Dr. Mohammad Harith Al- saaty BLEEDING TENDENCY Dr. Mohammad Harith Al- saaty

Bleeding can occur after surgery or trauma , pathological bleeding occur when structurally abnormal vessels rupture or when a vessel is breached in the presence of a defect in hemostasis , this may be due to 1.Platelets deficiency 2. Platelets dysfunction 3. Coagulation defects.

Clinical assessment : History : a. Site of bleeding : bleeding into the muscles and joints , along with retroperitoneal & intracranial hemorrhage indicates a likely defect in coagulation factor . Purpura , prolonged bleeding from superficial cuts , epistaxis , or menorrhagia is more likely to be due to thrombocytopenia , platelets dysfunction or von willebrand disease . b. Duration of history : since childhood ? , recent onset ?

c. Precipitating factors : if there is trauma or occur spontaneously c. Precipitating factors : if there is trauma or occur spontaneously. Bleeding that occur spontaneously indicate a more severe defect . d. Surgery : ask about operations , dental extraction , tonsillectomy and circumcision . Immediate post-surgical bleeding suggest defective platelet plug formation and primary hemostasis , delayed hemorrhage is more suggestive of coagulation defect e. Family history : It is important to ask about family history , because it may be positive in patient with inherited disorders , but keep in mind that the absence of affected relatives does not exclude a hereditary bleeding disorders ( one third of cases of hemophilia arise in individuals without family hx) , it is also important to ask about consanguineous marriage because autosomal recessive disorders are common in those populations .

f. Drug history : Many drugs can cause bleeding like antiplatelets ( aspirin , clopidogrel ..) , anticoagulants ( heparin , warfarin ) , thrombolytics ( alteplase , streptokinase …) & even herbal remedies like ginseng , ginkgo biloba … Clinical examination : Signs of bleeding tendency include : 1. Petechial purpura : minor bleeding into the dermis , flat & non blanching , it may indicate thrombocytopenia or platelets dysfunction .

petechi

petechi

2. Palpable purpura Associated mostly with vasculitis .

Other causes of purpura :. Senile purpura. Factitious purpura Other causes of purpura : * Senile purpura * Factitious purpura * Purpura fulminans : e.g in DIC secondary to sepsis * Paraprotenemia

purpura

3. Ecchymosis or bruising : More extensive bleeding into the deeper layers of the skin , initially dark red or purple then blue , then green & then yellow as hemoglobin degraded.

bruises

Full examination is important in case of bleeding tendency e Full examination is important in case of bleeding tendency e.g in abdominal examination u may find flank hematoma ( retroperitoneal bleeding ) , joint examination may reveal hemarthrosis ) Systemic examination may give u a clue to the underlying disease such as hematological malignancy , liver disease , renal failure , CT diseases … etc.

Investigations - CBC , specially concentrating on platelets ( normal range : 150 -400 * 10^9/l) - Prothrombin time ( PT) : ( NR. 9-12 second ) Causes of elevated PT : 1. Factor VII deficiency ( isolated PT prolongation) ! 2. Liver disease 3. Warfarin therapy 4. Vitamin k deficiency

- Activated partial thromboplastin time ( APTT) ( NR. 26 – 36 sec - Activated partial thromboplastin time ( APTT) ( NR. 26 – 36 sec.) causes of isolated elevation of APTT a. Factor VIII deficiency ( hemophilia A ) b. Factor IX deficiency ( hemophilia B ) ( christmas disease) C. Factor XI & factor XII deficiency d. Heparin therapy e. Von willebrand disease ( mild elevation )

causes of elevated both ( PT & APTT) : 1. Factor II deficiency 2 causes of elevated both ( PT & APTT) : 1. Factor II deficiency 2. Factor V deficiency 3. Factor X deficiency 4. Fibrinogen deficiency 5. DIC 6. Severe liver disease & severe vitamin K deficiency ** don’t forget that there are diseases that can cause bleeding with normal PT , APTT & platelets like : platelet dysfunction ( congenital or acquired ) , factor XIII deficiency ….

Investigation ( continue..) - Fibrinogen concentration : ( NR : 1.5 – 4 g/l) Occur in diseases that cause hypofibrinogenemia Like : DIC & liver failure - Factors assay : like factor VIII , factor IX … etc - Platelet function : previously has been assessed by bleeding time ( the time to stop bleeding after an incision ) ( normally less than 8 min. ) , but now more recent studies has been done to assess platelets function like measuring platelets aggregation in response to adrenalin, ADP , collagen ,,, etc.

Thrombocytopenia Causes of thrombocytopenia : 1. Decrease or abnormal production 2. Increased consumption (1) Decreased production : -aplastic anemia -fanconi anemia - Megaloblastic anemia - Leukemia -drugs : chemotherapy

(2) Increased consumption : - ITP ( immune thrombocytopenic purpura) - DIC - Hypersplenism - HUS ( hemolytic uremic syndrome) -TTP ( thrombotic thrombocytopenic purpura) -liver disease Note : there is what is called pseudothrombocytopenia or sporious throbocytopenia due to platelet clumping in the sample specially when the sample contain EDTA as anticoagulant , in such case reviewing the peripheral blood smear will show the clumps , furthermore drawing blood into a sample that contain citrate instead of EDTA will eliminate the clump .

Immune thrombocytopenic purpura ( ITP) This condition is caused by autoantibodies mainly directed against the platelet membrane glycoprotein IIb/IIIa , resulting in premature removal from the circulation . It is usually associated with underlying diseases like : - C.T. diseases - HIV infection - Malignancies - Pregnancy

Clinical feature of ITP : Depend on the degree of thrombocytopenia , there may be bruising , epistaxis , petechi . Spontaneous bleeding usually occur when platelet count below 20 * 10 ^9/l . There may be feature of the underlying disease e.g SLE . b. Film will show reduced no. of platelets , Bone marrow will show increased no. of megakaryocytes ( but bone marrow is rarely needed in ITP , bone marrow is indicated in pt. older than 60 years , resistant cases & to exclude marrow fibrosis before splenectomy is done ) .

Management of ITP : Treatment indicated when there is bleeding , severely reduced platelet count & when there is upcoming surgery or biopsy to be taken . 1st line therapy is steroid ( prednisolon 1mg /kg daily to suppress the antibody . When there is slow response to steroids or there is severe bleeding : IV IG ( immunoglobulin) . In more severe cases : platelet transfusion , splenectomy , thrombopoietin analogue ( romiplostim ) or the thrombopoietin receptor agonist eltrombopag , & if no response immunosuppressants should be considered like rituximab , ciclosporin …

Haemophilia A Is a very common congenital coagulation disorder caused by deficiency of factor VIII , factor VIII is synthesized in the liver & endothelial cells & protected in the circulation by binding to von willebrand factor . Haemophilia A is sex linked disorder because the gene is located on X chromosome , all daughters of hemophiliacs are obligate carriers , & in turn have 1 in 4 chance in each pregnancy resulting in the birth of of an affected male , normal male , carrier female & normal female . Antenatal dx. By chorionic villous sampling is possible .

Severity of hemophilia A according to factor level

Clinical feature The main feature is bleeding , & this is depend on the severity of factor VIII D- , severe cases present with spontaneous bleeding into the skin , muscles , & joints , retroperitoneal & CNS bleeding are also features of severe cases . Mild to moderate cases also present with bleeding but it is usually provoked bleeding , i.e. after trauma or surgery . Hemarthrosis & muscle hematoma are characteristic , common sites for hemarthrosis are the knee joint & ankle joint , for the muscle , calf & psoas muscle hematoma are also common .

Recurrent hemarthrosis can lead to secondary osteoarthritis ( due to synovial hypertrophy & destruction of the cartilage). Psoas M. hematoma can lead to compression of the femoral nerve , calf hematoma can lead to compartment syndrome ( ( ischemia , necrosis & fibrosis of the fascial sheath) . CNS bleeding is the most dangerous form of bleeding & always should be suspected in hemophilic pt. with headache or other neurological symptoms.

Hemarthrosis

Ct scan : bleeding

Management of hemophilia A All patients should avoid trauma & any drug that can cause bleeding , the main treatment is to give factor VIII intravenously. Factor VIII should be stored at refrigerator & thus pts can treat themselves at home at the earliest indication of bleeding . The dose can be calculated by : Wieght * % of bleeding / 2 e.g. 70 kg , bleeding 100% The dose will be : 70 * 100 = 7000/2 = 3500 IU the half life is 8-12 hours , so it should be given twice daily

- Desmopressin ( DDAVP) is vasopressin receptor agonist , it raise the von willebrand factor & factor VIII by 3-4 fold , it is useful in treatment of mild to moderate bleeding .the dose is usually 0.3 ug / kg IV or SC or intranasal adminstration of 300 ug ( be ware of water retention , hyponatremia , & it is contraindicated in severe arterial disease because of risk of thrombosis ) . - Tranexamic acid ( cycklokapron) : antifibrinolytic drug , used as adjunctive therapy to control mild to moderate bleeding from the gum or oral cavity & sometimes GIT , BUT it is contraindicated when there is hematuria bec. There is risk of clot formation in the lumen of GU tract .

If Factor VIII is not available , cryoprecipitate can be used sometimes , bec each bag contain around 80 unit of factor VIII. * Complication of therapy : 1. Inhibitor formation : One of the major complication of factor VIII therapy is the development of anti factor VIII antibodies , occur in about 20 % of severe hemophiliacs . Such antibodies neutralise the therapeutic infusion making treatment relatively ineffective . When u suspect inhibitors formation , we should do what is called ( mixing study ) , which include mixing plasma of hemophilic pt. with normal plasma ( 1:1) , in normal pt. ( no inhibitors ) such mixing will correct the APTT completely , while if there is inhibitors , the APTT will not be corrected . Treatment of such problem is to give activated clotting factor like factor VII a or factor VIII inhibitor bypass activity ( FEIBA).

2. Transmission of infections : specially hepatitis C virus which is major cause of morbidity in hemophilic patient . Other type of infections include HBV , HIV , CJD … Recombinant factor VIII associated with decrease risk of viral infection .

VON WILLEBRAND DISEASE a common but mild bleeding disorder , caused by deficiency of von willebrand factor which is involved in both platelet function & coagulation . VWF act as a carrier protein for factor VIII. So deficiency of VWF lower the plasma factor VIII level. Clinical feature : the patient presented with bleeding tendency similar to those with reduced platelet function , superficial bruising , epistaxis , & commonly menorrhagia in females, the bleeding is usually less severe than hemophilia .

Treatment : Many mild cases can be treated by local means only or with desmopressin ( enhance release of VWF from endothelial cells ) Tranexamic acid may be useful in mucosal bleeding , for more serious bleeding using selected factor VIII concentrate which contain considerable quantities of VWF in addition to factor VIII .

Disseminated intravascular coagulation ( DIC) Characterized by activation of the pathways involved in coagulation & its regulation , this may result in generation of intravascular fibrin clots causing multiorgan failure with consumption of both platelets & coagulation factors causing bleeding Clinically there will be bleeding , oozing from venipuncture sites , petechi , ecchymosis , GIT blleding & even CNS bleeding . There is also hypercoagulability state resulting in occlusion of the vessels in the microcirculation resulting in organ failure & shock state .

Causes of DIC

Investigations 1. Low platelets 2. Low fibrinogen 3. Prolonged PT 4. Prolonged APTT 5. Elevated D dimer . 6. Evidence of organ failure

Management Treatment is mainly to correct the underlying cause , the pt. is usually treated at the ICU , to deal with the concomitant issues like , dehydration , acidosis , multiorgan failure & hypoxia . Fresh frozen plasma , cryoprecipitate & platelet transfusion may be necessary if the patient has bleeding . If there is evidence of thrombosis , treatment with heparin ( cautiously !! ) should be done with close monitoring .

Acquired bleeding disorders -liver disease : In severe parenchymal liver disease bleeding may arise from different causes : *GIT bleeding from esophageal varices or peptic ulcer * Reduced hepatic synthesis of of factor V, VII , VIII ! , IX, X, XI , prothrombin & fibrinogen . *thrombocytopenia secondary to hypersplenism *vitamin K deficiency ( specially in cholestatic jaundice).

Renal failure : This is mainly proportional to the elevated urea level , the causes of bleeding are multifactorial including platelets dysfunction & blood loss during dialysis .

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