Abnormalities of haemostasis Flashcards
(83 cards)
1
Q
what are some examples of minor bleeding?
A
bruising
gum bleed
menorrhagia
2
Q
name for nose bleed
A
epistaxes
3
Q
what are examples of abnormal bleeding?
A
o Epistaxes not stopped by 10 minutes of compression.
o Cutaneous haemorrhage/bruise without apparent trauma.
o Prolonged (>15m) bleeding from trivial wounds.
o Menorrhagia requiring treatment or leading to anaemia.
o Heavy, prolonged or recurrent bleeding after surgery.
4
Q
what are the 2 main causes of abnormal bleeding
A
- lack of a specific factor (production failure can be genetic or acquired, increases consumption/clearance)
- defective factor function (genetic or acquired), can be a defect of a drug
5
Q
which components of primary haemostasis can have defects?
A
platelets
VWF
collagen
6
Q
what are some causes of thrombocytopenia?
A
- low number platelets
- BM failure e.g. leukaemia, B12 deficiency.
- accelerated clearance e.g. ITP –> reduces lifespan
- pooling and destruction in splenomegaly
7
Q
what are two causes of impaired function of platelets?
A
o Hereditary absence of glycoproteins/storage-granules.
o Acquired from drugs
– e.g. aspirin (NSAIDs), Clopidogrel.
8
Q
what drugs cause platelet defects?
A
aspirin, other NSAIDs, Clopidogrel.
(anti-platelets)
aspirin impairs platelet aggregation by preventing TXA2 synthesis via COX-1 inhibition
9
Q
what is ITP?
how does it increase platelet clearance?
what does this cause?
A
Immune Thrombocytopenia
Anti-platelet antibodies attack platelets that get engulfed by splenic macrophages.
Very common cause of thrombocytopenia.
10
Q
what are the consequences for platelets due to thrombocytopenia
A
o Failure of platelet production by megakaryocytes.
o Shortened half-life of platelets.
o Increased pooling and decreased half-life of platelets in spleen.
11
Q
hereditary diseases affecting platelets
A
Glanzmann’s thrombasthenia
Bernard Souiler syndrome
Storage Pool disease
12
Q
hereditary VW disease
what are the types of VWD?
A
common form of vWD.
vWF two functions – bind collagen (to catch platelets) and stabilise F8.
- Type 1, 3 – deficiency of vWF.
- Type 2 – abnormal function of vWF.
13
Q
types of hereditary VWD
A
- Type 1, 3 – deficiency of vWF.
* Type 2 – abnormal function of vWF
14
Q
what causes the rare acquired form of VWD
A
an antibody
15
Q
abnormal haemostasis diseases
A
thrombocytopenia (platelets)
VWD (VWF)
Ehlers-Danlos syndrome (collagen)
16
Q
inherited conditions of collagen defect
A
Hereditary haemorrhagic telangiectasia
Ehlers-Danlos syndrome [excessively stretchy skin]
17
Q
acquired collagen defect
A
scurvy
steroid therapy
ageing (senile purpura)
vasculitis
18
Q
typical bleeding patterns
A
o Immediate. o Prolonged from cuts and after trauma/surgery. o Epistaxes. o Gum bleeding. o Menorrhagia. o Easy bruising.
19
Q
what is characteristic in thrombocytopenia?
A
petechiae bruising (characteristic of low platelets)
20
Q
tests for abnormal bleeding investigation
A
o Platelet count.
o Bleeding time (PFA100 lab test).
o Assays of vWF.
o Clinical observation.
21
Q
where do the defects lie in secondary haemostasis
A
- in coagulation factors
- in the crosslinked fibrin
22
Q
what occurs in the haemophilia type 8?
A
failure of generation of thrombin burst due to defects in F8
(thrombin provides +feedback to F8)
Thrombin converts fibrinogen to fibrin)
23
Q
what is the importance of fibrin in larger vessels?
A
The primary platelet plug is sufficient for small vessel injury but in the larger vessels, the plug will break apart unless it is stabilised by fibrin.
24
Q
what can cause the decrease in cross-linked fibrin
A
- deficiency in factor 13 production
- increase consumption of factors
25
hereditary deficiencies in factor production
F8/9 – Haemophilia A/B,
Haemarthrosis is hallmark (the bleeding into joint spaces)
F2 (thrombin) – lethal.
F11 – bleed after trauma but not spontaneously.
F12 – no excess bleeding at all.
26
acquired (more common) deficiencies in factor production
1) Liver disease (production site)
2) Dilution – e.g. transfusions.
- RBC transfusions don’t contain plasma unless they’re major.
3) Anticoagulant drugs – e.g. Warfarin.
27
what are 2 acquired increased consumptions causes?
1) DIC – Disseminated Intravascular Coagulation.
• Generalised activation of coagulation via TF.
• Associated with sepsis, major tissue damage and inflammation.
• Consumes and depletes coagulation factors, platelets and fibrinogen.
• Deposition of fibrin in vessels causes organ failure.
2) Immune – auto-antibodies.
28
typical bleeding patterns in secondary haemostasis
o Superficial cuts DO NOT bleed.
o Bruising is common, nosebleeds are rare.
o Spontaneous bleeding is deep, into muscles and joints (haemarthrosis)
o Bleeding after trauma may be delayed but is prolonged.
o Bleeding frequently restarts after stopping.
29
what precaution must be taken with haemophiliacs considering deep bleeding
intramuscular injections must be avoided due to deep tissue bleeds possible
30
tests for defective secondary haemostasis
o Screening tests (‘clotting screen’):
- PT – Prothrombin Time.
(Extrinsic & Common pathway defects)
- APTT – Activated Partial Thromboplastin Time.
(Intrinsic & Common pathway defects)
- FBC – Full Blood Count (for platelets).
o Factor assays – e.g. for F8 etc.
o Tests for inhibitors.
31
PT and TT and APTT resulst in haemophilia
- Prothrombin time =normal
- Thrombin time =normal
- Activated partial thromboplastin time = abnormal
(due to defective intrinsic pathway)
remember Prothrombin time does not include F8
(1,2,5,7,10) therefore remains normal
APTT is best to measure for haemophilia
32
bleeding disorders not detected by routine clotting tests
```
Mild factor deficiencies.
vWD.
F13 deficiency (to cross-link the fibrin) – common pathway is measured in BOTH APTT and PT.
Platelet disorders.
Excessive fibrinolysis.
Vessel wall disorders.
Metabolic disorders – e.g. uraemia.
Thrombotic disorders.
```
33
hereditary cause of excessive fibrinolysis
anti-plasmin deficiency therefore less plasmin deactivation
plasmin causes fibrinolysis
34
what are the acquired causes of poor fibrinolysis?
1) Drugs – e.g. affecting tPA and bacterial streptokinase.
tPA activates plasmin
2) Disseminated Intravascular Coagulation (DIC)
35
what are some genetic bleeding disorders?
1) Haemophilia : Sex-linked recessive.
2) Von Williebrand disease: Autosomal dominant usually
- -> Dominant – Type 1, 2.
- -> Recessive – Type 3.
- 3) Factor V Leiden: autosomal recessive
these are usually treated with replacement therapy
36
treatment of production/function failure
o Replace missing factors/platelets – prophylactically or therapeutically.
o Stop drugs causing it.
37
treatment of immune destruction
o Immunosuppression – e.g. prednisolone.
| o Splenectomy for ITP.
38
treatment of increased consumption
treat cause or replace
39
factor replacement therapy
o Plasma – contains ALL coagulation factors.
o Cryoprecipitate – rich in fibrinogen, F8, vWF, F13.
o Factor concentrates – concentrates available for all factors except F5.
o Recombinant forms of F8 and F9 are available.
40
platelet replacement therapy
o Pooled platelet concentrates available.
41
DDAVP (Desmopressin- vasopressin alternative/derivative)
only when you don’t have enough (not for intrinsic dysfunctions):
- use in VWD and Haemophilia A (mild to moderate cases only i.e. not absolute deficiencies)
- Results in a 2-5x rise in vWF and F8 (more F8 rise) by stimulating endothelial cells to release internal stores.
Only really good for mild disorders.
42
what is the effect tranexamic acid on haemostasis?
slows down the breakdown of clots and therefore prevents excessive blood loss:
- inhibits fibrinolysis – competes with tPA.
- It is widely distributed in the body and can cross the placenta.
- However, it does have a low concentration in breast milk.
- Delivered by IV, oral or mouthwash.
43
what are the causes of thrombocytopenia?
-Bone marrow failure e.g. Leukaemia
- Accelerated clearance of platelets
e.g. Disseminated intravascular coagulation (DIC)
uses up clotting factors and platelets
- Pooling and destruction in splenomegaly
44
what are some hereditary conditions causing defects in primary haemostasis?
1) Glanzmann’s thomboasthenia
(no GlpIIb/IIIa--> no platelet activation)
2) Bernard Soullier syndrome (no GlpIb -->no vWF binding )
3) Von Willebrand Disease (low or abnormal vWF)
45
what are the causes of deficiency in coagulation factors?
- Liver failure (production site of factors)
| - Haemophilia (8 and 9)
46
which haemophilia is more prevalent?
A x5 than B
47
what causes the excess consumption of coagulation factors?
- Autoimmune diseases
- DIC (disseminated intravascular coagulation)
use up clotting factors
48
what are the defects in primary haemostasis?
1) thrombocytopenia (low platelets)
| 2) hereditary conditions
49
what are the defects in secondary haemostasis?
1) coagulation factor deficiency e.g. haemophilia
| 2) overconsumption of coagulation factors
50
what is the presentation of primary haemostasis defect?
- Immediate
- Prolonged bleeding from superficial cuts
Epistaxes
Gum bleeding
Menorrhagia
Easy bruising (seen in thrombocytopenia)
51
what is the presentation of secondary haemostasis defect?
Spontaneous bleeding is deep, into muscles and joints (haemarthrosis) --> typical in haemophiliacs
- Bleeding after trauma may be delayed and is prolonged
- Superficial cuts do not bleed
52
what is a key characteristics in presentation of thrombocytopenia?
Petechiae 1-2mm
| purpura up to 1cm
53
what are 3 causes of prolonged APTT?
- heparin
- Haemophilia A
- Haemophilia B
- Vitamin K deficiency
APTT is a measure of intrinsic pathway
F8 and F9 are intrinsic pathway factors
F8 and F9 are involved in haemophilia
54
what are the 3 physiological inhibitors of the clotting cascade?
protein C
protein S
anti thrombin
55
what is the MoA of warfarin?
Vitamin K inhibitor
action of gamma-glutamyl carboxylase in activation of factors 2,7,9,10
inhibits the post translational Gla modifications of certain clotting proteinases, thus reducing their activities
56
what does heparin act on so have its anticoagulant effect?
anti thrombin
accelerates the inhibition of thrombin and other clotting proteinases by antithrombin
57
what pathway does prothrombin time measure?
extrinsic pathway and common
58
what pathway does Activated Partial Thromboplastin Time measure?
intrinsic pathway and common pathway
59
what is haemoarthrosis?
bleeding into joint cavity
60
what factors are involved in the intrinsic pathway?
what measures it?
F8,9,
F10, 11, 12
12--> not significant in symptoms
11--> rare
8 and 9--> haemophilia
measure with Activated Partial Thromboplastin Time
61
what factors are involved in the extrinsic pathway?
what measures it?
TF (3) and F7
Prothrombin Time
62
what factors are involved in the common pathway?
what measures it?
F5
thrombin (2)
fibrin (1)
F13 (cross linker)
Thrombin time :
measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added
63
how is haemophilia treated?
with recombinant F8/9
64
what does normal fibrinogen production suggest in a jaundiced patient?
functional liver so not hepatic jaundice
key: liver is the production site of fibrinogen therefore a healthy liver is needed for fibrin clot formation
65
which factors are Vitamin K dependent?
2,7,9,10
Warfarin inhibited
66
how can jaundice cause malabsorption of vitamin K?
bile is used to emulsify vitamin K so can be absorbed
obstructive jaundice (gall stones or tumour) would reduce vitamin K absorption
67
what pathways would Vitamin K deficiency/malabsorption affect? why?
both extrinsic and intrinsic as well as common
factors dependent on Vit K are 2,7,9,10
68
how is vitamin K def treated?
IV Vitamin K
or replace factors in emergency
69
what are 2 acquired platelet disorders?
1) thrombocytopenia
| 2) drug-induced
70
what are the 3 mechanisms leading to thrombocytopenia?
1) failure of platelet production e.g. aplastic anaemia, leukaemia, vitamin b12/folate def
2) shortened platelet half life e.g. AI thrombocytopenia, thrombotic thrombocytopenia, infections, drugs
3) increased pooling of platelets in enlarged spleen
71
what are the 3 tests to monitor platelets?
1) platelet count
2) bleeding time
3) platelet aggregation e.g vWF activity
platelet count is the most important (as a massive decrease increases risk of bleeding)
72
what is the role of F13a?
cross linkage of fibrin
activated by thrombin
73
which of the pathways plays the minimal role in haemostasis?
intrinsic (started by factor 12)
Tissue factor is main, framing complex with F7a
74
what do factors 7,9,10 and prothrombin need to do to activate their substrate?
bind to phospholipid
this requires Vitamin K dependent post translational modification of certain amino acids (“Gla” residues) and is mediated by Ca2+ ions.
75
what occurs on the platelet membrane phospholipid surface to cause activating of thrombin?
```
11--> 11a
- 11a complexes with 8a enables:
10--> 10a
- 10a complexes with 5a enables:
prothrombin--> thrombin
```
76
what are the main tests for coagulation?
1) activated partial thromboplastin time (APTT)
- monitors the function of the intrinsic and common pathways and is used to control the level of heparin in patients.
2) prothrombin time (PT)
- monitors the extrinsic and common pathways and is used to control levels of oral anticoagulant (warfarin) in patients.
77
what drug is monitored by APTT?
heparin
78
what drug is monitored by PT?
warfarin
79
what test can detect haemophilia?
APTT (F8 and F9 def)
80
what can both the PT and APTT test identify?
acquired disorders such as disseminated intravascular coagulation (increased coagulation factor consumption)
81
what converts plasminogen to plasmin?
plasmin will lyse the fibrin clot
tissue plasminogen activator (tPa)
Alteplase drug
82
how can bleeding due to platelet-vWF (primary haemostasis) be distinguished from defects in coagulation (secondary haemostasis)?
1) Defect in platlet-vWF:
- characterised by SUPERFICIAL bleeding into the skin and mucosal membranes
- bleeding immediately following injury.
2) Defect in coagulation (deficiencies):
- tends to be into DEEP tissues, muscles and joint
- Often delayed after injury
- prolonged and can be severe
83
characteristics of Von Williebrand Disease
- nosebleeds, menorrhagia and prolonged bleeding from superficial cuts
- due to its importance of vWF in the platelet-vessel wall interaction
remember that defects in primary haemostasis leads to a lot of superficial bleeds
