BLEEDING DISORDERS CLINICAL FEATURES PROF.DR.G.SUNDARAMURTHY’S UNIT M7 BHARGAVI.K
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