1. Dr. Ahmed Hassaneen
Coagulation disorders

2. Clinical differences between diseases of platelets/vessel wall and of coagulation factors.

3. ►Haemophilia A (factor VIII deficiency)
Hereditary coagulation disorders
● Hereditary deficiencies of each of the coagulation factors have been described. The most frequent are :
►Haemophilia A (factor VIII deficiency)
►Haemophilia B (Christmas disease, factor IX deficiency).
►von Willebrand disease (VWD)
■ Other disorders are rare.

4. Hemophilia A
Hemophilia A is the most common of the hereditary clotting factor deficiencies.
Prevalence: 30 – 100 per million population.
Inheritance : sex - linked but up to one - third of patients have no family history and result from recent mutation.
Molecular genetics
The factor VIII gene is situated near the tip of the long arm of the X chromosome and consists of 26 exons.
The defect is an absence or low level of plasma factor VIII.
Approximately half of the patients have missense or frame shift mutations or deletions in the factor VIII gene.

5. In others a characteristic ‘flip - tip’ inversion is seen in which the factor VIII gene is broken by an inversion at the end of the X chromosome. This mutation leads to a severe clinical form of hemophilia A.
Clinical features:
1-Infants may develop profuse post – circumcision hemorrhage.
2-Joint and soft tissue bleeding and excessive bruising occur when they start to be active and walk.
3-Recurrent painful hemarthroses and muscle hematomas occur in severely affected patients and if inadequately treated lead to progressive joint deformity and disability.

6. 4- Prolonged bleeding occurs after dental extractions.
5-Spontaneous hematuria and gastrointestinal hemorrhage.
6-The clinical severity of the disease correlates inversely with the factor VIII level.
7-Spontaneous intracerebral hemorrhage , although not common, occurs more frequently than in the general population and is an important cause of death in patients with severe disease.

7. Hemophilic pseudotumours :
Large encapsulated hematomas with progressive cystic swelling from repeated hemorrhage.
They are best visualized by magnetic resonance imaging (MRI).
Occur in large muscles , long bones and pelvic bones.

8. Correlation of coagulation factor activity and disease severity in Haemophilia A or B .

9. Laboratory findings:
1- Activated partial thromboplastin time (APTT):Prolonged
2- Prothrombin time (PT) : Normal
3- Bleeding time : Normal
4- Platelet function analysis (PFA - 100) : Normal.
5- Factor VIII assay : Low level

10. Hemarthrosis in right knee

11. Factor IX deficiency (Hemophilia B, Christmas disease): ● The inheritance and clinical features of factor IX deficiency (Christmas disease, hemophilia B) are identical to those of hemophilia A. ● Factor IX is coded by a gene close to the gene for factor VIII near the tip of the long arm of the X chromosome ● The two disorders can only be distinguished by specific coagulation factor assays. ● The incidence is one - fifth that of hemophilia A. ● Its synthesis, like that of prothrombin , factor VII, factor X and protein C , is vitamin K - dependent.

12. Laboratory findings
1- Activated partial thromboplastin time (APTT):Prolonged
2- Prothrombin time (PT) : Normal
3- Bleeding time : Normal
4- Platelet function analysis (PFA - 100) : Normal.
5- Factor IX assay : Low level

13. Von Willebrand disease
● In this disorder there is either a reduced level or abnormal function of von Willebrand factor (VWF) as a result of mutation.
● It is the most common inherited bleeding disorder.
● The inheritance is autosomal dominant.
● VWF is produced in endothelial cells and megakaryocytes.
● It has two functions:
1-Promotes platelet adhesion to subendothelium.
2-It is the carrier molecule for factor VIII, protecting it from premature destruction. The latter property explains the reduced factor VIII levels found in VWD.
● Chronic elevation of VWF is part of the acute phase response to injury, inflammation, neoplasia or pregnancy.

14. ● Three types of VWD have been described (Table) .
Type 1 (Partial quantitative deficiency) accounts for 75% of cases.
Type 2 (Functional abnormality) is divided into 4 subtypes depending on the type of functional defect.
Type 3 (Complete quantitative deficiency)
Clinical picture:
▪ The severity of the bleeding is highly variable.
▪ Women are worse affected than men at a given VWF level.
▪ Typically, there is mucous membrane bleeding (e.g. epistaxis, menorrhagia), excessive blood loss from superficial cuts and abrasions, and operative and post – traumatic hemorrhage.
▪ Hemarthroses and muscle hematomas are rare, except in type 3 disease.

16. Laboratory findings
1-The PFA test and bleeding time is abnormal.
2- VWF levels are usually low.
3- Factor VIII levels are often low.
4- The APTT may be prolonged.
6- Defective platelet aggregation by patient plasma in the presence of ristocetin.
7-Aggregation to other agents (adenosine diphosphate (ADP), thrombin or adrenaline) is usually normal.
8- Collagen - binding function is usually reduced.
9- Multimer analysis is useful for diagnosing different subtypes.
10- The platelet count is normal except for type 2B disease (where it is low).

17. Hereditary disorders of other coagulation factors
►They include :
Deficiency of : fibrinogen, prothrombin , factors V, VII, combined V and VIII, factors X, XI, XIII).
► All of them are rare.
► The inheritance is autosomal recessive in all except for factor XI deficiency where it is variable.
► Factor XI deficiency is seen mainly in Ashkenazi Jews.

19. Acquired coagulation disorders
●The acquired coagulation disorders are more common than the inherited disorders.
● Unlike the inherited disorders, multiple clotting factors deficiencies are usual.
Vitamin K deficiency
Vitamin K is obtained from green vegetables and bacterial synthesis in the gut.
Deficiency may present in the newborn (hemorrhagic disease of the newborn) or in later life.
Caused by an inadequate diet, malabsorption or inhibition of vitamin K by drugs such as warfarin which act as vitamin K antagonists.

20. Hemorrhagic disease of the newborn
Vitamin K - dependent factors are low at birth and fall further in breast - fed infants in the first few days of life.
♦ Causes of low level of Vitamin K in newborn :
1-Liver cell immaturity.
2-Lack of gut bacterial synthesis of the vitamin.
3-Low quantities in breast milk.
Hemorrhage usually occurs on the second to fourth day after birth.
Diagnosis
1- The PT and APTT are both abnormal.
2- The platelet count and fibrinogen are normal.

21. Liver disease
Multiple haemostatic abnormalities contribute to a bleeding tendency in liver diseases:
1-Biliary obstruction results in impaired absorption of vitamin K and therefore decreased synthesis of factors II, VII, IX and X by liver cells.
2 -With severe hepatocellular disease, in addition to a deficiency of these factors, there are often reduced levels of factor V and fibrinogen.
3-Functional abnormality of fibrinogen (dysfibrinogenaemia) is found in many patients.
4- Disseminated intravascular coagulation (DIC) may occur due to release of thromboplastins from damaged liver cells.

22. Disseminated intravascular coagulation (DIC)
Widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets occurs as a consequence of many disorders that release procoagulant material into the circulation or cause widespread endothelial damage or platelet aggregation.
It may be associated with a severe hemorrhagic or thrombotic syndrome with organ dysfunction.
The main clinical presentation is bleeding but 5 – 10% of patients manifest thrombotic lesions (e.g. with gangrene of limbs).

23. Causes of disseminated intravascular coagulation (DIC)

24. Pathogenesis:
The key event is increased activity of thrombin in the circulation that exceeds its normal rate of removal by natural anticoagulants. This can result from :
1-Tissue factor (TF) release into the circulation from damaged tissues e.g in malignancy.
2- Entry of procoagulant material into the circulation in the following situations: Severe trauma, amniotic fluid embolism, acute promyelocytic leukemia , severe falciparum malaria , and some snake bites.
3-May also be initiated by widespread endothelial damage and collagen exposure (e.g. endotoxaemia) and severe burns.

25. ● Intravascular thrombin formation in large amounts → deposition of fibrin in the microcirculation →depletion of fibrinogen and all coagulation factors. ● Intravascular thrombin also causes widespread platelet aggregation in the vessels (platelets consumption).

27. Clinical features
These are usually dominated by bleeding, particularly from venepuncture sites or wounds.
There may be generalized bleeding in the lungs, urogenital tract and in obstetric cases.
Laboratory findings

28. Tests of hemostasis 1- The platelet count is low
Tests of hemostasis 1- The platelet count is low. 2- Fibrinogen concentration low. 3- High levels of fibrin degradation products such as D - dimers are found in serum. 4- The PT and APTT are prolonged 5-Bleeding time is prolonged 6- The thrombin time is prolonged. Note: In many acute syndromes the blood sample may even fail to clot in the lab. because of severe fibrinogen deficiency.

30. Please send your feedback : a.hassaneen@sr.edu.sa