Bleeding Disrders Flashcards
Causes of abnormal bleeding
- Vascular disorders
- Thrombocytopenia
- Defective platelet function
- Defective coagulation
Common symptoms of bleeding disorders
• Epistaxis
• Gingivalbleeds
• Bruising
• PurpuraorPetechiae
• Menorrhagia
• Jointbleeds
• Musclebleeds
• Chronicanaemia
Platelets /vessel wall diseases
-mucosal bleeding is common
-petechiae is common
-deep haematomas are rare
-persistent bleeding from skin cuts
-equal in both genders
Coagulation diseases
-rare mucosal bleeding
-rare petechiae
-deep heamatomas
-minimal bleeding from skin cuts
-more than 80% affected are males
2 types of bleeding disorders
• Quantitative (reduced number) ,(<150 x 109/L)
• Thrombocytopenia
• Qualitative (reduced function)
• Acquired
• Inherited (rare)
THROMBOCYTOPENIA
Thrombocytopenia
• QuantitativeDisorder
• Plateletcountbelow150x109/L • Mostcommonplateletdisorder • Mostcommonlyacquired
• Reducedproduction(moresevere)orincreaseddestruction
• Plateletcounts>50×109/L-donotleadtoclinicalproblems.
• Plateletcounts<30×109/L-bruisingandpurpuraandprolongedbleedingtimes. • Plateletcount<10×109/L-Clinicallysignificantspontaneousbleeding
Causes of thrombocytopia
• Conditions that cause systemic thrombosis
• Thrombotic thrombocytopenic purpura (TTP) • Disseminated intravascular coagulation (DIC)
• Cause consumption of platelets.
• Autoimmune diseases
• Immune thrombocytopenia (ITP)
• Form antibodies against platelets initiating their removal
• Drug-induced thrombocytopenia
• Heparin induced thrombosis (HIT)
• Vaccine-induce thrombosis and thrombocytopenia (VITT)
• Conditions that alter the bone marrow
• Aplastic anaemia
• Cancer and cancer treatments
• Infections
• Hypersplenism
• Removes too many platelets • Pregnancy
• Surgery
Inherited bleeding disorders
-they are qualitative disorders
-are rare
-they affect various platelet function eg:adhesion,secretion and aggregation
Examples of inherited bleeding disorders
Bernard-Soulier Syndrome
Glanzmann Thrombasthenia
Gray Platelet Syndrome
Hermansky-Pudlak Syndrome
Bernard-Soulier Syndrome
GPIb/XI deficiency
Glanzmann Thrombasthenia
AIIbb3 (GPIIb-IIIa) deficiency
Gray Platelet Syndrome
-granule deficiency
Hermansky-Pudlak Syndrome
Dense granule deficiency
ACQUIRED PLATELET DYSFUNCTION DISORDERS
• Qualitative Disorders
• Anti-platelet drugs e.g. Aspirin and Clopidogrel
work to inhibit platelet function
• These effects last for the life of the platelet, approximately 7 to 10 days.
• During this time, exposed platelets have reduced function and do not respond effectively.
• Anti-platelet drugs are often associated with increased bleeding risk.
COAGULATION RELATED BLEEDING DISORDERS
2 types:
• Quantitative (reduced amounts of coagulation factors) • Acquired
• DIC
• Vitamin K deficiency • Inherited
• Haemophilia A and B • VWD
• Qualitative (reduced function of coagulation factors) • Inherited
• VWD
DIC(acquired coagulation)
• Inappropriate activation of blood coagulation
• Generation and deposition of fibrin
• Microvascular thrombi form in
various organs
• Consumption and subsequent exhaustion of coagulation proteins and platelets
• Clinical features usually dominated by bleeding
• Caused by a wide variety of conditions such as trauma, shock, infection and pregnancy complications
Pathogenenis meaning
Development of for example a disease
Pathogenesis of DIC
Pro inflammatory cytokines are generated and monocytes are activated.
Bacteria cause up regulation of tissue factor aswell as the release of micro practicals expressing tissue factor activating coagulation
Cytokines cause the activation of endothelial cells=imparting anti coagulation mechanism and down regulates Fibrinolysis by generating increased amounts of plasminogen activator inhibitor
Vitamin k deficiency(acquired coagulation disorder)
Vitamin K serves as an essential cofactor for a carboxylase that catalyses carboxylation of glutamic acid residues on vitamin K-dependent proteins
• Key vitamin K-dependent proteins include:
• Coagulation factors: factors II (prothrombin), VII, IX and X
• Coagulation inhibitors: proteins C, S and Z
• Need carboxylation to be active
Vitamin k cycle
-Gamma carboxylated
2+ glutamic acid bind Ca ions
-Induces a shape change in Vitamins dependent proteins
-This then allowsthese proteins to bind phospholipids
CAUSES OF VITAMIN K DEFICIENCY
• Malabsorption of fat-soluble vitamins
• Oral anticoagulation therapy (e.g. warfarin)
• Liver disease – alters absorption
• Dietary deficiency associated with antibiotic treatment that destroys gut bacteria that can synthesize vitamin K
• Newborn infants have low levels of vitamin K and are at risk of intracranial bleeds – given vitamin K injections
LIVER DISEASE
The clotting factors that are produced by the liver are I, II, V, VII, IX and X and some FVIII
• The order in which the levels of these are reduced in liver disease is:
• VII - the earliest to be reduced
• II, X - next to be reduced
• I, V - these persist despite severe liver disease
• Patientswithliverdiseasethereforehaveprolonged prothrombin times
• PatientswithseverediseasewillhaveprolongedPT and APTT times
• Patients have a tendency to bleed
MASSIVE BLOOD LOSS/TRAUMA
• Defined as the loss of:
• One blood volume within a 24-hour period
• 50% blood volume loss within 3 hours
• Rate of loss of 150 ml/hour.
• Packed red blood cells contain very little plasma so patients usually given replacement clotting factors using fresh frozen plasma.
• Platelets and fibrinogen (cryoprecipitate) should be replaced as required.
• Surgical control of bleeding should be obtained as soon as possible
AUTO/ALLOIMMUNE COAGULATION DISORDERS
Caused by circulating antibodies to coagulation factors
• Alloantibodies to factorVIII occur in5-10% of haemophiliacs
Lupus anticoagulant
• Interferes with lipoproteins and the
phospholipid-dependant stages of coagulation
• Anti-phospholipidsyndrome–LA orAPS inhibitor
is detected in 10%of systemic lupus erythematosus(SLE)patients
Laboratory tests to check if the patient has acquired coagulation disorder
Platelet count :
1)liver disease=low
2)DIC=LOW
3)massive transfusion=low
4)Circulating anticoagulant=normal
Pt
Liver disease/DIC/massive transfusion/circulating anticoagulant =prolonged
Activated partial thromboplastin time
Prolonged for everything
Haemophilia
X chromosome-linked bleeding disorders
• Deficiency of FVIII is haemophilia A
• Deficiency of FIX is haemophilia B (Christmas disease)
• Prolonged and excessive bleeding
GENETICS OF HAEMOPHILIA
• HaemophiliaAandBareX-linkedrecessive–predominantlyaffectsmales
• GenesareclosetogetheronthelongarmoftheXchromosome.
• Deletionsaccountfor5%ofcasesframeshift,missenseandinversionsarealsoseen.
• ‘Flip’inversion-50%ofseverecases
• Femalecarrierswillhave variable levels of FVIII of FIX due to random inactivation of theX chromosome
HAEMOPHILIA B – FACTOR IX
• FactorIXisakeyfactorofthe INTRINSIC pathway
• WhydoesFIXdeficiencyresultina profound bleedingdisorder?
FIX activation to FIXaby thrombin
Amplification!
HAEMOPHILIA A – FACTOR VIII
• Inheritedbleedingdisorderresultingfromlowfunctionallevelsofbloodcoagulation factor VIII
• CausedbymutationsinthecoagulationfactorVIIIgene
• Mostcommonofthesevereinheritedbleedingdisorders
• (1caseper5,000male births)
• Bleedingepisodesmaybemorefrequentinchildhoodandadolescencethanin adulthood.
• Approximately10%ofcarrierfemalesareatriskforbleeding
HAEMOPHILIA - DIAGNOSIS
• Family history - Usually diagnosed in the neonatal or prenatal period.
• In sporadic cases (30%–40% of cases), the severe patients are diagnosed < 1 year
old because of mucosal or soft tissue haemorrhages, usually after trauma
• Haemophilia A is diagnosed in individuals with low factor VIII clotting activity in the
presence of a normal von Willebrand factor (VWF) level
• Molecular genetic testing of F8, the gene encoding factor VIII, identifies pathogenic variants in as many as 98% of individuals with haemophilia A
HAEMOPHILIA - SYMPTOMS
➢ General - Weakness and orthostasis
➢ Musculoskeletal(joints)
➢ Tingling, cracking, warmth, pain,
➢ Centralnervoussystem(CNS)
➢ Headache,stiff neck,vomiting,lethargy irritability, spinal cordsyndromes
➢ Gastrointestinal(GI)
➢ Haematemesis, abdominal pain
➢ Genitourinary
➢ Haematuria,post-circumcisionbleeding
➢ Excessivebleeding with routinedental procedures
Lab tests for haemophilia
Abnormal
• Activated Partial Thromboplastin Time (APTT) - increased
• Factor VIII/FIX clotting assay – Low
Normal
• VWF levels normal and normal function
• Plateletcount
• Prothrombintime(PT)
• Platelet function analysis (PFA-100)
HAEMOPHILIA - TREATMENTS
• Severe–concentratedfactorsusually prophylactically to prevent bleeds
• Moderate–concentratedfactorswhenneeded • DDAVP(Desmopressin)whichinducesashort
term rise in FVIII and von Willebrandfactor • Prothrombincomplexconcentrates(FIX)
• Mild –DDAVPorProthrombinconcentrateswhen compromised ie surgical procedures
Von willebrands disease(inheritd)
• Most common hereditary coagulation abnormality affecting ~1% of the population
• QuantitativeorqualitativedefectinvonWillebrandfactor
• Divided into three major categories
1. Type I – Partial quantitative vWF deficiency
2. Type II – Qualitative vWF deficiency
3. TypeIII -TotalvWFdeficiency
• Affects individuals of all ethnic backgrounds, and the clinical symptoms can present at any age
VON WILLEBRANDS FACTOR (VWF)
• VWF is a large multimeric glycoprotein.
• Synthesised by endothelial cells and in megakaryocytes
• Endothelial cells are the main source of circulating VWF
• Mature VWF is stored as Weibel-Palade bodies in endothelial cells
and in the alpha granules of platelets
• VWF is important for both PRIMARY and SECONDARY Haemostasis
• Primary: Serves as a bridge between GPIb/IX receptors on activated
platelets and subendothelial collagen exposed when the vessel is injured
• Secondary: Complexes and stabilises FVIII in plasma
VON WILLEBRANDS DISEASE (VWD) - CLASSIFICATION
• Type 1: mild to moderate quantitative deficiency of VWF
• Type 3: severe quantitative deficiency of VWF
• Type 2: qualitative deficits in VWF.
• Types 1, 2A, 2B, and 2M autosomal dominant trait
• Type 3 and 2N is inherited as autosomal recessive
Symptoms of VWD
• Nosebleeds (epistaxis) and haematomas
• Easy bruising - common but nonspecific
• Prolonged bleeding - after minor trauma to skin or mucous membranes
• Oralcavitybleeding
• Excessive menstrual bleeding (menorrhagia)
• Improvement of bleeding symptoms with use of oral contraceptives
• Gastrointestinal bleeding (but rarely occurs)
• Delayed bleeding - may occur up to several weeks after surgery
• Exacerbation of bleeding symptoms - After ingestion of aspirin
Lab finding for vwd
Abnormal
• Plateletfunctionanalysis(PFA)–prolonged
• VWF levels low or abnormal function
• Activated Partial Thromboplastin Time (APTT) – normal or increased
• Factor VIII clotting assay – may be slightly reduced
Normal
• Factor IX assay
• Plateletcount
• Prothrombintime(PT)
Lab assays for vwd
• Quantitative – VWF:Ag assay
• Determines the level VWF in the blood by measuring the vWF protein (antigen)
• Measures the concentration of VWF, gives no indication as to function.
• Typically by ELISA or immunoassays
• Qualitative - VWF activity (Ristocetin Induced Platelet Aggregation)
• Multimer analysis – differential diagnosis (distinguish between different types of VWD)
VON WILLEBRANDS ACTIVITY ASSAY
• Ristocetin–bindstoVWFandplateletGPIbtocause agglutination
• Ristocetinusedasanantibioticuntilitwasrecognisedto causethrombocytopenia
• RistocetinCofactor[vWF:RCo]assay
measures the ability of a patient’s plasma to agglutinateplateletsinthepresenceof theantibiotic Ristocetin.
• TherateofRistocetininducedagglutinationis relatedtothe concentrationandfunctional activity of the plasma von Willebrand factor.
VON WILLEBRANDS DISEASE – MULTIMER ANALYSIS
Absence of multimers depending on the type of disease
VON WILLEBRANDS DISEASE (VWD) - TREATMENT
• TwomaintreatmentoptionsforpatientswithvonWillebranddisease(vWD)
• Desmopressin (DDAVP)
• von Willebrand factor/factor VIII (vWF/FVIII)concentrates
• DDAVPcausesthereleaseofVWFfromWeibelPaladebodies
• PlatelettransfusionsmaybehelpfulinsomepatientswithvWD(eg,type3)
• CryoprecipitateandfreshfrozenplasmacontainfunctionalvonWillebrandfactor(vWF) but should be avoided if at all possible because of the potential transmission of viral disease.
