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 1

2. Bleeding disorders caused by vascular and platelets abnormalities By/ Dr. Walid ZAMMITI; Phd M.Sc; MLT

3. Objectives • To have a look on the clinical aspects of bleeding, and to be able to distinguish between different types of bleeding disorders. • Be aware of the rare inherited coagulation disorders. • Classify and categorize Bleeding disorders caused by vascular and platelets abnormalities. • List the causes of thrombocytopenia. • Discuss the diagnosis of Bleeding disorders caused by platelets abnormalities

4. Introduction • Abnormal bleeding may result from: 1 .Vascular disorders; 2 .Thrombocytopenia; 3 .Defective platelet function; or 4 .Defective coagulation. • The pattern of bleeding is predictable depending on the aetiology. Vascular and platelet disorders : associated with bleeding from mucous membranes and into the skin. • coagulation disorders: bleeding is often into joints or soft tissues.

5. Clinical differences between diseases of platelets/wall vessels or coagulation factors

6. Definition of terms • Bruisingنزف with mild traumaإصابة • Bruising without trauma Petechiae– a : typical of platelet disorders Ecchymosis– b : the purple or black-and-blue area resulting from a bruise. Typical of coagulation factor disorders Hematoma – c : usually with trauma, coagulation disorders

7. Petechiae: tiny pin-point hemorrhages in skin or mucous membranes due to not enough platelets to plug up the micro-leaks in small vessels each day

8. Purpura: hemorrhages larger than petechiae seen in the skin

9. Ecchymosis : the purple or black-and-blue area resulting from a bruise

10. Vascular bleeding disorders • Vascular disorders are a heterogeneous group of conditions characterized by easy bruising and spontaneous bleeding from the small vessels, • The underlying abnormality is either in the vessels themselves or in the perivascular connective tissues. • Most cases of bleeding caused by vascular defects alone are not severe. • Frequently, the bleeding is mainly in the skin causing petechiae, ecchymoses or both. • Inherited or acquired

11. Inherited vascular disorders • Hereditary haemorrhagic telangiectasia. • Connective tissue disorders. • Giant cavernous haemangioma

12. Hereditary haemorrhagic telangiectasia • Transmitted as an autosomal dominant trait. • Dilated micro vascular sweelings which appear during childhood and become more numerous in adult life. • Telangiectasisa develop in the skin, mucous membranes and internal organs.

14. Connective tissue disorders • Pseudoxanthomaelaticum is associated with arterial haemorrhage and thrombosis. • Mild cases may present with superficial brusing and pupura following minor trauma.

15. Giant cavernous haemangioma • These congenital malformation occasionally cause chronic activation of coagulation to laboratory features of disseminated intravascular coagulation (DIC). • In same cases thrombocytopenia

16. Acquired vascular defects • Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of child-bearing age. • Senile purpura caused by atrophy of the supporting tissues of cutaneous blood vessels is seen mainly on dorsal aspects of the forearms and hands. • Purpura associated with infections.(immune complex formation) • Scurvy. vitamin C deficiency

17. Acquired vascular defects • Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of child-bearing age. • Senile purpura caused by atrophy of the supporting tissues of cutaneous blood vessels is seen mainly on dorsal aspects of the forearms and hands. • Purpura associated with infections.(immune complex formation). • Scurvy. vitamin C deficiency

18. Platelets disorders : 1. Thrombocytopenias • Characterized by spontaneous skin purpuraand mucosal haemorrhage and prolonged bleeding after trauma.

19. Causes of thrombocytopenia • Failure of platelet production • Megakaryocyte depression (congenital defects drugs, chemicals, viral infections). • Part of general bone marrow failure (cytotoxic drugs, radiotherapy, aplastic anaemia, leukaemia, myelodysplastic syndromes, myelofibrosis, megaloblastic anaemia) • Increased consumption of platelets (immune, DIC, TTP, ITP) • Abnormal distribution of platelets (Splenomegaly) • Dilutional loss (Massive transfusion of stored blood to bleeding patients )

20. Thrombocytopenia in Megaloblastic anemia

21. Immune Thrombocytopenic Purpura (ITP) • The most common cause of acute thrombocytopenia in children. • Cause • Antiplateletantibodies • Antigen - platelet membrane glycoprotein complexes IIb-IIIa and Ib-IX • Morphology • Peripheral Blood • thrombocytopenia, abnormally large platelets (megathrombocytes or Giant platelets), • Marrow • Normal or Increased magakaryocytenumber • Diagnosis - by exclusion • Bleeding time - prolonged, but PT & PTT - normal

22. Thrombotic Thrombocytopenic Purpura • Is a rare condition characterized by the formation of small clots (thrombi) in the circulation, resulting in the consumption of platelets (thrombocytopenia). • This is due to a lack of enzyme activity, called vWF cleaving protease, that breaks down von Willebrand factor into smaller molecules. • In TTP, vWF is synthesised normally, but its subsequent break down (cleavage) is defective. Circulating large vWF molecules leads to the inappropriate formation of platelet clumps (thrombi). • Hemolysis, thrombocytopenia, fever, neurological and renal abnormalities.

23. 2. Disorders of platelet function: THROMBOCYTOPATHY • Disorders of platelet function are suspected in patients who show skinandmucosalhaemorrhage and in whom the bleeding time is prolonged despite a normal platelet count. • These disorders may be hereditary or acquired.

24. Hereditary disorders • Thrombasthenia (Glanzmann's disease): Failure of primary platelet aggregation because of deficiency of membrane GPIIb • Bernard-Soulier syndrome: Large platelets with defective binding to VWF, defective adherence to exposed subendothelial connective tissues and platelets do not aggregate with ristocetin • Storage pool diseases: Absence of α OR dense granules.

25. Acquired disorders • Antiplatelet drugs: Aspirin is the most common; causing Abnormal Bleeding Time. • Hyperglobulinaemia:interfer with platelet adherence, release and aggregation. • Myeloproliferative and myelodysplastic disorders :essential thrombocythaemia and other myeloproliferative and myelodysplastic diseases • Uraemia: associated with various abnormalities of platelet function.

26. Diagnosis of platelet disorders

27. When the blood count, including platelet count and blood film examination, are normal, a PFA-100 (platelet function analysis) or, much less frequently, a bleeding time is used to detect abnormal platelet function.

28. PFA-100 System Measures the complex process of primary hemostasis and aids in the rapid detection of platelet dysfunction.

29. Rare hereditary defects of platelet function • These are detected using : • Platelet aggregation studies (Light transmission aggregometry using PRP) • Nucleotide pool measurements (specific deficiency in dense granule numbers or their content (e.g. storage pool disease), or specific defect(s) in degranulation ) • Flow cytometry(quantification of glycoprotein receptor density , e.g in BSS) ** If von Willebrand disease is suspected, assay of VWF and coagulation factor VIII are required.

30. H.W • A 28-year-old woman has a 3-month history of easy bruising and bleeding gums. She feels otherwise well. Medical and family histories are unremarkable, and she takes no medications. • On physical examination, temperature is normal. Petechiae are present on the buccal mucosa and pretibial areas, and ecchymoses are noted on the upper thighs. There is no lymphadenopathy or splenomegaly. • Laboratory studies: • Hemoglobin 10.4 g/dL (104 g/L)Leukocyte count 5200/µL (5.2 × 109/L)Absolute neutrophil count 1200/µL (1.2 × 109/L) (normal >1500/µL [1.5 × 109/L])Platelet count 18,000/µL (18 × 109/L)Reticulocyte count 0.9% of erythrocytesDirect antiglobulin (Coombs) test Negative • A peripheral blood smear shows no circulating blasts. The platelets are decreased and are not clumped and enlarged. Bone marrow examination shows hypoplastic marrow (<20% cellularity) with trilineage normoblastic maturation and normal iron stores. There are no findings suggesting an infiltrative disease and no increases in CD34 blasts or reticulin fibrosis. • Which of the following is the most likely diagnosis? • A) Acute myeloid leukemiaB) Aplastic anemiaC) Immune thrombocytopenic purpuraD) Myelodysplastic syndrome • Please explain.