1 Tabuk University Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3 rd Year – Level 5 – AY

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

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 3

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. 4

FindingPlatelet/Vessel wallsCoagulation Mucosal bleedingCommonRare PetechiaeCommonRare Deep haematomas Bleeding from skin cuts Sex of patient Rare Persistant Equal Characteristic Minimal >80% Clinical differences between diseases of platelets/wall vessels or coagulation factors

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

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 7

Purpura : hemorrhages larger than petechiae seen in the skin 8

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

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

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

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.

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Connective tissue disorders  Pseudoxanthoma elaticum is associated with arterial haemorrhage and thrombosis.  Mild cases may present with superficial brusing and pupura following minor trauma.

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

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 16

Acquired vascular defects 1. Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of child-bearing age. 2. Senile purpura caused by atrophy of the supporting tissues of cutaneous blood vessels is seen mainly on dorsal aspects of the forearms and hands. 3. Purpura associated with infections.(immune complex formation). 4. Scurvy. vitamin C deficiency 17

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

Causes of thrombocytopenia  Failure of platelet production 1. Megakaryocyte depression (congenital defects drugs, chemicals, viral infections). 2. Part of general bone marrow failure (cytotoxic drugs, radiotherapy, aplastic anaemia, leukaemia, myelodysplastic syndromes, myelofibrosis, megaloblastic anaemia)  Increased consumption of platelets  Increased consumption of platelets (immune, DIC, TTP, ITP)  Abnormal distribution of platelets  Abnormal distribution of platelets (Splenomegaly)  Dilutional loss  Dilutional loss (Massive transfusion of stored blood to bleeding patients ) 19

Thrombocytopenia in Megaloblastic anemia 20

Immune Thrombocytopenic Purpura (ITP)  The most common cause of acute thrombocytopenia in children.  Cause antibodies  Antiplatelet antibodies  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 magakaryocyte number  Diagnosis - by exclusion  Bleeding time - prolonged, but PT & PTT - normal 21

Thrombotic Thrombocytopenic Purpura small clots  Is a rare condition characterized by the formation of small clots (thrombi) in the circulation, resulting in the consumption of platelets (thrombocytopenia). vWF cleaving protease  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. 22

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

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. 24

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

Diagnosis of platelet disorders 26

 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. 27

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

Rare hereditary defects of platelet function  These are detected using : 1. Platelet aggregation studies (Light transmission aggregometry using PRP) 2. Nucleotide pool measurements (specific deficiency in dense granule numbers or their content (e.g. storage pool disease), or specific defect(s) in degranulation ) 3. 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. 29

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 × 10 9 /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 erythrocytes Direct 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 leukemia B) Aplastic anemia C) Immune thrombocytopenic purpura D) Myelodysplastic syndrome  Please explain.