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.

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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)

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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%.

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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)