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8/14/2019 Coagulation Disorders.mansfans.com

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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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