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`
.Dr.Dr
Maha El-ZaafaranyMaha El-ZaafaranyLecturer of Medical OncologyLecturer of Medical Oncology
Oncology CenterOncology Center
)Mansoura University )OCMU)Mansoura University )OCMU
CoagulationCoagulationDisordersDisorders
By
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:These may be e i therThese may be e i ther1.1. Hereditary: usually due to deficiencyHereditary: usually due to deficiency
of one the coagulation factors.of one the coagulation factors.
2.2. Acquired: usually due to involvementAcquired: usually due to involvement
of several coagulation factors.of several coagulation factors.
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HEREDIT ARY COA GULAT IONHEREDIT ARY COA GULAT IONDIS ORDERSIS ORDERSAbout 90% are due to factor VIII deficiency.About 90% are due to factor VIII deficiency.
Factor VIII is a complex protein made up ofFactor VIII is a complex protein made up of
two components:two components:
1.1. Factor VIII: C, a small protein molecule, synthesized inFactor VIII: C, a small protein molecule, synthesized in
the reticuloendothelial system and concerned withthe reticuloendothelial system and concerned with
coagulant activity.coagulant activity.
2.2. Von Willibrand's factor (VIII; vWF): a larger proteinVon Willibrand's factor (VIII; vWF): a larger proteinmolecule synthesized in vascular endothelium andmolecule synthesized in vascular endothelium and
megakaryocytes and detected immunologically as factormegakaryocytes and detected immunologically as factor
VIII:CVIII:C www.MansFans.comwww.MansFans.com
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HAEMO PH EL IA AAEMO PH EL IA AThis is an X-linked disorder whichThis is an X-linked disorder which
affects males and transmitted byaffects males and transmitted byfemale carriers. It is characterizedfemale carriers. It is characterized
by low or absent factor VIII:cby low or absent factor VIII:c..
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Cli n i ca l p ic tu re :li n ic a l p ic t u re :If the plasma level of factor VIII:C is moreIf the plasma level of factor VIII:C is more
than 50% of normal, the disease manifeststhan 50% of normal, the disease manifests
with post traumatic bleeding. Only levelswith post traumatic bleeding. Only levels
less than 1% are associated withless than 1% are associated with
spontaneous bleeding from early life.spontaneous bleeding from early life.
Bleeding often occurs in joints and muscles.Bleeding often occurs in joints and muscles.
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I nves t iga t r i on :nves t iga t r i on :1.1. Activated partial thromboplastin time (APTT) isActivated partial thromboplastin time (APTT) is
prolonged. Bleeding and prothrombin times are normal.prolonged. Bleeding and prothrombin times are normal.
2.2. Factor VIII: C assay reveals its decreased level whichFactor VIII: C assay reveals its decreased level whichcorrelates with clinical severity of the disease.correlates with clinical severity of the disease.
3.3. Female carriers are identified by family historyFemale carriers are identified by family history(daughters of heamophilics are obligate carriers),(daughters of heamophilics are obligate carriers),assessment of the ratio of factor VIII: C/VIII: vWF Agassessment of the ratio of factor VIII: C/VIII: vWF Agand more recently by DNA analysis of factor VIII:and more recently by DNA analysis of factor VIII:
gene.gene.
4.4. Prenatal diagnosis of male carriers is possible by factorPrenatal diagnosis of male carriers is possible by factorVIIIC assay in fetal blood or analysis of DNA fromVIIIC assay in fetal blood or analysis of DNA fromchorionic villous samples.chorionic villous samples.
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Treatment :
1.1. Bleeding is treated by administration of factor VIIIBleeding is treated by administration of factor VIII
concentrates by IV injection. For minor bleeding,concentrates by IV injection. For minor bleeding,
factor VIII level should be raised to 25% of normalfactor VIII level should be raised to 25% of normal
and for severe bleeding to at least 50% for majorand for severe bleeding to at least 50% for major
surgery, it should be raised to 100% preoperativelysurgery, it should be raised to 100% preoperatively
and maintained above 50% until healing occur.and maintained above 50% until healing occur.
2.2. Desmopressin (deamino-D-arginin vasopressin-Desmopressin (deamino-D-arginin vasopressin-DDAVP) increases the release of factor VIII: C by 2-DDAVP) increases the release of factor VIII: C by 2-
3 folds. This may be adequate for mild bleeding.3 folds. This may be adequate for mild bleeding.
(Continue )
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1.1. Oral anti-fibrinolytic e.g. tranexamic acid mayOral anti-fibrinolytic e.g. tranexamic acid may
aid haemostasis especially in mild cases.aid haemostasis especially in mild cases.
2.2. Supportive measures include resting the affectedSupportive measures include resting the affected
part, narcotic analgesics and prevention of furtherpart, narcotic analgesics and prevention of furthertrauma. Patients are advised to have regulartrauma. Patients are advised to have regular
conservative medical care and avoid bodyconservative medical care and avoid body
contact sports.contact sports.
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Complications of therapy :
1.1. Antibodies to factor VIII develop in 10% of severeAntibodies to factor VIII develop in 10% of severe
cases, making them refractory to treatment. This maycases, making them refractory to treatment. This may
be helped by using massive doses of factor VIII, be helped by using massive doses of factor VIII,
immunosuppression or even plasmapharesis.immunosuppression or even plasmapharesis.
2.2. Transmission of viral infection like hepatitis andTransmission of viral infection like hepatitis and
human immunodeficiency virus (HIV). The use ohuman immunodeficiency virus (HIV). The use o
recombinant factor VIII averts this problem. The risk isrecombinant factor VIII averts this problem. The risk is
reduced by heat treatment of plasma.reduced by heat treatment of plasma.
3.3. Narcotic analgesic abuse.Narcotic analgesic abuse.
4.4. Ps choneurosis.Psychoneurosis.
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vonvon WILLEBRAND'S DISEASEWILLEBRAND'S DISEASE
The disorder is due to inheritedThe disorder is due to inherited
deficiency of von Willebrand's factordeficiency of von Willebrand's factor
which is essential for normal platelewhich is essential for normal platelet
adhesion to damaged endotheliumadhesion to damaged endothelium
and for stabilizing factor VIII: C inand for stabilizing factor VIII: C in
plasma.plasma.www.MansFans.comwww.MansFans.com
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Clinical picture:l ini c al pi cture:
1.1. Type I and II are mild forms inherited as autosomalType I and II are mild forms inherited as autosomal
dominant and characterized by mucosal bleedingdominant and characterized by mucosal bleeding
and prolonged bleeding after dental treatment orand prolonged bleeding after dental treatment or
surgery.surgery.
2.2. Type III is a severe form, recessively inherited withType III is a severe form, recessively inherited with
clinical feature similar to haemophelia.clinical feature similar to haemophelia.
there are three typesthere are three types
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I nves t iga t r i on :nves t iga t r i on :1.1. Prolonged bleeding time due to defective plateletProlonged bleeding time due to defective platelet
adhesion.adhesion.
2.2. Prolonged activated partial thromboplastin time as aProlonged activated partial thromboplastin time as a
result of deficiency of factor VIII: C whose half life isresult of deficiency of factor VIII: C whose half life is
reduced when not bound to VIII: vWF.reduced when not bound to VIII: vWF.3.3. Defective platelet aggregation with restocitin (anDefective platelet aggregation with restocitin (an
antibiotic that aggregate platelets only in presence ofantibiotic that aggregate platelets only in presence of
VIII: vWF).VIII: vWF).
4.4. Assay of factor VIII: C, VIII: vWF Ag reveals lowAssay of factor VIII: C, VIII: vWF Ag reveals lowvalues.values.
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Treatment :
1.1.
For the mild forms: desmopressin (DDAFor the mild forms: desmopressin (DDA
VP) and tranexamic acid.VP) and tranexamic acid.
2.2. For the severe form: Factor VIII or vonFor the severe form: Factor VIII or von
Willebrand factor concentrates freshWillebrand factor concentrates fresh
frozen plasma.frozen plasma.
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It is caused by factor IX deficiency.It is caused by factor IX deficiency.
Inheritance and clinical picture areInheritance and clinical picture aresimilar to those of haemophilia A butsimilar to those of haemophilia A but
incidence is much less.incidence is much less. Treated by factor IX concentratesTreated by factor IX concentrates..
CHR ISTMA S DI SEASEHR ISTMA S DI SEASE(HA EMO PHI LIA B)HA EMO PHI LIA B)
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Vitamin K is necessary for the gamma-Vitamin K is necessary for the gamma-
carboxylation of glutamic acid residues ocarboxylation of glutamic acid residues o
factors II, VII, IX and X. This enables them tofactors II, VII, IX and X. This enables them to
bind to phospholipid in presence of CA++ andbind to phospholipid in presence of CA++ and
exert their coa ulation function.exert their coagulation function.
ACQ UI RE D COAG UL AT IO NCQ UI RE D COAG UL AT IO NDISO RDE RSISO RDE RS
Vitamin K deficiency:Vitamin K deficiency:
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Inadequate stores e.g. haemorrhagicInadequate stores e.g. haemorrhagic
disease of the newborn, protein energydisease of the newborn, protein energymalnutrition.malnutrition.
Malabsorption of vitamin K: obstructiveMalabsorption of vitamin K: obstructive
jaundice.jaundice. Oral anticoagulantsOral anticoagulants
Vitamin K deficiency may result from:Vitamin K deficiency may result from:
Patients may present with bruising, haematuria,Patients may present with bruising, haematuria,
gastrointestinal and cerebral bleeding. Both PT andgastrointestinal and cerebral bleeding. Both PT andAPTT are prolonged but TT is normal.APTT are prolonged but TT is normal.
Treatment: is with phytomenadione (Vit. K1) 10mgTreatment: is with phytomenadione (Vit. K1) 10mg
IV. Severe bleeding is treated with fresh plasma.IV. Severe bleeding is treated with fresh plasma.
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This can result in coagulation abnormalities for aThis can result in coagulation abnormalities for a
:variety of reasons:variety of reasons
:Liver disease:Liver disease
1.1. Hepatocellular damage results in decreased production ofHepatocellular damage results in decreased production of
many coagulation factors. Vitamin K is not helpful but ismany coagulation factors. Vitamin K is not helpful but is
generally given because of associated malabsorption.generally given because of associated malabsorption.
Occasionally, there is production of abnormal fibrinogenOccasionally, there is production of abnormal fibrinogen(dysfibrinogenamia).(dysfibrinogenamia).
2.2. Cholestasis leads to malabsorption of Vit. K.Cholestasis leads to malabsorption of Vit. K.
3.3. Portal hypertension leads to splenomegaly withPortal hypertension leads to splenomegaly withhypersplenism.hypersplenism.
4.4. Acute hepatic failure leads to disseminated intravascularAcute hepatic failure leads to disseminated intravascular
coagulation (DIC), defective degradation of activatedcoagulation (DIC), defective degradation of activated
coagulation factors and platelet abnormalities.coagulation factors and platelet abnormalities.
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IS SEMINAT ED I NTRAV ASCULAS SEMINAT ED I NTRAV ASCULACOAGULATI ON (DIC )OAGULATI ON (DIC )This occurs in a number of conditions thatThis occurs in a number of conditions that
activate coagulation. The resulting thrombinactivate coagulation. The resulting thrombin
aggregates platelets and deposit fibrin in theaggregates platelets and deposit fibrin in themicrocirculation with consequent consumption omicrocirculation with consequent consumption o
coagulation factors and platelets Fibrinolysis iscoagulation factors and platelets Fibrinolysis is
also stimulated producing fibrin degradationalso stimulated producing fibrin degradation
products (FDPs) which further inhibit platelet products (FDPs) which further inhibit platelet
function and fibrin ol merization.function and fibrin polymerization.
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Ca use s :a u se s :1.1.Sepsis (commonest cause): gram-veSepsis (commonest cause): gram-ve
septicemia, meningococcal septicaemia.septicemia, meningococcal septicaemia.
2.2.Shock: hypovolaemic, anaphylactic.Shock: hypovolaemic, anaphylactic.
3.3.
Obstetric: amniotic fluid embolism,Obstetric: amniotic fluid embolism,
intrauterine fetal death, abruptio placentae.intrauterine fetal death, abruptio placentae.
4.4.Tissue factor release: severe trauma, burns,Tissue factor release: severe trauma, burns,
promyelocytic leukaemia, haemolyti promyelocytic leukaemia, haemolytitransfusion reactions, acute pancreatitis.transfusion reactions, acute pancreatitis.
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Cli n ica l p ic tu re :li n ic a l p ic t u re :DIC is more often subclinical and is merelyDIC is more often subclinical and is merely
a laboratory finding. In severe cases,a laboratory finding. In severe cases,
widespread bruising and bleeding fromwidespread bruising and bleeding from
mucous membranes and venepuncturemucous membranes and venepuncturesites occur. Although small vesselsites occur. Although small vessel
occlusions occur, clinically apparentocclusions occur, clinically apparent
thrombosis is not commonly detected.thrombosis is not commonly detected.
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Investigations :
1.1.Normocytic anaemia with red cell fragmentationNormocytic anaemia with red cell fragmentationdue to passage through fibrin strands in smalldue to passage through fibrin strands in small
vessels. Thrombocytopenia occurs.vessels. Thrombocytopenia occurs.
2.2.Prolonged PT, APTT and. The last being mostProlonged PT, APTT and. The last being most
affected.affected.
3.3.Decreased serum fibrinogen level.Decreased serum fibrinogen level.
4.4.Elevated serum level of FDPs.Elevated serum level of FDPs.
However, these are also raised in major trauma,However, these are also raised in major trauma,surgery and renal failure without DIC, so its valuesurgery and renal failure without DIC, so its value
as a screening test for DIC is only when TT isas a screening test for DIC is only when TT is
markedly prolonged.markedly prolonged.
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Whether bleeding is a local or generalizedWhether bleeding is a local or generalized
problem.problem.
Type of bleeding: purpura and mucosal bleedingType of bleeding: purpura and mucosal bleedingsuggest a platelet disorder but confluent skinsuggest a platelet disorder but confluent skin
bruises, muscle haematoma and haemathrosisbruises, muscle haematoma and haemathrosis
suggest a coagulation disorder.suggest a coagulation disorder.
Family history of bleeding tendency.Family history of bleeding tendency.
Detailed drug history.Detailed drug history.
Diagnosis of bleeding disorders:Diagnosis of bleeding disorders:
1) History and examination: these indicate:1) History and examination: these indicate:
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Blood count and film to detect thrombocytopenia,Blood count and film to detect thrombocytopenia,
abnormal platelet morphology. A cause of bleeding may beabnormal platelet morphology. A cause of bleeding may be
revealed e.g. disseminated intravascular coagulation (DIC)revealed e.g. disseminated intravascular coagulation (DIC)
or acute leukaemia.or acute leukaemia.
Bleeding time. It is prolonged in vascular wall and plateletBleeding time. It is prolonged in vascular wall and platelet
defects and in von Willebrands disease.defects and in von Willebrands disease.
Prothrombin time (PT). It is prolonged in defects of theProthrombin time (PT). It is prolonged in defects of the
extrinsic and common coagulation pathways.extrinsic and common coagulation pathways.
Activated partial thromboplastin time (APTT). It isActivated partial thromboplastin time (APTT). It is
prolonged in defects of the intrinsic and commonprolonged in defects of the intrinsic and common
coagulation pathways.coagulation pathways.
Thrombin time (TT). It is prolonged with fibrinogenThrombin time (TT). It is prolonged with fibrinogen
deficiency, dysfibrinogenaemia and coagulation inhibitorsdeficiency, dysfibrinogenaemia and coagulation inhibitors
e.g. heparin and fibrin degradation products (FDPs).e.g. heparin and fibrin degradation products (FDPs).
2) Screening tests:2) Screening tests:
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