Haematology 3: Haemostasis And Bleeding Disorders Flashcards
List 4 Pro-coagulant factors in the body?
Platelets
vWF
Endothelium
Coagulation cascade
List 4 Anti-coagulant factors in the body ?
AT (antithrombin)
Protein S + Protein C
TFPI (Tissue factor pathway inhibitor)
Fibrinolysis
List 2 thrombopoietic factors ?
Thrombopoietin
IL-6
IL-12
Which Surface glycoprotein do platelets use to bind to vWF ?
GpIb (more important route)
Which glycoprotein do platelets use to bind directly to collagen ?
GpIa
Which glycoproteins do platelets use to bind to other platelets when aggregating ?
GpIIb/IIIa (fibrinogen receptor)
Which 2 mediators do platelets release when they bind to subendothelial structures (vWF or collagen) to cause platelet aggregation ?
ADP
Thromboxane A2
How does Aspirin inhibit platelet aggregation?
aspiring irreversibly Inhibits Cyclo-oxygenase (COX)
This prevents Arachidonic acid being converted to cyclic endoperoxides
This prevents formation of thromboxane A2
Less Thromboxane A2 means less platelet aggregation
List 2 drug targets for inhibiting platelet aggregation ?
Thromboxane A2 production - Aspirin
ADP receptors - Clopidogrel
Which pathway is more important for coagulation in the human body ?
A) Intrinsic pathway
B) Extrinsic pathway
C) Contact activation pathway
B) extrinsic pathway
Describe the sequence of events in the Initiation phase of the Clotting cascade ?
1) Damage to endothelium causes TF to be exposed
2) Factor 7 binds to TF and becomes activated to F7a
3) F7a/TF complex activate F9 and F10 to F9a and F10a
4) F10a binds to F5a –> first step in the coagulation cascade
TF7a - 9a + 10a - 10a+5a
note: people with factor V leiden cannot beind factor 5a to factor 10a
Describe the sequence of events in the amplification phase of the clotting cascade ?
1) activated factors 10 + 5 results in formation of a small amount of thrombin
2) thrombin will activate platelets
3) also activates factor 11 which activates factor 9. activated factor 8 and recruits more factor 5a
4) factors 5a, 8a, 9a bind to the activated platelet - last phase of clotting cascade
thrombin - F11a -9a, 8a, 5a - 5a,8a,9a –
Describe the sequence of events in the propagation phase of the clotting cascade ?
1) the activated platelet with factors 5,8+9 recruit factor 10a
2) results in generation of large amounts of thrombin (thrombin burst)
3) converts fibrinogen to fibrin
4) enables formation of a stable fibrin clot
Which 4 clotting factors are vitamin K dependent ?
10
9
7
2
Think 1972
made in the liver
vitamin K required as a coenzyme for gamma carboxylation of the clotting factors
What is the role of tPA (tissue plasminogen activator) ?
- Converts plasminogen to plasmin
- Plasmin cleaves The fibrin clot
tPA is produced by the endothelium
Which of these molecules does not promote Plasminogen conversion to Plasmin ?
A) tPA B) Urokinase C) FXIIa D) FXIa E) PAI 1
E) PAI1
Plasminogen activator inhibitor inhibits Plasminogen conversion to Plasmin by inhibiting Urokinase and tPA
What does TAFI do ?
TAFI (thrombin Activated Fibrinolysis inhibitor) is a Thrombin dependent inhibitor of Fibrin breakdown
Deficiency of which component is the most Thrombogenic ?
A) TAFI B) FVIIIa C) AT3 D) vWF E) Protein S
C) AT3
Deficiency of Antithrombin (AT) is very rare but is the most thrombogenic
What is the role of Protein C and protein S ?
Inhibit FVIIIa and FVa
What is the role of Thrombomodulin ?
Thrombomodulin is an endothelial receptor for Protein C
It first needs to be activated by Thrombin.
EPCR is another receptor which helps Thrombomodulin bind to protein C
When Thrombomodulin binds to Thrombin and Protein C the complex is called APC (activated protein C)
What is the role of APC (activated protein C) ?
APC inactivates FVa and FVIIIa
Requires protein S as cofactor
What is different in the interaction between APC and FVa in people with Factor V Leiden ?
People with Factor V Leiden have APC resistance.
This means activated factor V is not inactivated by APC.
What is the physiological role of TFPI as an anticoagulant ?
TFPI neutralises the TF/FVIIa complex.
TFPI is produced as a result of TF/FVIIa complex formation in order to stop activation by the extrinsic pathway. (TF/FVIIa is only required for a very short time to activate FX and FIX)
What disease is associated with large platelets ?
grey platelet syndrome
What is ITP (immune thrombocytopenia purpura) ?
Autoantibodies against platelets
This causes the platelets to b e removed and destroyed by the immune system
List 2 common inherited disorders of coagulation (bleeding disorders) ?
Haemophilia A / B
Von willibrand disease
Which coagulation factors are deficient in:
Haemophilia A
Haemophilia B
Haemophilia A - Factor 8
Haemophilia B - Factor 9
What is the inheritance pattern of haemophilia A /B ?
X-linked
What happens to APTT and PT in Haemophilia A/B ?
APTT - INCREASED
PT- normal
APTT Is a measure of the intrinsic pathway
List 3 clinical features of haemophilia A/B ?
Haemarthroses (bleeding into joints)
Prolonged bleeding after surgery
Ecchymoses
How is vWD inherited ?
Autosomal dominant
What are the differences in type1, type 2 and type 3 vWD ?
Type 1- partial quantitative defficiency in vWF
Type 2- Partial Qualitative decency in vWF
Type 3- Complete quantitative deficiency in vWF
How does most of vWF circulate in the blood ?
Most of it is bound to factor 8
What happens to APTT, PT, TT and fibrinogen in DIC ?
APTT- prolonged
PT- prolonged
TT- prolonged
Fibrinogen- decreased
What are 3 treatments of Vitamin K deficiency ?
I.V Vitamin K
FFP
PCC (Prothrombin complex concentrate) Vit K dependent coagulation factors
List 3 differences in clinical presentation of Coagulation and platelet disorders ?
Platelet disorders
- Superficial bleeding (petechia)
- mucous membrane bleeding - epistaxis, gym, vaginal, GI
- bleeding immediately after surgery
- small, superficial ecchymoses
Coagulation disorders
- Deep bleeding into Joints (haemarthroses)/muscles
- delayed bleeding after surgery/trauma
- no prolonged bleeding after cuts
List 2 congenital causes of Vascular defects of coagulation ?
Older-Weber-rendu syndrome
Ehler’s danlos syndrome
List 3 acquired vascular defects of coagulation ?
Dengue haemorrhagic fever
Scurvy
Meningococcal infection
What is the treatment of Haemophilia A / B ?
Factor 8 / 9 concentrates replacement therapy
Which drug is used in the treatment of Haemophilia A ?
Desmopressin (causers increased vWF release from the endothelium. vWF is a factor VIII carrier)
Name 1 carrier protein of Factor VIII ?
vWF
Describe how you can used Ristocetin to test for vWD ?
Add Ristocetin to the patients vWF and platelets in a test tube. Ristocetin normally causes vWF to find to Gp1b on platelets causing platelet aggregation. If there is no platelet aggregation then this means there is a qualitative defect in vWF or Gp1b (Bernard soulier syndrome).
what 3 responses does vessel injury stimulate
vasoconstruction
platelet activation
activation of the coagulation cascade
what is the role of the endothelium in coagulation
barrier produce: - prostaglandins - vWF - plasminogen activators - thrombomodulin
where do platelets originate from
bone marrow
made by megakaryocytes
life span of 10 days
production regulated by thrombopoietic factors (thrombopoietin, IL-6, 1L-12)
describe the structure of platelets
glycoproteins - cell surface proteins use dto interact with the endothelium, vWF and other platelets
dense granules - contain energy stores (ATP, ADP)
open canalicular system, microtubules, actomyosis - pl can expand their surface area
how are aspirin and NSAIDs different
NSAIDs reversibly inhibit COX
aspirin reversibly blocks COX
role of prostaglacyclin PGI2 in platelet function
inhibits platelet aggregation
what other receptor is also important for platelet aggregation
ADP receptors
inhibitors = clopidogrel, ticagrelor
what is the rate limiting step for fibrin formation
factor Xa
what are the 5 main effects of thrombin
activates fibrinogen activates platelets activates pro-cofactors (5 and 8) activates zymogens (7,11,13) all link together to form a prothrombinase complex - activates prothrombin to thrombin
what is the role of the prothrombinase complex
made up of factor 10a and factor 5a
converts prothrombin - thrombin
what are some causes of vitamin K deficiency
most common = warfarin
antibiotics
obstruction of biliary tree
describe the process of fibrinolysis
plasminogen - plasmin - fibrin –> fibrin degradation products
tPA - made by endothelium and converts plasminogen to plasmin
urokinase can also activate plasminogen to plasmin
tPA and urokinase are inhibited by plasminogen activator inhibitor 1+2
plasmin is inhibited by alpha 2 antiplasmin + alpha 2 microglobulin
TAFI (thrombin-activatable fibrinolysis inhibitor) is an important inhibitor of fibrin breakdown
describe the action of physiological anticoagulants
ANTITHROMBINS:
- bind thrombin 1:1 then excreted in the urine
- most active = AT III
- lack or deficiency = the most thrombogenic condition
PROTEIN C+S:
- to stop thrombin generation, f 5 and 8 need to be inactivated
- trace amounts of thrombin generated at the start of the cascade activate thrombomodulin
opens up the receptor for thrombomodulin to bind protein C through EPCR
- forms APC
- APC, in the presence of protein S fully activates protein C
- inactivates factor 5a and 8a
TISSUE FACTOR PATHWAY INHIBITOR:
- as soon as tissue factor and factor 7 released in the first step of the coagulation cascade - TFPI is activates to neutralise the TF-F7a complex
what are two causes of APC resistance
mutated factor 5 (eg factor V leiden) - factor 5a resistant to breakdown by APC –> prothrombotic state
high levels of factor 8
list some genetic causes of excessive bleeding
platelet abnormalities
vessel wall abnormalities
clotting deficiencies
excess clot breakdown
list some inherited causes of excessive bleeding
liver disease vitamin K deficiency AI disease trauma anticoagulants/antiplatelets
what causes pseudothrombocytopaenia
platelets clump together
list different platelet disorders
decreased number (thrombocytopaenia):
- decreased production
- decreased survival (ITP)
- increased consumption (DIC)
- dilution
defective platelet function:
- acquired (aspirin, end-stage renal failure)
- congenital (thrombasthenia)
- cardiopulmonary bypass
list things that can cause thrombocytopaenia
IMMUNE:
drug induced -quinine, rifampicin, vancomycin
rheumatoid arthritis, SLE
sarcoidosis
NON-IMMUNE :
DIC
MAHA
IDIOPATHIC THROMBOCYTOPAENIC PURPURA
describe features of ITP
autoantibodies generated against platelets
platelets then destroyed in the reticuloendothelial system (spleen, liver, bone marrow - anywhere with macrophages)
childhood ITP - acute following illness, self-limiting
adult - chronic and indolent
hematomas and subconjunctival haemorrhages
how can we treat ITP
depends on platelet count and symptoms
steroids
IVIG - cometes with anti-platelet antibodies
list inherited and acquired coagulation factor disorders
inherited:
- haemophilia A dn b
- vWD
acquired:
- liver disease
- vitamin K deficiency/warfarin
- DIC
what is haemophilia
congenital deficiency of factor 8 or 9
deep bleeding into joints and muscles
x-linked recessive
abnormality of intrinsic pw so get PROLONGED APTT , NORMAL PT
need clotting factor replacement for life
haemophilia A - factor 8 deficiency, B - factor 9 deficiency
clinical features of haemophilia
haemarthroses (most common)
soft tissue haematomas
prolonged bleeding after surgery or dental extractions
describe features of VWD
most common coagulation disorder
autosomal dominant
mucocutaneous bleeding
measure vwf antigen/ vwf activity/multimer
classification of VWD
type 1 - partial quantitative deficiency
2 - qualitative deficiency
3 - total quantitative deficiency
describe vitamin K deficiency `
sources: green veg and intestinal flora
factors 1972 and protein C,S,Z need vit K
causes: malnutrition, biliary obstruction, malabsorption, antibiotic therapy
treat: vit K and FFP
features of DIC
emergency activation of coagulation and fibrinolysis triggered by: - sepsis - trauma - obstetric complications - malignancy - vascular disorders - reaction to toxins eg snake venom
systemic activation of coagulation - deposition of fibrin in small vessels - kidney damage, brain damage, damage to extremities
clotting study results in DIC
prolonged APTT prolonged PT prolonged TT decreased fibrinogen decreased FDP decreased platelets schistocytes
treatment of DIC
treat underlying disorder anticoagulation with hepatin platelet transfusion FFP coagulation inhibitor concentrate (APC concentrate)
why does liver disease lead to bleeding disorders
decreased synthesis of 2,7,9,10,11 and fibrinogen dietary vitamin K deficiency dysfibrinogenaemia enhanced haemolysis DIC thrombocytopenia due to hypersplenism
describe treatment for prolonged PT/PTT
vitamin K 10mg od
FFP
treatment for low fibrinogen
cryoprecipitate
list some new anticoagulants
tissue factor pathway inhibitors factor 9a inhibitors protein C activators factor 10a inhibitors - fondaparinux, rivaraxaban, apixaban thrombin inhibitors
key features of the intrinsic pathway
APTT
monitor heparin therapy
starts with factor 12 ( - 11 - 9 - 8 - 10 )
key features of the extrinsic pathway
PT
monitor warfarin therapy (INR)
starts with factor 7
key features of the common pathway
TT
starts with activated factor 5
diagnosis and treatment of haemophilia A
high APTT, normal PT, low factor VIII assay
avoid NSAIDs and IM injections, factor VIII concentrate replacement life-long
diagnosis and treatment of haemophilia B
clinically similar to haemophilia A
treat with factor IX concentrates
diagnosis of vWD
low platelet function
low factor VIII (vWF faces factor VIII in the circulation)
mainly AD
high APTT, high bleeding time, low factor VIII, low vWF, normal INR and platelets
diagnosis of DIC
low platelets, low fibrinogen, high FDP/D-dimer, long PT/INR
