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Coagulation Disorders

By
.Dr Maha El-Zaafarany Lecturer of Medical Oncology Oncology Center )Mansoura University )OCMU

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:These may be e

ither

1. Hereditary: usually due to deficiency of one the coagulation factors. 2. Acquired: usually due to involvement of several coagulation factors.

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HEREDIT ARY COA GUL AT ION DIS OR DERS
About 90% are due to factor VIII deficiency. Factor VIII is a complex protein made up of two components:
1. Factor VIII: C, a small protein molecule, synthesized in the reticuloendothelial system and concerned with coagulant activity. 2. Von Willibrand's factor (VIII; vWF): a larger protein molecule synthesized in vascular endothelium and megakaryocytes and detected immunologically as factor VIII:C www.MansFans.com

HAEMO PH EL IA A
This is an X-linked disorder which affects males and transmitted by female carriers. It is characterized by low or absent factor VIII:c.
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Cli nical p ic ture:
If the plasma level of factor VIII:C is more than 50% of normal, the disease manifests with post traumatic bleeding. Only levels less than 1% are associated with spontaneous bleeding from early life. Bleeding often occurs in joints and muscles.

1. Activated partial thromboplastin time (APTT) is prolonged. Bleeding and prothrombin times are normal. 2. Factor VIII: C assay reveals its decreased level which correlates with clinical severity of the disease. 3. Female carriers are identified by family history (daughters of heamophilics are obligate carriers), assessment of the ratio of factor VIII: C/VIII: vWF Ag and more recently by DNA analysis of factor VIII: gene. 4. Prenatal diagnosis of male carriers is possible by factor VIIIC assay in fetal blood or analysis of DNA from chorionic villous samples.

Inve st ig atrion:

Treatment :
1. Bleeding is treated by administration of factor VIII concentrates by IV injection. For minor bleeding, factor VIII level should be raised to 25% of normal and for severe bleeding to at least 50% for major surgery, it should be raised to 100% preoperatively and maintained above 50% until healing occur. 2. Desmopressin (deamino-D-arginin vasopressinDDAVP) increases the release of factor VIII: C by 23 folds. This may be adequate for mild bleeding.
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1. Oral anti-fibrinolytic e.g. tranexamic acid may aid haemostasis especially in mild cases. 2. Supportive measures include resting the affected part, narcotic analgesics and prevention of further trauma. Patients are advised to have regular conservative medical care and avoid body contact sports.

Complications of therapy :
1. Antibodies to factor VIII develop in 10% of severe cases, making them refractory to treatment. This may be helped by using massive doses of factor VIII, immunosuppression or even plasmapharesis. 2. Transmission of viral infection like hepatitis and human immunodeficiency virus (HIV). The use of recombinant factor VIII averts this problem. The risk is reduced by heat treatment of plasma. 3. Narcotic analgesic abuse. 4. Psychoneurosis.

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WILLEBRAND'S DISEASE

The disorder is due to inherited deficiency of von Willebrand's factor which is essential for normal platelet adhesion to damaged endothelium and for stabilizing factor VIII: C in plasma.www.MansFans.com

Cl ini cal pi cture:
there are three types
1. Type I and II are mild forms inherited as autosomal dominant and characterized by mucosal bleeding and prolonged bleeding after dental treatment or surgery. 2. Type III is a severe form, recessively inherited with clinical feature similar to haemophelia.

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Inve st ig atrion:
1. Prolonged bleeding time due to defective platelet adhesion. 2. Prolonged activated partial thromboplastin time as a result of deficiency of factor VIII: C whose half life is reduced when not bound to VIII: vWF. 3. Defective platelet aggregation with restocitin (an antibiotic that aggregate platelets only in presence of VIII: vWF). 4. Assay of factor VIII: C, VIII: vWF Ag reveals low values.

Treatment :
1. 2. For the mild forms: desmopressin (DDA VP) and tranexamic acid. For the severe form: Factor VIII or von Willebrand factor concentrates fresh frozen plasma.

CHR ISTMA S DI SEASE (HA EMO PHI LIA B)
• It is caused by factor IX deficiency. • Inheritance and clinical picture are similar to those of haemophilia A but incidence is much less. • Treated by factor IX concentrates.

ACQ UI RE D COAG UL AT IO N DISO RDE RS
Vitamin K deficiency:
Vitamin K is necessary for the gammacarboxylation of glutamic acid residues of factors II, VII, IX and X. This enables them to bind to phospholipid in presence of CA++ and exert their coagulation function.

Vitamin K deficiency may result from:
• Inadequate stores e.g. haemorrhagic disease of the newborn, protein energy malnutrition. • Malabsorption of vitamin K: obstructive jaundice. • Oral anticoagulants
Patients may present with bruising, haematuria, gastrointestinal and cerebral bleeding. Both PT and APTT are prolonged but TT is normal. Treatment: is with phytomenadione (Vit. K1) 10mg IV. Severe bleeding is treated with fresh plasma.

:Liver disease
This can result in coagulation abnormalities for a :variety of reasons
1. Hepatocellular damage results in decreased production of many coagulation factors. Vitamin K is not helpful but is generally given because of associated malabsorption. Occasionally, there is production of abnormal fibrinogen (dysfibrinogenamia). 2. Cholestasis leads to malabsorption of Vit. K. 3. Portal hypertension leads to splenomegaly with hypersplenism. 4. Acute hepatic failure leads to disseminated intravascular coagulation (DIC), defective degradation of activated coagulation factors and platelet abnormalities.

DIS SEMINAT ED I NTRAV ASCULA R CO AGULATI ON (DIC )
This occurs in a number of conditions that activate coagulation. The resulting thrombin aggregates platelets and deposit fibrin in the microcirculation with consequent consumption of coagulation factors and platelets Fibrinolysis is also stimulated producing fibrin degradation products (FDPs) which further inhibit platelet function and fibrin polymerization.

Ca use s :
1.Sepsis (commonest cause): gram-ve septicemia, meningococcal septicaemia. 2.Shock: hypovolaemic, anaphylactic. 3.Obstetric: amniotic fluid embolism, intrauterine fetal death, abruptio placentae. 4.Tissue factor release: severe trauma, burns, promyelocytic leukaemia, haemolytic transfusion reactions, acute pancreatitis. www.MansFans.com

Cli nical p ic ture :
DIC is more often subclinical and is merely a laboratory finding. In severe cases, widespread bruising and bleeding from mucous membranes and venepuncture sites occur. Although small vessel occlusions occur, clinically apparent thrombosis is not commonly detected.

Investigations :
1.Normocytic anaemia with red cell fragmentation due to passage through fibrin strands in small vessels. Thrombocytopenia occurs. 2.Prolonged PT, APTT and. The last being most affected. 3.Decreased serum fibrinogen level. 4.Elevated serum level of FDPs. However, these are also raised in major trauma, surgery and renal failure without DIC, so its value as a screening test for DIC is only when TT is markedly prolonged.

Treatment :
1. 2. 3. That of the underlying cause. Replacement of platelets, red cells and clotting factors by fresh frozen plasma and factor VIII concentrates. Heparin is no longer used except in low doses to prevent the disease during the induction therapy for acute promyelocytic leukaemia.

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Diagnosis of bleeding disorders:
1) History and examination: these indicate:  Whether bleeding is a local or generalized problem.  Type of bleeding: purpura and mucosal bleeding suggest a platelet disorder but confluent skin bruises, muscle haematoma and haemathrosis suggest a coagulation disorder.  Family history of bleeding tendency.  Detailed drug history.

2) Screening tests:
 Blood count and film to detect thrombocytopenia, abnormal platelet morphology. A cause of bleeding may be revealed e.g. disseminated intravascular coagulation (DIC) or acute leukaemia.  Bleeding time. It is prolonged in vascular wall and platelet defects and in von Willebrand’s disease.  Prothrombin time (PT). It is prolonged in defects of the extrinsic and common coagulation pathways.  Activated partial thromboplastin time (APTT). It is prolonged in defects of the intrinsic and common coagulation pathways.  Thrombin time (TT). It is prolonged with fibrinogen deficiency, dysfibrinogenaemia and coagulation inhibitors e.g. heparin and fibrin degradation products (FDPs).

3) Further tests
 If an abnormality is detected in the coagulation cascade, the test is repeated using 50/50 mixture of patient’s plasma and normal plasma. If full connection does not occur, it implies the presence of a coagulation inhibitor.  Specific factors can be measured functionally by the use of mixtures of patients serum and serum known to be deficient in a single factor. Thus if a prolonged APTT is obtained which is corrected by normal plasma, but not by plasma from a patient with factor IX deficiency, the patient is also deficient in factor IX. Some factors can also be measured immunologically.  Platelet aggregation studies to detect von-Willebrand’s factor activity and congenital platelet abnormalities.  Other tests include estimation of fibrinogen and fibrin degradation products (FDPs), assays of the coagulation factors and tests of the fibrinolytic pathway.

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