BLEEDING DISORDERS CLINICAL FEATURES

PROF.DR.G.SUNDARAMURTHY’S UNIT M7

BHARGAVI.K

Bleeding disorders

Vascular abnormalities

***Platelet disorders

Clotting factorabnormalities

DIC

Platelet Disorders - Features:

Mucocutaneous bleeding Petechiae Purpurae ecchymosis spontaneous bleeding after trauma CNS bleeding (severe)

Petechiae

PETECHIAE:minute 1-2 mm hges into skin,mucous membranes or serosal surfaces Do not blanch with pressure

(typical of platelet disorders)

Petechiae

Purpura:slightly larger 3 mm haemorrhages

Bleeding disorders

Platelet disorders

↓production ↑destruction

SequestrationHypersplenism

Primary/IdiopathicITP

Acute/Chronic

SecondaryDrugs, HIV

Classification of thrombocytopeniaPSEUDO-ARTIFACTUAL

THROMBOCYTOPENIAPlatelet agglutination

Platelet satellitism

Giant platelets

IMPAIRED PLATELET PRODUCTION

congenital

autosomal dominant

MYH9 RELATED May hegglin,fetchner,epstein,sebastian

syndromes Mediterranean macrothrombocytopenia Familial platelet syndrome with predisoposition to AML Thrombocytopenia with linkage to ch 10 Paris-trousseau syndrome

AUTOSOMAL RECESSIVE Congenital amegakaryocytic TAR syndrome Bernard soulier syndrome Gray platelet syndrome

X-LINKED WISKOTT-ALDRICH syndrome WITH DYSERYTHROCYTOSIS

ACQUIRED Marrow infiltration Infectious disease-HIV,parvo,CMV Radiotherapy n chemotherapy Folic acid and vit b12 deficiency PNH Acquired aplastic anemia Myelodysplastic syndromes

ACCELELERATED PLATELET DESTRUCTION IMMUNE MEDIATEDAutoimmune thrombocytopenic purpura

Idiopathicsecondary-infections,pregnancy

Alloimmuneneonatalposttransfusion purpura

Autoimmune diseasesMDSLymphoproliferative disorders

NONIMMUNE THROMBOCYTOPENIA

THROMBOTIC MICROANGIOPATHIES DIC KASSABACHMERIT SYNDROME PLATELET DESTRUCTION BY ARTIFICIAL

SURFACES HEMOPHAGOCYTOSIS

ABNORMAL DISTRIBUTION OR POOLING Splenomegaly Hypersplenism Hypothermia Massive transfusion

DRUG INDUCED

HEPARIN INDUCED

OTHERS

Immune Thrombocytopenic Purpura (ITP) Cause1-4 weeks following exposure to a common viral infection, small number of children develop an autoantibody directed against platelet surface. Following binding of the antibody to the platelet surface, circulating antibody coated platelet are recognized by receptor on splenic macrophage, ingested & destroyed. The virus that has been described in association with ITP including EBV,HIV.Morphology

Peripheral Bloodthrombocytopenia, abnormally large platelets (megathrombocytes or Giant platelets),

MarrowNormal or Increased magakaryocyte

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

Same

Clinical Manifestation:-

1-the classic presentation of ITP from 1-4 years old who has sudden onset of generalized petechiae & purpura.

2-often there is bleeding from gums & mucous membrane.

3- splenomegaly are rare, so also lymphadenopathy or hepatosplenomegaly.

4-70 to 80% of children who present with acute ITP with have spontaneous resolution of their ITP within 6 months.

5-less than 1% of cases develop intracranial hemorrhage.

Thrombotic Microangiopathies

1. Thrombotic thrombocytopenic Purpura (TTP)

2. Hemolytic-Uremic syndrome (HUS)

TTPHUS Exist on a continuum Diagnosed by a common pentad

Microangiopathic Hemolytic Anemia: Schistocytes membranes are sheared passing through microthrombi

Thrombocytopenia: More sever in TTP Fever Renal Abnormalities: More prominent in HUS:

include Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure

Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: confusion, CN palsies, seizure,coma

Thrombotic Microangiopathies

HUS TTPAbsent Neurological symptoms

Prominent

Prominent Acute Renal Failure Less prominent

Children Age Adults

Infection

( E.coli O157 : H7)

Cause Genetic

(vWF metalloprotease-

ADAMTS 13) deficiency

Feature

PLATELET FUNCTION DISORDERS

• Inherited• Acquired

Inherited Disorders: 1.GLYCOPROTEIN RECEPTOR ABNORMALITIES

Bernard-Soulier disease Glanzmann’s thrombasthenia

2.ABNORMALITIES OF PLATELET GRANULES

-D-storage pool deficiency

-gray platelet syndrome: a-storage pool deficiency

-PARIS TROUSSEAU/JACOBSON syndrome(giant a granule)

-QUEBEC platelet factor V disorder3.PLATELET COAGULANT ACTIVITY ABNORMALITY

SCOTT SYNDROME-failure of normal microvesiculation in response to stimuli

-not primarily mucocutaneous.

Glanzmann

Thromasthenia

BSS

Inheritance Autosomal Recessive

Autosomal Recessive, rarely AD

Platelet

Count

Normal Low

Size Normal Giant

Glycoprotein

Deficiency

IIb/IIIa

aggregation

Ib-IX-V

adhesion

Platelet functional disorders

Bleeding in glanzmann thrombasthenia Menorrhagia Easy bruising,purpura Epistaxis Gingival bleeding GI haemorrhage Hematuria Hemarthrosis Intra cerebral haemorrhage Visceral hematoma

Bleeding in Bernard soulier

Epistaxis Echymoses Menometrorrhagia Gingival haemorrhage GI bleeding Post traumatic bleeding Hematuria Cerebral hge Retinal hge

Drugs affecting platelet function NSAIDS Theinopyridines Gp iib- iii a antagonists Antibiotics Anticoagulants fibrinolytics

Uremia associated abnormal platelet function Renal failure associated anemia Reduced fibrinogen binding Defective aggregation Concurrent medications

Liver Disease and Hemostasis

1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen

2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion)

3. Dysfibrinogenemia

4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)

5. DIC

6. Thrombocytoepnia and platelet function defects

HIV associated

Accelerated destruction because of immune complexes

Decreased production Splenic sequestration TTP Medications Concurrent infections

CLINICAL DISTINCTIONDIORDERS OF COAGULATION DISORDERS OF PLATELET OR

VESSELS

SITE OF BLEEDING DEEP SKIN,MUCOUS MEMBRANES

PETECHIAE RARE CHARACTERISTIC

ECCHYMOSIS LARGE,DEEP SMALL, SUPERFICIAL

DEEP DISSECTING HEMATOMAS

CHARACTERISTIC RARE

SUPERFICIAL ECCHYMOSES

COMMON-LARGE N SOLITARY CHARACTERISTIC-SMALL N MULTIPLE

HEMARTHROSIS CHARACTERISTIC RARE

DELAYED BLEEDING COMMON RARE

BLEEDING FROM SUPERFICIAL CUTS

MINIMAL PERSISTENT N PROFUSE

SEX MALES MC IN FEMALES

POSITIVE FAMILY HISTORY

COMMON RARE-EXCEPT IN VWB N HHTELENGIECTASIA

PlateletCoagulation

Petechiae, Purpura Hematoma, Joint bl.

Bleeding disorders

Vascular abnormalities

Platelet disordersClotting factorabnormalities

DIC

Clotting factor abnormalities Congenital disorders

Factor VIII Deficiency - Hemophilia A or Classic Type Factor IX Deficiency – Hemophilia B

Acquired disorders Vit. K deficiency =Due to deficient carboxylation of factors

II, VII, IX &X or liver disease Accelerated catabolism or thrombolytic therapy Antibody mediated neutralisation Accelerated clearance

Hemophilia A Hemophilia B

factor deficiency Factor VIII Factor IX

Inheritance X-linkedrecessive

X-linkedrecessive

Incidence 1/10,000 males 1/50,000

Classification

Levels Clinical features

Severe <1% Spontaneous he from early infancy

Frequent spontaneous hemarthroses

Moderate 1-5% Hge secondary to trauma or surgery

Occasional spontaneous hemarthroses

Mild 6-30% Hge secondary to trauma or surgery

Rare spontaneous hge.

Hemophilias

Clinical manifestations (hemophilia A & B are indistinguishable)

Clinical features

Excessive bleeding into various parts of the body hemarthroses hematomas hematuria hemorrhage into the central nervous system mucous membrane hemorrhage pseudotumors (blood cysts) dental and surgical bleeding

Ecchymosis

Ecchymoses

(typical of coagulation factor

disorders)

Hemarthroses

Bleeding into joints accounts for about 75% of bleeding episodes in severely affected patients

The joints most frequently involved: knees, elbows, ankles, shoulders , wrists and hips

Repeated hemarthroses results in destruction of articular cartilage, synovial hypertrophy and inflammation

The major complication of repeated bleeding is joint deformity complicated by muscle atrophy and soft tissue contractures

Target joint

Hemarthrosis (acute)

Hemarthrosis

hematomas

Subcutaneous Retro peritoneal Retro pharyngeal Iliopsoas muscle

CT scan showing large hematoma CT scan showing large hematoma of right psoas muscleof right psoas muscle

Neurologic complications

Hemorrhage into the central nervous system is the most dangerous event in hemophilic patients

Intracranial bleeding may be spontaneous or follows trauma, which may be trivial.

SUBDURAL OR EPIDURAL HEMATOMA Hemorrhage into the spinal canal can result in

paraplegia Peripheral nerve compression is a frequent

complication of muscle hematomas, particularly in the extremities

HAEMOPHILIA C Factor XI deficiency, autosomal recessive The only type of haemophilia that can

occur in girls.

PARAHAEMOPHILIA Factor V deficiency. Combined factor V – VIII deficiencies-

mutations in ERGIC 53, MCFD 2

Von Willebrand Disease

Coagulation + PLT disorder vWF: F-VIII & PLT function

von Willebrand factor Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets

.

Classification of von Willebrand disease

Type 1 vWD- the most common variant autosomal dominant in inheritance normal vWF in structure and function but

decrease in quantity- range 25-50% of normal Type 2 vWD (2A, 2B, 2M, 2N)

autosomal dominant in inheritance vWF is abnormal in structure and/or function

Type 3 vWD autosomal recessive in inheritance the most severe form characterized by very

low or undetectable level of vWF

Type Defect

2A Inc.susceptibility to cleavage by ADAMTS 13-loss of high n intermediate multimers

2B Inc.spontaneous binding of vWF to platelets

2M Dysfn of vWF molecule

2N Mutations in vWF precluding binding of FVIII.-autosomal haemophilia

Clinical symptoms

Mucocutaneous bleeding- the most common symptom epistaxis easy bruising and hematomas menorrhagia gingival bleeding gastrointestinal bleeding

spontaneous hemarthroses occur almost exclusively in patients with type 3 vWD

Pseudo/platelet type vwb disease Due to enhanced interaction between an

abnormal platelet GP Ib-IX receptor n normal vwb disease.

Mild to moderate mucocutaneous hge.

ACQUIRED VWD

lymphoproliferative disorders-MGUS,multiple myeloma, waldenstrom’s

HEYDE’s syndrome.

Hemophilia A Hemophilia B

Von Willebrand Disease

Inheritance X linked X linked Autosomal dominant

Factor deficiency VIII IX VWF

Bleeding site(s) Muscle,joint

Surgical

Muscle ,joint Mucous

Skin

Prothrombin time Normal Normal Normal

Activated PTT Prolonged Prolonged Prolonged

Bleeding time Normal Normal Prolonged or normal

Platelet aggregation

Normal Normal Normal

Bleeding disorders

Vascular abnormalities

Platelet disordersClotting factorabnormalities

DIC

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

HEREDITARY HAEMORRHAGIC TELENGIECTASIA-CURACAO CRITERIA Epistaxis-spontaneous and recurrent Telengiectasias-multiple at characteristic

sites-lips,oral cavity,fingers,nose Visceral lesions-with or without

bleeding(GI,pulmonary,cerebral and hepatic) Positive family h/o

Henoch-Schőnlein Purpura (Vaculitis)

Definition:-It is hypersensitivity vasculitis involving the small

blood vessels of skin ,joints,gut & kidneys. Etiology:-

in most cases there is history of preceding upper respiratory tract infection. Hypersensitivity vasculitis may be due to virus-antigen/antibody reaction.

Age:-It can occur at any age , it is more common in

children than in adult. Most commonly between 2-8 years , boys are affected twice as often as girls.

Clinical Manifestation:-1-Skin rash (100% of cases)

Appear in lower extremities and buttocks.The classic lesion begins as a small maculopapular

lesion initially blanch on pressure but later loses this feature & generally become petechial or purpuric rash. There is erythemia multiform & angioedema involving the scalp, eyelid , lips,ears, dorsum of hand & feet.

2-Arthritis(65% of cases)

Occur in 2/3 of affected children,large joints-particularly the knee & ankles-,joint may be swollen,tender , painful on motion. When present effusion reveal serious fluid ,they are not hemorrhagic. It resolves after a few days without residual deformity or damage

Henoch-Schonlein purpura

3-Abdominal Manifestation(65% of cases)There is severe colicky pain ,vomiting is

common & may be associated with hematemesis, malena or occult blood in stool may be present,the most important complication in intussusception.

4-Renal Manifestation(20% of cases)There is hematuria Nephrotic syndrome ,hypertension, oliguria

may occasionally occur.5- C.N.S. (not commonconvulsion,paresis & coma.

Henoch-Schonlein purpura

Bleeding disorders

Vascular abnormalities

Platelet disordersClotting factorabnormalities

DIC

Disseminated Intravascular Coagulation (DIC)Mechanism Systemic activation

of coagulation

Intravasculardeposition of fibrin

Depletion of plateletsand coagulation factors

BleedingThrombosis of smalland midsize vessels

with organ failure

Common clinical conditions

Sepsis

Trauma Head injury Fat embolism

Malignancy DRUGS LIVER DISEASE

Obstetrical complications Amniotic fluid embolism Abruptio placentae

Vascular disorders

Reaction to toxin (e.g. snake venom, drugs)

Immunologic disorders Severe allergic reaction Transplant rejection

Clinical Manifestations:-

--bleeding first occur from site of venipuncture or surgical incision with associated petechiae & ecchymoses.

--anemia caused by hemolysis may develop rapidly.

-Minimal to profound shock, renal failure, dyspnea, cyanosis, convulsions, and coma

-Hypotension is characteristic

Kidney =microinfarcts in the renal cortex In severe cases = bilateral renal cortical necrosis

Adrenals = bilateral adrenal hemorrhage resembles waterhouse - Friderichsen syndrome

Brain= Microinfarcts surrounded by foci of hemorrhage Heart and anterior pituitary= show Similar changes

Organ damage due to Micro thrombi