Hemorrhagic diathesisHemorrhagic diathesisis a disease, characterized by excessive is a disease, characterized by excessive bleeding. According to pathogenesis, it is bleeding. According to pathogenesis, it is classified into coagulopathy, platelet classified into coagulopathy, platelet disorder (thrombocytopenia and disorder (thrombocytopenia and thrombocytopathy) and vasopathy. Each thrombocytopathy) and vasopathy. Each type is subdivided into congenital and type is subdivided into congenital and acquired. acquired.
platelet plug
fibrin clot
vasoconstriction
vascular injury
incompleteplatelet plug
incomplete or delayedfibrin clot
vasoconstriction
vascular injury
NORMAL BLEEDING DISORDER
Petechial-ecchymosis
Hematoma
Mixed (Petechia & Hematoma)
Vasculatic
Angiomatosic
The main bleeding types
The main bleeding sickness typesThe 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-hematomamacula-hematoma
vasculitic purpuravasculitic purpura
angiomaangioma
The main coagulogram indexesThe main coagulogram indexesIndexIndex HypoHypo
coagulatiocoagulationn
NormoNormo
coagulatiocoagulationn
HyperHyper
coagulationcoagulation
Bleeding time (by Bleeding time (by Lee-White methods), Lee-White methods), minmin
>>55 5-35-3 << 33
Platelets numberPlatelets number <<180180 180-320180-320 >>320320
Platelet adhesivenessPlatelet adhesiveness <<2323 23-4423-44 >>4545
Time of plasma Time of plasma recalcification, secrecalcification, sec
>>120120 120-60120-60 <<6060
Heparin tolerance Heparin tolerance test, mintest, min
>>1111 11-811-8 <<88
Prothrombin index, %Prothrombin index, % <<8080 80-10080-100 >>100100
U-factorU-factor <<8080 80-10080-100 >>100100
Procorventin (VII Procorventin (VII factor), %factor), %
<<8080 80-10080-100 >>100100
Fibrinogen, g/lFibrinogen, g/l <<22 2-42-4 >>44
Screening tests for bleeding disordersScreening tests for bleeding disordersTestTest Abnormality detectedAbnormality detected
Blood count and filmBlood count and film Anaemia, leukaemia, disseminatedAnaemia, leukaemia, disseminatedintravascular coagulationintravascular coagulation
Platelet countPlatelet count ThrombocytopeniaThrombocytopenia
Activated partial Activated partial thromboplastin timethromboplastin time
Deficiency of all coagulation factorsDeficiency of all coagulation factorsexcept VII, especially follows VIII except VII, especially follows VIII and IX;and IX;heparinheparin
Prothrombin timeProthrombin time Deficiency of factors I, II, V, VII, and Deficiency of factors I, II, V, VII, and X;X;warfarinwarfarin
Thrombin time or Thrombin time or fibrinogenfibrinogen
Hypofibrinogenaemia or Hypofibrinogenaemia or dysfibrinogenaemia; heparin; fibrin dysfibrinogenaemia; heparin; fibrin degradation productsdegradation products
Bleeding time Bleeding time Test of platelet-vessel wall Test of platelet-vessel wall interactioninteraction
CoagulopathyCoagulopathyI. 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)
CoagulopathyCoagulopathyII. Acquired1) 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 disordersPlatelet disorders
ThrombocytopathyI. Congenital (deficiency of platelet membrane glycoprotein) – Glanzmann's ThrombastheniaII. 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 anemiasThrombocytopenia (decrease in the number of platelets)I. Werlhof’s disease - autoimmune thrombocytopenic purpuraII. Symptomatic• Immune (heteroimmune, isoimmune,) • Toxic (in phosphorus poisoning etc.)• Methaplastic (in hematological malignancies or myelocarcinosis)• Drug-induced (cytostatics)
ThrombocytopeniaThrombocytopeniao 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 Syndromeo - Chronic liver disease
VasopathyVasopathyI. 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
IXVIII
Coagulation pathwayCoagulation 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 - continuedCoagulation 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
Bleeding disorders
Vascular abnormalities
Platelet disordersClotting factorabnormalities
DIC
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.
www.themegallery.com
Company Logo
factor IX deficiency
factor VIII deficiency
factor XI deficiency
А В С
Haemophilia
X-Linked Recessive InheritanceX-Linked Recessive Inheritance
Carrier femaleCarrier female
Affected maleAffected male
Normal maleNormal male
• Affected males (XY):Affected males (XY):–sons unaffected (no male to male sons unaffected (no male to male transmission)transmission)–daughters obligate carriersdaughters obligate carriers
• Carrier female (XX): Carrier female (XX): –½ sons affected; ½ daughters carriers½ sons affected; ½ daughters carriers
• Affected females: very rare.Affected females: very rare.
New New mutation in mutation in germ cellgerm cell
New New mutation in mutation in maternal or maternal or
paternal paternal germ cellgerm cell
46, XX 46, XY
Factor VIII allele - normal
Mutant VIII allele - normal
Germline /Gonadal Mosaicism
ovary testes
FormsForms 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)
Company Logo
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 %
Classification (F VIII C level)
Clinical severity of haemophilia A and BClinical severity of haemophilia A and B
Factor value*Factor value* Bleeding tendencyBleeding tendency
Less than 0.02Less than 0.02 Severe - frequent spontaneous bleeding Severe - frequent spontaneous bleeding into joints, muscles, and internal organsinto joints, muscles, and internal organs
0.02-0.050.02-0.05 Moderate—some “spontaneous” Moderate—some “spontaneous” bleeds,bleeds,bleeding after minor traumableeding after minor trauma
More than More than 0.050.05 Mild—bleeding only after significant Mild—bleeding only after significant trauma ortrauma orsurgerysurgery
* Normal value of factors VIII and IX is 0.5-1.5* Normal value of factors VIII and IX is 0.5-1.5
Arhtropathy
Hematomic bleeding sickness types
Diagnostic criteria
Hemophilia
Diagnostic Diagnostic CriteriaCriteria
Family_history_of_coagulation_disorders: positive APTT:abnormal
Mixing_APTT:corrected Factor_VIII:C_activity: abnormal
Condition Prothrombin time
Partial thromboplastin time
Bleeding time Platelet count
Vitamin K deficiency or warfarin
prolongednormal or mildly prolonged
unaffected unaffected
Disseminated intravascular coagulation
prolonged prolonged prolonged decreased
von Willebrand disease
unaffected prolonged prolonged unaffected
Hemophilia unaffected prolonged unaffected unaffectedAspirin unaffected unaffected prolonged unaffected
Thrombocytopenia
unaffected unaffected prolonged decreased
Uremia unaffected unaffected prolonged unaffectedGlanzmann's thrombasthenia
unaffected unaffected prolonged unaffected
Bernard-Soulier syndrome
unaffected unaffected prolongeddecreased or unaffected
TreatmentTreatment
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
TreatmentTreatmentThe 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 BHemophilia B
DEFICIENCY OF FACTOR IXFactor IX deficiencyFactor IX deficiencyX-linked recessiveX-linked recessiveMuch less commonMuch less commonClinically= Clinically= indistinguishableindistinguishable from Hemophilia from Hemophilia
A with A with Similar lab findingsSimilar lab findingsDiagnosis by factor IX levelsDiagnosis by factor IX levelsTreat with recombinant IXTreat with recombinant IX
Diagnostic CriteriaDiagnostic Criteria
Family_history_of_coagulation_disorders:positive Mixing_APTT:corrected Factor_IX_assay:abnormalAPTT:abnormal
TreatmentTreatmentFor 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
15-20 UN/kg
1 2
Moderate
35-40 UN/kg
3
Severe.
70 UN/kg
Mild
Hemophilia A Treatment (cryoprecipitate)
von Willebrand's Disease
Essentials of DiagnosisFamily 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 Signsvon 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 typesThe main bleeding sickness typesMixed (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)
TreatmentTreatmentThe 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 activityPlatelet hemostatic activity
1. Pl stimulate vasoconstriction of injured vessels2. Pl form hemostatic plug (platelet adhesion) + platelet
aggregation to seal small vessel wall3. Pl play role in fibrin clot formation
Bleeding disorders
Vascular abnormalities
***Platelet disorders
Clotting factorabnormalities
DIC
Bleeding disorders
Platelet disorders
↓production ↑destruction
SequestrationHypersplenism
Primary/IdiopathicITP
Acute/Chronic
SecondaryDrugs, HIV
INCREASED DESTRUCTIONINCREASED DESTRUCTIONImmune 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
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 symptomsOften, 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.
ThrombocytopeniaThrombocytopenia
Petechial-ecchymosic
Diagnostic criteria
1. Decreased platelets
Immune Thrombocytopenic PurpuraImmune Thrombocytopenic PurpuraCause
◦ Antiplatelet antibodies ◦ Antigen - platelet membrane glycoprotein
complexes IIb-IIIa and Ib-IXMorphology
◦ 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 EvaluationNecessary Evaluation• History: Isolated bleeding symptoms consistent withthrombocytopenia 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 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.
Bone Marrow Bone Marrow EvaluationEvaluation
• History: Isolated bleeding symptoms consistent withthrombocytopenia 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 typesThe main bleeding sickness typesPetechia-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 PurpuraImmune Thrombocytopenic Purpura
FeatureFeature AcuteAcute ChronicChronic
Age / SexAge / Sex ChildrenChildren Adult/FemaleAdult/Female
OnsetOnset AbruptAbrupt GradualGradual
Predisposing Predisposing FactorsFactors
Viral infection/ Viral infection/ vaccinevaccine
--
DurationDuration <2 months<2 months >6 mnoths>6 mnoths
PathogenesisPathogenesis -- Ig G against Ig G against Platelet GPPlatelet GP
Peripheral Peripheral smearsmear
Thrombocytopenia & Thrombocytopenia & Giant PLTSGiant PLTS
SameSame
Bone marrowBone marrow Normal or Normal or ↑Megakaryocytes↑Megakaryocytes
SameSame
ITPITP
FeatureFeature AcuteAcute ChronicChronic
TestsTests Prolonged BT Prolonged BT & Normal PT & & Normal PT & PTTPTT
SameSame
Complication Complication (most (most dangerous)dangerous)
Intracranial Intracranial bleedbleed
SameSame
Clinical courseClinical course Spontaneous Spontaneous remissionremission
NoNo
TreatmentTreatment PLT. PLT. TransfusionTransfusion SplenectomySplenectomy
If <20,000If <20,000
NoNoIf <50,000If <50,000
Yes (refractory Yes (refractory cases)cases)
ConditionProthrombin time
Partial thromboplastin time
Bleeding time Platelet count
Vitamin K deficiency or warfarin
prolongednormal or mildly prolonged
unaffected unaffected
Disseminated intravascular coagulation
prolonged prolonged prolonged decreased
von Willebrand disease unaffected prolonged prolonged unaffected
Hemophilia unaffected prolonged unaffected unaffected
Aspirin unaffected unaffected prolonged unaffected
Thrombocytopeniaunaffected
unaffected
prolonged decreased
Uremia unaffected unaffected prolonged unaffectedGlanzmann's thrombasthenia
unaffected unaffected prolonged unaffected
Bernard-Soulier syndrome
unaffected unaffected prolongeddecreased or unaffected
Initial Management of ITPInitial Management of ITPAssessment of Disease Status:• What bleeding is the patient experiencing?• Determine the timing, location, and severity ofbleeding 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 General Considerations for Initial ManagementManagement
• 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 thrombocytopeniaDrug induced thrombocytopeniaHeparin induced thrombocytopenia (HIT)Heparin induced thrombocytopenia (HIT)
Seen in 3-5% of patients treated with unfractionated heparin thrombocytopenic after 1-2 weeks of RxCaused 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 disordersPlatelet functional disorders
Bleeding disorders
Vascular abnormalities
Platelet disordersClotting factorabnormalities
DIC
VascularVascular abnormalities abnormalities
CausesInfectionsMeningococcemia, Rickettsioses, Infective endocarditisDrug reactions Hereditary hemorrhagic telangiectasia
Autosomal dominant Cushing syndromeHenoch - 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 typesThe 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 The main bleeding sickness typestypes
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)