1. hemorrhagic diathesis

2. 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. 

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

4. 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)

5. hematoma

6. petechia-spotted (macula)

7. macula-hematoma

8. vasculitic purpura

9. angioma

10. The main coagulogram indexes1
Index
Hypo
coagulation
Normo
Hyper
Bleeding time (by Lee-White methods), min
>5
5-3
< 3
Platelets number
<180
>320
Platelet adhesiveness
<23
23-44
>45
Time of plasma recalcification, sec
>120
120-60
<60
Heparin tolerance test, min
>11
11-8
<8
Prothrombin index, %
<80
80-100
>100
U-factor
Procorventin (VII factor), %
Fibrinogen, g/l
<2
2-4
>4

11. Screening tests for bleeding disorders
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

12. 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)

13. 1) Hypoprothrombinemia
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

14. 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)

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

16. 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

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

18. 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)

19. 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

22. Clotting factor abnormalities
Congenital disorders
Von Willebrand disease –MC with minimal bleeding
Factor VIII Deficiency - Hemophilia A or Classic Type
Factor IX Deficiency – Hemophilia B
Acquired disorders
Vit. K deficiency
Oral anti-coagulants
Coumarin derivatives = warfarin – inhibit Vit. K factors
Liver diseases ↓ synthesis of factors

23. Haemophilia А В С www.themegallery.com Company Logo
factor VIII deficiency
factor IX deficiency
factor XI deficiency
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24. Haemophilia B - factor IX deficiency, "Christmas disease" (X-linked)
Forms
Haemophilia A - factor VIII deficiency, "classic haemophilia" (X-linked)
Haemophilia B - factor IX deficiency, "Christmas disease" (X-linked)
Haemophilia C - factor XI deficiency (Ashkenazi Jews, autosomal recessive)
The unrelated type 1 and type 2 von Willebrand disease (vWD)

25. Classification (F VIII C level)
Mild form 1 2
F VIII C level 1-5 %
Moderate
form 3
F VIII C level less than 1 %
Severe form
F VIII C level 5-25 %
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26. 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

27. Hemophilia A MC hereditary disease with serious bleeding
X-linked recessive
In 30% No family history (new mutations)
15% of severe cases develop factor VIII inhibitors
↓ amount or activity of factor VIII
factor VIII = cofactor for activation of factor X in the coagulation cascade
Symptoms usually – hemoarthrosis, bruising, hemorrhage after trauma or surgery

28. SIGNS & SYMPTOMS
Symptoms of hemophilia are usually first noticed during infancy or childhood. However, some people with milder forms of hemophilia may not develop symptoms until later on. The following are signs of hemophilia that may be noticed shortly after birth: Bleeding into the muscle, resulting in a deep bruise after receiving a routine vitamin K shot. Prolonged bleeding after a male child is circumcised.
Other symptoms of hemophilia include: Bleeding into a joint or muscle that causes pain and swelling. Abnormal bleeding after an injury. Easy bruising. Frequent nosebleeds. Blood in the urine (hematuria).
The most common bleeding problem a person with severe hemophilia has is bleeding into a joint (hemarthrosis), often without an injury.

30. Hemophilia Diagnostic criteria Hematomic bleeding sickness types
Arhtropathy

34. Biochemical aspects:
Factor VIII circulates in the plasma as a complex of factor VIII and von Willebrand factor. The molecular weight of human factor VIII has been estimated to be 285,000. Hemophelia A in which factor VIII (antihemophelic factor) is either absent or dysfunctional is transmitted by X chromosomal inheritance. Hemophelia A is at least four times more common than hemophelia B.

36. Diagnostic Criteria
Family_history_of_coagulation_disorders: positive APTT:abnormal
Mixing_APTT:corrected Factor_VIII:C_activity:abnormal

37. Condition
Prothrombin time
Partial thromboplastin time
Bleeding time
Platelet count
Vitamin K deficiency or warfarin
prolonged
normal or mildly prolonged
unaffected
Disseminated intravascular coagulation
decreased
von Willebrand disease
Hemophilia
Aspirin
Thrombocytopenia
Uremia
Glanzmann's thrombasthenia
Bernard-Soulier syndrome
decreased or unaffected

38. 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

39. 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.

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

41. Diagnostic Criteria Family_history_of_coagulation_disorders:posit ive
Mixing_APTT:corrected
Factor_IX_assay:abnormal
APTT:abnormal

42. 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.

43. Treatment
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.

44. Treatment
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%.

45. A Treatment (cryoprecipitate)
Hemophilia
A Treatment (cryoprecipitate)
15-20 UN/kg 1 2
Moderate
35-40 UN/kg 3
Severe .
70 UN/kg
Mild
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46. 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.

48. 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)

49. 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.

50. 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

53. 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 mm3.
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.

54. Deacrease of platelets
Thrombocytopenia
Diagnostic criteria
Petechial-ecchymosic
Deacrease of platelets

55. Platelet disorders Thrombocytopenia = Reduced platelet number Causes
Decreased production of platelets
vitamin B12 or folic acid deficiency
Decreased platelet survival
Immunologic or Nonimmunologic etiology
Sequestration- Hypersplenism
ameliorated by splenectomy
Dilutional
Massive transfusions

56. Immune Thrombocytopenic Purpura (ITP)
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 ?????

57. 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.

58. Necessary Evaluation
• Complete blood count: Isolated thrombocytopenia (platelet count <100 x 109/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.

59. Bone Marrow Evaluation
• Bone marrow examination is unnecessary in patients with the typical features of ITP outlined above, irrespective of the age of the patient.
• Bone marrow examination is felt to be unnecessary in children with typical ITP prior to initiation of treatment with corticosteroids, prior to splenectomy, or in patients who fail intravenous immunoglobulin (IVIg) therapy.

60. Bone Marrow Evaluation
• 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.

61. Additional Evaluations
• All adult patients with newly diagnosed ITP should undergo testing for HIV and HCV.
• There is insufficient evidence to support the routine use of anti-platelet, antiphospholipid, and anti-nuclear antibodies, thrombopoietin levels, or platelet parameters obtained on automated analyzers in the evaluation of patients with suspected ITP.

62. Diagnostic Criteria: Plt_count:abnormal (low)
Peripheral blood smear:no increase in schistocytes
Bone_marrow:megakaryocytosis

63. 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)

64. ITP Feature Acute Chronic Age / Sex Children Adult/Female Onset Abrupt
Gradual
Predisposing Factors
Viral infection/ vaccine -
Duration
<2 months
>6mnoths
Pathogenesis
IgG against Platelet GP
Peripheral smear
Thrombocytopenia & Giant PLTS
Same
Bone marrow
Normal or ↑Megakaryocytes

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

66. Thrombocytopenia Condition Prothrombin time
Partial thromboplastin time
Bleeding time
Platelet count
Vitamin K deficiency or warfarin
prolonged
normal or mildly prolonged
unaffected
Disseminated intravascular coagulation
decreased
von Willebrand disease
Hemophilia
Aspirin
Thrombocytopenia
Uremia
Glanzmann's thrombasthenia
Bernard-Soulier syndrome
decreased or unaffected

67. MANAGEMENTof ITP
The goal of all treatment strategies for ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count. The decision to treat should involve a discussion with the patient and consideration of the severity of bleeding, anticipated surgical procedures, medication side effects, and health-related quality of life.

68. 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?

69. General Considerations for Initial Management
• The majority of patients with no bleeding or mild bleeding (defined here as skin manifestations only, such as petechiae and bruising) can be treated with observation alone regardless of platelet count.
• First-line treatment includes observation, corticosteroids, IVIg, 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.

70. 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???

71. Platelet functional disorders

73. 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

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

76. 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)

78. Thank you for attention!