% crescents, creatinine >5mg/dL, oliguria, acute dialysis
  • Treatment
    • Plasmapheresis
    • Pred + cyclophosphamide
    • Transplant is possible but at risk for disease recurrence

Alport’s Syndrome

  • Presentation
    • Triad of renal involvement, sensorineural deafness and eye abdnormalities
    • May rarely present with retardation or leiomyomatosis
    • Renal
      • Haematuria
      • Thinning and splitting of GBM
      • Mild proteinuria late in the course
      • Progressive glomerulosclerosis
    • Eye
      • Lenticonus of anterior lens capsule
      • Dot and fleck retinopathy
  • Genetics
    • 85% X-linked α5 mutations
      • Female carriers have variable penetrance dependent on type of mutation, mosaicism and X inactivation
    • 15% autosomal recessive disease of α3 or α4
    • Rarely some have autosomal-dominant or dominant-negatie mutations in α3 or α4
  • Diagnosis may be supported in skin biopsy (since skin has α5) or renal biopsy
  • Treatment
    • ACE-I
    • Control of systemic hypertension
    • Renal allograft (develop AB against non-native epitopes but overt anti-GBM disease is uncommon)

Thin Basement Membrane Disease / Benign Familial Haematuria

  • Persistent haematuria NOT associated with proteinuria, hypertension, renal impairment or systemic symptoms
  • Usually presents in childhood
  • Genetic disorder of type IV collagen
  • GBM shows diffuse thining but is otherwise normal
  • Usually benign with a good prognosis

Nail-Patella Syndrome

  • Presentation
    • Iliac horns on pelvis
    • Dysplasia of the dorsal limbs (nail, patella, elbow)
    • Variable
      • Neurosensory hearing loss
      • Glaucoma
      • Haematuria / heavy proteinuria / FSGS
  • Autosomal dominant – deficits in LMX1B which regulates α3 and α4 chains of collagen IV, interstitial type III collagen, podocin and CD2AP which contribute to the porous membranes connecting podocytes
  • Renal transpant for end-stage disease

Platelet Disorders

Heparin-Induced Thrombocytopaenia

  • Presentation
    • Patient is taking heparin
      • 10X more common with UFH than LMWH
      • Develops after 5-14 days
      • May develop <5 days if previous sensitising exposure
      • May present after heaprin is stopped (delayed-onset HIT)
    • Thrombocytopaenia usually not severe, usually >20,000/ul
    • Paradoxical elevated thrombosis risk (instead of bleeding)
  • Pathophysiology
    • Antibody formation to heparin/platelet factor 4 complex
    • Antibody activates the FcγRIIa receptor on platelets
    • Many patients develop antibodies without overt disease
  • Labs
    • Anti-heparin/PF4 ELISA (not that useful because antibody does not equal disease)
    • Platelet activation assay
    • Diagnosis still a clinical one due to insufficient sensitivity/specificity
  • Treatment
    • Swtich to direct thrombin inhibitor (e.g. argatroban)
    • Introduction of warfarin as the sole agent may worsen thrombosis as due to initial reduced levels of protein C and S; introduce warfarin after resolution of thrombocytopaenia and overlapping with a DTI and mantain for 3-6 months

Immune Thrombocytopaenic Purpura (ITP)

  • Immune destruction of platelets and platelet release from megakaryocytes
  • Presentation
    • Children – usually acutely post-infection
    • Adults – more chronic
    • Associations with autoimmune disorders (esp. SLE), HIV, hep C, H. pylori
    • Ecchymoses, petechiae and mucocutaneous bleeding
    • Very low platelet count with otherwise normal FBC and film
  • Labs
    • Peripheral smear – may show large platelets
    • Identify secondary causes
      • HIV
      • Hep C
      • SLE
      • Protein electrophoresis + Ig levels
        • Hypogammaglobulinaemia
        • IgA deficiency
        • Monoclona gammopathy
      • If anaemia present, Coombs (Evans syndrome)
  • Treatment
    • Prednisolone
    • Rh0(D) immune globulin
      • Use only in Rh+ patients
      • Leads to limited haemolysis > saturation of Fc receptor with antibody-coated cells > saturation of Fc receptor
    • IVIG – direct blockade of Fc receptor
    • Rituximab
    • Thrombopoietin receptor agonism
    • Splenectomy – prevent reticulo-endothelial destruction of platelets
    • Transfusion doesn’t really work – destruction occurs just as fast

Thrombotic Thrombocytopenic Purpura

  • Pentad of
    • MAHA
    • Thrmbocytopaenia
    • Renal failure
    • Neurological findings
    • Fever
  • Pathophysiology
    • Deficiency of / antibodies to ADAMTS13, a metalloproteinase that cleaves vWF
    • Persisting large vWF multimers > platelet adhesion + aggregation > predisposed state that requires unknown trigger to cause disease
  • Labs
    • ADAMTS13 activity can be detected but correlation to disease is unclear
    • Diagnosis is clinical
    • Coagulation profile to rule out DIC
    • Haemolytic screen – elevated LDH, indirect bilirubin, decreased haptoglobin, negative direct-antiglobulin test
    • Blood smear – reticulocytosis, schistocytosis, polychromasia
  • Treatment
    • Plasma exchange is mainstay
    • Rituximab, vincristine, cyclophosphamide, splenectomy if failure of plasma exchange

Haemolytic Uraemic Syndrome

  • Triad of
    • MAHA
    • Thrombocytopaenia
    • Acute renal failure
  • Presentation
    • Seen mostly in children
    • Preceding diarrhoea is suggestive (hemorrhagic diarrhoea even more so)
    • Associations with E. coli O157:H7
    • ADAMTS13generally normal
  • Treatment
    • Supportive
    • Dialysis may be required
    • Plasma exchange does not alter the cause

Infection-induced thrombocytopaenia

  • Common
  • Keep an eye out for DIC
  • Platelets are also an acute-phase reactant (so may be elevated)

Drug-induced thrombocytopaenia

  • Antibodies against drug antigens react with platelet antigens
    • Common with quinine and sulphonamide
    • Typical 3/52 after exposure (or faster if previous sensitisation)
    • Resolves 1/52 after withdrawal
  • Anti-drug/platelet complex
    • Occurs with Gp2b3a inhibitors
    • Occurs within 1/7