1. Bleeding disorders.
By Dr Abiodun Mark .A

3. HEMOSTASIS.
Hemostasis is defined as the series of event leading to cessation of bleeding by the formation of a fibrin stable haemostatic plug.
The haemostatic process involves an interplay between: -platelets -vascular wall -coagulation system.

4. Classification of Hemostasis.
● Primary hemostasis: initial step of forming platelet plug to stop bleeding from damaged vessel ● Secondary hemostasis: platelet plug is reinforced by fibrin clot; then fibrin clot is stabilized by activated factor XIII, which cross-links fibrin strands ● Tertiary hemostasis: as fibrin clot is formed, plasmin is generated to break down the clot

5. PLATELETS.
They are derived from the megakaryocytes of the bone marrow.
Normal count in peripheral blood smear k.
Decreased levels is referred to as thrombocytopenia.
Increased platelet count is referred to as thrombocytosis.
During hemostasis platelets undergo adhesion, activation and aggregation.

7. Vascular wall
The inner walls of blood vessel is lined by endothelial cells.
Endothelial cells modulate several frequently opposing aspects of hemostasis. Ecs normally have an antiplatelet ,anticoagulant and fibrinolytic abilities.
But with an injury or after activation, they exhibit procoagulant function.

9. Coagulation cascade.
This is a sequence of conversion of inactive pro-enzymes into active enzymes, culminating in the generation of insoluble fibrin from soluble plasma protein fibrinogen.
Traditionally the coagulation cascade is divided into the extrinsic and intrinsic pathways which both culminates at the activation of factor X

11. Coagulation factors.
Majority of the coagulation factors are produced by the liver.
The factors are pro-enzymes that must be converted to active forms.
Some of the conversion process require phospholipids and calcium (factor iv)

13. Intrinsic pathway.
The intrinsic pathway is activated by the -contact with subendothelial collagen -HMWK -kallikrein.
This culminates in the conversion of inactive factor xii into activated factor xii.(Hageman's factor).

14. Lab test for the Intrinsic pathway.
The PTT(partial thomboplastin time ) tests for the functionality of this pathway and the common coagulation pathway.
The PTT tests factors xii, xi, ix, x, v, ii(prothombin), i(fibrinogen)
The normal range of the PTT is about 25-35sec.
An abnormal (too long) PTT result may also be due to:
Disseminated intravascular coagulation (DIC)
Hemophilia A, Hemophilia B
Hypofibrinogenemia, Liver disease
Lupus anticoagulants
Malabsorption, Vitamin K deficiency
Von Willebrand's disease

15. The extrinsic pathway
This pathway is activated by the release of tissue factor.
Tissue factor is a protein present in subendothelial tissue and leukocytes necessary for the initiation of thrombin formation from the prothombin.

16. Lab test for the extrinsic pathway.
The prothrombin time tests this pathway and also the common coagulation pathway.
The PT tests factors vii, x, v, ii, i.
Normal PT is about sec.
The INR(international normalized ratio) standardizes the PT test so that the results can be compared worldwide.

17. Regulation of the coagulation cascade.
Once activated the coagulation cascade must be restricted to the site of injury to prevent a runaway clotting of the entire vascular tree.
3 major categories of endogenous anticoagulants help with bleeding control.

18. 1. Anti-thrombins
Antithrombins like antithrombin iii inhibits the activity of thrombin and other serine proteases, including factors 9a,10a,11a and 12a.
Anithrombin iii is activated by binding to heparin like molecules on the endothelial cells.
Heparin used clinically also works in the same way to control bleeding.

19. 2. Protein C and S
Protein c and S are vitamin k dependant proteins and they act on a complex that proteolytically inactivates factor Va and VIIIa.
Protein C activation is via thrombomodulin.

20. 3. TFPI
Tissue factor protease inhibitor is produced by the endothelium and by other cells.
TFPI causes the inactivation of tissue factor-factor VIIa complexes.

22. Bleeding disorders.
Bleeding disorders aka hemorrhagic diatheses may be caused by either of the following or a combination. -increased blood vessel fragility. -platelets dysfunction. -coagulation defects.
Laboratory evaluation of bleeding disorders involves checking the platelet counts, bleeding time, prothrombin time ,partial thromboplastin time etc.

23. Thrombocytopenia
This is a decrease in platelets counts characterized principally by petechial bleeding mostly from the small vessels of the skin and mucous membranes.
The causes of thrombocytopenia are: -decreased production. -decreased survival/increased destruction. -splenic sequestration. -hemodilution. -HIV -drug induced.

24. ITP.
Immune thrombocytopenic purpura involves 2 forms of immune mediated platelets destruction.
Acute ITP: this is an acute self limiting disorder, usually affecting children after an episode of viral illness, here there is a transient immune mediated platelet destruction.
Chronic ITP: here platelets autoantibody produced in the spleen are directed against one or both platelet associated glycoproteins(gpib or gpiib/iiia).
Destruction of the platelet coated antibodies eventually occurs within the spleen. Mostly seen in pregnant women and women of child bearing age.

25. Labs finding for ITP Platelet count: decreased.
Bleeding time: increased.
PT: normal.
PTT: normal.
Peripheral blood smear: thrombocytopenia and megathrombocytes (enlarged immature platelets)

26. Treatment for ITP. Corticosteroids: decreases antibody production.
Immunoglobulin therapy: floods the fc receptors on the splenic macrophages.
Splenectomy.

27. TTP & HUS
Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are 2 related conditions characterized by: -fever -thrombocytopenia -microangiopatic hemolytic anemia. -transient neurologic deficits(in TTP) -renal failure(in HUS)

28. TTP
This is associated with an inherited/acquired defect in ADAMTS13,a serum mettaloproteinase that limits the size of VWF multimers in the plasma.
In the absence of this, very high molecular VWF multimers accumulate and are capable of promoting platelet aggregation throughout the microcirculation.
In the case of acquired TTP auto antibodies are directed against ADAMTS13.

30. HUS
This mostly follows a G.I infection with E.coli. the verotoxin injures the endothelial cells an thereby promotes a dysregulated platelet aggregation and activation.

31. Lab finding in TTP. Platelet counts: decreased.
Bleeding time: increased.
PT and PTT: Normal.
Peripheral blood smear: thromboytopenia and schistocytes.

32. Schistocytes/Helmet cells.

34. Coagulation disorders:
Bleeding in patients with coagulation disorders is slightly different form those seen in patients with platelets disorders.
The spontaneous formation of petechiae and purpura are uncommon, instead bleeding manifests as large areas of ecchymoses, hematomas or prolonged bleeding after a laceration or surgery.
Bleeding into joints(hemathrosis) is also common.

35. Von Willibrand’s disease.
This is an inherited bleeding disorder characterized by either a qualitative or quantitative defect in the von willibard’s factor.
The VWF is normally produced by the Weibel Palade bodies of the endothelial cells and also by megakaryocytes.

37. Clinical features of VWD
Spontaneous bleeding from the mucous membrane.
Prolonged bleeding from wounds.
Menorhagia in young females.
Bleeding into joints.

38. Lab findings in VWD. Platelet count: normal. Bleeding time: prolonged.
PT: normal.
PTT: prolonged(recall that vwf also function as a scarfold/ligand for factor 8-intrinsic pathway).

39. Treatment of VWD.
Treat mild cases with DESMOPRESSIN-synthetic ADH analogue.
MOA: causes the release of VWF from the weibel Palade bodies of the endothelial cells.

40. HEMOPHILIA.
Hemophilia is a group of x-linked recessive genetic disorder.
Hemophilia is of 2 major type.
HEMOPHILIA TYPE A(CLASSIC HEMOPHILIA)
HEMOPHILIA TYPE B(CHRISTMAS DISEASE)

41. HEMOPHILIA A. This is due to the deficiency of factor viii.
It predominantly affect males
The symptoms vary based on the degree of deficiency.
Newborn males may bleed severely at the time of circumcision.
Spontaneous bleeding into joints also common.
Easy bruising and hematoma formation after minor trauma.

42. Hemarthrosis.

43. Lab finding and treatment.
Platelet counts: normal
Bleeding time: normal
PTT: prolonged
PT: normal.
Treatment: factor viii concentrate.

44. HEMOPHILIA B. Also x-linked recessive inherited disease.
Here there is the deficiency of factor ix.
It is clinically indistinguishable for hemophilia A.

46. Summary.
The process of normal hemostasis involves -Reflex neurogenic vasoconstriction. -Platelet adhesion, activation and aggregation. -Activation of the coagulation cascade. -Activation of a counter-regulatory mechanism that restricts the haemostatic plug to the site of injury.
Any deviation form the above during hemostasis gives rise to a hemorrhagic diathesis.

48. Muchas gracias Al final.