Bleeding Disorders Flashcards
what is haemophilia
the second most common inherited hemorragic disorder
what are the 2 types of haemophilia
A = decreased / deficient VIII B = decreased / deficient IX
what is the genetics for haemophilia A
1:10000 of the population (5 times more common than haemophilia B)
the gene which codes for FVIII is on the tip of he q arm of the X chromosome
Haemophilia results from mutations of this gene and its inherited as an X linked chromosomal disorder
what is the genetics for Haemophilia B
1:50000
the genes which encodes for the FIX is located on the terminus of the long arm of the x chromosome, close to fragile X locus and the FVIII gene
the basic approach and underlying principles of carrier detection and treatment are identical for both haemophilia A and B
what happens when the father has haemophilia
daughter of haemophiliac will inherit his X and be carrier
genetic defect causing haemophilia on that part of X chromosome not on Y.
Sons of a haemophiliac will not be affected as they inherit fathers y chromosome which does not carry the two genes
what happens when the mother is a carrier
chances carrier mother passing defective gene to a child are 50:50
each daughter has a 50:50 chance being a carrier
each son has the same chance of being a haemophiliac
what happens when there is a spontaneous mutation
in some 30% cases of haemophilia there is no known family history.
haemophilia is probably the result of spontaneous genetic mutation in these families
what are the pathophysiology of haemophilia
a shortage of clotting factor FVIII or FIX halts the chain reaction that is the coagulation cascade.
primary haemostatic is normal
substantial damage occurs from the formation of week clots which are highly susceptible to mechanical or finbrinolytic breakdown
haemorrhage in weight bearing joints
haemorrhage in weight bearing muscles
irreversible crippling oftern require joint replacements
cerebral bleeds
haematuria
nose bleeds
gastro intestinal hemorrhage
bleeding is not any faster but typically continues for longer periods and reoccurs several times
support, advice and treatment, avoiding injury, haemophiliacs lead a damage limitation lifestyle
what is the treatment for haemophilia
the defective factor is usually given, various on the market
desmopressin synthetic hormone which works by stimulating the production of FVIII
benefix engineered version of FIX
children are given preventative injections up to 3 times a week ensuring adequate levels
adults inject on injury
what are the inhibitors
as these drugs mimic the bodies own response 30% will go on a developed inhibitors
the lab must monitor inhibitors via “bethesda” assay at a 6 monthly intervals
inhibitor patients are given high dose FVIIa for bleeds and surgery
eradication of the inhibitor by high doses of FVIII and FIX in a process called immune tolerance
Describe the Von Willibrand disease
the most common inherited disorder 1% of the population
all bleeding histories, bruising and adnormal APTT are investigated for vWD
VIIIcirculates in combination with vW factor and serves to stabilise VIII from degradation
vW factor also seves to deliver FVIII to platelets at site of vascular injury
what are the genetics of vWD
autosomal dominant disease
extremely heterogeneous disorder with more than 20 sub types (variable phenotypic expression)
chromosome 12, occurs equally in males and females
three main types 1,2,3
what is the testing of vWD
any bleeding history prolonged bleeding time, low FVIII levels, high APTT
vWD screen; FVIII, vWF antigenadn ristocetin co factor
diagnosis is based on all three results and clinical analysis
if suspected three samples are tested at different intervals
what is the treatment vWD
DDAVP if responsive
replacement with von Willibrand concentrate
name three types of aquired disorders of haemostasis
liver disease
DIC
vitamin K deficiency
how does Vitamin K deficiency cause Haemostasis
Fat soluble produced in the gut by bacteria
Essential co-factor in the synthesis of factors FII, VII, IX , X and proteins C and S
Deficiency in vitamin K = deficiency in the above factors.
Accumulation of non functional proteins known as PIVKA’s
PIVKA’s – Proteins Induced by Vitamin K absence
Vitamin K dependent factors are synthesised in the liver as inactive precursors
Vitamin K is required for the carboxylation of the precursors glutamate residues to form carboxyglutamate.
what is the history of warfarin
Vitamin K deficiency in chickens results in bleeding
Drug Dicoumarol cause haemorrhagic disease in cattle
Warfarin used for many years
Inhibits factors FII, VII, IX, X proteins C and S
Mode of action : Block the vitamin K reductase and vitamin K epoxide reductase which in turn inhibits the gamma carboxylase
Result is accumulation of PIVKA’s
Inactive precursors = reduced clotting
Discoveries result in the synthetic production of Warfarin an antithrombotic treatment
how does liver disease cause haemo stasis
site of syntehsis for most common factors and for natural anticoagulants
involved in clearing activated factors and plasmin
what are the three types of liver disease
acute hepatocellular failure
chronic hepatocellular failure
obstructive jaundiced
what is acute hepatocellilar failure
failure to synthesis coagulation factors
increased risk of DIC and primary fibrinolysis
factor v levels correlate well with liver damage
vitamin K dependent proteins all reduced
thrombocytopenia common
what is chronic hepatocellular failure
thrombocytopenia platelet dysfunction failure to synthesis coagulation factors dysfibrinogaemia increased finbrinolytic activity severity of haemostatic disturbances = level of liver disease
how does obstrucive jaundiced cause problems
impairment of vitamin K dependent factors
circulating PIVKSs are earliest and most sensitive markers of hepatic failure
what is the treatment for haemostasis
vitamin K plasma or cryoprecipitate, platelets rFVIIIa desmopressin antiplatelet hypertension therapy
what is DIC
disseminated intravascular coagulation
what is disseminated intravascular coagulation
common complicaion of a wide range of disorders
characterised by widespread activation of all haemostatic mechanisms
haemorrhage, consumption of coagulation factors and platelets. thrombosis
coagulation cascade gets out of control
thrombosis ? formation of micro thrombi, throughout the microcirculation as a result of fibrinogen activation
ischemic damage
what can cause bleeding disorders
INFECTION/ SEPTICEMIA
any microorganism
triggered by membrane components of microorganism
TRAUMA and BURNS
soft tissue injury, fat embolism, head injury
combination of triggers : fat, phospholipids haemolysis, endothelial injury, activation of cytokines
MALIGNANCY
solid tumours, especially metastatic tumours and haemotologic
tissue factor, involved in mechanism
OBSTETRICAL COMPLICATIONS
abruptionplacenta, amniotic fluid embolism, retained deceased feotus, second trimester abortion
due to leakage of thromboplastin - like material
degree of placental seperation correlates with severity of DIC
usually short lived and self limited
VASCULAR DISORDERS
haemangioma, aortic aneurysm
local activation of coagulation leads to systemic depletion of factors; activated factors reach systemic circulation, causing DIC
ORGAN DESTRUCTION
pancreatitis, hepatic failure
TOXINS
snake bites drugs
IMMUNOLOGIC MEDIATORS
transfusion reaction, transplant rejections
what are the three mechanisms of DIC
release of tissue factor or progoagulant
damage to vascular endothelium= activation of the platelets, coagulation, fibrinolysis
direct activation of the platelets
what is the pathophysical of DIC
irrespective of the triggering mechanism the pathophysiology of DICis the same
systemic thrombin generation = activation of the coagulation cascade
deposition of micro thrombi
widespread occlusion of microcirculation
ischemic damafe = amplifies coagulation cascade
activation of the platelets= thrombocytopenia
drop in coagulation factors
depletion of circulating antithrombin
secondary fibrin deposition and local endothelial injury
secondary finbrinolysis
more plasmin generation
digestion of fibrinogen,FV VIII plasma proteins
fibrinogen degradation products increase (D Dimer)
complement= vascular permeability
hypotension and shock
paradoxical thrombohaemorraghic state
what are the signs and symptoms
DIC results from big stimuli or from a week sustained stimuli
DIC said to “breakout”
Both chronic and acute DIC are identical
Speed of recognition essential to preserve life
Bleeding, thrombosis, symmetrical cyanosis of extremities, organ failure.
Autopsy show diffuses bleeding haemorrhagic tissue damage, thrombi of small and larger vessels, fibrin deposition in organs, organ failure
what is the treatmetn DIC
Primary treatment = eliminate the triggering mechanism as quickly and as completely as possible
Replacement therapy and in some cases anticoagulant therapy
Replacement include FFP, cryoprecipitate valuable sources of coagulation factors and natural anticoagulants, platelets, red cells and human albumin solutions
? Heparin
Used to interrupt the coagulation cascade
Slow the consumption of platelets and secondary fibrinolysis
Restoration of haemostatic control
In extreme cases antithrombin concentrates may be helpful
