Haematology Flashcards
Classify Haemolytic anaemia by Site ??
Intravascular H: Free Hb is released which then binds to Haptoglobin. As Haptoglobin gets saturated, Hb binds to Albumin => Methaemalbumin (detected by Schumm’s test). Free Hb is excreted in the urine as Hbnuria, Haemosiderinuria
IVH :
- Mismatched BT, - G6PD deficiency,
- PNH, - Cold AIHA,
- Red cell fragmentation: Heart valves, TTP, DIC, HUS
Extravascular Haemolysis
- Hb-opathies: SickleCD, Thalassaemia
- H Spherocytosis
- Haemolytic disease of Newborn
- Warm AIHA
Hallmark about the type of Haemolysis seen in G6PD ??
Majorly undergoes IVH but it also has an element of Extravascular H
Causes of Normocytic Anaemia ??
[Low Hb + Normal MCV] => Check Reticulocyte Count
If R count Normal
- Anaemia of Chronic disease
- CKD (Renal Failure)
- Early Folate deficiency
- Early B12 defiiency
- Effect of drugs
- Blood loss
If R count Increased
- Haemolytic anaemia
- Blood loss
Aplastic Anaemia is also a cause Normocytic Anaemia
Causes of Macrocytic Anaemia ??
With Megaloblastic Bone Marrow
- B12 deficiency
- Folate deficiency
With Normoblastic BM
- Secondary to MTX
Other causes
- [-OH]
- Liver disease
- Hypothyroidism
- Pregnancy
- Reticulocytosis
- Myelodysplasia
- Drugs: Cytotoxics
Microcytic Anaemia causes ??
IDA
Congenital Sideroblastic Anaemia
Aneamia of Chr. disease (more commonly N N picture)
LEAD Poisoning
Thalassaemia
- In Beta T Minor, microcytosis is disproportionate to anaemia
Rx. of Aplastic anaemia ??
1) Supportive
- Blood products
- Prevention & Rx. of infection
2) Anti-Thymocyte Globulin (ATG) & Anti-Lymphocyte Globulin (ALG)
- Prepared in animals (rabbit, horse) by injecting human lymphocyte
- Is highly allergenic & may cause SERUM SICKNESS (fever, rash, Arthralgia), so Steroid is cover usually given
- Immunosuppression (CICLOSPORIN)
3) Stem Cell Transplantation
- Allogeneic Transplants (80% success rate)
Hallmarks of B12 deficiency ??
Needed for RBC synthesis & Nervous System maintenance
- Absorbed by IF (Parietal cells) & actively absorbed in Terminal Ileum
- Small amount is absorbed without binding to IF
CAUSES
- Pernicious anaemia : MCC
- Post Gastrectomy
- Disorders or Sx. of Terminal Ileum (Crohn’s : Disease activity or Post Ileocaecal resection)
- Metformin (Rare)
Features of B12 deficiency ??
Macrocytosis; Sore tongue & Mouth
CNS c/f
- DORSAL Column affected 1st : Joint position, Vibration) prior to distal paraesthesia (numbness)
Psychiatric c/f: eg Mood disturbances, Cognitive decline
Rx.-
- If NO CNS c/f 1mg of IM Hydroxycobalamin 3x each week for 2 wks, then 1x every 3 months
What should be treated 1st when both B12 & Folate deficiency is present ??
Treat B12 first to avoid ppt. Subacute Combined Degeneration of the Cord
Hallmarks of Autoimmune Haemolytic anaemia ??
AIHA is classified based on the Temperature at which the antibodies best cause Haemolysis
- Warm AIHA
- Cold AIHA
General Features of Haemolytic anaemia
- Anaemia, - Reticulocytosis
- LOW Haptoglobin
- Raised LDH & Indirect Bilirubin
- Blood film: Spherocytosis & Reticulocytes
Special Features of AIHA
- (+)ve Direct Antiglobulin test (Coombs’ test)
Warm AIHA features ??
MC type of AIHA
Antibody (IgG) cause haemolysis best at Body Temperature
- Occurs at Extravascular sites eg.- Spleen
CAUSES
- Idiopathic
- Autoimmune diseases eg.- SLE
- Neoplasia: Lymphoma, CLL
- Drugs: Methyldopa
C/F: Splenomegaly, DVT
- Dizziness, Palpitations, Dark urine, Pale skin, Jaundice, Fatigue
Rx.-
- Treat the underlying cause
- 1st line: Steroids (+/- Rituximab)
- Severe: BT
Cold AIHA features ??
Antibody IgM involved & causes Haemolysis best at 4 C
- Complement mediated
- Intravascular H
Features: C/F of Raynaud’s & Acrocyanosis
General Features: Dizziness, Pale Skin , Palpitations, Dark urine, Jaundice, Fatigue
Responds less well to Steroids
Causes of Cold AIHA ??
Neoplasia: eg.- Lymphoma
Infections: Mycoplasma, EBV
SLE (rarely be a/w a MIXED type AIHA)
Hallmarks of PNH ??
Acquired disorder leading to Haemolysis (mainly Intravascular) of RBCs
- Due to Lack of Glycoprotein glycosyl Phosphotidyl Ionsitol (GPI) => Increased Sensitivity of Cell memb. to Complement
- GPI anchors surface proteins to Cell memb.
- Complement-regulating surface proteins eg.- Decay Accelerating Factor (DAF), are not properly bound to cell memb. due to lack of GPI
- Lack of CD59 on Plt. memb. => Plt. aggregation => THROMBOSIS
Features of PNH ??
1)Haemolytic Anaemia (Intravascular)
2) RBCs, WBCs, Platelets or Stem cells may be affected
- PANCYTOPAENIA
3) Haemoglobinuria: Dark-coloured urine in the morn (occurs throughout the day)
4) Thrombosis (Budd-Chiari Synd.)
5) Aplastic anaemia
Dx. & Rx. of PNH ??
1st line: FLOW Cytometry of blood
- Detects low CD59 & CD55 levels
- Has now replaced Ham’s test (Acid-Induced Haemolysis - Normal RBCs would not)
Rx.-
- Blood product Replacement
- Anti-Coagulation
- ECULIZUMAB: directed against C5 (terminal protein) has been shown to reduce IV Haemolysis
- Stem Cell Transplantation
Beta-Thalassaemia Major
Absent Beta-Globulin chain
- Chromosome 11
Features
- Presents in 1st year of life with FTT & Hepatosplenomegaly
- Microcytic Anaemia
- HbA2 & HbF raised
- HbA is absent
Rx.- Repeated BT
- Can cause Iron overload : Organ Failure
- Iron Chelation therapy (Desferrioxamine)
Beta-Thalassaemia Trait ??
Thalassaemia are a group of disorders characterised by a reduced production rate of either ALPHA or BETA chains
- Beta-T trait is an A R Condition
Features
- Mild Hypochromic, Microcytic anaemia
- Usually asymptomatic
- Microcytosis is disproportionate to anaemia
HbA2 raised (> 3.5%)
Alpha-Thalassaemia
Deficiency of ALPHA chain in Hb
- 2 separate Alpha-globulin genes are located on each Chr. 16
Severity depends on no. of Alpha globulin alleles affected
If 1 or 2 alleles affected
- Hypochromic & Microcytic
- Hb is Normal
If 3 alleles affected (aka Hb H disease)
- Hypochromic Microcytic + Splenomegaly
- aka Hb H Disease
If all 4 alleles affected (Homozygote)
- Death in-utero (Hydrops fetalis, Bart’s Hydrops)
Hallmarks of Sickle Cell Anaemia ??
A R condition => results in synthesis of Abnormal Hb chain “HbS”
- MC in African descent as heterozygous states offer protection against Malaria
Hb alleles seen in SCD ??
Normal Hb : HbAA
Sickle cell TRAIT: HbAS
Homozygous SCD: HbSS
HbSC : Some pts. inherit 1 HbS & another abnormal Hb (HbC) => Milder form of SCD
Pathophysiology of SCD ??
Polar aa GLUTAMATE is substituted by Non-Polar aa VALINE in each of the 2 Beta chains (Codon 6).
- This decreases Water solubility of Deoxy-Hb
In Deoxy. states, the HbS molecules Polymerise & cause RBCs to sickle
- HbAS pts. sickle at: pO2 [2.5- 4 kPa]
- HbSS pts. sickle at: pO2 [5- 6 kPa]
Sickle cell are Fragile & Haemolyse => Block small BV => Infarction
Ix. done in SCD ??
Hb Electrophoresis
Rx. of SCD ??
CRISIS Management
- Analgesia (Opiates)
- Rehydrate & O2 therapy
- Abx.- If Infection suspected
- BT
- CNS Features: Exchange Transfusion
LONG TERM Management
- Hydroxyurea
- Increases HbF levels & is used for Prophylaxis of SC Anaemia to prevent painful episodes
- Pneumococcal Polysacchride Vaccine every 5 yrs
Types of Sickle-Cell Crises ??
Thrombotic ‘Painful’ Crises
Sequestration Crises
Aplastic Crisis
Haemolytic Crisis
Acute Chest Syndrome
Thrombotic Crisis ??
Painful or Vaso-Occlusive Crisis
- Ppt. bt Infection, Dehydration, Deoxygenation
Dx. made Clinically
Infarcts occur in various organs
- AVN of Hip
- Hand-Foot Syndrome in Children
- Lung, Spleen, Brain
Sequestration & Aplastic Crisis ??
Sequestration Crisis
- Sickling within organs (Spleen, Lungs) causes pooling of blood => Anaemia worsening
- a/w Increased Reticulocyte count
APLASTIC Crisis
- Cause: PARVOVIRUS B-19 infection
- Sudden fall in Hb
- BM Suppression => REDUCED reticulocyte count
Acute Chest Syndrome ??
Vaso-occlusion within Pulm. Micro-Vasculature => Lung parenchyma Infarction
- Dyspnoea, Chest pain, Pulm. infiltrates on CXR, Low pO2
MANAGEMENT
- Pain relief
- Resp. Support: O2 therapy
- Abx.- Infection may ppt. Acute C S & C/F can be difficult to distinguish from pneumonia
- Transfusion: improves Oxygenation
MCC of death after Childhood in SCD ??
Acute Chest Syndrome
What are Porphyrias ??
Abnormality in enzymes responsible for Biosynthesis of HAEM
- Results in the overproduction of Intermediate compounds (Porphyrin)
They are broadly classified into
- ACUTE Porphyrias
- CUTANEOUS Porphyrias
Types of ACUTE Porphyrias ??
ACUTE Intermittent P (A D condition)
- Porphobilinogen Deaminase (PBGD) deficiency
2) HEREDITARY Coproporphyria
- Coproporphyrinogen Oxidase (CPOX) deficiency
3) VARIEGATE Porphyria
- Protoporphyrinogen Oxidase defect
4) ALAD deficiency Porphyria (ADP)
- Delta Aminilevulinic acid Dehydratase deficiency
Types of Cutaneous Porphyrias ??
1) PORPHYRIA CUTANEA TARDA (PCT)
- Uroporphyrinogen Decarboxylase (UROD) deficiency
2) ERYTHROPOIETIC Protoporphyria & X-Linked Dominant Protoporphyria
- EPP : FECH mutation => Ferrocheletase deficiency
- XLDP : ALAS2 mutation => Gain in function mutation : Protoporphyrin synthesis exceeds the required amount [MC & More severe in MEN]
- MC Porphyria in Children
3) CONGENITAL Erythropoietic P (CEP)
- Uroporphyrinogen 3 Cosynthase (UROS) defect
4) HEPATOERYTHROPOIETIC Porphyria (HEP)
- UROD deficiency
- A R form of Familial PCT
Hallmarks of PCT ??
Two types of PCT
- PCT-1 : Sporadic or Acquired PCT
- PCT-2 : Familial PCT
MC is the Hepatic form (HEP)
- UROD defect
Caused by Hepatocyte damage
- eg.- [-OH], Oestrogen
Photosensitive Rash + Bullae, Skin Fragility on face & Dorsum of Hand
Ix.-
Urine: Uroporphyrinogen elevated
Urine under Wood lamp: Pink florescence
Rx.- CHLOROQUINE
Variegate Porphyria ??
A D condition
- Protoporphyrinogen Oxidase defect
Abd. signs + CHS c/f + Photosensitive Blistering Rash
MC in South Africans
Hallmarks of Acute Intermittent Porphyrias ??
A D condition (PBGD defect)
Toxic accumulation of
- Delta-ALA & Porphobilinogen
MC in Females in 20-40 yrs
C/F
Abdomen: Abd. pain, Vomiting
CNS: Motor Neuropathy
Psychiatric: Depression
HTN & Tachycardia are common
Dx. & Rx. of AIP ???
Urine turns Deep Red on Standing
- Raised Urinary Porphobilinogen (Elevated b/w attacks & to a greater extent during acute attacks)
Assay RBCs for PBGD
Raised Delta-ALA & Porphobilinogen
Rx.-
- Avoid Triggers
Acute Attacks
- IV Haematin or Haem Arginate
- IV Glucose (if the above 2 are not immediately available)
Hallmarks of Sideroblastic Anaemia ??
RBCs fail to completely form Haem, whose biosynthesis takes place partly in Mitochondrion
- This leads to Fe deposits in Mitochondria => forms a ring around the nucleus called Ring Sideroblast
- Congenital or Acquired
Causes of Sideroblastic Anaemia ??
Congenital Cause
- Delta-ALA Synthase-2 deficiency
Acquired Causes
- Myelodysplasia
- Alcohol
- Lead
- Anti-TB drugs
Ix. & Rx. of Sideroblastic Anaemia ??
Hypochromic Microcytic Anaemia
- MC in Congenital
Iron Studies
- High: Ferritin, Fe
- High Transferrin Saturation
Basophillic Strippling
BM: Prussian blue stain shows Ringed Sideroblasts
Rx.- Supportive
- Treat the Cause
- PYRIDOXINE may help
Hallmarks of Lead Poisoning ??
Along with AIP, Lead poisoning is considered if a combination of Abd. Pain + CNS signs are seen
- Lead poisoning results in Defective Ferrochelatase & ALA Dehydratase function
Features
- Abd. Pain, - Constipation, - Fatigue
- Peripheral Neuropathy (MC- Motor)
- Neuropsychiatric features
- BLUE Lines on Gum margins (20% cases & is very rare in Children)
Ix. & Rx. of Lead Poisoning ??
Blood levels: > 10mcg
FBC: Microcytic; Basophilic strippling & Clover-Leaf Morphology
Raised S./ Urine Delta-ALA seen but difficult to differentiate b/w AIP
Urine Coproporphyrin is increased
Children: Lead accumulates in METAPHYSIS of bone
Rx.- Chelating agents
- Dimercaptosuccinic Acid (DMSA)
- D-Penicillamine
- EDTA
- Dimercaprol
Hallmarks of G6PD Deficiency ??
MC in Mediterranean & Africans
Inherited in X-linked R form
G6PD is the 1st step in Pentose Phosphate pathway which converts G6P ==> 6-Phosphogluconolactone
- This reaction results in NADP==> NADPH
- G6P + NADP => 6-Pgluconolactone + NADPH
NADPH is imp. for converting oxidised Glutathione back to its reduced form
REDUCED Glutathione protects RBCs from Oxidative damage by Oxidants such as Superoxide anion (O2-) & H2O2
Pathology in G6PD Deficiency ??
Decreased G6PD => Decreased ‘Reduced NADPH’ => Decreased ‘Reduced Glutathione’ => Increased RBCs susceptibility to Oxidative Stress
Features of G6PD Deficiency ??
Neonatal Jaundice often seen
INTRAVASCULAR Haemolysis
Gallstones are common
Splenomegaly may be present
Blood Film
- HEINZ Bodies, Bites & Blister cells
Dx.- G6PD Assay
- Levels are checked around 3 months after an Acute Haemolysis episode
- Older RBCs with severely Reduced G6PD activity will be haemolysed ==> So Reduced G6PD activity is NOT measured in the assay => FN results as newer reticulocyte-rich cells with higher G6PD activity are present
Drugs causing Haemolysis in G6PD Deficiency ??
Anti-Malarials: Primaquine
Ciprofloxacin
Sulph-group drugs: Sulfanamides, SUs, Sulfasalazine
Drugs that are SAFE
- Penicillins
- Cephalosporins
- Macrolides
- Tetracyclines
- Trimethoprim
G6PD deficiency v/s H Spherocytosis ??
Males (X-L R) = Male & Females (AD)
2) African & Mediterranean descent = Northern European descent
3) Heinz bodies = Spherocytes (round, lack of central pallor)
4) G6PDd: Neonatal Jaundice, Infection or Drug ppt. Haemolysis, Gallstones
5) H Spherocytosis: Nn Jaundice, Gallstones, Splenomegay, Chr. C/F although haemolytic crises may be ppt. by infection
Dx. test for
- G6PD Deficiency ??
- Hereditary Spherocytosis ??
- Measure G6PD levels 3 months after an Acute attack
- EMA Binding
Hallmarks of Hereditary Spherocytosis ??
MC in Northern European descent
- A D defect in RBC Cytoskeleton
- Normal Bi-Concave disc shape is replaced by a Sphere-shaped RBCs
C/F
- FTT
- Jaundice, Gall stones
- Splenomagaly
- APLASTIC Crisis by Parvovirus
- Variable degree of Haemolysis
- MCHC & Reticulocytes: ELEVATED
Dx. of H Spherocytosis ??
1) FHx of HS + Typical C/F & Lab. Ix. (Spherocytes, Elevated MCHC & Reticulocytes) do NOT require any additional test
2) Equivocal Dx, do
- EMA Binding test & Cryohaemolysis test
3) ATYPICAL Presentation
- Electrophoresis Analysis of RBC membrane is the method of choice
[Osmotic Fragility test was used in the PAST]
Rx. of H Spherocytosis ??
ACUTE Haemolytic Crisis
- Supportive
- Transfusion if necessary
LONG TERM Rx
- Folate replacement
- Splenectomy
Hallmarks of Methaemoglobinaemia ??
Hb has been oxidised from Fe2+ to Fe3+.
This is Normally regulated by NADH Met-Hb reductase which transfers electron from NADH to Met-Hb => Reduction of M-Hb => Hb.
- Tissue Hypoxia as Fe3+ cannot bind O2
- O2 curve is mover to LEFT
Causes of Met-Hb-aemia ??
CONGENITAL
- Hb chain variants: HbM, HbH
- NADH Met-Hb Reductase deficiency
ACQUIRED
- Drugs: Sulfonamides, Nitrates (includes Recreational Nitrates- Amyl Nitrite ‘Poppers’), Dapsone, Na Nitroprusside, Primaquine
- Chemicals: Aniline Dyes
Features & Rx. of Met-Hb-aemia ??
Chocolate Cyanosis
Dyspnoea, Anxiety, Headache
Severe: Acidosis, Arrhythmias, Seizures, Coma
Normal pO2 but Decreased O2 sats.
Rx.-
- NADH Met-Hb Reductase deficiency: ASCORBIC Acid
-Acquired cause- IV Methylthioninium Chloride (Methylene blue)
Hallmarks of Fanconi’s Anaemia ??
A R condition (Defect in DNA repair)
- Increased risk of AML, Solid tumours
Features
Haematological:
- Aplastic anaemia
- Increased risk of AML
CNS
Skeletal abnormalities
- Short stature
- Thumb (absent or hypoplastic) or Radius abnormalities
- Low set ears,
Deafness, Strabismus
Renal Abnormalities
Skin Hypopigmentation
- CAFE-AU-LAIT-Spots
Rx.- BM TRANSPLANT
Types of Polycythaemia ??
RELATIVE Causes
- Dehydration
- Stress: GAISBOCK Syndrome
PRIMARY Cause
- Polycythaemia Rubra Vera
SECONDARY Cause
- COPD
- Altitude
- OSA
- Excessive EPO : Cerebellar Haemangioma, Hypernephroma, Hepatoma, Uterine Fibroids (can cause menorrhagia => blood loss, polycythaemia is rarely a clinical problem)
How to differentiate b/w True (Primary & Secondary) Polycythaemia & Relative P ??
Red Cell Mass studies; In true P, the Total Red cell mass is
- Males > 35 ml/kg
- Females > 32 ml/kg
Hallmarks of PcRV ??
Myeloproliferative disorder due to Clonal proliferation of a marrow stem cell => increased RBC volume a/w overproduction of Neutrophils & Plt.
- JAK2 mutation in 95% cases
- Incidence peaks at 6th decade
Features of PcRV ??
Hyperviscosity
Pruritus, typical after a Hot Bath
Splenomegaly
Haemorrhage (2ndary to Abnormal Platelet function)
Plethoric appearance
HTN in 1/3rd pts.
Low ESR & Raised Leukeocyte Alk. P
Tests done in PcRV ??
BCHS recommends the following
- FBC/Film (Raised Haematocrit; Neutrophils, Basophils, Platelets raised in 1/2 of pts.)
- JAK2 mutation
- Serum Ferritin
- RFT, LFT
If JAK2 mutation is (-)ve & No obvious 2ndary causes BCHS suggests the following tests
- Red Cell mass
- Arterial O2 Sats.
- Abd. USS
- S. EPO levels
- BM aspirate & Trephine
- Cytogenetic analysis
- Erythoid Burst-forming unit (BFU-E) culture
Dx. Criteria for PcRV in JAK2 (+)ve pts. ??
1) JAK2 (+)ve PcRV : Dx. requires BOTH criteria to be present
A1: High Haematocrit (Men >0.52 & Women >0.48) (OR) Raised Red Cell Mass (>25% above predicted)
A2: JAK2 mutation
Dx. criteria in JAK2 (-)ve PcRV ??
Requires A1 + A2 + A3 + Either another A or Two B criteria
A1: Red cell mass >25% above predicted (OR) Haematocrit >0.60 in Men & >0.56 in Women
A2 : Absent JAK2 mutation
A3:No cause of 2ndary Erythrocytosis
A4 : Palpable Splenomegaly
A5 : (+)ve Acquired genetic abnormality (excluding BCR-ABL) in Haematopoietic Cell
B1: Thrombocytosis (Plt. >450)
B2: Neutrophil Leukocytosis (N >10 in Non-smokers; >12.5 in smokers)
B3 : Radiological evidence of Splenomegaly
B4: Endogenous Erythroid Colonies or Low Serum EPO
Rx. of PcVR ??
ASPIRIN
- Reduces risk of Thrombotic events
VENESECTION
- 1st line Rx. to keep Hb in normal range
CHEMOTHERAPY
- Hydroxyurea (slight increased risk of 2ndary Leukaemia)
- Phosphorus-32 therapy
Prognosis of PcVR ??
Thrombotic events are a significant cause of Morbidity & Mortality
- 5- 15% progress to Myelofibrosis
- 5-15% progress to Acute Leukaemia (risk increased with CT)
Hallmarks of TTP ??
Abnormally large & sticky multimers of vWF cause Plt. to clump within vessels
- In TTP, there is a deficiency of ADAMTS13 (a Metalloprotease enzyme) which cleaves large multimers of vWF
- Overlaps with HUS
- More common in Adult FEMALE
- Microthrombi & Ruptured RBCs (Clumps tearing RBCs apart)
Causes & Features of TTP ??
CAUSES
- Post-infection (UTI, GIT)
- Pregnancy
- Tumours, - SLE, - HIV
- Drugs: Ciclosporin, OCPs, Penicillin, Clopidogrel, Aciclovir
C/F
- Fever
- Fluctuating Neuro. signs (Microemboli)
- MAHA, - Thrombocytopaenia
- Renal Failure
- Affects Small BV of Brain & Renals
- Bleeding under skin
Rx. of TTP ??
NO Antibiotics
- Can worsen outcome
ToC: PLASMAPHERESIS
Steroids, Immunosuppressants
Vincristine
Hallmarks of HUS ??
Seen in YOUNG Children; Triad of
- AKI, - MAHA, - Thrombocytopaenia
Most cases are 2ndary cases (Typical HUS)
- STEC O157:H7 (Verotoxigenic, Enterohaemorrhagic). This is the MCC in Children 90% cases
- Pneumococcal infection
- HIV
- Rare: SLE, Drugs, Cancer
Ix. of HUS ??
FBC: Anaemia, Thrombocytopaenia, Fragmented RBCs
U&E: AKI
Stool Culture
- Look for STEC infection evidence
- PCR for Shiga toxin
Rx. of HUS ??
Supportive: Fluids, BT, Dialysis (if required)
NO role of Abx.
Plasmapheresis ONLY in
- Severe + HUS not a/w Diarrhoea cases
ECULIZUMAB (C5 inhibitor)
- Greater efficacy than Plasmapheresis alone in Adult Atypical HUS Rx.
Hallmarks of ITP in Adults ??
Immune mediated reduction of Platelet counts
- Antibodies against [GP2b/3a] or [1b-V-IX] complex => Plt. destroyed
Children: ACUTE Thrombocytopaenia after vaccination or infection
Adults: tend to have a CHRONIC condition
MC in Older Females
Features of ITP ??
May be detected incidentally after a Routine Bloods
Symptomatic Cases presents with
- Petichae, Purpura
- Bleeding (eg. Epistaxis)
- Catastrophic bleed (eg.-Intracranial) is NOT a common presentation
Rx. of ITP ??
1st line: Oral Prednisolone
Pooled Normal Human IVIG
- Used in Active Bleeds or if an Urgent Invasive procedure is necessary
- Raises Plt. count quicker than Steroids
Splenectomy is now less commonly used
EVAN’S Syndrome ??
ITP a/w AIHA
Ix.-
Anti-Platelet autoantibody (IgG)
BM aspirate : Megakaryocytes in BM.
- Should be carried out PRIOR to commencement of Steroids to rule out Leukaemia
Rx.-
- Oral PREDNISOLONE (80% respond)
- Splenectomy if Plt. < 30 after 3 months of Steroid therapy
- IVIGs
- Immunosuppressants: Ciclosporin
Hallmarks of Hemophagocytic Lymphohistiocytosis ??
HLH is an aggressive & potentially fatal syndrome of extreme immune dysregulation (MC in Children)
- Occurs when certain Immune cells (Lymphocytes & Macrophages) become excessively activated => wide spread tissue inflammation & organ damage. Classified into
1) PRIMARY (Familial) HLH
- Genetic form, manifests in Infancy or Early childhood, due to mutations is gene involved in immune regulation. (eg- PRF1, UNC13D)
2) SECONDARY (Acquired) HLH
- Triggered by external factors, Infections (VIRAL, - EBV), Malignancy, Autoimmune disease, Rheumatologic
Pathophysiology of HLH ??
Failure in Cytotoxic activity of NK cells & Cytotoxic T lymphocytes (CTLs) results in Immune dysregulation by
- Uncontrolled Immune activation: Macrophages & T-lymp. release high levels of Cytokines (IFN-gamma, TNF-Alpha, IL-6) ==> ‘Cytokine Storm’
- Systemic Tissue Damage: Excess Cytokine release, damages organs includine- Liver, Spleen & BM causing the hallmarks C/F of HLH
In PRIMARY HLH, genetic mutation disrupts the mechanisms by which NK cells & CTLs kill infected or abnormal cells
In SECONDARY HLH, immune Hyper-activation is triggered by External factors
C/F of HLH ??
Spectrum of C/F reflecting Systemic Inflammation
Initially mistaken to Sepsis or other inflammatory disorders
- Persistent Fever: Resistant to anti-pyretics
- Hepatosplenomegaly a/w Abd. pain
- Cytopaenias: Anaemia, Leukopenia, Thrombocytopaenia due to BM involved
- CNS features: Headaches, Seizures, Altered Mentation
- Rash & Jaundice (due to Systemic inflammation & Liver dysfunction)
Dx. Criteria of HLH ??
5 of 8 clinical & lab. criteria set by the HLH-2004 guidelines
1) Fever > 38.5 C
2) Splenomegaly
3) Cytopaenias (affecting >= 2 cell lineages)
4) Hypertriglyceridaemia (Fasting TGs > 3.0 mmol/L) (OR) Fibrinogen < 1.5 g/L
5) HemoPhagocytosis in BM, Spleen, LN or Liver
6) HyperFerritinemia (> 500ng/ml)
7) Elevated Soluble CD25 (soluble IL-2 receptor) reflects T cell activation
8) Low NK cell activity, indicative of impaired immune regulation
Ix. done in HLH ??
Initial Work up: Lab. tests
- Ferritin : Rapid elevation of Ferritin, typically > 10,000 ng/ml, is a hallmark but NOT specific to HLH
- Triglycerides
- LFTs
- FBCs
- Fibrinogen levels
Bone Marrow Biopsy: essential for identifying HemoPhagocytosis
Genetic Testing: Recommended for Primary HLH targeting common HLH- associated Gene mutation
Rx. of HLH ??
Early & Aggressive Rx. is necessary to control Hyperinflammatory response & prevent organ failure
1) Initial Stabilisation
- Supportive care: Fever Rx, IVF, correct cytopaenias
- Treat the underlying Triggers: In Secondary HLH (Infection, Neoplasia, Autoimmune disorders)
2) PHARMACOLOGICAL Intervention
- Dexamethasone (reduce inflam.)
- ETOPOSIDE (anti-Ca drug, reduces Immune cell proliferation)
- Severe Cases: CICLOSPORINE may be added
IVIGs occasional added particularly in Infection-Triggered HLH
3) Primary HLH or Not responding to above Rx. => Haemopoietic Stem Cell Transplant (HSCT) is Curative
- Usually started after achieving disease control with Chemotherapy
Prognosis & Long term monitoring in HLH
Depends heavily on EARLY Dx. & Rx
- Without Rx., it is fatal
- Secondary HLH: survival rates improve significantly
- Primary HLH: Rx. id challenging, requires HSCT
Primary HLH: Life long follow up
Regular follow-up includes
- Organ Function: LFT, RFT
- Immune Surveillance: Regular blood counts & Inflammatory markers
- BM Health: For those treated with HSCT, BM function assessment is critical
HLH in Adults & Children ??
Primary HLH is mostly seen in Children & Secondary HLH is seen in all age groups
HLH is MC in Children but
Adult cases are increasing, particularly with Malignancy associated HLH
Hallmarks of Thrombocytosis ??
Abnormally high Platelet count > 400
Causes
REACTIVE
- Plt. are Acute phase reactants
- Increases in response to Stress, severe infection, Sx
- IDA can also cause a Reactive Thrombocytosis Malignancy
ESSENTIAL Thrombosis
- As a part of another MP disorder (CML, PcRV)
- Hyposplenism
Hallmarks of Essential Thrombocytosis ??
MP disorder which overlaps with CML, PcRV & Myelofibrosis
- Megakaryocyte proliferation results in overproduction of Platelets
Features
- Plt. count > 600
- Both Thrombosis & Haemorrhage can be seen
- “Burning Sensation in hand”
- JAK2 mutation found in 50% cases
Rx.-
- Hydroxyurea (Hydroxycarbamide)
- IFN-Alpha in younger pts.
- Low dose ASPIRIN (reduces thrombosis risk)
Hallmarks of Myelofibrosis ??
MP Disorder (Fibrosis of BM)
- Due to Hyperplasia of abnormal Megakaryocytes
- Resultant release of Plt. Derived GF =(+)=> Fibroblasts
- Haemotopoiesis develops in Liver & Spleen
Features of Myelofibrosis ??
Elderly with symptoms of Anaemia
- Fatigue (MC symptom)
- Massive Splenomegaly
- Hypermetabolic C/F: Wt. loss, Night sweats, etc.
Lab. Findings
- Anaemia
- Hign WBC & Platelet counts early in the disease
- ‘Tear-drop’ poikilocytes
- BM Biopsy: DRY Tap => TREPHINE Biopsy needed
- High Urate & LDH (Increased cell turnover)
Hallmarks of ALL ??
Malignancy of Lymphoid Progenitor cells affecting B or T cell lineage
- Results in ARRESTING of Lymphoid cell maturation & proliferation of Immature blasts (Lymphoblast) ==> BM & Tissue infiltration
MC Childhood Cancer
Peak age: 2- 5 yrs
80% of Childhood leukaemias
What are the Good & Poor Prognostic factors of ALL ??
GOOD Prognostic Factors
- FAB- L1 type
- Common ALL
- Pre-B phenotype
- Low Initial WBC
- Del (9p)
POOR Prognostic Factor
- FAB-L3 type, - Male Sex
- T or B cell Surface marker
- Philadelphia T, t(9;22)
- Age < 2yrs or > 10 yrs
- CNS Involved, - Non-Caucasians
- High Initial WBS (eg. > 100)
Hallmarks of AML ??
MC form of Acu. Leukaemia in adults
- Seen as a Primary disease (OR)
- Secondary transformation of MP disorder
Features (Largely related to BM Failure)
- Anaemia: Pallor, Lethargy, Weakness
- Neutropenia: Even though WBC counts are very high, functioning N levels can be low; Frequent infections
- Thrombocytopaenia
- Splenomegaly
- Bone Pain
Poor Prognostic features of AML ??
> 60 yrs
20% Blasts after 1st course of CT
Cytogenetics: Chr. 5 or 7 deletion
Features of Acute Promyelocytic Leukaemia M3 ??
- a/w t(15;17) which causes Fusion of PML & RAR-Alpha gene
- Presents Younger than other types of AML (average= 25 yrs)
- AUER Rods (On MyeloPeroxidase stain)
- Heavy cytoplasmic Granulation
Presentation - DIC or Thrombocytopaenia
- Good Prognosis
FAB Classification of AML ??
M0 : Undifferentiated
M1 : Without Maturation
M2 : With Granulocyte maturation
M3 : Acute Promyelocytic
M4 : Granulocytic & Monocytic Maturation
M5 : Monocytic
M6 : Erythroleukaemia
M7 : Megakaryoblastic
Hallmarks of CLL ??
Monoclonal proliferation of Well-differentiated Lymphocytes
- Almost always B-cells (99%)
- MC leukaemia in Adults
Features
- Often none (Incidental finding)
- Anorexia, Wt. loss
- Bleeding, Infection
- LNpathy more marked in CML
Ix. & Indication for Rx. ??
FBC: Lymphocytosis, Anaemia
Smudge or Smear cells
IoC: IMMUNOPHENOTYPING
- CD5/ CD19/ CD23 positive
Rx. Indications in CLL ??
Progressive BM Failure
- Devt. or Worsening of Anaemia &/or Thrombocytopaenia
Massive (>10cm) or Progressive LNpathy
Massive (>6cm) or Progressive Splenomegaly
Progressive Lymphocytosis:
- > 50% increase over 2 months (or)
- Lymphocyte doubling time < 6m
Systemic Symptoms
- Wt. loss > 10% in past 6m
- Fever > 38 C for > 2wks
- Extreme Fatigue, Night Sweats
- Autoimmune Cytopaenias (eg.-ITP)
Prognosis of CLL ??
Poor P factors (Median survival 3-5yr)
- Male Sex
- Age > 70yrs
- Lymphocyte count > 50 yrs
- Prolymphocytes comprising >10% of blood lymphocytes
- Lymphocyte 2x time < 12 months
- Raised LDH
- CD 38 expression (+)ve
- TP53 mutation
- Chr. 17p deletion (5- 10%)
Good Prognosis
- Chr. 13q deletion; MC abnormality seen in 50% cases a/w good P
Rx. & Complications of CLL ??
If NO indications for Rx
- Monitor with regular FBCs
1st Line : Fludarabine, Rituximab, Cyclophosphamide (FCR)
2nd line: IBRUTINIB (used if FCR fails)
Complications
- Anaemia
- HYPOGammaglobulinaemia => Recurrent infection
- Warm AIHA (10-15% cases) => Rx.- Prednisolone
- RICHTER’S Transformation (Convert to High-grade Lymphoma)
What is Richter’s Transformation ??
Occurs when Leukaemia cells enters LN & changes to High-grade, fast growing Non-HL
- Pt. often becomes suddenly Unwell
C/F (Indicated by 1 of the following)
- LN Swelling
- Fever without infection
- Wt. loss
- Night Sweats
- Nausea
- Abdominal Pain
Hallmarks of CML ??
Philadelphia Chr. is present in more than 95% pts
- Translocation t[9(q34);22(q11)]
- This results in ABL proto-oncogene from Chr 9 to fuse with BCR gene on Chr. 22
- This resultant BCR-ABL gene codes for fusion protein that has an excess of Tyrosine Kinase activity
C/F & Rx. of CML ??
Anaemia: Lethargy
Wt. loss & Sweating
Massive Splenomegaly: Abd. discomfort
Increase in Granulocytes at different stages of maturation +/- Thrombocytosis
DERCEASED Leukocyte Alk. P
May undergo Blast transformation
Type of Blast transformation seen in CML ??
AML in 80% cases
ALL in 20% cases
Rx. of CML ??
1st line: IMATINIB Mesylate
- Inhibitor of TK a/w BCR-ABL defect
- Very High response rate in Chr. Phase CML
Hydroxyurea
IFN-Alpha
Allogenic BM Transplant
Hallmarks of Leukaemoid Reaction ??
Presence of Immature cells such as
- Myeloblasts, Promyelocytes, Nucleated RBCs in peripheral blood
- Due to BM infiltration causing Immature cells to be ‘pushed out’ (or)
- Sudden demand for New cells
CAUSES
- Severe Infection
- Severe Haemolysis
- Massive Haemorrhage
- Metastatic Ca with BM infiltration
CML & Leukaemoid reaction ??
The following helps in differentiating CML from LR
1) Leukaemoid Traction
- High LAP
- Toxic granulation (Dohle bodies) in WBCs
- Left shift of Neutrophils ie <= 3 segments of nucleus
2) CML
- Low LAP
Hallmarks of Hairy Cell Leukaemia ??
Malignant proliferation disorder of B Cells
- 4x MC in males
Features
- Pancytopaenia
- Splenomegaly
- Skin vasculitis in 1/3rd pts.
- ‘Dry tap’ despite BM hypercellurity
- Tartrate Resistant Acid Phosphatase (TRAP) stain (+)ve
RX.-
- 1st line: CT with Cladribine, Pentostatin
- 2nd line: Immunotherapy with Rituximab, IFN-Alpha
Hallmarks of Hodgkin’s Lymphoma ??
Malignant proliferation of Lymphocytes characterised by presence of RS cells
- Bimodal age distribution 3rd & 7th Decade
Features
- LNpathy (75%): Painless, Non-tender, Asymmetrical
- Systemic (25%): Wt. loss, Pruritus, Night sweats, Fever (Pel-Ebstein)
- Alcohol pain in HL
- Normocytic anaemia, Eosinophilia
- LDH is raised
Histological Classification of HL ??
NODULAR SCLEROSING
- MC 70% cases
- Good Prognosis
- MC in Women, a/w Lacunar cells
MIXED Cellularity (20% cases)
- Good Prognosis
- a/w Large no. of RS Cells
Lymphocyte Predominant (5% cases)
- BEST Prognosis
Lymphocyte DEPLETED (Rare)
- WORST Prognosis
Prognosis of HL ??
POOR Prognosis
‘B’ Symptoms
- Wt. loss > 10% in last 6 months
- Fever > 38 C
- Night Sweats
Age > 45 yrs
Stage 4 disease
Hb < 10.5 g.dl
Lymphocyte count < 600/ul or < 8%
Male sex
Albumin < 40g/l
WBC >15,000/ul
Staging of HL ??
Ann-Arbor Staging of HL
1 : Single LN
2 : >= 2 LN/ regions on I/L Diaphragm
3 : LN on Both sides of Diaphragm
4 : Spread beyond LNs
Each Stage is divided into A or B
A : No systemic C/F other than Pruritus
B : (Poor Prognosis)
- Wt. loss > 10% in last 6m,
- Fever > 38 C,
- Night sweats
How to differentiate b/w HL & NHL ??
Mainly done by BIOPSY but
- LNpathy in HL can experience [-OH] induced pain in LN
- B symptoms occurs Early in HL & Late in NHL
- Extra-Nodal disease is much more common in NHL than in HL
Hallmarks of NHL ??
Malignant proliferation of Lymphocytes which accumulate in LN & Other organs
- Can affect either B or T cells & is further classified as High or Low grade
- 6th MCC of Cancer in UK
- NHL is much more common than HL
Typically affects Elderly
- 1/3rd cases in > 75 yrs old
- MC in Men than in Women
RFs & C/F of NHL ??
- Elderly, - Caucasians
- H/o Viral Fever (specifically EBV)
- FHx, - H/o CT & RT
- Chemicals (Pesticides, Solvents)
- Immunodeficiency (Transplant, HIV, DM)
- Autoimmune (SLE, Sjogren’s, Coeliac’s)
Symptoms & Signs of NHL ??
Painless LNpathy
- Non-tender, Rubbery, Asymmetrical
B Symptoms
- Fever, Wt. loss, N sweats, Lethargy
Extra-Nodal Diseases
- Gastric: Dyspepsia, Dysphagia, Abd. Pain,
- BM : Pancytopaenia, Bone pain
- Lungs, - Skin, - CNS (Nerve Palsies)
SIGNS
- LNpathy: Cervical, Axillary, Inguinal
- Palpable Abd. Mass: Hepatomegaly, Splenomegaly, LNs
- Testicular Mass
- Fever
Ix. of NHL ??
1) Dx. IoC: Excision Node Biopsy
- Certain types will have classical appearance of Burkitt’s (Starry sky)
2) Staging: CT Chest, Abd., Pelvis
3) HIV testing
4) FBC & Blood Film (Normocytic anaemia, rules out Leukaemias)
5) ESR & LDH: (Prognostic Indicator)
6)LFT (if Liver metastases suspected)
7) PET-CT or BM Biopsy if Bone involved &
8) LP if CNS symptoms
Staging of NHL ??
Ann Arbor System
1 : 1 LN or 1 organ affected
2 : > 1 LN affected on I/L Diaphragm
3 : LN affected on Both sides above & below Diaphragm
4 : Extra Nodal Spread (eg.- Spleen, BM or CNS) +/- LN involvement
Each stage is sub-divided into
- A : If no ‘B’ symptoms seen
- B : If ‘B’ symptoms (+)ve
Rx of NHL ??
1) Dependent on Subtype of NHL
- Watchful wait/ CT/ RT
2) ALL pts. must receive Flu/ Pneumococcal vaccines
3) Antibiotics Prophylaxis : Pts. with Neutropaenia
Complications & Prognosis of NHL ??
BM Infiltration: Anaemia, Neutropaenia, Thrombpcytopaenia
SVC Obstruction
Metastasis
Spinal Cord Compression
Rx. related (S/E of CT)
Prognosis
- LOW Grade NHL : Better Prognosis
- HIGH Grade NHL : Worse Prognosis but HIGH Cure rate
Hallmarks of Neutropaenia ??
Low N counts < 1.5; Normal levels are 2.0 to 7.5
Subdivided into
- Mild : 1.0 to 1.5
- Moderate : 0.5 to 1.0
- Severe : < 0.5
Causes of Neutropaenia ??
Viral: HIV< EBV< Hepatitis
Drugs: Cytotoxics, Carbimazole, Clozapine
Hamaetological Malignancy
- Myelodysplastic malignancies
- Aplastic anaemia
Rheumatological conditions
SLE : circulating Antineutrophil antibody
RA : Hypersplenism in Felty’s
Severe Sepsis
Haemodialysis
What is Benign Ethnic Neutropaenia ??
Common among Black Africans & Afro-Caribbeans ethnicity
- Requires no Rx.
Hallmarks of Neutropaenic Sepsis ??
Relatively common complication of Cancer therapy, a consequence of Chemotherapy
- Occurs 7- 14 days after Chemo
Neutrophil < 0.5 in a pt. on Anti-Ca Rx & has one of the following
- Fever > 38 C
- Signs & C/F consistent with Sepsis
Rx. of Neutropenic Sepsis ??
Prophylaxis
- It is anticipated in Pts. on Chemo that N will go < 0.5 as a result of Rx. so FLUOROQUINOLONES are offered
Rx
- Abx. started immediately (do NOT wait for WBC results)
- Empirical Abx.- TAZOCIN is started
After Initial Rx., risk assessment & stratification is done to see if Rx. on OPD basis is possible
- If pt. still Febrile & Unwell after 48 hrs, alternative Abx.- Meropenam +/- Vancomycin
- If not responding after 4- 6 days: Ix for Fungal infection rather than starting on Antifungals
- G-CSF is used in some pts.
Hallmarks of Burkitt’s Lymphoma
High grade B cell Neoplasia
There are 2 major forms
- Endemic (African) form: Typically involves Maxilla or Mandible, EBV infection is strongly implicated
- Sporadic form: Abdominal (Ileo-caecal) tumours are MC forms & is MC in HIV pts. a/w EBV to a lesser extent
A/W c-myc gene translocation t(8;14)
HP: ‘Starry Sky’ appearance: Lympho-cytes sheets interspersed with macrophages containing dead apoptotic tumour cells.
Rx. of Burkitt’s Lymphoma ??
Chemotherapy (a/w Tumour Lysis S)
- Rasburicase is given before CT
Complications
- Hyper: K+, PO4-,
- Hypocalcaemia
- Hyperuricaemia
- Acute Renal Failure
Hallmarks if Mantle cell lymphoma ??
Type of B-cell Lymphoma
Genetics
- CD5+, CD19+, CD22+, CD23-, CD10-
- t(11;14) causing over-expression of Cyclin D1 (BCL-1) gene
C/F: Widespread LNpathy
- Poor prognosis
Hallmarks of Multiple myeloma ??
Is a Neoplasia of BM Plasma cells
Peak incidence: 60- 70 yrs
C/F
1) Bone disease: Bone pain
- Osteoporosis + Pathological # (typically Vertebral)
- Osteolytic lesions
2) Lethargy, Hyperviscosity, Infection
3) Hypercalcaemia
- Primarily due to INCREASED Osteoclast bone resorption by local Cytokines (IL-1, TNF) released by Myeloma cells
- Secondarily due to Impaired Renal function, Increased R-tubule Ca2+ reabsorption & elevated PTH-rP
4) Renal Failure
5) Amyloidosis eg.- Macroglossia, CTS, Neuropathy
Ix. done in Multiple Myeloma ??
Monoclonal proteins (IgG or IgA) in Serum & Urine- Bence J proteins
BM: Increased Plasma cells
Whole body MRI
X-rays: ‘Rain drop skull’ random pattern of dark spots
- NOTE: very similar to but subtly different from Pepper-pot skull seen in Primary HyperPTH
Dx. Criteria for Multiple Myeloma ??
1M + 1m or 3m in pts. with C/F of MM
MAJOR Criteria
- Biopsy: shows Plasmacytoma
- BM sample: 30% plasma cells
- Elevated M proteins in blood/ urine
MINOR Criteria
- BM sample: 10%- 30% Plasma cells
- Blood/Urine: Minor rise in M protein
- Imaging: Osteolytic lesions
- Blood: Low levels of Antibodies (not produced by cancer cells)
Prognosis of M Myeloma ??
Raised B2-Microglobulin & Low levels of Albumin indicate POOR Prognosis
Stage = Criteria = Median Survival
- 1 = B2-M < 3.5mg/l & Albumin > 35 g/l = 62 months
- 2 = Not Stage 1 or 3 = 45 months
- 3 = B2-M > 5.5 mg/l = 29 months
Hallmarks of Haemophilia ??
COAGULATION Disorder [Intrinsic Pathway Coagulation defect]
X-linked Recessive (No FHx in 30%)
Dx. in Infant Males with Bleeding or prolonged BT
INHERITED Haemophilia (X-l R)
- MC form of Hamophilia
ACQUIRED Haemophilia
Due to Inhibitory Autoantibody a/w autoimmune disorder =(+)=> F-VIII inhibitors production
Other causes
- Idiopathic (50% cases)
- Postpartum period
- Malignancy (solid tumour or Lymphoproliferative disorder)
- Medications
Types of Haemophilia ??
H- A (Classic H)
- Clotting factor VIII deficiency
H- B (Christmas disease)
- Clotting factor IX deficiency
H- C (Rosenthal Syndrome)
- Clotting factor XI deficiency
- A R inheritance
- MC in Ashkenazi Jewish population
How is Haemophilia classified based on Severity ??
Within those categories, H can further be classified on Severity-
- Mild: 5- 40% of normal Clotting Factor Levels (CFL)
- Moderate: 1-5% of normal CFL
- Severe (50% cases): < 1% of normal CFL
Features
- Haemoarthroses
- Haematomas
- Prolonged Bleeding after Sx. or Trauma
Blood tests done in Haemophilia ??
Suspected in YOUNG pts. with Prolonged Haemorrhage, Ecchymosis , or Haemarthrosis
1) Clotting Studies
2) Prolonged aPTT (hallmark)
- Represents INTRINSIC pathway
3) Normal PT
- Can rule out EXTRINSIC & COMMON coagulation pathway pathologies
- Causes: Liver diseases, Vit.K def. or DIC
4) LFT (5) F-VIII & IX assay
6) Mixing studies (Sample plasma + Normal plasma for 2 hrs)
7) vWF antigen testing
How to differentiate Acquired Haemophilia b/w Clotting F deficiency & CF Antibodies ??
MIXING Studies
- [sample Plasma + normal Plasma] for 2 hrs
- CF Deficiency: APTT should correct
- CF Antibodies: APTT will not correct
Clotting disorder can be due to
- CF Deficiency or
- Acquired CF inhibitors (MC against F-VIII
Coagulation disorders Blood Tests ??
Prothrombin Time
- Tests Common & Extrinsic pathway
- Factors- 1, 2, 5, 7, 10
- PT: Play Tennis OUTside (Extrinsic)
INR : Pt. PT/ Control PT
- 1 = normal; > 1 = Prolonges
PTT Tests
- Tests Common & Intrinsic pathway
- All Factors except: 7 & 13
- PTT: Play Table Tennis INside
TT
- Measures the rate of conversion or Fibrinogen to Fibrin
- Prolonged by: AC, DIC, Liver disease, Hypofibrinogenemia
Rx. of Haemophilia ??
Acute episode of Mild H- A
- Desmopressin (promotes vWF release)
- CFs Conc. used only if Bleeding persists after DDAVP use
Severe disease: IV CFs (prophylactically & Self administered)
- Rx. goal: 30-50% of normal CFLs
- 1-3 infusions/wk. for 45wks in 1 yr.
REPLACE the missing CFs
H- A : F-VIII replaced
- Emicizumab
H- B : F-IX replaced
Over time, Antibodies can develop to the replacement CFs called- Factor Inhibitors
- Higher doses of missing CFs are needed for the same effect
- Inhibitors MC in A (30%) > B (3%).
NSAIDs & Aspirin is AVOIDED
Hallmarks of vWD ??
MC inherited BLEEDING Disorder
- Maj. inherited in A D fashion
- Type 3 vWD is A R fashion
vWF is a large glycoprotein which forms massive multimers upto 1,000,000 Da in size
- Promotes Plt. adhesion to damaged Endothelium
- Carrier molecule for F-VIII
Types of vWD ??
Type-1 (80% cases)
- Partially reduced vWF
Type-3 (A R form)
- Total lack of vWF
- Most severe form
Type-2 (abnormal vWF form):-
Defective Plt. adhesion due to Decreased molecular wt. of vWF
- Type-2B : Pathological increase of vWF-Plt. interraction
- Type-2M : Decrease in vWF-Plt. interaction (not related to wt. of vWF)
- Type-2N : Abnormal Binding of vWF to F-VIII
Ix. done in VWD ??
Intrinsic Coagulation pathway defect
- Decreased quantity/ func. of vWF => Elevated PTT (vWF carries F-VIII)
- Defect in Plt. Plug formation: Low vWF => Defect in Plt-vWF adhesion
Prolonged BT
APTT may be prolonged
F-VIII levels are moderately reduced
Defective Plt. aggregation with Ristocetin
Rx. of VWD ??
Mild bleed: Tranexemic acid
Desmopressin : Induces vWF release from Weibel-Palade bodies in Endothelial cells
F-VIII concentrate
Chromosomal translocations seen in
- Burkitt’s lymphoma ??
- Mantle cell lymphomas ??
- Marginal zone lymphoma ??
- Follicular lymphoma ??
- APL (M3 type of AML) ??
- CML & ALL (Less common) ??
- t(8;140) : c-myc activation
- t(11;14) : cyclin D1 activation
- t(11;18)
- t(14;18) : BCL-2 activation
- t(15;17)
- t(9;22) : CML (BCR-ABL)
Medications predisposing to VTE ??
COCPs (3rd gen > 2nd gen)
HRT
- Higher risk in women on Oestrogen + Progestogen preparation than those taking O-only pills
Raloxifene & Tamoxifene
Antipsychotics (specially Olanzapine)
Which Central Venous catheter has an increased risk of VTE ??
Femoral»_space;> Subclavian
What is Two-level DVT Well’s score ??
1) Active Ca (On Rx./ within 6m/Palliative) : 1
2) Paralysis,Paresis or Recent Plaster Immobilisation of LL : 1
3) Recent bedridden for >= 3 days or Maj. Sx. in < 12 wks requiring GA or Regional Anaesthesia : 1
4) Localised tenderness along the Deep vein system distribution : 1
5) Entire Swollen leg : 1
6) Calf swollen >=3cm than normal : 1
7) Pitting edema in symptomatic leg:1
8) Collateral superficial veins (Non- Varicose) : 1
9) Previous documented DVT : 1
10) Alternative Dx. is at least as likely as DVT : (-2)
Ix. if Well’s score >= 2 in DVT ??
If 2-level DVT Well’s score >= 2
Proximal Leg USS in < 4hrs (OR)
D-dimer (if not done) + Interim Therapeutic AC + Scan in < 24hrs
1) If Scan (+)ve => DVT diagnosed
2)If Scan (-)ve => Do D-dimer (if not done)
- If D-d (+)ve : Stop AC+ Repeat scan in 1wk => If repeat (+)ve => DVT dx. & If 2nd scan (-)ve => Consider alternate Dx. & Stop AC
- If D-d (-)ve : Consider alternate Dx. & Stop AC
Ix. if DVT Well’s score <=1 ??
DVT Unlikely
D-dimer with results in 4hrs (OR) Interim Therapeutic AC while waiting
- If (+)ve => Follow Well’s score >=2 DVT likely algorithm
- If (-)ve => Consider alternative Dx.
Pregnancy & DVT/ PE ??
Pregnancy is a Hypercoagulable state
- Maj. happens in LAST Trimester
The following changes occur
- Increase in Factor 7, 8, 10 & Fibrinogen
- Decrease in Protein S
- Uterus presses on IVC => venous stasis in LL
Rx.-
- S/C LMWH
- Warfarin CI
What is Antiphospholipid syndrome ??
Acquired disorder characterised by predisposition to
- Venous or arterial thromboses
- Recurrent Fetal loss
- Thrombocytopaenia
It can occur as a Primary or Secondary disorder
- MCC is SLE
Features of APLS ??
In Pregnancy, the following can occur
- Recurrent miscarriages
- IUGR, - Pre-Eclampsia
- Placental abruption
- Pre-term delivery
- VTE
Rx.-
- Low dose ASPIRIN : started as soon as pregnancy is confirmed on UPT
- LMWH : once Fetal heart is seen on USS. This is usually discontinued at 34 wks POG
- These interventions increase the live birth rate by 7x
Normal Homeostasis of Coagulation & Fibrinolysis in body ??
Coagulation cascade activation yields Thrombin that converts Fibrinogen => Fibrin; stable Fibrin Clot being the final product of Homeostasis
Fibrinolytic system breaks down Fibrinogen & Fibrin
Fibrinolytic system activation generates Plasmin (in the presence of Thrombin), which lyse the fibrin clots
Fibrinogen & Fibrin breakdown result in Fibrin Degradation product
In Homeostasis, PLASMIN is critical, as it is the central proteolytic enzyme of coagulation
Mechanism of DIC ??
Process of Coagulation & Fibrinolysis are dysregulated => results in Wide spread Clotting with resultant bleeding
- Critical mediator of DIC: Transmemb Glycoprotein (Tissue Factor: TF)
- TF is present on surface of many cell types (including Endothelial cells, Macrophages, Monocytes) & is not normally in contact with general circulation, but is exposed to the circulation after Vascular damage
- Eg.- Exposure to IL-1, TNF, Endotoxin => TF released
TF is abundant in: Lungs, Brain, Placenta
- Once activated, TF binds with CFs =(+)=> Extrinsic CP (via F-VIII) => subsequently (+) Intrinsic (12 to 11 to 9) CP
Dx. of DIC ??
Typical blood picture includes
- Decreased Platelets
- Decreased Fibrinogen
- Increased PT & APTT & BT
- Increased Fibrinogen degradation products
- Schistocytes due to MAHA
Causes of DIC ??
Sepsis
Trauma
Obstetric complications eg.- Amniotic fluid embolism or haemolysis, HELLP
Malignancy
Clotting profile of the following
- Warfarin ??
- Aspirin ??
- Heparin ??
- DIC ??
- PT is prolonged; APTT, BT, Plt.C are all normal
- BT is prolonged; PT, APTT, Plt.C are all normal
- APTT is prolonged, PT if often normal (may be prolonged); BT, Plt.C are normal
- PT, APTT, BT are prolonged; Plt.C is Low
Causes of Thrombophilia ??
These result in Hypercoagulable states (increased tendency to develop Thrombosis)
INHERITED Causes
Gain in Func. Polymorphisms
- F-5 Leiden (activated Protein-C resistance) is the MCC
- PT gene mutation: 2nd MCC
Deficiencies of Naturally occurring AC
- AT-3 deficiency
- Protein-C deficiency
- Protein-S deficiency
ACQUIRED Causes
- APLS
- Drugs: COCPs
What are the Prevalence & Relative Risk of VTE in different Inherited Thrombophilias ??
Condition = Prevalence = RR of VTE
F-5 Leiden (Heterozygous) = 5% = 4
F-5 Leiden (Homozygous)= 0.05% = 10
PT gene mutation (Heterozygous) = 1.5% = 3
Protein C deficiency = 0.3% = 10
Protein S deficiency = 0,1% = 5-10
AT-3 deficiency = 0.02% = 10-20
Hallmarks of Factor-V Leiden ??
F-5 Leiden (activated Protein-C Resistance) is the MC inherited form of Thrombophilia in UK
Gain in func. mutation in F-5 Leiden protein. => Mis-sense mutation => F-5 is inactivated 10x more slowly by activated protein C than normal
- Guanine => Adenine DNA Point Mutation => Arg506Gln mutation
- So F-5 Leiden or Activated Protein-C Resistance
VTE risk & Screening done in Activated Protein-C Resistance ??
Heterozygous: 4x- 5x increase in VTE
Homozygous: 10x increase in VTE but prevalence is much lower at 0.05%
Screening for F-5 Leiden is NOT recommended, even after VTE
- Previous H/o VTE itself is a risk factor for further episodes; dictates specific Rx. rather than the particular thrombophilia identified
Complications of F-5 Leiden ??
DVT
Cerebral Vein Thrombosis
Recurrent pregnancy loss
MC in Caucasian descents
Hallmarks of Protein C & S deficiency ??
Autosomal Co-dominant condition
Decreased ability to INACTIVATE F-5a & F-8a.
Increased risk of Warfarin-induced Skin Necrosis.
- “Together protein C Cancels & protein S Stops, coagulation”
Features of Protein C & S deficiency ??
VTE
Skin necrosis following Warfarin initiation
- When W is 1st Initated, protein C synthesis is reduced => Temporary Pro-Coagulant state => Thrombosis in venules => Skin Necrosis; This is normally avoided by concurrent Heparin administration
Hallmarks of Anti-Thrombin III deficiency ??
A D Inherited cause of Thrombophilia
- AT-III (-) several CFs primarily: Thrombin, F-10, 9. It mediates the effects of Heparin
AT-III deficiency comprises of Heterogenous group of disorders, with some pts. having a
- Deficiency of normal AT-III (or)
- Produce abnormal AT-III
Blood film picture of Hyposplenism ??
Post-Splenectomy, Coeliac’s
- Target cells
- Howell-Jolly bodies
- Pappenheimer bodies
- Siderotic granules
- Acanthocytes
Features & Rx. of AT-III deficiency ??
Recurrent VTE
Arterial thromboses do occur but are uncommon
NOTE: AT-III deficiency have a degree of resistance to Heparin anti-Xa; levels should be monitored carefully to ensure adequate AC
Rx.-
- VTE are treated with Lifelong WARFARIN
- Pregnancy: HEPARINISATION
- AT-III concentrates
RR of VTE is 10-20
Blood films of IDA ??
Target cells
‘Pencil’ poikilocytes
Dimorphic film (Micro- & Macro- cytic)
- If combined with B12 deficiency
Blood film features seen in
- Myelofibrosis ??
- Intravascular Haemolysis ??
- Megaloblastic Anaemia ??
- ‘Tear-drop’ poikilocytes
- Schistocytes
- Hypersegmented Neutrophils
Leukocyte Alkaline Phosphatase is
- Raised in ??
- Low in ??
Raised in
- PcRV
- Myelofibrosis
- Leukaemoid Reaction
- Infections, - Pregnancy, - OCPs
- Steroids, - Cushing’s syndrome
Low in
- CML
- Pernicious Anaemia
- PNH
- Infectious Mononucleosis
Haptoglobuline are decreased in ??
Intravascular Haemolysis
- Haptoglobulins binds to free Hb
MCHC are
- Raised in ??
- Decreased in ??
Raised in
- H Spherocytosis
- AIHA (a/w Spherocytosis)
Decreased in
- Microcytic anaemia (eg IDA)
CMV (-)ve & Irradiated blood
CMV is transmitted in Leucocytes. As most blood products (except Granulocyte transfusions) are now Leucocyte depleted, CMV (-)ve are rarely required
Irradiated blood products are T-lymphocyte depleted & is used to avoid Transfusion associated GVHD (TA-GVHD) caused by the variable donor T lymphocytes
Indications of CMV & Irradiated blood ??
Situations that need BOTH CMV (-)ve & Irradiated blood product
- Granulocyte transfusions
- Intrauterine transfusions
- Neonates up to 28 days post expected date of delivery
Needs only CMV (-)ve product
- Pregnancy: Elective transfusion during pregnancy (not during labour or delivery)
Needs only Irradiated blood product
- BM or Stem cell transplant
- Immunocompromised (eg.- CT or Congenital)
- Pts. with/ previous Hodgkin L
Do not need any of the 2
- HIV
Hallmarks of FFP ??
‘Clinically significant’ but without ‘Major bleed’ in pts. with PT ratio or APTT ratio of > 1.5
- Typically 150 to 220 ml
- Used prophylactically in pts. under going Invasive Sx. where there is a significant bleeding risk
Universal Donor of FFP is “AB Blood” as it lacks anti-A or anti-B antibodies
Hallmarks of Cryoprecipitate ??
Contains conc. F-8, vWF, Fibrinogen, F-13 & Fibronectin produced by further processing of FFP
- MC used to replace FIBRINOGEN
- Vol.- 15- 20 ml only
Indication: Clinically significant + No major Bleed + Fibrinogen < 1.5g/L
Use: DIC, Liver failure, 2ndary to massive BT (Hypofibrinogaenaemia)
- In Haemophiliacs (when specific factor NOT available) & in VWD
- Prophylactically in Invasive Sx. with a risk of significant bleed + Fibrinogen < 1.0 g/L
Hallmarks of PTC ??
Used in emergency reversal of AC in pts. with either
- Severe bleed (OR)
- Suspected Intracranial Bleed
Used prophylactically in pts. under going emergency Sx.
Hallmarks of Platelet Transfusion in Active bleeding ??
Indications
Plt. Count < 30 + Bleeding grade 2 (eg.- Haematemesis, Malaena, prolonged epistaxis)
Severe Bleed (Bleeding grade 3 or 4) OR Bleeding at critical sites line CNS + Plt.C < 100
Plt. transfusion has the HIGHEST risk of Bacterial Contamination
Prophylactically given in Thrombo-cytopaenia before Sx./ Invasive procedure; Aim for a level of
- > 50 for most pts.
- 50- 75 in High risk bleeding pts
- > 100 if Sx. at Critical sites
Plt. Transfusion is CI in which conditions ??
Threshold of 10 except where the Plt. transfusion is CI or there are alternative Rx. available
Plt. Transfusion is CI in
- Chr. BM failure
- Autoimmune Thrombocytopaenia
- HIT
- TTP
What is IgG4 Related disease ??
It has been described in virtually every organ system: Biliary tree, Salivary glands, Periorbital tissues, Kidneys, Lungs, LNs, Meninges, Aorta, Breast, Prostate, Thyroid, Skin & Pericardium
HP: Similar across organs, regardless of site - Analogous to Sarcoidosis
- Raised IgG4 conc. in tissue & serum
Waldenstrom’s M ??
Is a Rare type of Blood Cancer
WM is seen Older Men
- Lymphoplasmacytoid malignancy characterised by secretion of a Monoclonal IgM pataprotein
Examples of IgG4 related diseases ??
Reidel’s Thyroiditis
Autoimmune Pancreatitis
Mediastinal & Retroperitoneal Fibrosis
Periaortitis/ Periarteritis/ Inflammatory aortic aneurysm
KUTTNER’S Tumour (Submandibular glands) &
Mikulicz Syndrome (Salivary & Lacrimal glands)
Possibly Sjogren’s & PBC
What is Cryoglobulinaemia ??
IGs which undergo reversible ppt. at 4 deg. C, dissolve when warmed to 37 deg. C
- 1/3rd cases are Idiopathic
Features
- Raynaud’s (only in Type-1)
- Cutaneous: Vascular purpura, Distal ulcerations, Ulceration
- Arthralgia
- Renal involved (Diffuse GN)
Types of Cryoglobulinaemia ??
Type-1 (25% cases)
- Monoclonal- IgG or IgM
- a/w: M Myeloma, Waldenstrom’s M
Type-2 (25% cases)
- Mixed Mono- & Poly- Clonal; usually with RF
- a/w: HCV, RA, Sjogren’s, Lymphoma
Type-3 (50% cases)
- Polyclonal; a/w RF
- a/w: RA, Sjogren’s
Ix. & Rx. of Cryoglobulinaemia ??
Low Complement (especially C4)
High ESR
Rx.-
- Immunosuppression
- Plasmapheresis
What is Monoclonal Gammopathy of Undermined Significance (MGUS) ??
aka Benign Paraproteinaemia & Monolonal Gammopathy
- Causes Paraproteinaemia & is often mistaken to Myeloma
- Around 10% pts. eventually develop Myeloma at 10 yrs, with 50% at 15 yrs
Features of Waldenstrom’s M ??
Monoclonal IgM Paraproteinaemia
Wt. Loss, Lethargy
Hyperviscosity : eg.- Vision probs
- IgM pentameric configuration increases the viscosity
Hepatosplenomegaly
LNpathy
Cryoglobulinaemia eg.- Raynaud’s
Features of MGUS ??
Differentiating features are
- Asymptomatic
- NO Bone pain or Increased risk of infection
- 10- 30% of pts. have Demyelinating Neuropathy
Differentiating features from M Myeloma
- Normal immune function
- Normal Beta-2-microglobulin levels
- Lower level of Paraproteinaemia than myeloma eg.- < 30g/l if IgG or < 20g/l if IgA
- Stable level of paraproteinaemia
- NO C/F of Myeloma (eg. Lytic features on x-ray or Renal disease)
Hallmarks of Wiskott-Aldrich Syndrome ??
Primary Immunodeficiency due to a combined B & T cell dysfunction
- X-linked-Recessive
- Mutation in WASP gene
Features
- Recurrent Bacterial infection
- Eczema
- Thrombocytopaenia (very few Plt.)
- Low IgM levels
Causes of Massive Splenomegaly ??
Myelofibrosis
CML
Visceral Leishmaniasis (Kala azar)
Malaria
Gaucher’s Syndrome
Causes of Splenomegaly ??
- Portal HTN (Cirrhosis)
- Lymphoproliferative disease eg.- CLL, Hodgkin’s L
- Haemolytic Anaemia
- Infection: Hepatitis, Glandular Fever
- Infective Endocarditis
- Sickle Cell (Maj. have an atrophied spleen due to repeated infarction)
- Thalassemia
- RA (Felty’s)
Causes of Hyposplenism ??
Splenectomy
Sickle Cell D
Coeliac’s, Dermatitis Herpetiformis
Grave’s
SLE
Amyloid
Blood Film : Howell Jolly bodies, Siderocytes
Primary Thrombocythaemia ??
aka Essential Thrombocythaemia, a Myeloproliferative disease
- Thrombocytosis
- Anaemia is present ONLY if there is bleeding
- Raised Reticulocyte count
Rx.- Hydroxyurea (Initial ToC)
- 2nd line: Anagrelide in pts. > 60yrs, was inferior with respect to arterial thrombosis, maj. bleed & myelofibrotic transformation to H-urea
- Anagrelide is better at reducing VTE than H-urea
What are the 2 major causes of Significant Splenomegaly in pts. of UK origin ??
CML (elevated WBCs)
Myelofibrosis (causes Pancytopaenia)
5q Minus syndrome ??
Sub-type of Myelodysplasia that is a/w Raised Plt. count
- Predominatly seen in women than in men
Heparin Induced T
Pt. on Heparin, presents with DVT after a few days of starting
> 50% fall in Plt. count
Anti-PF-4 antibodies are responsible
Stop Heparin based AC & start Non-Heparin based therapy
