Tabuk University

1. Tabuk University Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3rd Year – Level 5 – AY 1434-1435 Hematology – 2, MLT 307

2. Coagulation disorders (Coagulopathies) By/ Dr. Walid ZAMMITI; Phd M.Sc; MLT

3. 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.

4. Coagulopathies • Aquired: -Deficiencies of the vitamin K dependentcoagulation 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)

5. Hereditary Coagulation Disorders

6. Haemophilia A 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 men Haemophilia B = factor IX deficiency (Christmas disease):28/million men Haemophilia C = factor XI deficiency : rare

8. 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.

9. 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.

10. Joint bleeding As 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.

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

14. Lab. diagnosis • An initial series of screeningtests 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.

15. 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

16. Hemophilia C • Hereditary deficiency of FXI. • Affecting Jewishmostly. • 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

17. 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.

18. 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

19. Von Willebrand Disease (vWD) Type 1: - partial quantitative deficiency of vWF - mucocutaneous bleeding - hematology consult prior to surgery - prolonged bleeding time, normal platelet count

20. 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

21. Diagnosis of vWD Bleeding time: prolonged Factor VIII levels: are often low VWF levels: low PT: normal. APTT: prolonged Platelet count : normal except for type2 B disease (low) Platelet aggregation in the presence of ristocetin: impaired.

22. Hemophilia ALaboratory investigations -Prolonged PTT – corrects on mixing with normal plasma. -Normal PT -Normal TT -Normal platelet count -Factor VIII level-decreased

23. Hemophilia BLaboratory investigations *Prolonged PTT – corrects with mixing with normal plasma *Normal PT * Normal TT * Normal platelet count *Factor IX levels – decreased

24. 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

25. Acquired Coagulation Disorders

26. 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 thrombopoietinproduction. 3- Dysfibrinogenemia. 4- Thrombocytopenia due to associated hypersplenism 5- Platelet dysfunction

27. Laboratory diagnosis of hepatic disease - PT, PTT, TT all prolonged - Decrease in all clotting factors except VIII

28. 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-carboxyglutamic acid on factors II, VII, IX, X • This conversion takes place in the hepatocyte and is necessary for proper function.

29. 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

30. Acquired coagulation disorders Laboratory finding in vit.K deficiency • PT prolonged • PTT prolonged • Functional assays of vitamin K dependent factors show low level

31. 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.

32. Causes of DIC *Obstetric *Infections *Neoplasia *Hematologic malignancies e.g. APL, AML-M3 *Vascular disorders *Massive tissue injury

33. 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

34. 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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