Tabuk University

Faculty of Applied Medical SciencesDepartment Of Medical Lab. Technology

3rd Year – Level 5 – AY 1434-1435

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HEMATOLOGY – 2, MLT 307

Coagulation disorders(Coagulopathies)

By/Dr. Walid ZAMMITI; Phd

M.Sc; MLT

Objectives

Following this lecture, the student will be able to • Explain the classification of disorders of

haemostasis.• Hereditary coagulation disorders and acquired

disorders such as Hepatic disease, vitamin K deficiency, hemorrhagic disease of newborn, ....

• List mechanisms of DIC.• Laboratory abnormalities associated with DIC.

Coagulopathies

• Aquired: -Deficiencies of the vitamin K dependent coagulation factors (FII, VII, IX, X) -Hepatic disorders -Accelerated destruction of blood coagulation (DIC) -Inhibitors of coagulation-Hemorrhagic disease of newborn-Oral anti-coagulants (warfarin – inhibit Vit. K factors ) -Others (massive transfusion, etc)

• Hereditary: deficiency or abnormality of a

single coagulation factor.

– Hemofilia A (FVIII)– Hemofilia B (FIX)– Hemophilia C (FXI)– Von Willebrand’s disease– Rare coagulopathies (FI. II. V. VII. X. XI. XIII deficiency)

Hereditary Coagulation Disorders

HaemophiliaA bleeding disorder in which clotting factor in a person's blood plasma is missing or is at a low level.

Prevalence:Haemophilia A = factor VIII deficiency: 105/million menHaemophilia B = factor IX deficiency (Christmas disease): 28/million menHaemophilia C = factor XI deficiency : rare

• In haemophilia, VIII, XI or IX clotting factor is missing, or the level of that factor is low.

• This makes it difficult for the blood to form a clot, so bleeding continues longer than usual.

The hemophilia gene is carried on the X chromosome in males who lack a normal allele, the defect is manifested by clinical haemophilia. Women may be carriers.

Clinical features• Post-circumcision haemorrhage in infants.• Joint and soft tissue bleeds•Bleeding after dental extractions.• Spontaneous haematuria and gastrointestinal

haemorrhage.•The clinical severity of the disease correlates with the

extent of the factor deficiency.

Joint bleedingAs blood fills the capsule, the joint swells and becomes painful and hard to move.

The most common joint bleeds happen in ankles, knees, and elbows. Bleeds into other joints can also happen.

Other types of bleeding: subcutaneous, intramuscular hematomas, gastrointestinal bleeding, hematuria, cerebral hemorrhage

Lab. diagnosis

• An initial series of screening tests are performed easily and rapidly;

• Platelet count, Blood film, BM• Bleeding time (BT)• Prothrombin Time (PT)• Partial Thromboplastin Time (PTT)• Thrombin Time (TT)• Assessment of Fibrinogen

• If screening is suggestive, specific special investigations are performed to confirm, the diagnosis.

Hemophilia A** hereditary disease with serious bleeding

*X-linked recessive but in 33% , no family history (new mutations).

*15% of severe cases develop factor VIII inhibitors*↓ amount or activity of factor VIII

*factor VIII = cofactor for activation of factor X in the coagulation cascade

*Symptoms usually develop in severe cases (factor VIII <1% of normal) – hemoarthrosis, bruising, hemorrhage after trauma or surgery or spontaneous bleeding in sever deficiency)

* Hemophilia B FIX deficiency : similar to Hemophilia A in clinical presentation

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Hemophilia C• Hereditary deficiency of FXI.• Affecting Jewish mostly.• Unlike with hemophilia A and B, the frequency of bleeding with

hemophilia C is not determined by the patient’s factor level.• Individuals with hemophilia C do not commonly bleed

spontaneously

Von Willebrand Factor

*VWF is produced in endothelial cells and megakaryocytes.*It has 2 roles: - it promotes platelet adhesion to damaged endothelium - it is the carrier molecule for factor VIII, protecting it from

premature destruction. *elevated in injury, inflammation, neoplasia or pregnancy.

Von Willebrand Disease

*Quantitative or qualitative abnormalities of vWF* Mild bleeding*TYPE I =Most common (75% of all cases)* Prolonged bleeding time but normal platelet count*↓Plasma vWF levels*Secondary ↓ in Factor VIII levels

Von Willebrand Disease (vWD)

Type 1:

- partial quantitative deficiency of vWF

- mucocutaneous bleeding

- hematology consult prior to surgery

- prolonged bleeding time, normal platelet count

Von Willebrand Disease (vWD)

Type 2: qualitative alterations in the vWF structure & function : it is 4 types (A,B,M,N)

Type 3: least common and most severe Complete absence of vWF in plasma Autosomal recessive

Diagnosis of vWD

Bleeding time: prolongedFactor VIII levels: are often lowVWF levels: lowPT: normal. APTT: prolongedPlatelet count : normal except for type2 B disease (low)Platelet aggregation in the presence of ristocetin: impaired.

Hemophilia ALaboratory investigations

-Prolonged PTT – corrects on mixing with normal plasma.

-Normal PT-Normal TT-Normal platelet count-Factor VIII level-decreased

Hemophilia BLaboratory investigations

*Prolonged PTT – corrects with mixing with normal plasma

*Normal PT* Normal TT* Normal platelet count*Factor IX levels – decreased

Differential Diagnosis of Prolonged PTT

- Haemophilia B-Factor XI or XII deficiency – BUT Factor XII deficiency is NOT associated with abnormal bleeding - von Willebrand Disease- Inhibitors to factors VIII, IX, XI, XII- Lupus anticoagulant – associated with thrombosis and not

bleeding

Acquired Coagulation Disorders

Acquired Coagulation Disorders

**Hepatic Disease• The liver is the principal site of synthesis of pro-coagulant,

fibrinolytic, and coagulation inhibitory proteins.

• Pathophysiology of bleeding in liver disease: 1- Deficient or absent synthesis of clotting factors (II,VII,IX, and X). 2- Decreased thrombopoietin production. 3- Dysfibrinogenemia. 4- Thrombocytopenia due to associated hypersplenism 5- Platelet dysfunction

Laboratory diagnosis of hepatic disease

- PT, PTT, TT all prolonged - Decrease in all clotting factors except VIII

Acquired coagulation disorders

**Vitamin K Deficiency• For coagulation factors (II, VII, IX, and X) to become active

they have to bind Calcium. This is preceded by carboxylation (glutamic acid ) which is mediated by Vitamin K

• Vitamin K is necessary co-factor for the conversion of terminal glutamic acid residues to gamma-carboxy glutamic acid on factors II, VII, IX, X

• This conversion takes place in the hepatocyte and is necessary for proper function.

Acquired coagulation disorders

Vitamin K• Is fat soluble vitamin, stored in the liver in small amounts

so can be depleted in 2-3 days

• Patients with depleted vitamin K or on K antagonists can not carboxylate these coagulation factors.

• Causes of vit K deficiency : Hemorrhagic disease of the newborn malabsorption nutritional deficiency drugs

Acquired coagulation disorders

Laboratory finding in vit.K deficiency• PT prolonged• PTT prolonged• Functional assays of vitamin K dependent factors

show low level

Disseminated Intravascular Coagulation (DIC)

*widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets, occurs as a consequence of many disorders.

*Associated with bleeding but some cases(5%) manifested with thrombosis.

*The key event is increased activity of tissue factor.

Causes of DIC

*Obstetric*Infections*Neoplasia*Hematologic malignancies e.g. APL,

AML-M3*Vascular disorders*Massive tissue injury

Laboratory diagnosis of DIC

*PT, PTT and TT are prolonged*Platelet count is reduced*Fibrinogen is decreased*FDP’s are increased*Blood film shows : Fragmentation, Polychromasia, Hemolytic

anemia

Hemorrhagic disease of newborn

*Vitamin K-dependent factors are low at birth and fall further in breast-fed infants in the first few days of life.

*Liver cell immaturity, lack of gut bacterial synthesis of the vitamin K and low quantities in breast milk may all contribute to a deficiency which may cause hemorrhage, usually on the second to fourth day of life

:*Diagnosis-The PT and APTT are both abnormal. The platelet count is normal with

absent fibrin degradation products .

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THANK you