1. dr msaiem Acquired Coagulation Disorders Dr Mohammed Saiem Al-dahr KAAU Faculty of Applied Medical Sciences

2. dr msaiem Acquired coagulation disorders Objectives Following this lecture, the student will be able to Following this lecture, the student will be able to Explain the classification of acquired disorder of haemostasis such as: Explain the classification of acquired disorder of haemostasis such as: Hepatic disease, vitamin K deficiency, renal disease, Hepatic disease, vitamin K deficiency, renal disease,  Explain the action of oral anticoagulants Name the most common laboratory tests used to monitor oral anticoagulant therapy Name the most common laboratory tests used to monitor oral anticoagulant therapy List mechanisms and clinical conditions associated with DIC. List mechanisms and clinical conditions associated with DIC. Define the three generalized clinical states of DIC Define the three generalized clinical states of DIC Laboratory abnormalities associated with DIC. Laboratory abnormalities associated with DIC. Identify therapies for treatment of DIC Identify therapies for treatment of DIC

3. dr msaiem Acquired coagulation disorders The normal haemostasis is a normal balance carefully designed so that hemorrhage arrested and inappropriate thrombosis does not occur. The normal haemostasis is a normal balance carefully designed so that hemorrhage arrested and inappropriate thrombosis does not occur. Acquired disorders of haemostasis occur with many, systemic diseases, drugs, physical states pregnancy and newborns. Acquired disorders of haemostasis occur with many, systemic diseases, drugs, physical states pregnancy and newborns. Diagnosis depends on; Diagnosis depends on; Careful history Careful history Physical Examination Physical Examination Properly directed lab tests. Properly directed lab tests.

4. dr msaiem Acquired coagulation disorders The initial difficulty is to distinguish local bleeding e.g. peptic ulcer from systemic disease. The initial difficulty is to distinguish local bleeding e.g. peptic ulcer from systemic disease. An initial series of screening tests are performed easily and rapidly; An initial series of screening tests are performed easily and rapidly; Platelet count + Blood film Platelet count + Blood film Bleeding time (BT) Bleeding time (BT) Prothrombin Time (PT) Prothrombin Time (PT) Partial Thromboplastin Time (PTT) Partial Thromboplastin Time (PTT) Thrombin Time (TT) Thrombin Time (TT) Assessment of Fibrinogen Assessment of Fibrinogen

5. dr msaiem Acquired coagulation disorders If screening is suggestive, specific special investigations are performed to confirm, the diagnosis. If screening is suggestive, specific special investigations are performed to confirm, the diagnosis. The acquired disorders of haemostasis that will be discussed here include the following; The acquired disorders of haemostasis that will be discussed here include the following; Hepatic Disease Hepatic Disease Vitamin K deficiency Vitamin K deficiency Vitamin K Antagonists Vitamin K Antagonists Renal Disease Renal Disease DIC DIC

6. dr msaiem Acquired Coagulation Disorders Hepatic Disease The liver is the principal site of synthesis of pro- coagulant, fibrinolytic, and coagulation inhibitory proteins. The liver is the principal site of synthesis of pro- coagulant, fibrinolytic, and coagulation inhibitory proteins. Liver disorders present two challenges: Liver disorders present two challenges: 1-Decreased synthesis of coagulation, lysis and inhibitory proteins 2-Impaired clearance of activated haemostatic components. The type of disorder differs in neonates and adults. The type of disorder differs in neonates and adults.

7. dr msaiem Acquired coagulation disorders Neonates display decreased levels of plasma contact factors secondary to hepatic immaturity. Neonates display decreased levels of plasma contact factors secondary to hepatic immaturity. They also lack sufficient levels of Plasminogen and anti- Thrombin III. They also lack sufficient levels of Plasminogen and anti- Thrombin III. Neonates express a unique fetal fibrinogen that does not behave in the same manner as adult fibrinogen, and they have decreased of fibrinogen. Neonates express a unique fetal fibrinogen that does not behave in the same manner as adult fibrinogen, and they have decreased of fibrinogen.

8. dr msaiem Acquired coagulation disorders In adults, liver diseases, such as cirrhosis, hepatitis, and diseases that infiltrate liver tissue, such as neoplasm, affect the synthetic capacity of the liver. In adults, liver diseases, such as cirrhosis, hepatitis, and diseases that infiltrate liver tissue, such as neoplasm, affect the synthetic capacity of the liver. Prolongation of the PT is considered a sign of worsening disease because of depression vitamin K-dependent factor synthesis, poor dietary intake or mal-absorption of vitamin K. Prolongation of the PT is considered a sign of worsening disease because of depression vitamin K-dependent factor synthesis, poor dietary intake or mal-absorption of vitamin K. Fibrinolytic events and thrombocytopenia may accompany liver disease. Fibrinolytic events and thrombocytopenia may accompany liver disease.

9. dr msaiem Acquired Coagulation Disorders Laboratory Findings Screening tests such as the PT, APTT, TT, bleeding Time, platelet count, fibrinogen levels, and FDP determinations are used to monitor haemostatic status in liver disease patients. Screening tests such as the PT, APTT, TT, bleeding Time, platelet count, fibrinogen levels, and FDP determinations are used to monitor haemostatic status in liver disease patients.Therapy Infusion of fresh plasma may increase the circulating levels of pro-coagulants and minimize the hemorrhagic risk. Infusion of fresh plasma may increase the circulating levels of pro-coagulants and minimize the hemorrhagic risk.

10. dr msaiem 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 which is mediated by Vitamin K For coagulation factors (II, VII, IX, and X) to become active they have to bind Calcium. This is preceded by carboxylation which is mediated by Vitamin K Vitamin K Is fat soluble vitamin, stored in the liver in small amounts so can be depleted in 2-3 days 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 cannot carboxylate these coagulation factors. Patients with depleted vitamin K or on K antagonists cannot carboxylate these coagulation factors.

11. dr msaiem Acquired coagulation disorders Vitamin K is necessary co-factor for the conversion of terminal glutamic acid residues to gamma- carboxyglutamic acid on factors II, VII, IX, X, as well as on protein C & S Vitamin K is necessary co-factor for the conversion of terminal glutamic acid residues to gamma- carboxyglutamic acid on factors II, VII, IX, X, as well as on protein C & S This conversion takes place in the hepatocyte and is necessary for proper function. This conversion takes place in the hepatocyte and is necessary for proper function. Laboratory finding. PT prolonged PT prolonged PTT prolonged PTT prolonged Functional assays of vitamin K factors show low level Functional assays of vitamin K factors show low level

12. dr msaiem Acquired coagulation disorders Vitamin K Antagonists Oral anticoagulants Oral anticoagulants Mechanism of Action Mechanism of Action All the vita K-dependent coagulation proteins, (F II, VII, IX, X, proteins S and C) are characterized in their structure by specific chain where some glutamic acid residues undergo a gamma-carboxylation. All the vita K-dependent coagulation proteins, (F II, VII, IX, X, proteins S and C) are characterized in their structure by specific chain where some glutamic acid residues undergo a gamma-carboxylation. This gamma-carboxylation is vitamin K-dependent. This gamma-carboxylation is vitamin K-dependent. The presence of carboxylated groups is necessary for the binding of Ca ions required for the formation of the various activation complexes during the activation of the coagulation. The presence of carboxylated groups is necessary for the binding of Ca ions required for the formation of the various activation complexes during the activation of the coagulation.

13. dr msaiem Acquired coagulation disorders

14. dr msaiem Acquired coagulation disorders The classic oral anticoagulant (Warfarin) presents a structural similarity with vitamin K The classic oral anticoagulant (Warfarin) presents a structural similarity with vitamin K Therefore, these anticoagulant are able to inhibit the regeneration step of reduced vitamin K. Therefore, these anticoagulant are able to inhibit the regeneration step of reduced vitamin K. The inhibition of the reduced vitamin K by anticoagulants blocks the final synthesis step of these vitamin K dependent proteins. The inhibition of the reduced vitamin K by anticoagulants blocks the final synthesis step of these vitamin K dependent proteins.

15. dr msaiem Acquired coagulation disorders Laboratory The most common laboratory test to monitor oral anticoagulant therapy is the PT The most common laboratory test to monitor oral anticoagulant therapy is the PT It is sensitive to the decrease of factors II, VII, X. It is sensitive to the decrease of factors II, VII, X. PT does not reflect the effect of the drug on factor IX. PT does not reflect the effect of the drug on factor IX. To promote standardization of the PT for monitoring oral anticoagulant therapy, HWO has developed an international reference thromboplastin from human brain tissue and has recommended that the PT ratio expressed as the International Normalized Ratio (INR). HWO has developed an international reference thromboplastin from human brain tissue and has recommended that the PT ratio expressed as the International Normalized Ratio (INR). INR value for a plasma depends on the international sensitivity index (ISI). INR value for a plasma depends on the international sensitivity index (ISI).

16. dr msaiem Acquired coagulation disorders Renal Disease. In acute and chronic renal diseases there is often bleeding tendency associated several haemostatic abnormalities. In acute and chronic renal diseases there is often bleeding tendency associated several haemostatic abnormalities. Thrombocytopenia frequently develop in uremia Thrombocytopenia frequently develop in uremia Vitamin K deficiency due to malnutrition, associated liver disease with factor V deficiency. Vitamin K deficiency due to malnutrition, associated liver disease with factor V deficiency.

17. dr msaiem Acquired coagulation disorders Isolated factors IX and XII deficiency were reported in nephrotic syndrome Isolated factors IX and XII deficiency were reported in nephrotic syndrome excessive loss of these proteins in the urine. excessive loss of these proteins in the urine. Antithrombin III and plasminogen are also lost in nephrotic syndrome through increased urinary loss. Antithrombin III and plasminogen are also lost in nephrotic syndrome through increased urinary loss. Patients with renal disease commonly have: A prolonged bleeding time (BT) A prolonged bleeding time (BT) Prolonged PT and PTT Prolonged PT and PTT Low platelet count Low platelet count Anemia Anemia