Hemorrhagic diathesis is a disease, characterized by excessive bleeding. According to pathogenesis, it is classified into coagulopathy, platelet disorder (thrombocytopenia and thrombocytopathy) and vasopathy. Each type is subdivided into congenital and acquired. Hemorrhagic diathesis is a disease, characterized by excessive bleeding. According to pathogenesis, it is classified into coagulopathy, platelet disorder (thrombocytopenia and thrombocytopathy) and vasopathy. Each type is subdivided into congenital and acquired.

platelet plug fibrin clot vasoconstriction vascular injury incomplete platelet plug incomplete or delayed fibrin clot vasoconstriction vascular injury NORMAL BLEEDING DISORDER

Petechial-ecchymosis Hematoma Mixed (Petechia & Hematoma) Vasculatic Angiomatosic The main bleeding types

The main bleeding sickness types Hematomic (massive, deep, painful; bleeding may occur anywhere. The most common sites of bleeding are into joints (knees, ankles, elbows), into muscles, from the gastrointestinal tract, cause of the bleeding can be intramuscular injection; characterized by early postoperative & posttraumatic bleeding)

hematoma

petechia-spotted (macula)

macula-hematoma

vasculitic purpura

angioma

The main coagulogram indexes IndexHypocoagulationNormocoagulationHypercoagulation Bleeding time (by Lee- White methods), min >5>5>5>55-3 < 3< 3< 3< 3 Platelets number < >320 Platelet adhesiveness < >45 Time of plasma recalcification, sec > <60 Heparin tolerance test, min > <8<8<8<8 Prothrombin index, % < >100 U-factor < >100 Procorventin (VII factor), % < >100 Fibrinogen, g/l <2<2<2<22-4 >4>4>4>4

Screening tests for bleeding disorders Test Abnormality detected Blood count and film Anaemia, leukaemia, disseminated intravascular coagulation Platelet count Thrombocytopenia Activated partial thromboplastin time Deficiency of all coagulation factors except VII, especially follows VIII and IX; heparin Prothrombin time Deficiency of factors I, II, V, VII, and X; warfarin Thrombin time or fibrinogen Hypofibrinogenaemia or dysfibrinogenaemia; heparin; fibrin degradation products Bleeding time Test of platelet-vessel wall interaction

Coagulopathy I. Congenital Deficiency of coagulation factor VIII (hemophilia A) Deficiency of coagulation factor IX (hemophilia B) Deficiency of coagulation factor XI (hemophilia C) Deficiency of other coagulation factors (I, II, V, VII, IX, X and XIII) Deficiency of XII factor, prekallikrein or kininogen, protein C and S (without excessive bleeding) von Willebrand’s disease (angiohemophilia)

Coagulopathy II. Acquired 1) Hypoprothrombinemia Deficiency of vitamin K due to acholia of GIT (in cholestatic jaundice) In overdose of indirect anticoagulant (antagonist of vitamin K) In liver cirrhosis (due to reduced protein production) 2) Consumption of coagulation factors (II stage of DIC) 3) Heparin overdose 4) Activation of fibrinolytic system In administration of streptokinase etc. In trauma, obstetrical or surgical operations In malignant neoplasms In shock, sepsis, hematological malignancies, III stage of DIC

Platelet disorders Thrombocytopathy I. Congenital (deficiency of platelet membrane glycoprotein) – Glanzmann's Thrombasthenia II. Acquired (normal platelet count in blood and bone marrow but its functions are decreased) Drugs (after intake of antiplatelet agents: aspirin, Ticlide®); Immune, toxic, septic processes; Hematological malignancies and anemias Thrombocytopenia (decrease in the number of platelets) I. Werlhof’s disease - autoimmune thrombocytopenic purpura II. Symptomatic Immune (heteroimmune, isoimmune,) Toxic (in phosphorus poisoning etc.) Methaplastic (in hematological malignancies or myelocarcinosis) Drug-induced (cytostatics)

Thrombocytopenia o Thrombocytopenia (decrease in the number of platelets) o - Idiopathic thrombocytopenic purpura (ITP) o - Thombotic thrombocytopenic purpura (TTP) o - Heparin-induced thrombocytopenia (HIT) o - Hemolytic-Uremic Syndrome o - Chronic liver disease

Vasopathy I. Congenital Telangiectasiae (Rendu-Osler-Weber disease) Aneurysm of fine vessels Ehlers-Danlos syndrome, Marfan’s syndrome, retinocerebral angiomatosis (von Hippel-Lindau syndrome), encephalotrigeminal angiomatosis (Sturge-Kalisher-Weber syndrome) II. Acquired Hemorrhagic vasculitis – Henoch-Schönlein purpura Immune vasculitis Systemic vasculitis Avitaminosis of vitamin C

THE CLOTTING MECHANISM INTRINSIC EXTRINSIC PROTHROMBIN THROMBIN FIBRINOGEN FIBRIN (II) (III) (I) V X Tissue Thromboplastin Collagen VII XII XI IX VIII

Coagulation pathway ◦ Two pathways for fibrin clot formation:  Intrinsic ◦ Initiated by negatively charged surface  Extrinsic ◦ Initiated on tissue injury ◦ Both pathways converge on a final common pathway  Prothrombin  Thrombin (Most critical step )  Fibrinogen Fibrin  Clot ◦ The pathways are complex and involve many different proteins (called blood clotting factors )

Coagulation Cascade - continued Control of coagulation Antithrombins (e.g., antithrombin III) ◦ Proteins C and S ◦ Fibrinolytic cascade  Plasminogen  plasmin  fibrin break down products (*FDP or FSP) – d-dimer is most important of the FDPs * FDP / FSP – Fibrin degradation products / Fibrin split products

A “Royal Disease ” Queen Victoria (1837 to 1901) passed hemophilia on to German, Russian and Spanish royal families. Her son, Leopold, had frequent hemorrhages (British Medical Journal,1868) and died of a brain hemorrhage at 31. His grandson also died of a brain hemorrhage in 1928.

Company Logo factor IX factor IX deficiency factor VIII factor VIII deficiency factor XI factor XI deficiency АВС Haemophilia

X-Linked Recessive Inheritance Carrier female Affected male Normal male Affected males (XY):Affected males (XY): –sons unaffected (no male to male transmission) –daughters obligate carriers Carrier female (XX):Carrier female (XX): –½ sons affected; ½ daughters carriers Affected females: very rare.Affected females: very rare. New mutation in germ cell New mutation in maternal or paternal germ cell

46, XX 46, XY Factor VIII allele - normal Mutant VIII allele - normal Germline /Gonadal Mosaicism ovary testes

Forms  Haemophilia A - factor VIII deficiency, "classic haemophilia" (X-linked) Haemophilia Afactor VIII  Haemophilia B - factor IX deficiency, "Christmas disease" (X-linked) Haemophilia Bfactor IX  Haemophilia C - factor XI deficiency (Ashkenazi Jews, autosomal recessive) Haemophilia Cfactor XIAshkenaziautosomal recessive  The unrelated type 1 and type 2 von Willebrand diseasedisease (vWD)

Company Logo Mild form 12 F VIII C level 1-5 % Moderate form 3 F VIII C level less than 1 % Severe form F VIII C level 5-25 % Classification (F VIII C level)

Clinical severity of haemophilia A and B Factor value* Bleeding tendency Less than 0.02 Severe - frequent spontaneous bleeding into joints, muscles, and internal organs Moderate—some “spontaneous” bleeds, bleeding after minor trauma More than 0.05 Mild—bleeding only after significant trauma or surgery * Normal value of factors VIII and IX is

Arhtropathy Hematomic bleeding sickness types Diagnostic criteria Hemophilia

Diagnostic Criteria Family_history_of _coagulation_disor ders: positive APTT:abnormal Mixing_APTT:corr ected Factor_VIII:C_act ivity: abnormal

Condition Prothrombin time Partial thromboplastin time Bleeding timePlatelet count Vitamin K deficiencyVitamin K deficiency or warfarin warfarin prolonged normal or mildly prolonged unaffected Disseminated intravascular coagulation prolonged decreased von Willebrand disease unaffectedprolonged unaffected Hemophiliaunaffectedprolongedunaffected Aspirinunaffected prolongedunaffected Thrombocytopeni a unaffected prolongeddecreased Uremiaunaffected prolongedunaffected Glanzmann's thrombasthenia unaffected prolongedunaffected Bernard-Soulier syndrome unaffected prolonged decreased or unaffected

Treatment In mild bleeding: 1-desamino-8-D-arginine vasopressin (DDAVP). The level of factor VIII must be maintained at least 30%. In non-life-threatening bleeding or pre-op: factor VIII concentrates. The minimal hemostatic level of factor VIII:C in this case is 50%. Central nervous system hemorrhage and severe bleeding: factor VIII concentrates. The level of factor VIII:C must be maintained at 80% - 100%.

Each unit of factor VIII concentrates will raise the level of factor VIII by 2%/kg of body weight. Adjunctive therapy in dental surgery for mild and moderate hemophelia A: epsilon-aminocaproic acid (EACA). Avoidance of aspirin-containing compounds. For monitoring therapy, factor VIII assay is the test of choice. Dosage: the (activity ) units of factor VIII required can be calculated from: 40*BW* (desired factor level-actual factor level)/100 where BW is body weight in kg

Treatment The dose of factor VIII concentrate is calculated assuming that one unit of factor VIII is the amount present in 1 mL of plasma. Plasma volume is 40 mL/kg, and the volume of distribution of factor VIII:C is 1.5 times the plasma volume. Thus, to raise the level 100%, the dose should be 40 x 1.5 = 60 units/kg, or approximately 4000 units for a 70-kg individual. To raise the levels to 25% would require 1000 units. The half-life of factor VIII:C is approximately 12 hours. Thus, during major surgery, to achieve an initial level of 100% and maintain it continuously at greater than 50%, a dose of 60 units/kg (approximately 4000 units) initially followed by 30 units/kg (approximately 2000 units) every 12 hours should be adequate. During surgery, initially verify that these doses give the anticipated factor VIII levels. If factor VIII levels fail to rise as expected, an inhibitor should be suspected.

Hemophilia B DEFICIENCY OF FACTOR IX Factor IX deficiency Factor IX deficiency X-linked recessive X-linked recessive Much less common Much less common Clinically= indistinguishable from Hemophilia A with Similar lab findings Clinically= indistinguishable from Hemophilia A with Similar lab findings Diagnosis by factor IX levels Diagnosis by factor IX levels Treat with recombinant IX Treat with recombinant IX

Diagnostic Criteria Family_history_of_coagulation_disorders:positive Mixing_APTT:corrected Factor_IX_assay:abnormal APTT:abnormal

Treatment For patients with mild form of factor IX deficiency with non-life- threatening bleeding, the treatment of choice is FFP. For the severe form of hemophelia B or in life- threatening situation, prothrombin complex concentrates are the treatment of choice. Target levels of factor IX for therapy: Severe hemorrhage: 20% - 50% for 3-5 days, then 10% - 20% for the next 10 days. Minor hemorrhage: 20% for 7 days. Surgery: 50% - 70% for 2 days, then 30% - 40% for 3 days, then 20% for 7 days. Dosage: the (activity) units of factor IX required can be calculated from: 80*BW*(desired factor level-actual factor level)/100 where BW is body weight in kg Note that in-vivo recovery of factor IX is about 50%.

Company Logo UN/kg 12 Moderate UN/kg 3 Severe. 70 UN/kg Mild Hemophilia A Treatment (cryoprecipitate)

von Willebrand's Disease Essentials of Diagnosis Family history with autosomal dominant pattern of inheritance. Prolonged bleeding time, either at baseline or after challenge with aspirin. Reduced levels of factor VIII antigen or ristocetin cofactor. Reduced levels of factor VIII coagulant activity in some patients. Symptoms and Signs von Willebrand's disease is a common disorder affecting both men and women. Most cases are mild. Most bleeding is mucosal (epistaxis, gingival bleeding, menorrhagia), but gastrointestinal bleeding may occur. In most cases, incisional bleeding occurs after surgery or dental extractions. von Willebrand's disease is rarely as severe as hemophilia, and spontaneous hemarthroses do not occur (except in the rare type III). The bleeding tendency is exacerbated by aspirin. Characteristically, bleeding decreases during pregnancy or estrogen use.

The main bleeding sickness types Mixed (Petechial & Hematomic) (combined features of both types, but there are some difference: in contrast to hematomic - bleeding are into joints very rare, mostly it is located in subcutaneous, retroperitoneal, mesenteric, subserous intestinal layer or into internal organ);in contrast to petechial-ecchymosic bleeding - hemorrhagic syndrome characterized by large bruise)

Treatment The bleeding disorder is characteristically mild, and no treatment is routinely given other than avoidance of aspirin. However, patients often need to be prepared for surgical or dental procedures. The bleeding time is probably the best indicator of the likelihood of bleeding, and prophylactic therapy may be reasonably withheld if the procedure is minor and the bleeding time is normal. Desmopressin acetate (DDAVP) is useful for mild type I von Willebrand's disease and should be considered first. The dose is 0.3 mcg/kg, after which vWF levels usually rise two- to threefold in 30– 90 minutes. It can also be given as a nasal spray; levels peak 2 hours after use. The antifibrinolytic agent aminocaproic acid (EACA) is useful as adjunctive therapy during dental procedures.

Platelet hemostatic activity 1. Pl stimulate vasoconstriction of injured vessels 2. Pl form hemostatic plug (platelet adhesion) + platelet aggregation to seal small vessel wall 3. Pl play role in fibrin clot formation

INCREASED DESTRUCTION Immune destruction ◦Platelets are destroyed by antibodies  Platelets with bound antibody are removed by mononuclear phagocytes in the spleen  Anti-platlet antibody tests to identify antibodies on platelets are available

Fibrin XIIIa Cross-linked fibrin

Thrombocytopenia Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. Generally speaking a normal platelet count ranges from 180,000 and 320,000 per mm 3. Signs and symptoms Often, low platelet levels do not lead to clinical problems; rather, they are picked up on a routine full blood count. Occasionally, there may be bruising, nosebleeds and/or bleeding gums. It is vital that a full medical history is elicited, to ensure the low platelet count is not due to a secondary process. It is also important to ensure that the other blood cell types red blood cells, and white blood cells, are not also suppressed.

Thrombocytopenia Petechial- ecchymosic Diagnostic criteria 1.Decreased platelets

Immune Thrombocytopenic Purpura Cause ◦ 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 # Diagnosis - by exclusion ◦ Bleeding time - prolonged, but PT & PTT - normal ↓ Marrow magakaryocyte # - your Diagnosis of ITP is ?????

Necessary Evaluation History: Isolated bleeding symptoms consistent with thrombocytopenia without constitutional symptoms (e.g. significant weight loss, bone pain, night sweats). Physical examination: Bleeding symptoms in the absence of hepatosplenomegaly, lymphadenopathy, or stigmata of congenital conditions. Complete blood count: Isolated thrombocytopenia (platelet count <100 x 10 9 /L). Anemia only if due to significant bleeding - otherwise normal red cell indices, white blood cell count and differential. Peripheral blood smear: Identified platelets should be normal to large in size. Red and white blood cell morphology should be normal.

Bone Marrow Evaluation History: Isolated bleeding symptoms consistent with thrombocytopenia without constitutional symptoms (e.g. significant weight loss, bone pain, night sweats). Physical examination: Bleeding symptoms in the absence of hepatosplenomegaly, lymphadenopathy, or stigmata of congenital conditions. The presence of abnormalities in the history, physical examination, or the complete blood count and peripheral blood smear should be further investigated, e.g. with a bone marrow examination or other appropriate investigations, before the diagnosis of ITP is made.

The main bleeding sickness types Petechia-ecchymosis (is usually localized to superficial sites such as the skin and mucous membranes, wich often combined with menorrhagia, nose bleeding, gumms bleeding; rare – with gastrointestinal bleeding or brain hemorrhage; it is small, painless, provoked by simple action like skin cleaning, measure of blood pressure etc; pinch test is positive) Plt_count: abnormal (low) Peripheral blood smear:no increase in schistocytes Bone_marrow:megakaryocytosis Diagnostic Criteria:

Immune Thrombocytopenic Purpura FeatureAcuteChronic Age / Sex ChildrenAdult/Female OnsetAbruptGradual Predisposing Factors Viral infection/ vaccine - Duration <2 months >6 mnoths Pathogenesis- Ig G against Platelet GP Peripheral smear Thrombocytopenia & Giant PLTS Same Bone marrow Normal or ↑Megakaryocytes Same

ITP FeatureAcuteChronic Tests Prolonged BT & Normal PT & PTT Same Complication (most dangerous) Intracranial bleed Same Clinical course Spontaneous remission No Treatment PLT. Transfusion PLT. Transfusion Splenectomy Splenectomy If <20,000 No If <50,000 Yes (refractory cases)

Condition Prothrombin time Partial thromboplast in time Bleeding timePlatelet count Vitamin K deficiencyVitamin K deficiency or warfarin warfarin prolonged normal or mildly prolonged unaffected Disseminated intravascular coagulation prolonged decreased von Willebrand diseaseunaffectedprolonged unaffected Hemophiliaunaffectedprolongedunaffected Aspirinunaffected prolongedunaffected Thrombocytopeniaunaffected prolongeddecreased Uremiaunaffected prolongedunaffected Glanzmann's thrombasthenia unaffected prolongedunaffected Bernard-Soulier syndrome unaffected prolonged decreased or unaffected

Initial Management of ITP Assessment of Disease Status: What bleeding is the patient experiencing? Determine the timing, location, and severity of bleeding symptoms. Does this patient have any additional risk factors for bleeding such as use of antithrombotic agents or high-risk occupation? Is a surgical procedure anticipated? Is this patient likely to comply with recommended treatments? Is the bleeding experienced by this patient interfering with his or her daily activities or causing significant anxiety?

General Considerations for Initial Management The majority of patients with no bleeding or mild bleeding (defined here as skin manifestations only, such as petechia and bruising) can be treated with observation alone regardless of platelet count. First-line treatment includes observation, corticosteroids, IV Ig, or anti-D immunoglobulin (anti-D). Anti-D should be used with caution given recent FDA warnings of severe hemolysis. It is therefore not advised in patients with bleeding causing a decline in hemoglobin, or those with evidence of autoimmune hemolysis.

Drug induced thrombocytopenia Heparin induced thrombocytopenia (HIT) Seen in 3-5% of patients treated with unfractionated heparin thrombocytopenic after 1-2 weeks of Rx Caused by IgG antibodies against platelet factor 4/heparin complexes on platelet surfaces Exacerbates thrombosis, both arterial and venous (in setting of severe thrombocytopenia) ◦ Antibody binding results in platelet activation and aggregation. Rx - cessation of heparin Other drugs???

Platelet functional disorders

Vascular abnormalities Causes Infections Meningococcemia, Rickettsioses, Infective endocarditis Drug reactions Hereditary hemorrhagic telangiectasia  Autosomal dominant  Cushing syndrome  Henoch - Schönlein Purpura  systemic hypersensitivity disease of unknown cause  polyarthralgia, and acute Glomerulonephritis  Palpable purpuric rash, colicky abdominal pain ◦ Scurvy and the Ehlers-Danlos syndrome ◦ Amyloid infiltration of blood vessels

The main bleeding sickness types Vasculatic (hemorrhage due to inflammatory changes of small vessels, the main cause are immune disorders or infectious agent)

The main bleeding sickness types Angiomatosic (hemorrhage due to vascular dysplasia, teleangiectasia; the main clinical criteria is relapsing bleeding without hemorrhage in skin, subcutaneous and other tissue; nose bleeding are most often, dangerous and massive)