Haematology and Oncology Flashcards
What’s the pathophysiology underlying TTP?
ADAMST3 activity deficiency! Either acquired (95%) or genetic mutation (5%)
This protease normally breaks down ultra large polymers of vWF.
Failure to do so. = platelet clumping, micro-thrombi and red cell fragmentation.
What are the steps involved in primary haemostasis (platelet plug)?
1) Platelet adhesion to damaged vessel wall (GP1a-collagen) and GP1b-vWF)
2) Platelet activation via interaction with one another and with collagen and mediated by thrombin. Involves release of contents of alpha and dense granules.
3) Platelet aggregation (ADP released from dense granules binds to Platelet P2Y12 receptor activating the GPIIB/IIIa complex. The aggregation happens through the linking of platelet exposed GPIIB/IIIa complexes with fibrinogen and vWF
Describe the extrinsic pathway (initiation phase)
Extrinsic pathway involves TF on exposed tissue vessel wall after injury
TF binds FVII -> FVIIa
FVIIa binds FX -> FXa….
FXa interacts with cofactor FVa to activate prothrombin (FII) -> thrombin (FIIa)
Thrombin activates platelets, activates fibrinogen and also stimulates FV, FVIII and XIII
Describe the intrinsic pathway
Intrinsic pathway is activated by contact with -be charged surfaces (in Vivo by expose of subendothelial CT of damaged vessels).
Deficiencies of factors don’t usually cause bleeding
Process…
FXII interact with -ve charge surface -> FXIIa
FXIIa binds FXI -> FXIa
FXIa binds FIX -> FIXa
FIXa activates FX -> FXa
FXa enters common pathway
Describe the final common pathway of haemostasis
FXa activates FII (prothrombin) -> FIIa (thrombin)
This process involves cofactors FV, Calcium and happens on platelet surface.
FIIa (thrombin) hydrolyses FI (fibrinogen) -> FIa (fibrin)
Fibrin monomers aggregate
FIIa (Thrombin) activates FXIII -> FXIIIa
FXIIIa links (FXIa) fibrin polymers to form insoluble fibrin clot.
Describe Fibrinolysis
Fibrinolysis = process of breaking down fibrin and fibrinogen
Activators of fibrinolysis:
tPA - secreted by endothelial cells
Urokinase - released by macrophages
Factor XIIa ( intrinsic pathway)
Process:
tPA bind fibrin then activates plasmin from plasminogen.
Activated Plasmin then cleaves fibrin and fibrinogen to fibrin degredation products and D dimers.
NB. D dimers are specifically products of cross linked fibrin breakdown
Describe the processes involved in natural anticoagulation
1) Preventing platelet activation and aggregation
Endothelial cells secrete vasodilatory and anti platelet substances:
i) NO - inc cGMP - dec intracellular Ca -> vasodilation and inhibits platelet aggregation
ii) PGI2 - vasodilates. Prostacyclin also binds directly to platelet surface preventing their activation ( Gs GPCR)
2) Preventing fibrin clot formation
Tissue Factor inhibitor - expressed on the surface of the normal endothelium and inhibits extrinsic pathway
Antithrombin III - inhibits thrombin as well as intrinsic pathway factors -
Thromomodulin is a protein which modulates thrombin and this activates Protein C
(NB - thrombin also activates Protein C)
Protein C with the help of Protein S - inhibits cofactors V and VIII
3) Fibrinolysis
Process of plasmin breaking down fibrin and fibrinogen to FDP.
Plasminogen is activated to plasmin by 1) Urokinase, 2) tPA 3) Factor XIIa
PT test and causes of prolonged PT
PT (play tennis outside!)
- tests extrinsic pathway
- thromboplastin added to citrated blood
- time taken to clot measured
- normal 10-13 secs
- tests FI, II, VII, X
- INR = ratio of sample PT to international standard, warfarin therapy
Abnormal prolonged PT
- warfarin
- FII, FVII deficiency -> remember II/VII/IX and X need Vit K
- Vit K deficiency
- DIC
- Artefact - incorrect sampling or if Hct is high
APTT test and causes of abnormal result
Remember play table tennis inside!
- tests intrinsic pathway
- kaolin added to citrated blood
- tests factors XII, XI, IX, VIII and factors common to both pathways.
- Normally 30-35secs
Causes of prolonged APTT
- Heparin
- Haemophillia - A (factor VIII def)
- Haemophilia- B (factor IX def)
- Liver disease
- DIC
Mixing tests are performed in cases of prolonged APTT to determine if it is a true factor deficiency or there is an inhibitor present. (Mix sample with normal blood 50:50 - if APTT corrects it was a factor deficiency…if it remains prolonged do further tests for inhibitor…
Antiphospholipid syndrome causes prolonged APTT which doesn’t correct with mixing blood sample with 50:50 normal platelet free plasma
Adding heparinise, if heparin is present and causing prolonged APTT, the result will normalise when heparin activity is inhibited.
Describe the thrombin time and causes of abnormal result
- Thrombin is added to undiluted plasma
- common pathway assessment
- Tests time to conversion of fibrinogen FI -> fibrin FIa
Prolonged in:
- DIC
- heparin activity (inhibits thrombin by potentiating antithrombin )
- low fibrinogen levels
- direct thrombin inhibitor
Causes of an abnormal fibrinogen
High - acute phase protein
Low - sepsis and DIC
Describe classic features of TTP
FAT R/N
- Fever
- Anaemia
- Thrombocytopenia
-Renal problems ( more so HUS > TTP)
-Neuro problems ( TTP > HUS)
Principles of Mx of TTP
1) Replacement
- Plasma exchange
- FFP or cryo replacement ( has ADAMST13)
- 1.5 plasma volumes daily until plt > 150
2) Immune modulation
- Steroids - methylpred for 3 /7
- If neuro or cardiac involvement -> Rituximab ( monoclonal Ab which binds to CD20 on B cells to inhibit autoantibody production)
3) Can inhibit vWF with ? Caplacizumab
Why do coagulation mixing studies?
Mixing Studies help differentiate between factor deficiencies or factor inhibitors
If your sample of plasma is giving a high PT or aPTT - grab your suspicious plasma sample, and mix it with normal blood, 50:50. Obviously, if some sort of “factor inhibitor” is present, the normal blood will also be affected, and the resulting mixture will give abnormal aPTT and PT results. If there is a factor deficiency, the mixed sample will result in a normal PT or aPTT.
An abnormal mixing study result implies that in spite of the addition of normal plasma, the coagulopathy persists. This suggests that a factor inhibitor is present.
Go onto check antiphospholipid anticoagulant and heparin assay
What will prolong your PT and your APTT?
- DIC
- Massive transfusion
- Massive warfarin overdose
- Primary fibrinolysis - e.g in trauma
- Post thrombolysis
- Snake bite - which can be pro or anti-coagulant
- Direct thrombin inhibitor toxicity - thrombin time should be prolonged in this case but reptilase time normal
Severe liver failure
List some of the common thrombophilia’s
Thrombophilia = predisposition to clotting!
- Antithrombin III deficiency ( inherited or acquired)
- Protein C deficiency ( normally inhibits FV + FVIII)
- Protein S deficiency (assists Protein C)
- Lupus anticoagulant
- Prothrombin gene mutation
- Factor V Leiden mutation
What are the causes of Antithrombin III deficiency
ATIII is a protein, it inhibits thrombin activity. ATIII also inhibits intrinsic pathway CF.
Deficiency may be:
- Hereditary or;
- Acquired (reduced production, inc. consumption or protein loss)
- Reduced production -> Liver disease
- Increased consumption -> DIC, ECMO / CRRT circuits
- Protein loss -> nephrotic syndrome, major blood loss, plasmapheresis where replacement fluid is albumin
How do you manage Antithrombin III deficiency ?
- AT III concentrate
- FFP if concentrate not available
NB if using heparin for VTE prophylaxis - may not work at all or demonstrate resistance if ATIII deficiency
What does the Thrombin time measure?
- Thrombin time measures conversion of Fibrinogen ( FI) -> fibrin ( F1a)
- Prolonged Thrombin Clotting Time ( TCT) seen in low fibrinogen levels, heparin use or the generation of fibrin degradation products
What is the Ecarin Clotting time test?
- Ecarin is a snake protease
- it activates prothrombin (FII) bypassing the intrinsic and extrinsic systems
- therefore insensitive to the most part of the clotting system (eg effects of heparin / warfarin or on cases of factor depletion)
- it IS a useful test for direct thrombin inhibitors
Advantages of TEG over fixed ratio massive transfusion
*patient specific POCT - guided transfusion
*reduce unnecessary products
*Teg detects fibrinolysis and
hyperfibrinolysis
*faster than traditional clotting profile
*can be used to demonstrate medical vs surgical cause of coagulopathy - I.e can exclude medical causes of bleeding in trauma patient
Define Tumour Lysis Syndrome
TLS is an oncological emergency resulting from massive turnover and lysis of tumour cells causing release of potassium, phosphate and nucleic acids (urate is product of metabolism) into the circulation. Hypocalcaemia is also seen.
Results in:
*High K
*High PO4
*High Urate
*Low Ca
List the risk factors associated with the development of TLS
Patient related RF:
- Lymphomas. esp Burkitts
- Leukaemia’s
- High burden of disease
-some solid tumours - e.g. breast, testes
-CKD
-Nephrotoxics
-Dehydration
-Gout
Treatment related RF:
- aggressive chemo
-specific agents e.g….
- R-CHOP - e.g. rituximab, cyclophosphamide, vincristine, doxorubicin, prednisilone
Principles of prevention of tumour lysis
*Anticipate
*Hydrate - enhance renal clearance of solutes and reduce r/o precipitation of urate crystals
*Frequent Electrolyte monitoring - K, Ca, Urate, PO4, UEC
Specific Rx:
*Allopurinol = xanthine oxidase inhibitor to reduce urate formation
*Rasburicase = recombinant urate oxidase, enhances degradation of urate to allatonin which is more soluble and excreted renally
Management of Tumour Lysis Syndrome
*Hydration and diuresis - to maintain volume and enhance renal clearance of K/PO4/Urate
*Rasburicase = recombinant urate oxidase to enhance degradation of urate to allantonin which is more soluble and renally excreted
*Treat electrolyte abnormalities e.g hyperkalaemia and symptomatic hypocalcaemia
*Haemodialysis, for standard indications; severe electrolyte abnormalities, oliguria, fluid overload, acidosis.
Basics of TEG or ROTEM
*Viscoelastic tests are POC tests of whole blood clotting
*Blood is added to cuvette ( cup) with suspended pin at 37degrees
*TF / kaolin added
*Rotation motion occurs and the resistance developing to rotation measured and displayed graphically
*In TEG the cup spins ( T - cup)
*In ROTEM the pin spins
List some of the uses for TEG
*Trauma
*Post cardiac surgery
*Post liver transplant
*To guide massive transfusion
*DIC
*Peripartum period
TEG interpretation of values
R time
*Reaction time - time from latency to initial fibrin clot formation
*dependant on CF
K time:
*time from end of R to certain fibrin clot strength
*dependant on fibrinogen
alpha angle:
*rate of fibrin clot strength
*dependant on fibrinogen
Max amplitude:
*Peak clot strength
*80 % dependant on platelets, 20% on fibrinogen
LY30:
*percentage decrease from MA after 30 mins
*correlates to rate of fibrinolysis
TEG as a guide to Treatment (by R/K/alpha/MA/LY30)
Prolonged R time = deficient CF = give FFP
Prolonged K time = deficient fibrinogen = give cryo
Decreased alpha angle = deficient fibrinogen = give cryo
Decreased MA = decreased overall clot strength = give platelets or DDAVP
Decreased Lysis 30 time = enhanced fibrinolysis = need TXA
List advantages and disadvantages of TEG/ROTEM
Advantages:
POCT
Tests whole blood coagulation
Real time evaluation of clot formation
Can test fibrinolysis - which normal coags cant
Predictor of post operative hypercoagulation states
Quick than full coagulation test
May guide balanced transfusion
Reduces products in e.g. cardiac surgery
Sensitive to heparin effect
Disadvantages:
Requires user training
Machine recalibration is needed frequently
Doesn’t measure effects of hypothermia
Describe the normal ROTEM tests
INTEM: Measures intrinsic pathway (APTT), phospholipid added
EXTEM: Measures extrinsic pathway (PT), TF added
FIBTEM: Measures fibrinogen function by using platelet inhibitor to block the platelet contribution to clotting
APTEM: uses aprotinin to inhibit fibrinolytic proteins. It is otherwise identical to EXTEM. A shortened CT (R time) and a higher MCF in an APTEM test ( c/w) EXTEM) suggest that hyperfibrinolysis is taking place.
Additional:
HEPTEM: heparinase added to sample - removes effect of heparin. A significantly shortened HEPTEM time c/o INTEM would suggest presence of heparin e.g. in CPB
ECATEM: Ecarin is a prothrombin ( FII) activator. In the presence of direct thrombin inhibitors the ECATEM will be prolonged
Classification of Heparin Induced Thrombocytopenia
HIT 1:
*benign
*non immune
*mild aggregation resulting from PF4/heparin complexes
*mild thrombocytopenia ~ plt count 100
*self limiting on cessation of heparin
*up to ~ 10% of patients on heparin
*no associated thrombosis
HITT 2 ( thrombosis and thrombocytopenia)
*life threatening
*IgG mediated antibodies to PF4/Heparin complex
*subsequent thromboycytopenia ( macrophage mediated)
*thrombosis and consumptive thrombocytopenia from activation and aggregation
*incidence higher with UFH > LMWH
*requires anticoagulation
Pathophysiology of life threatening HITTs
IgG mediated response to PF4/Heparin complexes
“Anti PF4 antibodies”
IgG coated platelets taken up by macrophages = thrombocytopenia
Abnormal platelet activation and aggregation = arterial and venous thrombosis
Anaphylactoid reactions can occur to heparin due to Ab presence
Risk factors for HIT and pre-test probability
R/F = cancer, trauma and surgery (increase PF4 release)
4T score:
- Thrombocytopenia severity
- Timing - day 5-10 most common, unless prior exposure to heparin
- Thrombosis presence
- Thrombocytopenia possibly due to other causes?
Indications for IVC filter placement
NB Weak evidence base:
-recurrent PE on full anticoagulation
- patients with absolute CI to anticoagulation
( e.g. SAH with unsecure aneurysm or HITTS (II) unable to use alternative agent)
-Life threatening proximal DVT (e.g ileofemoral) despite anticoagulation
-high risk trauma patients: ( TBI / Spinal / Pelvic #)
List advantages /disadvantages of IVC filters
Advantages:
- May decrease r/o of fatal PE in patients with HIGH risk DVT e.g. proximal iliofemoral even on anticoagulation
= Can be used to reduce r/o PE in patients with absolute contraindication to anticoagulation - Newer devices are removable
Disadvantages:
- Weak evidence base for their use
- Insertion complications - failure / vessel injury/ perforation / air embolus
- Delayed complications - infection / IVC clot with thrombosis -> venous stasis, IVC can occlude ( 20% patients at 5 years), device # and displacement risks
- IVC filters don’t prevent new DVT formation
Causes of thrombocytopenia
Platelet < 150
1) Pseudothrombocytopenia
- clumping
2) Dilution:
- Massive transfusion (also causes platelet consumption)
-Fluid resuscitation
3) Reduced Production ( BM suppression or infiltration)
-Drugs e.g. linezolid / valproate
-Viral infection
-Liver disease (reduced thrombopoeitin)
-B12 / folate deficiency
-Haematological malignancy
4) Increased destruction:
-Drugs - heparin / antiplatelets
-Sepsis
-DIC
- Immune - ITP
-TTP
-HUS / HELLP
-Haemolysis ( MAHA)
-Intravascular circuit loss - CBP / ECMO / Dialysis / IABP
- Sequestration:
-splenomegaly - e.g. malaria and other causes - increased aggregation
- sepsis
-MODS
-Massive PE
Thrombocytopenia work up
General approach to likely cause involves history, examination and investigation:
Basic bloods:
1) blood film - clumping / spherocytes / signs of infiltration
2) LFTS - liver disease causing dec thrombopoietin?
3) B12 / Folate
4) Haemolytic screen
5) Coags - ?DIC
Infection screen:
1) Viral - EBV / CMV/ Malaria if splenomegaly / HIV / Hepatitis
2) Septic screen
Disorder specific:
1) Vasculitis screen
2) ADAMST13 activity - for TTP
3) ELISA Test for PF4 antibody - HITTS
4. BM aspirate: malignancy / aplastic anaemia
What is the ECHIS coagulation time
ECHIS is a snake venom added to blood sample which activates prothrombin without requiring vitamin K.
If PT prolonged but ECHIS time normal = Vit K deficiency or warfarin use
If ECHIS time and PT prolonged then liver dysfunction present (ie factor deficient)
What is a HITT screen
HITT screen performed if preprobability (4T score) is high (4 or more) for HITTS.
Test is an immunoassay for anti PF4 antibodies.
Sensitive but not specific
Don’t perform if pre test probability is low
NB gold standard test for HITTS is a functional assay if the pre test probability was high and the screen is equivocal.
Mechanism of DDAVP action on platelet function in bleeding
- V2 vascular endothelial release of Vwf and FVIII enhanced
- Increases the density of platelet surface glycoprotein receptors
- Enhances the ability to form procoagulant platelets and increases platelet-dependent thrombin generation by enhancing Na+/Ca2+ mobilisation.
- Thus, increases platelet aggregation
It is not a blood product, and can be used in bleeding Jehovah’s witnesses
What is von willebrand disease? What are the types, investigations and treatment options?
*most common inherited bleeding disorder ( 1-2% prevalence)
*Autosomal dominant
*results in abnormal platelet adhesion and prolonged bleeding time
Types:
1) mild form, reduced vWF levels ( ~ 90% cases)
2) dysfunctional vWF -> DDAVP is CI
3) absent vWF -> most severe form
Ix:
Plt count will be normal
Prolonged bleeding time
APTT might be slightly prolonged ( due to decreased FVIII)
vWF level and FVIII level correlate with disease severity
Mx:
-DDAVP if patient is DDAVP responder ( as prophylaxis 0.3mcg/kg)
-Consider Replacement therapy with FVIII or vWF
-Consider cryo as source of vWF is acute bleeding
-avoid antiplatelets
List the common causes of macrocytosis
MCV>100
*alcoholism
*B12/folate def
*myelodysplastic syndromes
*chronic liver diseases
*hypothyroid
*chemo / valproate / trimethoprim / metformin
What are RBC rouleaux and list some causes
Rouleaux are stacks of RBC which abnormally aggregate together
Causes are anything which increases your ESR -> Infection / dehydration/malignancy e.g. multiple myeloma
When do you see Howell-Jolly bodies on Blood films
Howell Jolly bodies are bits of DNA left over in RBC
They are seen post splenectomy or in functional asplenia
Also associated with steroid use and in macrocytosis of any cause
What do Heinz bodies on a blood film indicate?
Heinz bodies are bits of denatured Hb within RBCS
Indicate oxidative stress
Either disorders of RBC metabolism or haemaglobinopathies
1) Drugs causing oxidative stress -> quinidine, primaquine
2) Disorders of metabolism -> dapsone / bactrim G6PD deficiency
3) Abnormal Hb’s - alpha thalasaemia, methylene blue metHb
4) Post splenectomy - no spleen to recognise and remove abnormal RBC
What do Pappenheimer bodies, blister cells or basophilic stippling on a blood film indicate?
Pappenhimer bodies = iron graunles in sideroblastic anaemias (disorders of iron utilisation)
Blister cells indicate oxidative stress similar to Heinz bodies and are seen in G6PD deficiency or in dapsone or primaquine toxicity
Basophilic stippling is suggestive of lead poisoning
What is polychromosia on a blood film
Polychromatic RBC are cells which stain blue/grey due to having left over bits of genetic RNA PO4 groups in them
Represents either increased bone marrow stress or a failure of normal regulatory mechanisms responsible for “quality control” of RBC e.g. post spenectomy
Immunisations post splenectomy
Boosters every 5 years:
Pneumococcal
Hib
Men C
Influenza
What causative organisms are post splenectomy patients at risk
Encapsulated organisms are the biggest risk to post splenectomy patients - the spleen normally removes these
-strep pneumo
-haemophillus influenzae
-neiserria meningitidis
-capnocytophagia - GNB from dogs/ cats
-malaria
-babeosis ( from ticks)
-
Describe features of post splenectomy blood films
Howell Jolly bodies - DNA fragments
Heinz Bodies - denatured Hb - oxidative stress
Thrombocytosis
Target cells - excess RBC membrane
Acanthocytosis -> spiky RBCS
Anisocytosis - variation in RBC size
What is a leukoerythroblastic reaction on a blood film
This refers to the presence of immature granulocytes ( neutrophils) and nucleated immature RBC on a blood film
Suggests bone marrow activation/stimulation
The possible causes are:
- BM infiltration = leukaemia / myelofibrosis / solid tumour infiltration eg. breast cancer - BM excess activity = sepsis, severe haemorrhage or haemolysis, marrow recovery following suppression, Inflammatory conditions ( e.g autoimmune conditions)
On a blood film what does ‘toxic changes’ mean
Toxic changes refers to presence of immature neutrophils
Includes at least 2 of the following:
Toxic granulocytosis - immature neutrophils
Toxic vacuolation - indicates phagocytosis
Dohle bodies - remnants of Rough ER
These are all evidence in severe inflammatory states e.g. infection
What are band forms?
Band forms are immature neutrophils
If there is > 5% band forms on a blood film this is a left shift
What is a left shift on a blood film?
Left shift =
* immature > mature cells.
* There is a higher number of band forms (aka. immature neutrophils)
*Causes of Left shift:
* Sepsis
* Haemorrhage - due to adrenergic mobilisation of marrow neutrophils
* Necrosis - of any sort
* Bone marrow infiltration
* Anaemia - in an exaggerated haemopoietic reaction the BM releases a lot of immature cells which include immature neutrophils.
On a blood film what does toxic vacuolation represent?
This is the presence of vacuoles in neutrophils, indicative of phagocytosis and is representative of severe infection e.g bactaraemia ( Part of toxic changes on blood film along with Dohle bodies and toxic granulation neutrophils)
What is a leukemoid reaction and what are the causes?
*Leukemoid reaction refers to transient rise in WCC count ( typically neutrophilia but can also have lymphocytosis)
*WCC ~ 50,000
*WCC counts higher than this may represent leukaemia - esp myeloid leukaemia
*Immature neutrophils seen - band forms with left shift
*Toxic changes present on blood film - neutrophil granulocytes, vacuolation and dohle bodies
*Seen mainly in severe infection and ischaemia - e.g. ischaemic colitis or hepatic necrosis or malignancy.
*Should get better with treating underlying condition
List some of the causes of plasmocytosis on blood film
Plasma cells are derived from B lymphocytes and present in BM - secret antibodies
Plasmacytosis causes grouped into haematological causes or infective causes:
PLASMA CELLS
Haem causes:
-Multiple myeloma
- B cell lymphoma
- Plasmocytoma
- Spherocytosis
- Serum sickness
- Plasma cell leukaemia
- MGUS
- Waldenström macroglobulinemia
Infectious causes:
- Varicella zoster
- Leprosy
- TB
- Hepatitis / HIV
What are the common causes of hyperviscocity syndrome?
-A haem emergency which usually results from increased circulating serum immunoglobulins
Examples:
* Multiple myeloma
* Waldenstoms macroglobinaemia - excess of IgM ( most hyperviscous as IgM is massive)*
* Leukaemias
* Polycythaemia rubra vera
Rx:
urgent plasmapheresis
What are smudge cell lymphocytes?
Smudge cells are deformed lymphocytes seen in CLL
Give a brief overview of HLH
HLH represents a hyperimmune state and may be underdiagnosed in ICU
It may be inherited or acquired
Pathophysiology:
*uncontrolled macrophage and T-cell activation from cytokine production
*may be triggered by infection / malignancy or rhem disease e.g. SLE
Diagnosis:
Either by molecular diagnosis or by clinical criteria (should have 5 of 8):
* Fever
* Splenomegaly
* Cytopenia of two or more cell lines (i.e. Hb <90 plt <100, Ne <1 x 10E3/L)
* Either elevated triglycerides or low fibrinogen
* BM evidence of haemophagocytosis
* Serum ferritin > 500 mcg/mL (much higher)
* Low or absent NK cell activity (by flow cytometry, if available)
* Soluble CD25 > 2400 U/mL
Ferritin usually > 10,000
Management:
Treat cause
Chemotherapy may be required in severe cases
Supportive care - i.e. transfusions / PJP and fungal prophylaxis
Brief notes on iron physiology (requirements / absorption and storage)
Requirement = 10mg/day
Iron in the body:
* Stored in Hb >70%
* Stored in myoglobin > 5%
* Stored as ferritin ~ 20%
* Circulating bound to transferrin
Physiology:
* Absorbed at small bowel ( duodenum)
* Ferrous Fe 2+ is soluble
* Ferric Fe3+ insoluble -> HCL helps facilitate conversion to Fe2+ for absorption
* Once in enterocyte bound to ferritin
* Carried in the blood bound to transferrin -> to BM to be used in Haem synthesis, or to liver to be stored as ferritin
Causes of abnormal serum ferritin
Ferritin is the gold standard marker of iron stores
Found in all cells -> most in liver / reticuloendothelial cells
Small amount of ferritin in plasma is proportional to body iron stores.
Normal = 15 – 300 ug/l
↓ ferritin = iron deficiency
↑ ferritin = inflammation (sepsis / kidney / liver disease), malignancy, pregnancy, chronically transfused patients ( e.g sickle cell)
↑↑↑ = HLH
Causes of abnormal transferrin or Total Iron Binding Capacity ( i.e marker of unbound transferrin)
Transferrin carries iron in the plasma
Total iron binding capacity (TIBC) is an alternative to measuring Transferrin - being a direct measure of level of transferrin.
transferring = inflammatory states / malnutrition / liver disease
↑transferrin = iron deficiency
What is % transferrin saturation and what are the normal /abnormal values?
%Transferrin saturation - is the % of transferrin which is saturated with iron.
Normal is ~ 20-45%
Low % Tsat < 20% = iron deficiency
High % Tsat > 45-50% = indicative of iron overload = Haemochromatosis or recent transfusion
List common causes of eosinophilia
*Eosinophils - (a type of granulocyte) - other granulocytes = basophils / monocytes and neutrophils
* Allergy * Addisons * parasitic infections * sarcoidosis * leukaemia * lymphoma * melanoma * irradiation Eosinophilia also seen in convalescence from infection
List the causes of pancytopenia
PANCYTOPAENIA = reduction in all cell lines
*Either due to BM failure (reduced production or infiltration) or peripheral cell destruction:
Reduced Marrow Production:
* Malignant infiltration * Drug Reaction (chloramphenicol, sulphonamides, phenytoin, carbamazepine, gold) * B12 deficiency * SLE * Myelofibrosis * Cytototoxic agents * Overwhelming infections
Increased Peripheral Cellular Destruction:
* SLE
* HIV infection
* Hypersplenism
* paroxysmal nocturnal haemoglobinuria
Causes of polycythaemia
Polycythaemia = Hb > 160
May be primary or secondary or relative
Primary = Polychythaemia rubra vera
Secondary = chronic hypoxia ( e.g. OSA/RHF), EPO injection or EPO secreting tumour, congenital cyanotic heart disease
Relative = dehydration - diuretics / burns
Clinical Features:
Fundal hyperviscocity / headaches/ APO, thrombosis, /hyperviscocity, HTN, PVD/ splenomegaly/ plethora / pruritis/ gout
Ix:
Hb > 160, HCT raised
In polycythaemia rubra vera - > increased WCC and platelets, microcytosis and slight anisocytosis (= variation in cell size)
JAK2 mutation found in >95% pts with polycythaemia rubra vera
List the R/F, clinical features and ix for occlusive upper limb DVT in critically ill patients.
(College QU)
Risk Factors:
*UL DVT associated with venous catheter placement ->
-subclavian vein > IJV
-catheter migration
-increased number of lumens/size of catheter
-blocked lines
-irritant infusions -> TPN/Chemo
UL DVT associated with underlying disease ->
-Thrombophilia - > Protein C/S deficiency / Factor V Leiden / ATIII deficiency /antiphospholipid syndrome
-malignancy
-previous DVT
-UL Trauma
Features:
-may be asymptomatic
-pain / phlebitis / blocked venous catheter
- Redness / swelling / paresthesia
- signs of SVC obstruction
Ix:
Compression USS - >95% sensitivity and specificity.
CT might be required to Dx SVC/ Intrathoracic DVT
Classify causes of anaemia in critical care
Anaemia may be due to dilution, reduced production or increased loss of RBC
Dilutional anaemia:
*fluid replacement
*incorrect sampling from IV line with running fluid
Reduced production:
*nutritional - > Fe deficiency / B12 / Folate deficiency
*anaemia of inflammation -> cytokine mediated
*reduced EPO production -> chronic renal disease
Increased loss (Extravascular)
*Bleeding - e.g trauma / GI loss
*Iatrogenic - freuquent sampling / surgical blood loss
Increased loss intravascular:
*Haemolysis - autoimmune
*Haemolysis - mechanical -> valve / ecmo or CRRT
*Appropriate sequestering of abnormal Hb - sickle cell / thalassaemia
*DIC
What do you see in anaemia of inflammation and what is the mechanism?
Anaemia of inflammation aka anaemic of chronic disease
Low haemoglobin
Low iron
normal to high ferritin
suppressed or normal erythropoietin
elevated CRP
Process is cytokine mediated (il-6) and involves increased hepcidin:
* iron trapping - iron stores are 'normal' but unable to utilise iron for erythropoiesis * macrophage mediated RBC phagocytosis * directly induced BM suppression of erythropoiesis
NB. in anaemia of chronic inflammation EPO may be normal or suppressed. Cytokine mediated direct suppression of erythropoiesis occurs independent of EPO
Causes of HLH and diagnostic criteria?
Haemophagocytic LymphoHistocytosis is a rare syndrome which can be congenital or acquired:
Acquired causes:
Infection - EBV,CMB, HIV, Leishmania (parasite)
Malignancy - Lymphoma
Inflammation - SLE
Diagnosis = molecular diagnosis or fulfilling 5 of 8 clinical criteria:
Criteria:
* Fever
* Splenomegaly
* Cytopenia of two or more cell lines
* Either elevated triglycerides or low fibrinogen
* Histopathological evidence of hemophagocytosis (on BM, spleen or lymph node biopsy)
* Serum ferritin > 500 mcg/mL (often much higher in HLH: ferritin > 3000 ng/mL is concerning for HLH and ferritin > 10 000 as highly suspicious (96% specific)
* Low or absent NK cell activity (by flow cytometry, if available)
* Soluble CD25 > 2400 U/mL
List available Mx options for UL DVT
Rx aims to alleviate symptoms, reduce r/o PE and further DVT, and prevent post thrombotic syndrome.
1) Anti-coagulation:
- Initial LWMH or UFH then…
- either LMWH or oral anticoagulants for 3 - 6 months
2) Thrombolysis:
- Limited evidence
- Catheter-directed thrombolysis if upper limb has extensive swelling and functioned impairment
- SVC filter:
-No evidence base
-Doesn’t prevent new DVT
-Only if absolute contraindication to anticoagulation and high risk of life threatening PE
-associated high risks - Surgical thrombectomy if no other option available
Describe the pathophysiology of DIC
DIC involves:
Activation of coagulation by inflammation - > microthrombi form.
* Cytokine release * Tissue factor (a potent procoagulant) is expressed on macrophages and monocytes * Endothelial dysfunction exposes more of the procoagulant surfaces behind the endothelium * Platelet activation and aggregation
Consumptive coagulopathy -> leading to haemorrhage
* Consumption of clotting factors * Consumptive thrombocytopenia
Fibrinolysis and / or inhibition of fibrinolysis (which is mainly seen in septic DIC
Define DIC
DIC is an acquired syndrome characterised by the intravascular activation of coagulation with loss of localisation arising from different causes.
It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction
Hemorrhage is often seen with DIC due to obstetric catastrophe or leukemia.
Thrombosis is often seen with sepsis-associated DIC.
List causes of DIC
*Sepsis - Esp GNB, viral haemorrhagic fever, GAS
*Obstetric catastrophes - (abruption, IUD, PPH, eclampsia, HELLP syndrome, amniotic embolism)
*Trauma- (Severe tissue injury - Head injury, burns, fat embolism)
*Major surgery
*Pancreatitis,
*Severe liver failure, toxicology (paracetamol OD)
*Transfusion reactions
*Snake venom
Give an overview of the scoring tools for DIC/SIC
ISTH Scoring tool for DIC:
-Components: INR, Fibrinogen, DDimer, Platelets
-Score >5 = Overt DIC
SIC score for sepsis induced coagulopathy -
(SIC is a DIC which still hasn’t had time to waste all your clotting factors, but which is already associated with the dysfunction of one or more organ systems)
-Components: INR, platelets, SOFA score
COVID-19 vaccine induced immune thrombotic thrombocytopenia (VITT): pathophysiology and RF, presentation, and management
VITT:
RF: young, female, AstraZeneca and J+J Covid 19 Vaccines
Pathophysiology:
Antibodies form to the complex of PF4 platelet surface proteins and adenoviral RNA from the vaccine
IgG mediated platelet activation and destruction
Presentation:
Hx + o/e: headache, visual change, features of CVST, PE, DVT, petechiae
Ix: Falling plt count, Ddimer usually >4 times upper limit normal
CT/USS: for thrombosis
- PF4 ELISA normally used for “HIT” appears to detect the VITT antibody
Management:
Avoid repeat vaccination.
Avoid Heparin due to overlap with HITTs
Alternative anticoagulation - fondaparinaux
IV immunoglobulin, 1-2g/kg over 2 days
Plasmapheresis +/- high dose methylprednisolone if not improving or if thrombosis is severe and extensive
Causes of Haemolysis
Haemolysis may be intravascular or extravascular.
INTRAVASCULAR
Immune:
*ABO incompatibility or Rhesus mediated.
*IgG warm AIHA - drugs (penicillin / ibuprofen / paracetamol), viral, CLL, Autoimmune - e.g. SLE/R.A
*IgM cold AIHA -post viral, (mycoplasma / EBV / influenza), Paroxysmal cold haemolgobinuria
Non-immune:
*Mechanical - valves, ECMO, CRRT
*Microangiopathic Haemolytic Anaemia - TTP/HUS/DIC
*Severe sepsis - malaria, clostridium perfinigens
*Heavy metals - e.g. lead/ mercury, copper poison
EXTRAVASCULAR:
RBC enzyme abnormalities:
*G6PD deficiency (X-linked, African or Mediterranean descent, exposure to fava beans or drugs e.g. primaquine, nitrofurantoin).
RBC membrane abnormalities
*hereditary spherocytosis
*paroxysmal nocturnal hemoglobinuria
Hemoglobinopathies
*sickle cell disease
*thalassemia
Hypersplenism of any cause
What bloods are included in a haemolysis screen?
FBC and blood film
LDH
Reticulocytes count
Haptoglobin
Free Haemoglobin
Indirect (unconjugated bilirubin)
DAT - direct antiglobulin test - if positive = Warm AIHA
List the causes of autoimmune haemolysis
*ABO /Rhesus incompatibility
*Warm IgG mediated AIHA
- SLE/RA
- Infectious
-Drugs - penicillin, probencid, ibuprofen, paracetamol
-CLL
*Cold-IgM mediated AIHA
-Post infectious -> EBV/CMV/Mycoplasma/Syphilis
-Paroxysmal cold hemoglobinuria
Lab features common to all haemolytic anaemia
RBC abnormalities: spherocytosis or fragmented RBCs, as well as pathognomonic erythrocytes such as sickle cells.
High reticulocyte count ( a normal bone marrow responds to anaemia by ramping up the production of RBCs.)
High LDH: An enzyme which leaks out of pretty much any damaged cells, and so is not specific for haemolysis
Haptoglobin: the protein responsible for iron transport will usually be low when there is too much iron to transport.
Free haemoglobin will be elevated as it spills out of RBCs.
There may even be hemoglobinuria
List the features and causes of a warm haemolytic anaemia and its management.
When haemolysis is “warm”, it is caused by antibodies maximally active at human body temperature, caused by IgG.
DAT is positive for both IgG and complement C3d.
Causes:
*Infection
*Drugs - penicillin, probenecid, mycophenolate, ibuprofen, paracetamol
*Malignancy ->CLL, myeloma
*SLE/RA/
Rx of warm haemolytic anaemia:
- Corticosteroids are first-line treatment.
- Splenectomy is the second-line treatment.
(The spleen’s macrophages are responsible for removing IgG-coated RBCs; also the spleen is a site of antibody production.) - Cyclophosphamide / azathioprine are reserved for those who fail steroids and splenectomy (or cannot have a splenectomy).
IV immunoglobulin is not strongly indicated: some reports show benefit, others don’t.
How do you treat Warm AIHA
Warm AIHA = DAT +vE (IgG and Complement C3d)
Rx:
1st Line = Steroids
2nd Line = Splenectomy
Cyclophosphamide / Azothioprine for those who fail steroids.
Give a brief overview of G6PD deficiency as a cause of haemolytic anaemia
G6PD is an enzyme found in RBC, providing reductive potential, as a source of NADPH in states of oxidative stress.
G6PD is an x-lined recessive disorder, more commonly seen in males and in areas where malaria is prevalent - southeast Asia, Africa, parts of India and the Mediterranean.
If there isn’t enough G6PD there will not be enough NADPH with oxidative stress, resulting in RBC abnormalities including Heinz bodies (= bits of denatured Hb)
This results in an acute haemolysis with certain triggers:
Triggers:
Foods - broad beans, blueberries
Drugs: dapsone / co-trimoxazole, methylene blue, nitrofurantoin
Infections
DKA
Management:
Remove trigger.
Supportive
Consider transfusion of RBCs with normal levels of G6PD!
List 3 causes of Massive Splenomegaly
Massive splenomegaly:
-CML
-Myelofibrosis
-Chronic Malaria
-Visceral Leishmannia (Kala-Azar)
-Sarcoidosis
NB: Kala azar is the second largest parasitic killer in the world after Malaria.
Antiphospholipid Sx -> diagnostic criteria and pathophysiology
APS consists of tendancy towards bleeding and to thrombosis.
Sapporo Criteria:
require at least 1 clinical and 1 laboratory feature:
Clinical:
-confirmed thrombosis
-pregnancy morbidity e.g. recurrent miscarriage
Lab:
-Lupus anticoagulant
-Anti-cardiolipin Ab,or Anti-B glycoprotein Ab
Pathophysiology
- autoantibodies to -ve charge phospholipid surfaces.
- this reduces platelet aggregation and prolongs APTT.
- Auto-antibodies also impair endothelial cell function leading to activation of complement and coagulation cascade.
Outline the features of and management options for Catastrophic APS (College Qu)
Catastrophic APS affects <1% of people with APS.
features:
1) History of APS or lab confirmation of lupus anticoagulant or Anti-cardiolipin/anti B-glycoprotein Abs
2) Acute < 1 /52 of onset
3) Severe,>3 organs involved
4) A / V thrombosis
5) Biopsy showing small vessel occlusion
Presentation
Neuro - CVST / Strokes
Resp - PE / ARDS
Renal - 70% have AKI, malignant HTN
Skin - necrosis
Lab -> APTT prolonged which doesn’t correct with mixing studies, may have evidence of haemolysis, thrombocytopenia
Management
M - HR / BP, Temp, Spo2, RR, u/o, GCS
E - likely critical care environment
T - specific teams per organ involvement, haematology, critical care.
**Supportive care - **
Specific care:
Anticoagulation and immunosuppression
1) LMWH -> Warfarin
2) Methyl pred 3/7
Second line - PLEX with FFP, IvIg may be considered.
List 3 types of sickle cell crisis
Vaso-occlusive crisis
-assume this is the cause of any painful presentations
-acute chest syndrome
-> life-threatening lung infarction
-> assume if hypoxia + chest pain
acute splenic sequestration
-typically occurs in infants
- associated with increased spleen size
- fall in Hb by >20 g/L, thrombocytopenia but normal or increased reticulocytes
aplastic crisis
- abrupt fall Hb as well as reticulocytes <1%
- triggered by parvovirus infection
What is the likely cause of acute liver injury with oedema and weight gain @ 3 weeks post BMT?
Veno occlusive Disease:
May be mild -> rapidly fatal (in 40%)
Pathogenesis -> thrombosis of the small central hepatic venules due to endothelial cell damage by high dose chemotherapy
Presentation:
During first 21 days following transplant, weight gain, painful hepatomegaly and jaundice.
50% go on to develop renal failure.
Diagnostic Criteria:
Seattle or Baltimore:
Both need presentation <21/7 from BMT
Investigations:
transaminitis, hyperbilirubinaemia
Doppler U/S showing reversal or diminished portal flow.
management:
-supportive, fluid restriction, diuresis, paracentesis
- avoid infections and hepatotoxic medications
- oral ursodeoxycholic acid (lowers bilirubin)
Which malignancy is linked to the Philidelphia Chromosome?
Philidelphia translocation is linked to CML
CML usually presents with slow then rapidly progressive phase
CML is a cause of massive splenomegaly
In which lymphoma do you see Reed-Sternberg cells on biopsy?
Hodgkin’s Lymphoma:
* Common in young people
* Presents with cervical LN and B symptoms
* Reed-Sternberg cells seen on biopsy
* Chemo +/- radiotherapy
* Curative in >75% patients
Common complications of myeloma
CRAB:
Calcium raised
Renal impairment - due to free light chains / hypercalcaemia
Anaemia - normochromic, normocytic
Bony pain / lytic lesions
List some of the common complications of BMT (HSCT)
Complications may be categorised as early -> late
Early < 30/7 from BMT - PRE-ENGRAFTMENT
Late > 100 /7 from BMT - POST ENGRAFTMENT
Early pre engraftment:
-neutropenic spesis
-acute tumour lysis - rare
- enteritis
-veoocclusive disease of liver ( Liver pain, weight gain, 3 weeks post)
- acute GVHD (allogenic HSCT)
Also, graft failure
Late post engraftment:
-chronic GVHD
Myopathy / neuropathy
CMV - chronc
second malignancies
What are the classical features of Veno-occlusive Disease of Liver
Presents with triad of painful hepatomegaly, jaundice and ascites ( weight gain) ~ 3 weeks after a stem cell transplant
Dx criteria: Seattle or Baltimore
Mx: supportive + Defibrotide - an antithrombotic, anti-inflammatory
Outline the pathophysiology of GVHD
GVHD occurs with allogenic stem cell transplants
Antigens on host cells are attacked by the donor T cells
Biopsy of tissue / skin shows lymphocytic infiltration
Risk Factors for GVHD
Occurs with allogenic transplants
RF:
Unrelated donor/recipient
Donor/recipient sex difference
Older age > 40 recipient
CMV +VE
Describe the clinical features of aGVHD vs cGVHD
aGVHD presents like a with:
triad of system involvement:
1) skin - maculopapular rash
2) liver - jaundice, elevated bilirubin
3) GI - n+v, diarrhoea anorexia
50% of patients with aGVHD develop cGVHD. cGVHD presents like a new autoimmune condition:
*absence of acute features
Skin - sclerosis, nail changes, alopecia
Ocular - chronic conjunctivitis
GI: mucositis, oesophageal strictures
MSK: Myositis
May have pleural or pericardial effusions
Give a brief overview of blood groups
Blood group describe the presence of antigens on RBCS
Most common = ABO then Rhesus then others ( Kell, Duffy, Lewis etc.)
ABO group
* Carbohydrate antigens present on RBC and on the surface of tissue cells
* Most common
* Antigens = A or B, or both or none
* IgM antibodies develop to foreign blood groups within 6/12 of life, usually due to environmental exposure
* ABO incompatibility is a severe T1 hypersensitivity reaction
Presence of blood groups in the population:
* O group - 49% (universal donor blood as NO antigens)
* A group - 38%
* B - 10%
* AB - 3% (Universal recipient = NO plasma antibodies)
85% of the population are Rh +ve
Give a brief overview of compatibility testing for blood transfusion
PRE-TRANSFUSION TESTING
-group - for ABO / Rh
-typing - for antibodies
-cross match
Involves:
*meticulous attention to request form – INVALID if there is any discrepancy
1) group and hold/ type and screen: takes 45 min
*ABO and Rh groups (forward and reverse typing tests) – takes 15 min
2) Antibody screen (for non-ABO Abs) – if found takes hours to resolve
3) Cross match (total 1-2 hours)
*electronic cross match only if negative Ab screen (takes 1 hour total, including G&H)
* serological cross match of patients plasma with donor cells if positive Ab screen (takes 2 hours total)
How does the Lab perform ABO grouping?
Forward grouping: patient RBCS mixed with known anti-A and anti-B antibodies.
Reverse grouping: patient’s plasma is mixed with known Type A or Type B red cells.
Both must agree to formally identify the blood group
How are blood products stored and for how long?
**RBC - ** 4 degrees, 35 days
**Platelets - ** 22 degrees, 7 days
**FFP /CRYO - ** - ve 25 for 12 months
Nb Cryo is extracted from FFP ~ -6 degrees and contains fibrinogen, fibrinectin, vWF, FVIII and FXIII
Strategy for blood conservation in ICU
- Anaemia and blood transfusion is common in the critically ill, and are associated with costs and morbidity/ mortality
- Blood testing in the ICU is often excessive and unnecessary and contributes to increased costs and morbidity
Strategies for blood conservation:
Blood sampling
* rationale approach to blood testing
* closed system blood sampling (risk of arterial embolism)
* use of point-of-care microsampling
* use of small volume sampling devices
Prevention and treatment of anaemia
* use of appropriate transfusion triggers
○ - restrictive strategy Hb>70 for most patients Plt >50 less doing a procedure or bleeding
* treatment of underlying cause of anaemia (e.g. iron, folate, treat underlying cause)
* avoid bone marrow suppressing agents
* consider EPO
* optimise nutrition -
* appropriate blood sampling (see above)
Limit acute blood loss
* find and stop bleeding early * correct coagulopathy (e.g. hemostatic resuscitation) autotransfusion and cell salvage
What are the general transfusion targets in ICU patients
Transfusion target depends on multiple factors:
Based on TRICC (1999) and NBA guidelines:
Bleeding - aim Hb > 100
Non bleeding - aim Hb > 70
IHD and elderly - higher target ~ 100
Post cardiac surgical - Hb > 80 is non inferior to Hb > 90
List the indications for irradiated blood products
Irradiated blood components are used to prevent Transfusion-associated graft-versus
host disease (TA-GvHD)
Indicated for:
Immunocompromised patients, and specifically:
Lymphoma
Stem cell transplants
Aplastic anaemia
Immunocompetent patients receiving donated blood from relatives
Anyone receiving granulocyte transfusions
Anyone receiving HLA-matched platelets.
Any neonates and any intrauterine transfusions
Classify and list transfusion reactions
Transfusion reactions may be immune mediated or non immune. They may also be early < 24 hours or late > 24 hours
Early < 24 hours:
Allergy
Acute Haemolytic reactions - ABO / Rh incompatability
Bacterial contamination
TACO
TRALI
Febrile - non immune reaction
Post Transfusion TTP
Late > 24 hours
Non-immune haemolytic reactions
Infection transmission - HIV / Hep B+C/malaria / CJD
Bacterial infection
Iron overload
Microchimerism - the persistence of an allogeneic cell population of leucocytes
transfusion mediated GVHD
What do you see in an acute haemolytic transfusion reaction?
Acute Haemolytic Transfusion reactions ( < 24 hours)
* Interactions between antibodies in recipients plasma and antigens present on donor RBC * ABO and Rh D account for the majority of reactions * Most important naturally occurring Ab's - Anti A and Anti B - usually IgM subclass * ABO incompatibility ~ 1 in 50,000 transfusions * As little as 10 mls of incompatible blood can produce rapid reaction Investigations -> blood group and DAT on both pre and post transfusion samples, haemolysis screen, urinalysis
Give a brief overview of TRALI
- Defined as hypoxia and bilateral pulmonary oedema occurring within 6 hours of transfusion in absence of alternative clear diagnosis
- Incidence ~ 1 in 5000 plasma containing transfusions ( whole blood / FFP / PRBC)
- Pathogenesis theory -> immune vs non immune
○ Immune -> presence of leukocyte antibodies in the donor plasma attach HLA antigens in recipient
○ Non-immune -> lipid mediated - Pathology: 2 hit model
1) Underlying illness primes e.g. critical illness initially makes patients more susceptible to acute lung injury
2) Transfusion leads to neutrophil activation -> complement activation -> endothelial cell damage and capillary leak (lungs) - DDx: Pulmonary oedema, TACO, neurogenic pulmonary oeeam, ARDS due to another causes. e.g. sepsis. Fat embolism
- Rx: supportive
- *Risk factor= e.g. FFP from multiparous women
In contrast to ARDS - recover usually occurs within ~ 8 hours
Give a brief overview of Post transfusion pupura
- Post-transfusion purpura (PTP) is a rare delayed transfusion reaction where a patient develops dramatic, sudden and self-limiting thrombocytopenia (platelet counts <10 x 109/L in 80% of cases), typically 7 to 10 days after a blood transfusion.
- RF: Females, young with either prior pregnancy or prior transfusion history
- Ix: anti-platelet antibodies in patient plasma
Rs: IvIg, steroids +/- PLEX
Give a brief overview of HUS ( typical versus atypical)
HUS AND TTP are very similar but renal involvement predominated in HUS
Types:
* Typical HUS (diarrhoea + infection)
* Atypical HUS - rare- complement dysregulation,
Typical HUS: (Diarrhoea)
* >90% of cases
* Preceding infection with a toxin producing bacteria - typically E.coli 0157:H7
Atypical HUS: (No diarrhoea)
* Rare
* Possibly familial, genetic predisposition
* Pathophysiology -> complement dysregulation
* Triggers:
Streptococcus pneumoniae - > aka P-HUS - a subtype of Atypical HUS
Pregnancy - usually at term or post partum
Drugs -> QUININE, CICLOSPORIN
Transplants - renal / HSCT
HIV
Classic Pentad (FAT R/N)
* fever
* anaemia (MAHA)
* thrombocytopenia
* renal problems (88% have renal problems, 15% haematuria) – more likely in HUS
* neurological problems (headaches, confusion, seizures) – more likely in TTP
Ix:
MAHA
Low platelets
Low Hb - with polychromasia
Shistocytes = ‘helmet cells - fragmented parts of RBC seen in MAHA
Positive Hamolysis screen
Renal injury
Renal biopsy - if safe to perform -> thrombotic microangiography, thrombi present
If suspected atypical HUS -> genetic testing
Management of HUS:
* Supportive care is mainstay
* Platelets are contraindicated - ongoing haemolysis
* Plasmapheresis if not sure whether this is HUS or atypical HUS
* PLEX avoided in Strep pneumoniae trigged P-HUS -anti-T IGM in the administered plasma may exacerbate disease
* Evidence poor for steroids
* Eculizumab for atypical HUS
