Haematology Flashcards
(160 cards)
1
Q
Anaemia PC and O/E
A
PC - asymptomatic, can be tired, SOB, chest pain and in high output cardiac failure if severe. Can potentiate angina and claudication
O/E - mucosal pallour, tachycardia
koilonychia - long standing iron deficiency
jaundice ?haemolysis
peripheral oedema or hyperdynamic circulation - HF
2
Q
Lymphoid progenitors
A
B cells maturing in bone marrows, T cells or NK cells formed from T cell progenitors in the bone marrow
3
Q
Reticulocytes
A
Young RBC should comprise <2% of the red cells. Gives a guide to erythroid activity in the BM
High in times of haemorrhage or haemolysis
Low = BM failure or haemtinic deficiency
4
Q
Myeloid progenitors
A
Granulocyte-macrophage progenitor = differentiates to neutrophils, dendritic cells and eosinophils
Megokaryocyte progenitor = Platelets
Erythroblast = RBC
5
Q
Inappropriate EPO production
A
RCC
6
Q
Microcytic anaemia causes
A
MCV <80
Thalassemia, Iron deficiency, sideroblastic anaemia
7
Q
Iron deficiency anaemia
A
Increased loss = menorrghia, GI loss - haemorrhage
Low intake = elderly with poor diet
Malabsorption = Crohns and coeliac
8
Q
Iron absorption
A
Cells in duodenal crypt can sense the bodys iron requirements allowing transport of iron across the apical membrane of the mucosal cells in the SI. Here it will stay stored in ferritin to be lost when the mucosal cells are shed or absorped into the plasma.
Hepcidin is a polypeptide which regulates the iron transport out of the cells binding to ferroportin and causing its internalisation and destruction. Therefore in low iron states such as anaemia hepcidin will be downregulated, Iron is transported in the blood bound to transferrin
9
Q
O/E iron deficient anameia
A
Kolinychia = spoon shaped nails
Angular stomatitis
Plummer-Vinson syndrome = dysphagia, glossitis, iron deficient anaemia and oesophageal webs
10
Q
Iron deficient anaemia Hx
A
NSAIDs - ?GI bleed, dietary iron intake = meat/cereal
PR bleeding - IBD, haemorrhoids, CRC
Females = ask about periods and menorrhagia
11
Q
Ivx Iron deficient anaemia
A
High total iron binding capacity
Low ferritin and transferrin saturations
Low MCV
On blood film = poikilocytosis = variation in shape
12
Q
Mx iron deficient anaemia
A
Find the cause
Iron supplements - ferrous sulphate 200mg TDS take when fasting
SE = nausea, constipation
13
Q
Macrocytic anaemia causes
A
MCV >96
Megaloblastic - B12 deficiency, folate deficiency
Normoblastic - hypothyroid, chronic alcohol, liver disease
14
Q
Causes of all anaemia
A
Reduced production = haematinic deficiency = B12, folate, iron and pernicious anaemia. BM failure, CKD and anaemia of chronic disease
Haemolyis
i) Intrinsic = sickle cell, G6PD, hereditary spherocytosis
ii) Extrinsic = AI haemolytic anaemia, DIC, TTP, HUS, malaria
Blood loss = haemorrhage, menorrhagia, GI tract = CRC, PUD, HHT, varices
15
Q
Megaloblastic microcytic anaemia
A
Presence of erythroblasts in BM with delayed nuclear maturation due to defective DNA synthesis. Large immature nuclei
On blood film = hypersegemented polymorphs with oval shaped.
16
Q
B12
A
Absorbed from the gut by binding to intrinsic factor produced by parietal cells presents insidiously with peripheral neuropathy, fatigue, SOB. Is linked to NO abuse
17
Q
Pernicious anaemia
A
AI atrophic gastritis which leads to destruction of gastric parietal cells hence reduced intrinsic factor production. This leads to B12 deficiency and a microcytic anaemia.
Seen in elderly . Linked to other AI conditions such as thyroid disease, addison and vitiligo. Increased risk of gastric cancer. Progressive insidious onset with parathesia of extremities
Inx - parietal cell Ab +ve 90% sensitive, intrinsic factor ab only present in 50% but are specific for the condition.
18
Q
Folate deficiency
A
Found in green veg, nuts, liver absorbed in the proximal jejunum.
Poor intake due to diet, GI malabsorption
Drugs such as methotrexate, trimethoprim and phenytoin
Increased use = pregnancy
19
Q
Subacute combined degeneration of the spina cord
A
Due to B12 deficient. PC with mixed UMN and LMN signs, spastic paresis, ataxia, +ve rombergs, brisk knee reflex and absent ankles. Lose vibration and proprioception early
Due to degeneration of the dorsal columns - pain and temperature are still intact.
Mx = hydroxocobalamin 1mg IM
20
Q
Normoblastic macrocytic anaemia
A
Hypothyroidism, chronic alcohol, lover disease
Aplastic anemia, myeloma and myelodysplasia
Crucially = normal vit B12 and folate
21
Q
Normocytic anaemia
A
CKD, anaemia of chronic disease, myeloma, haemolytic anaemia, BM infiltration or fibrosis
22
Q
Myeloma
A
Malignant disease of BM plasma cells leading to mass proliferation of monoclonal Ab. Often IgG or IgA
This leads to IL-6 production, inhibiting osteoblasts, therefore unopposed osteoclast activity leads to lytic bone lesions and high Ca2+
23
Q
PC myeloma
A
Osteolytic bone lesions leading to # - spinal cord compression due to vertebral collapse
Hyperviscosity syndrome - headache, visual changes
Renal impairment due to build up of light chains and hypercalcemia - ATN
Recurrent infections due to neutropenia
24
Q
Epidimology of myelomas
A
Increased risk in the elderly, afrocarribean and males
25
Inx myeloma
diagnosis = serum free light chains or urine electrophoresis, biopsy >10% clonal plasma cells
Normocytic anaemia
high Ca2+ , low PTH, U+E derangement, increased total protein
BM infiltration may = pancytopenia
CXR = lytic lesions - peppepot skull, vertebral collapse
26
Mx myeloma
Prevent complications i.e. bisphosphantes for hypercalcamiea, plasmapheresis for hyperviscosity.
Epo for anaemia, good hydration
Mx of pathological #
Chemo = lenalidomide + steroids. Then BMT
27
Polycythemia
>55% Hb
Causes =
1 - polycythemia vera
2 - hypoxia = epo increase - athletes, altitude, smokers, chronic lung disease
inappropriate epo - RCC, HCC, steriods - androgens
relative - stress, dehydration
28
Thrombocytosis
Platelets >450
1 = myeloproliferative disorder
2 = reactive - Infection, inflammation, surgery, IBD, RA
29
Myeloproliferative neoplasms
Clonal stem cell disorders characterised by the uncontrolled proliferation of one of the erythroid, myeloid or megakaryocyte lines
30
Polycythemia vera
Excessive proliferation of erythroid, myeloid and megakaryocytes. 95% of suffers have a JAK2 mutation which allows proliferation without epo stimulation
31
JAK2
Cytoplasmic tyrosine kinase that transduces signals from epo. Its discovery allows easy diagnosis and a target for treatment
32
PC polycythmia vera
Insidious usually pt >60y/o with tiredness, headache and visual disturbance
Hyper viscosity syndorme = headaches, visual disturbance and tinnitus - increased VTE risk
Puritis post warm water exposure
Erythromelagia - burning pain in hands and feet combined with a reddish/blue discolouration of the skin
Gout
33
Complications of PV
Huge increase in VTE risk = stroke, DVT, MI,PE
Gout due to increased cell turnover
PUD due to increased histamine levels
Splenomegaly - hypersplenism (Not seen in 2ndary)
34
Inv PV
JAK2 +ve 95%
high RBC, WCC, plts, high Hb
low EPO
Biopsy = hypercellularity, with prominent myeloid and erythroid proliferation
35
Mx PV
Aspirin 75mg OD, Venesection to keep PCV <0.45
Hydroxycarbamide used for poorly controlled disease
30% = myelofibrosis
36
Pseudopolycythemia
Due to low plasma volume
Acute = shock, burns, dehydration
Chronic = diuretics
37
Essential thrombocythemia
Rare condition = overproduction of platelets. Usually isolated thrombocytopenia with plts >600
38
PC ET
Incidental finding. May present with erythromelgia, with a thromboembolic event, warm of the extremities or bleeding (less common)
39
Inv and Mx ET
Platelets >450 with absence of a 2nardy cause. JAK2 mutation in 50%.
Mx - Platelets 400-1000 = aspirin 75mg OD
>1000 = hydroxycarbimide
40
Primary myelofibrosis
Clonal proliferation of stem cells and abnormal myeloid cells in the BM, spleen and the liver. It can develop late secondary to PV or ET
Fibrosis is due to hyperplasia of megakaryocytes which release fibroblast growth factor such as PDGF. This leads to replacement of the BM tissue with connective and fibrotic tissue. Gradually will lead to pancytopenia
41
PC myelofibrosis
Massive splenomegaly due to extramedullary haematopoeisis. Lethargy, weakness, wt loss and fever. Bruising and easy bleeding
42
Inv myelofibrosis
BM biopsy = dry tap due to fibrosis
50% JAK2 +ve, tear drop polkilocytes
Initially high WCC and platelets progression to pancytopenia
43
Mx myelofibrosis
No cure - 5yr survival
| Ruxolitinib
44
BM failure
Pancytopenia = aneamia, neutropenia and thrombocytopenia
On biopsy - hypocellular = fibrois/aplastic
hypercellular = Invasion of marrow = cancer
45
Causes of pancytopenia
Increased destruction = severe sepsis, hypersplenism
Reduced production = BM failure
Aplastic anaemia, severe megaloblastic anaemia, drugs-chemo or radiotherapy, BM infiltration = leukaemia, lymphoma, myeloma or 2ndary mets.
46
PC pancytopenia
Anaemia - tiredness, SOB, angina, pale tachycardia, high output HF
Neutropenia - huge infection risk of bacterial infections leading to uncontrollable sepsis, fungal infections = intracerebral abcess, reactivation of shingles
Thrombocytopenia = bleeding from gums, nose, petichae, purpura. Increased risk of GI and cerebral haemorrhage.
47
Assessment pancytopenia
Check B12/folate, rule out medications - clozapine, phenytoin, chemotherapy
USS to check size of spleen
BM biopsy - hypo vs hypercellular
48
Definition of neutropenic sepsis
Neutrophils <1.0
Pyrexia >38 for 1hr or >38.3 once
Seen commonly in those on immunosuppressive therapy and with BM failure
Crucial to sent cultures and start broad spectrum Abx within 1hr. Hunt for the source
49
Aplastic anemia
Pancytopenia + hypocellular bone marrow. Due to a reduction of pluripotent stem cells and a fault in the remaining ones meaning they are unable to repopulate the BM.
Present 15-24 and >60y/o
50
Causes of aplastic anaemia
60% idiopathic possibly due to HBV/HCV, AI
35% drug induced = chemotherapy, benzene, gold, penicillinamine, phenytoin, carbamazepine, ionising radiation
5% inherited = Fanconi's anaemia
51
PC and Inv aplastic anemia
Anaemia, bleeding and infection
Inv = pancytopenia, no reticulocytes, hypo cellular BM
52
Mx aplastic anaemia
Intensive chemotherapy. Supportive and prophylactic ABx
BM transplant -
Autologous stem cells from pt. Radiation destroys leukaemia/BM
Allogenic HLA matched donor
53
Chronic myeloid leukemia (CML)
14% of leukaemias. In the family of myeloproliferative disorders. Exclusively a disease of adults 40-60
Increased and unregulated growth of the myeloid cells in the BM. 97% have philadelphia chromosome
54
Philadelphia chromosome
9:22 cr reciprocal translocation.BCR gene from cr 22 fused with the ABL gene on cr 9
When translated has enhanced tyrosine kinase and phosphorylation activity compared to normal protein. This gives a cascade of proteins that increase cell division
55
PC CML
Asymptomatic for long periods of time
Wt loss, fever, night sweats, hyper viscosity syndrome
Hepatosplenomegaly - bruising and bleeding
O/E - pallour = anaemia, massive splenomegaly,
If in blast phase - lymphadenopathy, extra medullary tissue deposit
56
Invx CML
increased WCC, basophils
platelets low or normal, may = normocytic anaemia
BM = hypercellularity with FISH for 9:22 translocation
57
Mx CML
Chronic phase <5% myeloblasts
Accelerated 10-19% myeloblasts
Blast phase - AML >20% with large clustered on BM
Imatinib - tyrosine kinase inhibitor
58
Chronic lymphocytic leukaemia (CLL)
Most common leukaemia in the western world. >70y/o 2:1 male to female ratio. Due to the clonal expansion of small B cells and their accumulation in the BM
59
PC CLL
Painless lymphadenopathy, fever, recurrent infection due to function leukopenia, anaemia
Wt loss, night sweat and fever
Complications - BM failure, infections often EBV, HZV, Richter syndrome - CLL to large B cell lymphoma
AI haemolysis
60
Inv CLL
High WCC, lymphocytosis > 5x109
BM - hyper cellular mass lymphocyte infiltration
Blood film - smudge cells
Rai and binet staging
61
Mx CLL
1/3 don't progress, 1/3 chronically progress, 1/3 actively progressing
Steroids, chlorambucil, rituxamab
62
Poor prognosis in leukaemia
age and males
slow remission/ rapid relapse
high blast count
extra medullary disease
63
Hyperviscosity syndrome PC
Headaches, retinopathy, bleeding membranes - gums and GI, thrombosis risk.
64
Causes of high viscosity
High WCC - leukaemia
High plasma proteins - sickle cell, myeloma
Any cause of polycythemia i.e. PV, ET, 2ndary hypoxia
65
Causes of splenomegaly
Cirrhosis/congestion
Haematological - lymphoma, leukaemia, myelofibrosis, Infections - EBV, mononucleosis, malaria, TB
AI - SLE, RA, sarcoidosis
66
Myelodysplastic syndromes
Increasing bone marrow failure with abnormalities in either platelets, RBC or monocytes
PC = elderly with pancytopenia, progressive BM failure with anaemia, neutropenia or thrombocytopenia.
30% to progress to AML
Inv - ringed sideroblasts, hypercellular BM,
67
Lymphoma
Malignancy of the lymphoid tissue, most commonly presents with lymphadenopathy. Common B symptoms are wt loss, night sweats and fever
68
When to refer lymphadenopathy to a specialist
Lymph node >1cm for 6 weeks
Supraclavicular lymphadenopathy
Generalised lymphadenopathy
69
Differential diagnosis of lymphadenopathy
Reactive viral or bacterial infection - cat scratch, EBV, mesenteric adenitis
Lymphoma often widespread and painless
HIV - Primary infection
AI = SLE, RA, Kawasakis, sarcoidosis, TB
70
History for lymphoma
Duration? painless - lymphoma
Risk factors for HIV/TB
B symptoms - wt loss, fever, night sweat
Cat scratch - tender swollen lymph nodes near site of injury may persist for months
71
Inv for lymphadenopathy
Monospot test for EBV, viral screen TB, HIV
Blood film
LDH - high levels linked to a high tumour burden
B2 microglobulin - seen in myeloma, lymphoma and amyloidosis
Excision biopsy is crucial !!
72
Hodgkin lymphoma
Reed sternberg cell - Owls eye
| Incidence peaks 20-29 and >60y/o, 2:1 M:F, 3x increased risk with EBV
73
PC Hodgkin lymphoma
Painless, asymmetric rubbery lymphadenopathy - usually at axilla, cervical or inguinal nodes
B symptoms = wt loss, fever, night sweats
Pel ebstein fever - cyclical fevers increasing then decreasing over a 1-2 week period
Splenomegaly and pruritis
Symptoms due to mass effect = cough, SVC obstruction
74
Inv Hodgkin lymphoma
LN excision biopsy = diagnostic Reed Sternberg cell , CD15/CD30 +ve. Only for those stage III, IV or with B symptoms
FBC, blood film, LFTs , LDH, CXR and CT abdo thorax pelvis for staging
PET imaging can be used with radio labelled glucose showing metabolically active tissues
75
B symptoms
>10% wt loss in 6 months, fever >38, drenching night sweats
76
Ann Arbour Staging
```
I = single lymph node involvement
II = 2+ nodes on the same side of the diaphragm
III = Lymph nodes both sides of the diaphragm + spleen
IV = Spread beyond nodes to bones, liver
```
77
Mx Hodgkin lymphoma
ABVD chemo
78
Infiltrative BM failure
Haematological = Leukemia, myeloma, lymphoma
| Non haematological = Metastatic breast, prostate, lung, renal and thryoid
79
Acute leukaemia
Classified as a rapid increase of immature blood cell due to ineffective haemopoiesis due to tissue infiltration by leukaemic cells.
80
Characteristics of a blast cell
Immature precursor of a myeloid or lymphoid cell. Larger than their normal counterparts with an immature nucleus. Highly suggestive of acute leukaemia or a chronic conditions transforming i.e. myeloproliferative disorders /CML blast crisis
81
Acute lymphocytic leukaemia (ALL)
Common in children <5y/o
82
Risks for ALL
Cancer syndromes - ATM, Li fraumeni, NF1, Bloom and Fanconi
Radiation and chemotherapy
Downs syndrome
Genetic susceptibility + AI conditions
83
PC ALL
BM failure = pancytopenia - anaemia (SOB, fatigue, palpitations) , neutropenia (fever, sepsis), thrombocytopenia (gum bleeding, petichae)
Wt loss, fatigue and night sweats
Tissue infiltration
84
Tissue infiltration ALL
Lymphadenopathy,
Testicular enlargement,
Thymus/mediastinal enlargement - SVC obstruction or SOB
CNS - cranial nerve palsies
85
Invx ALL
TdT+ lymphoblasts, high WCC
low RBC, platelets,
BM biopsy >20% blasts - T/B cells
CSF analysis crucial to determine if CNS involvement
86
Mx ALL
98% children in remission and 85%@ 5 years
85% adults and 55% @ 5 years
Chemo aims to induce remission, given intrathecally to cross BBB and kill CNS progenitors.
Give allopurinol and hydrate to reduce risk of tumour lysis syndrome.
87
AML
Common in adults 65-70y/o. Neoplastic proliferation of myeloid progenitors high levels of monocytes and granulocytes
Can be 2ndary to MDS and CML
88
Classification of AML
```
M2 = granulocyte maturation
M3 = Promyelocytic high risk of DIC t15,17
M4 = Acute monocytic - Gum hypertrophy, skin deposits
M7 = Megakaryocytic high risk in Downs
```
89
PC AML
```
Pancytopenia due to BM failure
Tissue infiltration
- gum hypertrophy
- Violaceous skin deposits
- Hepatosplenomegaly
- DIC if M3
```
90
Inv AML
high WCC, low plts and Hb
| BM aspirate >20% blasts, auer rods = diagnostic of myeloperoxidase crystals
91
Mx AML
ABVD - adrimycin, bleomycin, vincristine and dacarbazine
Acute SE - alopecia and myelosuppression
Delayed SE - peripheral neuropathy, infertility, bleomycin - 20% lung fibrosis, cardiac toxicity, increased risk of leukemia
92
Non-hodgkin lymphoma
85% of lymphomas no reed sternberg cells on biopsy
- 80% B cell and 20% T cell
Incidence increases with age 55-70y/o. Superficial lymphadenopathy painless at multiple sites. Frequency of B symptoms - wt loss, fever and night sweats
High incidence of extra nodal symptoms - splenomegaly, CNS, GI tract
93
T cell lymphomas
Enteropathy T cell lymphoma = increased risk in coeliac disease.
Adult T cell = Japanese / carribean people
94
Low grade B cell NHL
Follicular, MALT, small cell lymphocytic and Waldenstomrs (lymphoplasmacytic). These are generally not curable, but relapse and remit
95
Follicular lymphoma
2nd most common NHL (20% of lymphoma worldwide)
No cure present, low grade long history
PC painless lymphadenopathy late onset 50-60y/o. Can transform to diffuse B cell lymphoma
Mx - anti-CD20 rituximab
96
MALT
Occurs in mucosa associated with lymphoid tissue often in the stomach and linked to chronic h.pylori infection
97
High grade B cell NHL
Diffuse large B cell, Burkitts
98
Diffuse large B cell
Most common adult lymphoma worldwide. Can evolve from CLL and follicular NHL. Aggressive but rapidly response to treatment
99
PC diffuse large B cell lymphoma
Painless lymphadenopathy at one or several sites, can have bowel symptoms from compression or infiltration of GI tract.
Death occurs within months if no treatment
100
Poor prognosis for diffuse large B cell
```
age >60y/o
stage III, IV
LDH high
ECOG performance status 2+
More than 1 extra nodal site
```
101
Burkitts lymphoma
Most rapidly proliferating lymphoma, most common in childhood, 3:1 M:F. t8,14
i) Endemic always EBV associated, occurs in africa corresponds to malaria distribution
ii) Sporadic 30% EBV linked
iii) AIDS related
102
PC Burkitts
Rapidly growing jaw tumours, abdominal mass associated with bone marrow involvement, kidney and the testis
103
Mx high grade lymphoma
RCHOP regime of chemotherapy. Beware tumour lysis syndrome!
104
Tumour lysis syndrome
Complication of cancer treatment involving large volume susceptible cancers i.e. myeloma, lymphoma high grade and leukemia
105
PC tumour lysis
high k+, urate and phosphate
low calcium - precipitates with the high phosphate levels
This can lead to AKI, uric acid nephropathy, arrthymias due to K+ and death
106
Mx tumour lysis syndrome
IV fluids to hydrate, allopurinol or rasburicase
107
Haemostasis
Complex process to stop bleeding following tissue injury
108
Vessel wall
Lined by endothelium which under normal circumstances prevents platelet adhesion and thrombus formation. This is due to to synthesis of NO and prostacyclin that cause vasodilation and inhibit platelet aggregation. Heparin sulphate and thrombomodulin expression
109
Tissue injury
Reflex vasoconstriction of blood vessel occurs to reduce blood flow to the area, serotonin and thromboxane released by platelets allow this. The injury to the vessel wall exposes collagen. Platelets adhere to the collagen with the help of vWF. Its releases a cascade of granules and ADP which allows platelets to bind to fibrinogen and aggregate together. This cycle of ADP and glycoprotein II allows perpetuation of the cycle forming the platelet plug. The presence of thrombin from the coagulation cascade leads to fibrin formation which is cross linked by factor XIII
110
Amplify and potentiate coag cascade
Factors XII, XI, IX, VIII lead to the thrombin burst
111
Extrinsic pathway
Tissue damage leads to endothelial cells releasing tissue factor (III) this activates factor VII. PT
112
Assessing the extrinsic pathway
PT. Looks at just factor VII. Increased in liver failure, vit K deficiency, DIC and very rarely = factor VII deficiency
113
Vit K dependent clotting factors
II, VII, IX, X
114
Liver dependent clotting factors
I,II, V
115
Common pathway
Factor X when activated converts prothrombin (II) to thrombin (IIa) this crucially converts fibrinogen to fibrin!. Factor XIII then crosslinks the fibrin
116
Intrinsic Pathway
Activated by collagen exposure. XII, XI, IX and XII. Assessed by the APTT. Increased in vWD, haemophilia A/B, DIC, hepatic failure and with lupus anticoagulant.
117
Bleeding History
Easy bruising to minimal trauma
Gum bleeding and epistaxis
Prolonged bleeding in surgery
FHx
118
Haemophilia A
X-linked disorder seen in 1/5000 males - deficiency of factor VIII. 1/3rd of cases sporadic
Classified according to residual factor VIII levels.
- severe <1%, mild >5%
119
PC haemophilia VIII
Haemoarthroses - bleeding into joint spaces causing chronic pain and deformity
Raised palpable haematomas
Haematuria and increased risk intracranial haemorrhage
120
Invx and Mx haemophilia
Increased APTT - crucially this correct when mixed with normal plasma due to availability of clotting factors, if this doesn't correct lupus anticoagulant
Mx - recombinate factor VIII IV injections
avoid aspirin, NSAIDs and heparin
mild disease = DDAVP stimulate vWF
121
Haemophilia B
Deficiency in factor IX. Seen in 1/25000, X-linked
PC = old age after surgery, investigations shows increased APTT.
Mx = Factor IX concentrates
122
vWF
Crucial to stabilise platelets binding to collagen at the site injury of the endothelium. Without out this platelets are unable to aggregate and form the platelet plug
123
Von Willebrand disease
Commonest inherited bleeding disorder 1/1000.
- Type 1 AD reduced levels of vWF
- Type 2 AD qualitative abnormality
- Type 3 AR - complete deficiency of vWF
124
PC vWF
Type 1+2 = easy bruising and increased risk of bleeding
Type 3 = More severe bleeding after surgery, GI bleeds
Inv = increased APTT, low VIII and vWF
Mx - DDAVP stimulates vWF release from endothelial cells, platelet derived factor VIII with vWF
125
Vit K deficiency
Will show as a raised PT and APTT as both intrinsic and extrinsic pathways use vit K dependent clotting factors.
Haemorraghic disease of the newborn due to short t1/2 of foetal RBC, low vit K stores and brusing that often occurs at delivery. 1mg IM vit K given at birth.
126
Acquired disorders of haemostasis
DIC, liver disease (low TPO), renal disease (high urea reduces platelet efficacy), vit K deficiency, anticoagulants
127
Disseminated intravascular coagulation (DIC)
Systemic activation of the coagulation cascade where balance of procoagulant and anticoagulant factors is overwhelmed by systemic procoagulant signal
Usually due to mass tissue factor release or inflammatory cytokines
Widespread generation of fibrin and deposition in blood vessels leading to thrombosis, tissue ischemia and multi organ failure. This leads to mass consumption of platelets and clotting factors, secondary activation of fibrinolysis leads to bleeding
128
Causes of DIC
```
Gram -ve sepsis
Trauma - burns, rhabdomyolysis,
Major haemorrhage
Malignancy - AML (M3)
Obstetric catastrophe - preeclampsia, PPH, placental abruption
```
129
Inv DIC
high d-dimer, high PT, APTT
low platelets <50 and fibrinogen
Fragmented RBC on film = schisocytes
May have bleeding from venipuncture sites, mouth, nose. Widespread ecchymoses
130
Mx DIC
Treat the underlying condition, FFP - clotting factors, cryoprecipitate - fibrinogen, platelets and transfusion
131
Thrombocytopenia
Reduced production - BM failure, megaloblastic anaemia,
Increased consumption - Immune = ITP, CLL, SLE, virus
non immune = DIC, TTP, HUS
Hypersplenism
132
Idiopathic thrombocytopenic purpura (ITP)
Immune destruction of platelets due to antibodies against platelet surface antigens leading to increased splenic sequestration and macrophage phagocytosis.
133
ITP PC
spontaneous bleeding and petichae, bleeding from nostrils and gums, menorraghia. Normal on physical exam
134
ITP adults vs children
Children - 2-6yrs acute bleeding with viral infection EBV/measles recently
Adults - Seen in women with other AI disorders such as SLE, thyroid disease. Can be linked to CLL or solid tumours
Mx = usually self-liming, steroids can be used
135
Thrombotic thrombocytopenic purpura (TTP)
Rare disorder where extensive microscopic clotting leads to a profound thrombocytopenia. Deficiency in ADAMS'S-13 enzyme which is responsible for breakdown of large vWF leading to large thrombi
PC - florid purpura, fever, altered mental state, microangiopathic haemolytic anaemia leading to AKI,
high LDH,
Mx = plasmapheresis
136
Thrombophilia
Inherited or acquired defects of haemostasis leading to a predisposition to venous or arterial thrombosis
137
Thrombus
A solid mass formed in the circulation from the constituents of blood
Arterial - Occurs in association with atheroma which tends to form at areas of turbulent blood flow such as bifurcation of arteries. Platelets adhere to the damaged endothelium and aggregate in response to ADP. Plaque rupture may expose tissue factor leading to coagulation cascade and thrombus
Venous- Virchow triads of hypercoagulabilty, stasis and endothelial damage. Consists of mainly fibrin and RBC
138
Predisposition to thrombosis
AF, ventricular assist device, metallic heart valve
Antiphospholipid
Cancer
Pregnancy
Nephrotic syndrome
Congenital - antithrombin III deficiency, factor V leiden
Trauma, surgery,
139
Patient risk factors for thrombosis
Age, female, immobility, smoking, obesity
PMHx
COCP
140
Roles of protein C and antithrombin III
Protein C when activated degrades factor V and VIII with the help of protein S. They dampen the response of the intrinsic pathway
Plasmin degrades fibrin
Antithrombin III adhesion to factor IX, X, XI, XII and thrombin (II). Increased activity by presence of heparin sulphate
141
Factor leiden V
Point mutation leads to arginine being replaced by glutamine @ position 506. This leads to slowed inactivation of Va as protein C is unable to bind to APC and degrade it. Seen in 5% of population
Homozygous - 80x VTE risk
Heterozygous - 8x VTE risk
142
Antithrombin III deficiency
AD approx 1/500 people. Low levels of antithrombin III lead to more circulating thrombin and increased clotting risk
Heterozygous - increased clotting risk
Homozygous not compatible with life
143
Protein C/S deficiency
AD conditons linked with increased risk of VTE
Homozygous = neonatal purpura fulminant fatal unless immediate replacement
Heterozygous = Increases risk of thrombosis and warfarin induced skin necrosis
144
Prothrombin gene mutation
Mutation in the 3' untranslated region of the prothrombin gene associated with 3x increased risk of VTE
145
Pre test wells and d-dimer
i) pre test <1 and d-dimer -ve = alternative diagnosis
ii) pre test >1 and d-dimer +ve = doppler USS
USS = +ve treat !
146
D-dimer
Breakdown product released when fibrin is broken down by plasmin. Sign of clot breakdown -ve predictive value of 96%
147
Warfarin
Inhibits vit K epoxide reductase preventing recycling of vit K which is crucial to produce clotting factors II, VII, IX and X
148
LMWH
Tinzaparin, enoxaparin ,dalteparin. All act by binding to anti-thrombin III and increasing the inactivation of thrombin.
149
DOAC's
IIa inhibitors = dabigatran
| Xa inhibitors = Rivoroxaban and apixaban
150
Treatment DVT/PE
a) LMWH - tinzaparin 175units/day continue until INR = 2 for 2 x readings. Then titrate warfarin dose up
b) Rivaroxaban - loading dose of 15mg BD for 21 days then 20mg OD
151
Warfarin therapeutic window
Narrow >1 = risk of ischemic stroke, >3 risk of bleeding
Target INR 2.5 AF, PE, DVT, cardioversion
Target INR 3.5 mechanical valve, recurrent VTE on warfarin
152
Reversal of warfarin
Omit warfarin = 2-4days
Oral vit K = 24hrs
IV vit K = 4-6hrs
PCC = 10 minutes
If INR >8 no bleeding = stop warfarin, 5mg oral vit K
INR 5-8 = stop warfarin and investigate
153
Reversal of warfarin in intracerebral bleed
To prevent haematoma expansion and allow surgery if needed
i) Significant bleed no haemodynamic compromise = IV vit K 2mg check INR 4-6hrs
ii) If life, limb sight threatening or surgery needed immediately vit K 5mg IV and PCC (beriplex) IV 30U/kg
154
Haemochromatosis
AR disorder involving HFE gene on cry leading to increased iron absorption and its subsequent deposition throughout the body
PC - bronzed skin, DM, arthralgia, cirrhosis, cardiomyopathy. Onset later in females as menstruation is protective
Invx = high ferritin, transferrin sats > 98%
155
Major haemorrhage protocol
FBC, group and save, clotting screen
FFP:RBC in 1:2 - Use 0-ve blood until G&S returns
- Crucial to pass blood through a warmer otherwise can precipitate hypothermia!
Communication with the lab is crucial replace when needed
i) low Hb = RBC
ii) APTT >1.5 = FFP 20ml/kg
iii) Fibrinogen <1.5g/L = cryoprecipitate
iv) Platelets <50 = platelets
If trauma and <3hrs since injury give 1g bolus of transexmic acid followed by 1g IV over 8hrs
156
Hereditary spherocytosis
AD abnormality of erythrocytes leading to malformed sphere shaped RBC due to membrane protein dysfunction . They have an increased risk of rupture = haemolytic anaemia
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PC = splenomegaly due to abnormal RBC getting trapped leading to macrophage recruitment and phagocytosis , pigmented gallstones and anemias
Inv = high MCV and reticulocyte count
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Mx = splenomegaly after 5 y/o due to risk from encapsulated organisms
157
Splenomegaly causes
Haem - hereditary spherocytosis, leukaemia, lymphoma, myeloproliferative
Portal HTN - cirrhosis, Budd-chairi
Connective tissue - RA, SLE, Sjogrens
Infiltrative - sarcoidosis, amyloidosis
Infective - EBV, CMV, HIV, TB, malaria
158
Splenomectomy
May be indicated trauma, rupture (EBV), AIHA, ITP, hereditary spherocytosis and hypersplenism
SE = LLL atelectasis, susceptibility to capsulated pathogens Hib, pneumococcus, meningococcus.
Therfore vaccines, life long Abx
159
Acute infection FBC?
High WCC, high platelets - crucial to check after resolution no evidence of myeloproliferative disorder
160
Acquired haemophilia
Autoimmune usually antibodies to factor 8 or factor 9
Elderly patients with elevated APTT
Do 50:50 mix – no correction
About 50% - occult malignancy
Tx: steroids, immunosuppression e.g. rituximab
