Bleeding disorders Flashcards
The process of coagulation requires
–Functioning platelets
–Functioning endothelium
–Coagulation factors
Balance
–Coagulant vs. anticoagulant factors
Imbalance
–Thrombosis
–Bleeding
What happens when you cut yourself?
Blood vessel damage
Disrupt endothelium
Exposure of
–Tissue Factor
–Collagen
Primary haemostasis
–Recruitment of platelets
Secondary haemostasis
–Activation of coagulation factors
Occur simultaneously
Primary haemostasis
Cut in the blood vessels exposes collagen and tissue factor
Also causes the exposure of von willebrand, which atrracts and binds platelets (through glycoprotein 1b_V-IX).
As platelets adhere to von willebrand, they become activated
Activation releases granular contents which cause aggregation and further activation of platelets
Secondary haemostasis
Activation of coaguation factors
Cascade of events:
- Initation - extrinsic pathway
- Propagantion- intrinsic pathway
- thromin generation
- fibrin producition - the clot
Initiation
ii- prothrombin
Prothrombinase complex- Xa + II (requires Va)
IIa- thrombin
thrombin activates XIII to cause cross linking of fibrin
Propagation
Thrombin feedsback to factor XI (becomes activated)
Interacts with IX and causes activation
Thrombin also activates factor VIIIa
VIIIa + IXa feedback to the prothrombinase complex and causes further fibrin to be made
Regulation
Antithrombin is a naturally occuring anti-coagulant that downreguates factor (7,10) (9,11) (10 +2) (9a + 2a)
Thrombomodulin is found on the endothelium. When thrombin is made it binds to thrombomodulin and then feedbacks and interacts with protein C. Protein C is activated to APC. APC plus another co-factor Protein S. Together these factors downregulate factor 5 and 8.
Tissue factor pathway inhibitor - downregulates pathway between tissue factor and factor VII
Fibrinolysis
Plasmin degrades fibrin
Plasmin comes from plasminogen (fibrin stimulates activation of plasminogen through tPA and uPA)
This process is regulated by alpha antiplasmin and PAI-1 and 2
Laborator analysis of coagulation
Assessment of primary haemostasis
–in vivo – Bleeding Time (cut the patient, measure clotting time)
–ex vivo – FBC (platelet count), platelet function
Assessment of secondary haemostasis
–Prothrombin time (PT)- measures the extrinsic system and the final common pathway- increased with warfarin
–Activated partial thromboplastin time (APTT)- measures the intrinsic and final common pathway - increased with heparin
–Thrombin clotting time (TCT) - measures the final part of the common pathway
–Individual coagulation factor assays
Samplle requirements
Plasma sample (blood thats not already clotted)
Prevent clotting
- citrate sample (chelates all calcium prevents clotting
- centrifugation (separates cellular component, add in synthetic phospholipid)
All results expressed
- seconds
- ration to normal plasma
What Clotting factors does PT measure?
Factors in extrinsic and common pathways
Factors VII
Factors X, V, II and fibrinogen
Acticated partial thromboplastin time (APTT) process?
Add
–Patient’s plasma
–Contact factor e.g. Kaolin or silica
–Phospholipid ( ‘partial thromboplastin’ )
Warm to 37°C
Add calcium
Time taken to clot
Normal range 26 - 38 secs
Ratio Patient/Average of 20 normals
Which clotting factors and clotting pathway does APTT measure?
–Factors in intrinsic and common pathways
–Factors VIII, IX, XI & XII
–and Factors X, V, II & Fibrinogen
Thrombin clotting time (TCT) process
Add at 37°C
–Patient’s plasma
–Bovine thrombin
–Less Calcium or phospholipid dependent
Time to clot
Normal 10-16 secs
Ratio Patient TT/Average of 20 normal TTs
What does TCT depend on and what is it inhibited by?
What does TCT depend on?
–How much fibrinogen is present in plasma
–How well that fibrinogen functions
But will also be prolonged by
–Inhibitors of thrombin (e.g. heparin, dabigatran)
–FDPs
Inhibitors of fibrin polymerisation (paraproteins
Simplified patterns of coagulation screen abnormality
Patterns of coaglation screen abnormality
Clotting factor disorder definition
Congeital or acquired conditions that impair the body’s ability to control blood clotting resulting in inappropriate bleeding
Congenital
- haemophillia A
- haemophilla B
- Von willebrands disease
Acquired
- Liver disease
- warfarin
- Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) definition
Acquired, consumptive process
–Activation of coagulation cascade (Microthrombi)
–Exhaustion of coagulation cascade(Bleeding)
Causes of disseminated intravascular coagulation (DIC)
–Sepsis
–Malignancy
–Massive haemorrhage
–Severe trauma
–Pregnancy complications e.g. pre-eclampsia, placental abruption, amniotic fluid embolism
Pathophysiology of disseminated intravascular coagulation
Laboratory Investigations DIC
LOOK FOR UNDERLYING CAUSE
–sepsis, trauma, cancer, obstetric disaster
- Coagulation PT, APTT, Fibrinogen
- D-dimers
- FBC + film platelets, RBC fragments
Treatment of DIC
TREAT UNDERLYING CAUSE
FFP +/- platelets if bleeding or high risk for bleeding
? Heparin 300-500u/h if thrombotic phenotype
? AT concentrate (reduces mortality 56% -> 44%)
? Protein C concentrate (meningococcal sepsis)
? Activated Protein C
Two types of clotting factor disorders
Inherited
Acquired
Clinical features of Disseminated intravascular coagulation
- pyrexia
- Acute abdomen
- Paracolic abscess at laparotomy
Raised PT time
Raised APTT
Very elevated D-DImers
How to treat warfarin bleeding ?
Any patients with haemorrhage and a raised INR
- stop warfarin
- Give coagulation factors ( II, VII, IX, X)
Prothrombin complex concentrates
Dabigatran
Direct factor II
PT- no effect
APTT- if normal, insifnificant dabigatran effect
TCT- highly sensitive at very low concentration
Rivaroxaban
DIrect factor Xa inhibitor
PT- most sensitive (if normal, minimal rivaroxaban effect)
APTT not useful s non-linear
Coagulopathy in liver disease
Liver produces all the coagulation factors except for vWf
liver disease is therefore, associated iwith clotting factor deficiency and poor clearance
In addition, biliary obstrucion can lead to malabsorption and deficiency of fat-soluble vitamin K
Portal hypertension can lead to splenomegaly resulting in increased spelnic sequestration of plates - low WBC and plts
Haemophllia A
Deficiency
Pattern of inheritance
Diagnosis
Presentation
Management
Normal primary haemostasis
Deficiency of Factor VIII
Sex linked recessive disorder (X-linked recessive)
Diagnosos: Prolonged APTT - factors 8, 9 , 11, 12 and decreased factor 8
Presentation: depends on severity and is often in early life or after surgery/trauma - with bleeds into joints leading to criplling arthropathy and into muscles causing haematomas
Management: Avoid NSAIDs, IM injections. Minor bleeds- desmopressin, pressure elevation. Major bleeds (e,g haemarthosis) require factor VIII
Haemophillia B
Christmas disease
- factor IX deficiency
inherited, x-linked recessive
Von willebrand disease
Pattern of inheritance
Cause :
Clinical features
Diagnosis
Treatment
Autosomal dominant condition
Commonest inherited coagulopathy in the UK
Caused by quantitative or qualitative abnormality of vWF production
vWF is made on endothelial cells. It is the glue that sticks platelets to damaged subendothelium
Disease manifests with bruising, superficial purpura, menoorhagia, nose bleeds, bleeding from cuts and mucous membranes - think primary haemostatic problem!!
Diagnosis is made by
a. low factor VIII;c
b. low factor vWF: Ag
c. Prolonged bleeding time
d. deficient ristocetin-induced platelet aggregation
Treatment is with ddAVP if mld and with vWF concentrate
Types of von willebrand factor disease
Type 3- no von willebrand facor
Type 2- Qualitative( von willebrand factor present but not functional)
Type 1- Quantitave (Partial von willebrand functional, other half not)
Thrombophillia types
Congenital
1. Deficencies of:
- anti-thrombin III
- Protein C
- Protein S
- Abnormal prothrombin molecule (increases prothrombin levels_
- Dysfibrinogenaemia
- Fibrinolytic defects
- Factor V leiden mutation (renders factor V less sensitive to APC)
Acquired causes
- Polycythaemia Rubra vera and essentiial thrombocythaemia
- Lupus anticoagulant/antiphospholipid syndrome
Treatment of platelet disorders
- Pressure
- Tranexamic acid / Desmopressin [DDAVP]
- Platelet transfusion [HLA matched]
- rFVIIa
Definition of thrombophillia
Disorders if haemostasis that increase the tendancy of blood to clot
Prolonged APPT test
Inhibits the coagulation process
Prolonged APTT test
Give 50:50 diltion (ml patient and ml of normal APTT)
If factor deficiency is corrected then factor deificency
If partial correction then inhibitor of APTT process - known as a lupus anticoagulant
Lupus anti-coagulant
- Phospholipid dependent antibody
- Interferes with phospholipid dependent tests i.e. APTT
- APTT prolonged
- If persistent, may be associated with prothrombotic state
- Persisting Lupus anticoagulant + thrombosis [or recurrent fetal loss] =Antiphospholipid Syndrome
Testing for lupus anticoagulant
APTT – often prolonged
APTT 50:50 dilution – only partially corrects
DRVVT ratio prolonged
DRVVT ratio corrects with XS phospholipid
Warfarin
- extrinsic pathway
- monitor with the INR (international normalized ratio) test
- vitamin K-dependent pathway (vitamin K is a fat-soluble vitamin essential for the production of factors II, VII, IX and X; it enables the γ-carboxylation of the profactors to their active state)
- the peak effect of warfarin occurs 48 h after ingestion –
- warfarin has an early prothrombotic effect action as a result of its effects on proteins C + S (the body’s natural anticoagulants).
Heparin Important facts
- intrinsic pathway
- monitor with the APTT (activated partial thromboplastin time) test
- heparin potentiates the action of anti-thrombin 3 (which in turn activates thrombin and clotting factors VIII, IX, XI and XII)
- half-life 2 h – low-molecular-weight heparins do not prolong the APTT; they have a predictable anticoagulant effect and do not require monitoring unless in long-term use; in this case use the factor Xa assay to assess the degree of anticoagulation
- heparin-induced thrombocytopenia (HIT) is an immune reaction; it occurs in 5 per cent of patients and presets with thrombosis. Platelet activating arhibodies cause platelets to clump. This causes simultaneous thrombosis and thrombocytopaenia.
Thrombophillia definition
Disorders of haemostasis that increas the tendancy of bloot to clot.
