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MD2 Haematology > Bleeding Disorders and Coagulopathies > Flashcards

Bleeding Disorders and Coagulopathies Flashcards

1
Q

Define haemostasis

A

Physiological process of stopping or arresting bleeding or keeping the blood within the damaged vasculature

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2
Q

Define thrombosis

A

Pathological process causing disease

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3
Q

What are the 3 key steps in haemostasis?

A

Initial response: vasoconstrction, endothelial activation

Platelet plug formation

Fibrin clot

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4
Q

Describe the coagulation pathway

A

Sequential activation of clotting proteins (serine proteases; activated by proteolytic cleavage), enhanced by co-factors V and VIII, ultimately leading to formation of fibro

Essential components: phospholipids, calcium

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5
Q

What is the significance of AT deficiency?

A

Strong risk factor for thrombosis

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6
Q

What is antithrombin?

A

Serine protease inhibitor (inhibits factors 9-12 and thrombin)

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7
Q

What is TFPI and what does it do?

A

Tissue factor pathway inhibitor

Inactivates Xa in the presence of VII and TF

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8
Q

What do deficiencies in the fibrinolytic pathway predispose to?

A

Thrombosis (increase risk 2x)

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9
Q

Describe the initiation phase of coagulation

A

Physiological clotting is initiated by exposure of TF due to vascular damage (aggregated platelets display integrin receptors and phospholipid surface markers which concentrates clotting factors)

TF interacts with VII/VIIa and activates fX to fXa

fXa then generates small amount of thrombin; this is not adequate to sustain haemostasis

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10
Q

What are the 3 phases of the “new coagulation model”?

A

Initiation

Propagation

Stabilisation

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11
Q

Describe the propagation phase of coagulation

A

Initial thrombin burst then activates XI to XIa and also generates Va and VIIIa (TF/VIIa can also generate IXa)

Activated platelets release fV

Thrombin and XIa set up a feedbook loop that generates even more thrombin that sustains propagation of coagulation

XII has no role in this cascade

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12
Q

What occurs in the stabilisation phase of cogulation?

A

Thrombin stimulates fibrin and XIIIa formation, which produces a cross-linked fibrin clot

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13
Q

What is the pathological process underlying DIC?

A

Systemic dysregulated clotting

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14
Q

What 3 processes enable undamaged endothelium to resist clotting, controlling the extent of clot formation by limiting it to the regions of endothelial damage?

A

Thrombomodulin (expressed on endothelial cell surface) binds thrombin to generate activated protein C, which inactivates Va and VIIIa

Soluble antithrombin inactivates thrombin and Xa

Thrombin activates fibrinolysis to modify clot size

NB All these processes occur simultaneously

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15
Q

What screening tests are performed to look for haemostatic defects?

A

Platelet count

APTT

PT

Thrombin time

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16
Q

What is the normal platelet count?

A

150-400

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17
Q

What is APTT and what is the normal reference range?

A

Activated Partial Thromboplastin Time

24-32 secs

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18
Q

What is PT and what is the normal reference range?

A

Prothrombin time

10-12 secs

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19
Q

What is the normal reference range for thrombin time?

A

14-22 secs

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20
Q

What physiological factors influence APTT?

A

Surface activating agents (ellagic acid, kaolin)

Phospholipid

Calcium

Thrombin

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21
Q

What physiological factors influence PT?

A

Thromboplastin

Tissue factor

Phospholipid

Calcium

Thrombin

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22
Q

What haematological tests are used to measure the intrinsic vs the extrinsic pathway?

A

Intrinsic: APTT

Extrinsic: PT

Common pathway: TT

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23
Q

What physiological factors influence the thrombin time

A

Thrombin

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24
Q

List 6 common sample collection errors made when performing screening tests for haemostatic defects

A

Partially filling tubes

Incorrect tube

Vacuum leak and citrate evaporation

Clot in tube

Underfilling

Heparin contamination (blood drawn from IV lines)

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25
What biological effects may cause error in screening for haemostatic defects?
Haematocrit \>55 or \<15 Lipaemia Hyperbilirubinaemia Haemolysis
26
What laboratory errors may influence the results of screening for a haemostatic defect?
Delay in testing Prolonged incubation at 37 degrees C Freeze/thaw deterioration
27
What correction studies should be performed following an abnormal APTT/PT test result, to ensure this is a true result?
Mix 1/2 patient's sample and 1/2 control (pooled plasma from normal individuals) and re-perform the APTT or PT If the patient has a factor deficiency, the APTT/PT will normalise (due to presence of factors from normal sample) If an "ïnhibitor" is present (e.g. lupus anticoagulant), there will be a persistent abnormality
28
If a prolonged APTT but normal PT result is obtained for a patient, and the APTT is corrected with a mixing study, what is the DDx?
Factor deficiency (VIII, IX, XI, XII) Early DIC Heparin Rx (correction is variable)
29
If an abnormal APTT but normal PT result is obtained for a patient, and the abnormality persists with a mixing study, what is the DDx?
Lupus anticoagulant (common) Inhibitors towards specific coagulant factors VIII, IX, XI
30
If a normal APTT but prolonged PT result is obtained for a patient, and the PT is corrected with a mixing study, what is the DDx?
Factor deficiency (VII; rare) Liver disease (common) Vitamin K deficiency (common) Warfarin (common)
31
If a normal APTT but prolonged PT result is obtained for a patient, and the abnormality persists with a mixing study, what is the DDx?
Antiphospholipid Abs (uncommon) Abs to VII (rare)
32
If a prolonged APTT and PT result is obtained for a patient, and the APTT/PT are corrected with a mixing study, what is the DDx?
Isolated deficiency in common pathway: factors V, X, II and fibrinogen Multiple factor deficiencies (common): liver disease, vit K deficiency, warfarin, DIC
33
If a prolonged APTT and PT result is obtained for a patient, and the abnormality persists with a mixing study, what is the DDx?
Inhibitors towards V, X, II, fibrinogen (rare) Antiphospholipid Abs
34
Factors in the intrinsic pathway
XII XI IX VIII
35
Factors in the extrinsic pathway
TF VII
36
Factors in the common pathway
X V Thrombin Fibrinogen XIII
37
Causes of prolonged PT
Warfarin (indirectly inhibits factors II, VII, IX, X) Liver disease Vit K deficiency DIC Factor VII deficiency
38
Causes of prolonged APTT
Heparin Rx Liver disease Lupus anticoagulant DIC von Willebrand's disease Haemophilia (factor VIII, IX deficiency) Factor XII, XI deficiency
39
Causes of prolonged TT
DIC (decreased fibrinogen) Liver disease Heparin
40
List 7 common bleeding disorders
Von Willebrand disease Haemophilias Disorders of platelet numbers and function DIC CLD with cirrhosis Renal failure Use and toxicity of anti-platelet drugs, heparins, warfarin and newer oral anticoagulants
41
What features on Hx are important to assess in a patient presenting with a possible bleeding disorder?
Age at onset Spontaneous or post-traumatic Sites/frequency of bleeds FHx Medicinal therapy (anti-platelet Rx and anti-coagulants) Therapy received and response Any convincing evidence of "excessive bleeding"?
42
Distinguish between purpuric and coagulation disorders in terms of presence/absence of petechiae and superficial echymoses, haematoma and haemarthrosis occurrence, frequency of late bleeding, gender and FHx
43
What are the 4 most common hereditary bleeding disorders?
Haemophilia A or B Von Willebrand disease Factor deficiency Platelet disorders (Glanzmanns thrombasthenia or Bernard Soulier)
44
What is Glanzmanns thrombasthenia?
Platelets lack glycoprotein IIb/IIIa As a result, no fibrinogen bridging of platelets to other platelets can occur, and bleeding time is significantly prolonged
45
What is Bernard Soulier?
Deficiency of glycoprotein Ib, the receptor for von Willebrand factor
46
List 5 common acquired bleeding disorders
Liver disease Vitamin K deficiency DIC Excessive anticoagulation ITP
47
What signs may be seen in a patient with a bleeding disorder?
Petechiae (including palatal) and purpura Gum bleeds Large ecchymoses Leg wasting and joint deformity from haemarthrosis Telangiectasia
48
What is senile purpura?
Common, benign condition seen in the elderly and characterised by recurrent formation of large purple ecchymoses on the extensor surfaces of the forearms following minor trauma Due to atrophy of dermal tissue and fragility of blood vessels
49
What is Von Willebrand disease?
Commonest bleeding disorder! Heterogeneous haemorrhagic disorder caused by deficiency or dysfunction of von Willebrand factor (may be inherited or acquired)
50
Where is von Willebrand factor synthesised?
Megakaryocytes and endothelial cells (undergoes dimerisation in the ER and multimerisation in the Golgi apparatus)
51
What are the functions of vWF?
vWF mediates platelet adhesion at site of injury and stablises FVIII in the circulation Wherever platelet aggregation is needed, coagulation is also necessary; vWF is like a "taxi" that carries FVIII to the proximity of a developing clot
52
How does blood group influence levels of vWF? How does this influence presentation with type I von Willebrand disease?
Blood group contributes to ~25% variation in vWF level ABO glycosylation of vWF influences clearance; people with non-O blood group have higher levels than those with O-group (AB has the highest) ABO group therefore also modifies the penetrance of type I von Willebrand disease
53
How is hereditary von Willebrand disease inherited?
Varies; there are AD and AR presentations (type I is AD)
54
What is type I von Willebrand disease and how common is it when compared with other types of von Willebrand disease?
Partial quantitative deficiency of vWF; mild presentation (depending on blood group) with many cases going undiagnosed 70-80% of cases of von Willebrand
55
What is type II von Willebrand disease?
Qualitative deficiency of vWF, resulting in mild to moderate bleeding Many subtypes, with differences in vWF multimers (including presence of abnormal multimers in some subtypes)
56
What is type III von Willebrand disease?
Virtually complete deficiency of vWF
57
Describe 4 subtypes of von Willebrand disease type II
2A: decreased affinity of vWF for platelet due to decrease in multimers 2B: increased affinity of vWF for platelet due to vWF mutation (causes thrombocytopaenia) 2M: decreased platelet binding due to vWF mutation 2N: defective factor VIII binding site, so decreased FVIII level (DDx would include mild haemophilia)
58
What screening tests can be performed to assess for von Willebrand disease and what results would be expected?
Bleeding time: prolonged Platelet count: low in type 2B or pseudo-vWD APTT: prolonged but variably (especially prolonged in type 2N, 3) PFA (platelet function analyser): prolonged
59
What specific tests can be performed for vWD?
vWAg: low (diagnostic if \<0.30 IU/mL) FVIII clotting activity (VIII C): may be decreased but often in normal range Functional assays (ristocetin co-factor activity/collagen-binding assay): low
60
Ix for vWD
Haemostatic screening tests Specific vWF tests Multimer analysis
61
Mx of vWD
Desmopression (DDAVP) Replacement therapy: FVIII/vWFAg concentrate, recombinant vWFAg concentrate, cryoprecipitate/FFP/platelets Antifibrinolytics (e.g. transexamic acid) Fibrin glue/fibrillar collagen preparation
62
When should an acquired vWD be considered?
Late onset bleeding diathesis in a patient with a negative FHx; clinical manifestations are similar to type 1 and type 2 vWD (mild to moderate bleeding)
63
What factors may predispose to vWD?
AI disease Lymphoproliferative/myeloproliferative disorders (thrombocythaemia) Monoclonal gammopathy Drugs (e.g. ciprofloxacin, valproic acid) Infectious disease Valvular heart disease (esp AS; large multimers of vWF are destroyed by mechanical stress)
64
What is the cause of pseudo-vWD?
Mutation in platelet integrin GpIb so that it has increased binding with vWF
65
Describe the pathophysiology of haemophilia A
Factor VIII deficiency (which normally circulates bound to vWF, protecting it from proteolysis)
66
How is haemophilia A inherited?
XR (males present with features of disease)
67
How do levels of F VIII and IX correspond with the clinical presentation?
\<1 U/dL: severe, spontaneous bleeding 1-5 U/dL: moderate bleeding with minimal trauma or surgery 5-30 U/dL: mild bleeding with trauma or surgery
68
Is it more common to have severe spontaneous bleeding in haemophilia A or B?
A
69
What is the typical clinical picture in haemophilia?
Most common presentation is severe spontaneous bleeding (70% in haemophilia A, 50% in haemophilia B)
70
List 5 common clinical presentations of haemophilia A
Haemarthrosis Subcutaneous and intramuscular haematomas Psoas and retroperitoneal haematomas Traumatic bleeding (bleeding from razor nicks uncommon, but delayed bleeding is common esp in tooth extractions, tonsillectomy, etc) Slow wound healing
71
What is the prognosis of haemophilia A?
Depends on severity Nearly normal life span with factor VIII replacement
72
Ix and expected results for haemophilia A
APTT: prolonged INR: normal Specific F VIII C assay: low
73
DDx for haemophilia A
Haemophilia B vWD (esp type 2N)
74
Mx of haemophilia A
Purified or recombinant F VIII therapy Transexamic acid Topical thrombin FFP (no longer therapy of choice)
75
What difficulties are encountered in the Mx of haemophilia A?
Patients can develop inhibitors to factor replacement therapy; these can be overcome by the use of "bypassing agents" (which usually consist of variable amounts of activated and precursor vit K-dependent clotting factors which generate thrombin by bypassing the coagulation cascade) Risk of HIV, HCV etc
76
What is haemophilia B? Is it more or less common than haemophilia A? How is it inherited?
Factor IX deficiency 4-8x less common than haemophilia A XR (and unlike haemophilia A, the spontaneous mutation rate is low so most patients have a FHx)
77
How does severe disease manifest in haemophilia B compared with haemophilia A?
Identically
78
Ix and results for haemophilia B
APTT: prolonged (although not sensitive to mild deficiency i.e. F IX 20-30%) INR: normal
79
Mx of haemophilia B
Prothrombin complex Purified or recombinant F IX
80
Why is Rx Hx and FHx so important to ask about in a patient with a suspected platelet disorder?
Rx: may be on antiplatelet or anticoagulant drugs, important to rule out drug causes when considering a Dx of ITP (ITP is a Dx of exclusion) FHx: will identify inherited platelet receptor abnormalities
81
What medications may cause thrombocytopaenia?
Heparin Alcohol Quinine/quinidine Sulfa drugs
82
What are some causes of thrombocytopaenia as a result of increased platelet destruction?
AI: ITP, SLE, drugs Allo-immune: post-transfusion purpura, neonatal allo-immune thrombocytopaenia Non-immune: hypersplenism, DIC/TTP/HUS
83
What are 5 causes of thrombocytopaenia as a result of decreased platelet production?
Aplastic anaemia Myelodysplasia Leukaemic infiltration Lymphoma infiltration Fibrosis
84
At what platelet count is there a risk of spontaneous bleeding?
\<10-20 x10^9/L
85
At what platelet count is there considered to be no significant increased risk of post-surgical bleeding?
\>50-60 x 10^9/L (provided normal platelet function)
86
What are some possible sources of error if a low platelet count is returned on routine FBE?
Spurious reduction in automated platelet count due to platelets clumping because of EDTA in collection tube, or blood clotting
87
What types/sites of bleeding are often observed in thrombocytopaenia?
Skin and mucous membranes: petechiae, ecchymoses, haemorrhagic vesicles, gingival bleeding, epistaxis Menorrhagia GI bleeding Intracranial bleeding
88
List 6 congenital causes of platelet dysfunction
Glanzmann thrombasthenia Bernard Soulier syndrome Storage pool deficiencies Wiskott-Aldrich syndrome Tar syndrome Constitutional
89
List 6 acquired causes of platelet dysfunction
Anti-platelet Rx Uraemia Extracorporeal circulation (e.g. haemodialysis) Myeloproliferative disorders Paraproteinaemia Hypothermia
90
How can platelet function be assessed?
Thromboelastography (TEG) Platelet aggregation studies (ADP, collagen, adrenaline, ristocetin) Platelet function analysis (PFA) Skin bleeding time (no longer preferred due to technical issues of standardisation and expertise)
91
What will standard haemostatic screening tests miss?
Mild vWD Mild haemophilia F XIII deficiency Platelet function disorder (platelet count will be normal)
92
What is cryoprecipitate?
Prepared by thawing FFP between 1-6 degrees C and recovering the precipitate Contains most of F VIII, fibrinogen, F XIII, vWF and fibronectin from the FFP

MD2 Haematology (4 decks)

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