471 BLEEDING: THERAPEUTIC PRODUCTS Recombinant VIIa and FEIBA Products used to treat patients with inhibitory antibodies to fa ctor VIII or IX. Recombinant factor VIIa also used for factor VII defi ciency and GT. rVIIa is not recommended for treatment of severe bleeding due to other causes. Reference 1. CRASH-2 (2011). The importance of early treatment with tranexamic acid in blee ding trauma patients: an exploratory analysis of the CRASH-2 randomized controlled trial. L ancet, 377, 1096 \200\223101. 472 CHAPTER 10 Haemostasis and thrombosis von Willebrand disease Commonest heritable bleeding disorder. Autosomal inheritance. Low vW F level or reduced vWF function, aff ects both sexes but presents more frequently in \231 \200 because of menorrhagia. Incidence of 1 per few hundred. Pathophysiology vWF, produced in endothelial cells and megakaryocytes, is a protein of 250k Da molecular weight. Initial dimerization and subsequent removal of propeptide allows polym erization and secretion of large multimers. The higher molecular weight (HMW) multimers, up to 20 \227 106Da, are particularly haemostatically active. vWF has 2 main functions: \200 Its principal haemostatic function is to act as a ligand for platelet adhesion and when this activity is reduced bleeding tendency increases. \200 It has a 2 function as a carrier protein for factor VIII protecting it from proteolysis. In most patients with vWD the associated mild reduction in factor VIII level i s not the cause of the haemostatic defect. Many cases of heritable/congenital vWD are currently thought to be caused by genetic mutati ons at the vWF locus but some may be due to defects in other genes which aff ect vWF levels (epigenetic factors such as ABO blood group). Increasingly, vWF is considered a continuous vari- able with low levels associated with an i bleeding tendency. VWD is classi \201 ed into 3 main types (See Table 10.1.) \200 Type 1 \200\224quantitati ve defi ciency of vWF (75% of cases). \200 Type 2 \200\224qualitative defi ciency of vWF (20% of cases). \200 Type 3 \200\224complete defi ciency of vWF (rare). Clinical features Presentation varies markedly but typically a mild-to-moderate bleeding te ndency. Symptoms may be intermittent possibly related to fl uctuating vWF levels. It may be necessary to test on repeated occasions to estab- lish that vWF levels may be abnormally l ow on occasion. \200 Bleeding type \200\224mucocutaneous, easy bruising, nose bleeds, prolonged bleeding from cuts, dental extractions, trauma, surgery, and menorrhagia. Haemart hroses do not typically occur (except in type 3). \200 Patients often present in 2nd or 3 rd decade after prolonged bleeding after dental extraction or surgery. \200 Type 2B causes thrombocytopenia. Laboratory diagnosis vWF is an acute phase protein \200\224increasing with stress, oestroge ns, preg- nancy, malignancy, thyrotoxicosis. vWF levels are dependent on ABO blood group be ing lower in group O than non-O. \200 Because vWF is the carrier protein for FVIII protec ting it from proteolysis there is a 2 defi ciency of FVIII associated with vWF defi ciency, but it is a low vWF level that is primarily responsible for bleeding in most patients. vWF level and function typically mildly or moderately reduced. 473 von WILLEBRAND DISEASE Table 10.1 Classifi cation of vWD Type VIII vWF Ag vWF activity RIPA low dose HMW multimer 1 n/d d d d/n n 2A n/d n/d d d/n d 2M n/d n/d d d/n n 2B n/d n/d d i d 2N d n n n n 3 Usually undetectable dd dd dd dd FVIII may be n, or low in some patients. Factor VIII is seldom low enough to cause the joint bleeds seen in hemophilia except in type 3 which is a severe blee ding disorder. In type 1 vWD the PT, APTT, and platelet count are often n (a 50% reduction in vWF is suffi cient to reduce platelet adhesion and cause bleeding but the associated 50% reduction in F VIII is not suffi cient to prolong the APTT). Bleeding time is often n and is no longer used as a routine test. It has been largely repla ced by automated in vitro platelet function analysis. When mild, the condition may be diffi cult to diagnose as many of the tests are n, including the VIII and variably the vWF level. Repeat testing is necessary . Family testing is useful. vWF activity measured as ristocetin cofactor activity (vWF:RCo) or collagen binding activity (vWF:CB), which is measured in plasma and is not the same as R IPA (E see p.464) which is the ability of ristocetin to agglutinate platelet-rich plasma. Type 2 often diagnosed when vWF level is low and vWF:RCo/ vWF:Ag ratio <0.7. The main subtypes of type 2 are 2A and 2M \200\224in 2A there is a qualitative defect with absent HMW multimers and in 2M there is a qualitative defect but wi th HMW multimers present. RIPA is ristocetin-induced platelet agglutination performed on a patient \200\231s platelet rich plasma. Only use of RIPA test is for detection of type 2B w hen RIPA is low due to high affi nity variant vWF which produces thrombocytopenia and reduc ed circulating level of vWF. Type 2N is rare autosomal recessive variant in which the FVIII:C carrier function of vWF is reduced. May be misdiagnosed as hemophilia A but the clue is that \231\200 are aff ected as well as \231\202 and autosomal recessive inheritance. Majority of patients will have type 1 disease which rarely causes life-threatening bleeds; may have little impact on quality of life/life expectancy. Management with vWF rich VWF/FVIII concentrates as for severe hemophilia should enable patients with severe VWD to have good QoL. 474 CHAPTER 10 Haemostasis and thrombosis Treatment \200 Mainstay of treatment is desmopressin. Avoid aspirin and NSAIDs. Mild bleeding symptoms \200\224easy bruising, bleeding from cuts may settle with local pres sure. Tranexamic acid is a useful antifi brinolytic drug (15mg/kg oral tds), e.g. for denta l extraction in conjunction with desmopressin. Vaccination against HBV and HAV recommended for all patients. \200 Inhibitors infrequent \200\224usually type 3 disease. Moderate disease and minor surgery \200 Desmopressin (0.3mcg/kg SC or by slow IV injectio n/infusion). Fewer side eff ects with SC route. Most responders have type 1 VWD but may work in some type 2 patients. Avoid in type 2B (may reduce platelets). Major surgery, bleeding symptoms, or severe disease \200 If desmopressin insuffi cient us e vWF (Wilfactin) or vWF/VIII con- centrate (intermediate purity VIII concentrate), e.g. Alphanate, BPL 8Y, Haemate P. A high purity vWF concentrate (Wilfactin) avoids extremely high FVIII levels when repeated dosing is required, e.g. surgery in type 3 patient. Monitor treatment with vWF:RCo or vWF:Ag assay. \200 Bleeding time or PFA-100 (E see p.46 4) may not correct despite good clinical response. Treat post-op for 7 \200\22310d. Pregnancy FVIII and vWF i in pregnancy so rarely presents a problem for type 1. Post-partum vWF declines quickly so watch out for PPH in moderate/ severely aff ected women. Give desm opressin or vWF concentrate to maintain levels >0.30U/mL if clinical problem. In type 2B ab normal HMW multimers can cause platelet aggregation and thrombocytopenia in pregnancy. Avoi d tranexamic acid in pregnancy/type 2B as there may be risk of thrombosis. Menorrhagia May be major problem. Tranexamic acid for fi rst 3d of the menstrual period can reduce blood loss by 50%. Combined oral contraceptive pill is useful. Levonorgestrel (horm one impregnated) coil very eff ective in some patients. Blood group O-associated low vWF levels Major modifi er of plasma vWF concentration is ABO blood group with vWF levels ranging from 0.35 to 1.50U/mL in group O and 0.50 \200\223>2.00 U /mL in non-O. Many people with vWF levels of 0.35 \200\2230.50U/mL do not bleed but minor bleeding in the general population is common which may be due to lowish vWF levels in some people. 475 von WILLEBRAND DISEASE Distinguishing vWD from low \200\223n vWF levels can be diffi cult. Some clinicians restric t diagnosis of vWD to patients with levels <0.30U/mL or a known mutation in the vWF gene an d label other patients with bleeding history and vWF level between 0.30 \200\2230.50U/mL as \200\230low-vWF-related bleeding tendency \200\231. Further reading Laff an, M. et al. (2004). The diagnosis of von Willebrand disease: a guide line from the UK Hemophilia Center Doctors \200\231 Organization. Hemophilia, 10(3), 199 \200\223217. Pasi, K.J. et al. (2004). Management of von Willebrand disease: a guideline fr om the UK Hemophilia Center Doctors \200\231 Organization. Hemophilia, 10(3), 218 \200\2233 1. Sadler, J.E. (2003). Von Willebrand disease type 1: a diagnosis in search of a disease. Blood, 101(6), 2089 \200\22393. 476 CHAPTER 10 Haemostasis and thrombosis Hemophilia A and B Congenital bleeding disorders with low levels of factor VIII (hemophilia A, classical hemophilia) or IX (hemophilia B, Christmas disease). Sex- linked inheritance. Males typically aff ected, female carriers are rarely symptomatic (see Table 10.2). Clinical presentation Hemophilia A and B are clinically indistinguishable. Symptoms depend on the factor level. Bleeds into joints particularly ankles, knees, and elbows and also mus cles, spontaneous bleeding into arms, legs, iliopsoas, or any site \200\224may lead to nerv e compression, compartment syndrome, muscle contractures \200\224look for these. Haematuria is common (1 or 2 episodes per patient per decade), retroperitoneal and CNS bleeds are lif e-threatening. Chronic arthropathy Repeated joint bleeds preventable but older patients often have arthrop - athy. Blood is highly irritant to synovium and causes synovial hypertrophy with hyperaemi a and a tendency to rebleed. Rapid degenerative arthritis with features both of OA (mechani cal pain \200\224intermittent, worse on move- ment) and RA (infl ammatory pain \200\224cons tant but variable, morning stiff ness, worse after rest) aff ecting predominantly ankles, k nees, and elbows. Pseudotumours Progressive cystic enlargement of an encapsulated haematoma. Due to recurrent subperiosteal bleeding and reactive new bone formation leading to destruction of bone, usu ally long bones in adults. Muscles also aff ected \200\224iliopsoas. Pathophysiology Factor VIII activated by thrombin, and factor IX activated by the TF/factor VIIa complex, together activate factor X, leading to thrombin generation and conversion of soluble Fgn to insoluble fi brin. Hemophilia A and B are disor- ders characterized by inab ility to generate cell surface-associated factor Xa. 1 \201\2043 of hemophilia B patients h ave dysfunctional molecule (type II defect). Genetic abnormalities Include inversions within intron 22 of factor VIII gene in 50%, point mutations, and deletions. Gross gene alterations common in haemo- philia A but infrequent in hemophilia B. This may account for low fre- quency of inhibitors in hemophilia B. Carrier detection and antenatal diagnosis now possible in many cases by direct gene mutatio n detection. Aff ected family member useful for identifying gene mutation. Linkage analysis no longer recommended as 1st-line method. Epidemiology \200 Hemophilia A occurs in 1:10,000, in 1 \201\2043 cases no family history as mutation is new. May present in neonatal period in previously unaff ected family with prolo nged bleeding from the cord or cephalhaematoma. May be erroneously diagnosed as \200\230no n-accidental injury \200\231. Hemophilia B occurs in 1:50,000 (i.e. 5 \227 less frequent than hemophilia A); no striking racial distribution. 477 hemophilia A AND B Table 10.2 Classifi cation of severity of hemophilia Severe disease (plasma level <0.01U/mL) Usually presents in the 1st years of life with easy bruising and bleeding out of proportion to injury Moderate disease (0.01 \200\2230.05U/ mL factor level) Intermediate and variable severity Mild disease (>0.05U/mL) May only present after trauma/surgery in later life General features Haemarthrosis; spontaneous bleeding into joints (knees>elbows>ankles>hips> wrists) produce local tingling, pain; later \200\224 swelling, limitation of movement, warmth, redness, sev ere pain Diagnosis Assess duration, type of bleeding, exposure to previous trauma/surgery and family history. Look for bruising, petechial hemorrhages, early signs of joint damage. Exclude ac quired bleeding disorders. Laboratory tests PT n, APTT prolonged depending on degree of defi ciency (note: a normal AP TT does not exclude mild disease). Assay FVIII fi rst, then FIX. Exclude VWD. Radiology Acute bleed \200\224US or CT scan if in doubt. In established disease \200\224chr onic synovitis, arthropathy, and other pathological changes seen. Complications Factor VIII inhibitors \200 Suggested by i frequency of bleeding and/or red uced response to concentrates; occurs in 15 \200\22325% hemophilia A patients following tre atment, usually after 5 \200\22320 treatment episodes (IX inhibitors are uncommon; <2%). Fa milial tendency, inhibitors occurring more often in patients with deletions or mutations wi thin factor VIII gene. The antibody acts against part of the amino-terminal component of th e A2 domain or the carboxyterminal part of the C2 domain of the VIII molecule. Inhibitor is detected by inhibitor screen and quantifi ed by Bethesda assay. In 50% of patients inhibitors are transient and low titre (<5BU/mL) being noted incidentally on review. In 50%, however, a permanent high-titre inhibitor develops (>5BU/ mL) and is a major complication. Diagnosis \200 Prolonged APTT with failure to correct with n plasma. \200 Inhibitor scr een \200\224APTT of mix of patient plasma and n plasma compared immediately after mixing and after 2h incubation at 37 C. 478 CHAPTER 10 Haemostasis and thrombosis Inhibitor assay \200\224factor assays performed on serial dilutions of patient \200\231s plasma in n plasma after 2h incubation (Bethesda assay) \200\224 inhibito r titre (BU/mL) calculated from dilution that produces 50% reduction of n factor VIII level . Treatment Requires a \200\230FVIII bypassing agent \200\231 for treatment of acute bleeds (rVIIa or FEIBA) and desensitization by immuntolerance with FVIII for high titre inhibitors . Various immune tolerance regimens have been tried \200\224suc- cessful in up to 80% of pa tients but may take up to 2 years to eliminate inhibitor. Treatment program requires superv ision in comprehensive care center or similar expert center with regular pharmacokinetic st udies. Example of immuntolerance program: \200 Phase 1: wait until FVIII titre <10BU/mL t reating acute bleeds with bypassing agent. Phase 2: commence 100U/kg FVIII od or bd until inhibitor undetectable in Bethesda assay. Phase 3: perform half-life (t1 \201\2042) study 4 \200\2236-weekly after 3d wash out when i nhibitor undetectable. When t1 \201\2042 >6h switch to 50U/kg 3 \227 weekly and continue t o monitor t1 \201\2042. Phase 4: When t1 \201\2042 >6h for 3 months reduce to standard prophylaxis 25U/kg 3 \227 weekly. Asymptomatic patients with low titre inhibitor \200\224observation may be all that is neces sary as the inhibitor may disappear. Transmission of HBV, HCV, and HIV Not a risk with recombinant products. Viral inactivation procedures for plasma-derived products in mid 1980s limited transmission. Treatment General regular medical and hemophilia review and lifelong support are essential. At presentation establish: \200 Factor level. \200 Inhibitor screen. \200 Mutation ( useful for subsequent carrier detection and/or antenatal diagnosis and some predictive value for risk of inhibitor development). FBC \200\224exclude anemia due to bleeds including iron defi ciency. \200 Blood group. \200 Liver function. \200 Baseline viral status (HIV, HCV including genotype and HCV RNA level, HBV, HAV). Early treatment of bleeding episodes is essential. Prophylaxis is preferable to demand treatment for many patients with severe hemophilia. Prophylaxis started in 1st or 2nd year of life can prevent most if not all joint damage and almost eliminate signifi can t bleeding. Port-A-Cath may be required to deliver prophylaxis. Factor concentrate needs to be administered every 2 or 3d. If not on prophylaxis, home demand treatment is preferable to hospital demand treatment. Regularly check inhibitor status, LFTs, FBC. \200 Avoid aspirin, antiplatelet drugs, and IM injections. \200 Vaccinate against HBV and HAV if not immune. 479 hemophilia A AND B HIV management Retroviral therapy requires HIV specialist involvement. HCV management Requires hepatologist involvement. HCV infected most patients with hemophili a treated with pooled human factor concentrates before 1985. 720% have chronic liver diseas e. HCV genotyping and RNA detec- tion by PCR is used to identify patients at higher risk of progressive liver disease. Liver biopsy if required is not contraindicated as factor level s are readily normalized with replacement therapy \200\224need for biopsy has diminished as genotyping and RNA detection has become more inform- ative. Combined antiviral therapy sup erior to IFN alone. Variant CJD No evidence as yet of transmission of vCJD by pooled human blood products. Hemophilia A-speci \201 c treatment \200 Minor bleeds may stop without factor concentrat e therapy. \200 Desmopressin for minor surgery and bleeds that fail to settle (0.3mcg/ kg SC or slow IVI/20min) \200\224may also be given by nasal spray. 30min later take blood sam ple to check response (if required) \200\224plasma level i 3 \200\2234-fold. Reduced respon se with repeated exposure sometimes observed. Tranexamic acid (15mg/kg tds oral) \200\224useful for cuts or dental extraction. Do not use when haematuria. \200 Cryoprecipitate no longer recommended. \200 Severe disease \200\224factor VIII concentrate therapy necessary. \200 Products \200 \224recombinant products are treatment of choice. 2nd generation recombinants do not contai n any human material in product. Human donor-derived products are now subjected to multiple viral inactivation steps lyophilization (dry heat), pasteurization (wet-heat), solvent-det ergent, nanofi ltration) \200\224good record of viral safety. High and intermediate purity human donor-derived products available for patients not receiving recombinant therapy. No p articular advantage for high purity over intermediate except possibly useful in patients wi th allergic reactions to intermediate purity. Factor concentrate not available for majority of patients worldwide. Principle of treatment \200\224raise factor VIII to haemostatic level (0.15 \200\2230.25U/mL for minor bleeds, 0.25 \200\2230.50U/mL for moderate bleeds, >0.50U/ mL for severe bleeds, >0.40U/mL minor ops, >0.50U/ mL for major surgery with achievement of 1.00U/mL for major surgery and life-threatening bleeds). Formula: 1U/kg body weight raises plasma concentration by about 0.02U/mL (2U/dL). t1 \201\2042 6 \200\22312h. Spontaneous bl eeds usually settle with single treatment if treated early. In major surgery replacement th erapy required for up to 10d. Do not give IM injections when factor is low. 480 CHAPTER 10 Haemostasis and thrombosis Hemophilia B-speci \201 c treatment \200 General approach as for hemophilia A. Desmopres sin typically of no value. Products \200\224recombinant factor IX treatment of choice. If not recombinant then high purity factor IX preferable to intermediate (intermediate known as pr othrombin complex concentrate) as high risk of thrombosis with intermediate purity product. Formula: 1U/ kg body wt raises plasma concentration by 0.01U/mL (1U/dL). t1 \201\2042 12 \200\22324h. Special considerations Antenatal diagnosis Carrier detection ideally by genetic mutation an alysis. Phenotypic detection by FVIII:vWF ratios is unreliable. Antenatal diagnosis in car- riers ideally performed by chorionic villus sampling (CVS) with mutation analysis at 10 \200\22312 weeks \200\231 gestation if termination preferred \200\224rarer now- adays becau se of improved treatment and prognosis. Issue is complex and counseling/testing should be a t comprehensive care center or similar expert center. Home treatment Home treatment has transformed QoL of patients. Parents, the local GP, the b oy himself from age 6 \200\2237 years onwards can be trained to give IV factor concentrates at home. Treatment usually starts in 1st or 2nd year of life and Port-A-Cath may be needed until age 4 years or more. Prophylaxis E.g. 3 \227 weekly injections of concentrate (average dose 15 \200\22325U/kg) given at home. Multidisciplinary support required Physiotherapy plays key role in preservation of muscle a nd joint function in patients with haemarthroses. Combined clinics with orthopedic sur- geo ns, dental surgeons, hepatologists, pediatricians, HIV physicians, and geneticists are requ ired to give comprehensive care. Clinical trials of gene therapy and long-acting factor concentrates (Fc-fusion and PEGylate d proteins) are under way. Further reading Key, N.S. and Negrier C. (2007). Coagulation factor concentrates: past, pre sent, and future. Lancet, 370, 439 \200\22348. 481 hemophilia A AND B 482 CHAPTER 10 Haemostasis and thrombosis Rare congenital coagulation disorders Clotting factor de \201 ciencies Defi ciency of coagulation factors other than vWF, FVIII, and FIX is rare with a prevalence of 1 \200\2232 per million. Autosomal recessive inherita nce, the defi ciency either due to reduced level (type 1) or production of a variant protei n (type 2). t1 \201\2042 of factors vary and will determine the fre- quency and ease of tre atment. Rare factor defi ciencies rarely produce haemarthrosis, except factor XIII defi ciency, and may only present at time of surgery. Many patients with inherited coagulation defi ciencie s will not bleed unless exposed to surgery or trauma, and may seldom require treatment. Whe n bleeding arises or cover for surgery is needed, the aim is to achieve a plasma factor con centration at least as high as the minimal haemostatic value and make sure it does not drop below this until haemostasis is secure. Factor concentrates should be considered when available, e.g. factor XI, factor XIII, recom binant VIIa for FVII defi ciency. FFP can be used, e.g. when appropriate concentrate not av ailable, and virally inactivated plasma should be used when available. FFP is a source of a ll coagulation factors but large volumes may be required and even with viral inactiva- tion there is risk of disease transmission. Speci \201 c conditions Factor XI de \201 ciency Defi ciency more common in certain ethni c groups such as Ashkenazi Jews. Clinically of variable severity, often mild \200\224even l ow factor levels may not produce symptoms whilst signifi cant bleeding can occur with mild defi ciency. \200 Diagnosis: n PT, n APTT unless factor XI <0.40U/mL. Therefore necessary to measure factor XI level to make diagnosis in many cases. Treatment: tranexamic acid and desmopressin for oral and dental surgery. Factor XI concentrate sometimes available. Otherwise, use virally-inactivated FFP. Hypo/a \201 brinogenaemia n range 2.0 \200\2234.0g/L. Produced by liver; acute phase prote in, raised in infl ammatory reactions, pregnancy, stress, etc. Converted to fi brin by the action of thrombin and is a key component of a clot. Abnormalities of Fgn are more often ac quired than inherited. Inherited defects are usually quantitative and include heterozygous hypofi brinogenaemia or homozygous afi brinogenaemia. Bleeding usually only in afi brinogenaemic patients, hypofi brinoge- naemia usually asympto matic. Bruising, bleeding usually after trauma or operations will depend on the concentrati on and are more severe when <0.5g/L. Afi brinogenaemia (Fgn <0.2g/L) is a moderate-to-sever e dis- order with spontaneous bleeding; umbilical stump bleeding common, cerebral and GI he morrhage and haemarthrosis less common. Epistaxis, menorrhagia and postpartum bleeding comm on. 483 RARE CONGENITAL COAGULATION DISORDERS Diagnosis: prolonged (unclottable in afi brinogenaemia) PT, APTT, and TT. Fgn level measured by Clauss assay. Acquired hypofi brinogenaemia needs to be excluded (DIC, liver disease) and family studies are necessary. Treatment: Fgn has a long t1 \201\2042 (3 \200\2235d), severe defi ciency managed by repeat ed (twice weekly) prophylactic injections with Fgn concentrates, FFP or cryoprecipitate. Fg n levels should be raised to 0.5 \200\2231.0g/L to achieve haemostasis. Dys \201 brinogenaemia Qualitative defects of Fgn \200\224the dysfi brinogenaemias \200 \224are inherited as incomplete autosomal dominant traits with >200 reported Fgn variants. Defective fi brin polymerization or fi brinopeptide release may occur. Most patients are he terozygous and asymptomatic, bleeding symptoms are not typical and usual clinical manifesta tion if any is arterial and/or venous thrombosis with some variants (although very rare at 71 per million of population, <1% of patients with venous thrombosis). More likely to prese nt with pregnancy-associated thrombosis. \200 Diagnosis: possible prolongation of PT and APTT with variable abnormalities of TT and RT and Fgn-dependent platelet function may be defective. Diagnosis usually by demonstrating normal immunological Fgn concentrations with reduced functional ac tivity in patient with a prolonged TT. Factor VII de \201 ciency Vitamin K-dependent factor playing a pivotal role in initiating coagula- tion but low level required. The t1 \201\2042 is short (4 \200\2236h). In severe d efi ciency (<0.05U/mL), bleeding symptoms (similar to hemophilia) are not common but sponta neous intracerebral hemorrhage at a young age has been reported. \200 Diagnosis: prolonge d PT with n APTT. Assay factor VII to assess severity. Treatment: recombinant VIIa (20mcg/kg) if available. Repeated doses required. Very short t1 \201\2042 makes management diffi cult, requiring repeated dos es. If using FFP, give initial IV injection (10 \200\22315mL/kg) and check response with su bsequent monitoring and repeat infusion. Factor XIII ( \201 brin stabilizing factor) de \201 ciency Characteristically produces de layed postoperative bleeding (6 \200\22324h later). Neonatal umbilical stump bleeding more common than with other defi ciencies. High risk of cerebral hemorrhage. \200 Diagnosis: P T and APTT both normal so diagnosis will be missed unless specifi cally looked for. Screeni ng tests are insensitive (clot solubility test with thrombin and acetic acid recommended if performed). Factor XIII antigen ( -subunit) level can be measured by ELISA. Treatment: very low levels required for haemostasis; t1 \201\2042 is very long. Severe defi ciency should be treated with once-monthly prophylactic replacement with factor XIII conce ntrate. 484 CHAPTER 10 Haemostasis and thrombosis Other de \201 ciencies Factor II, V, X defi ciencies very rare. Bleeding less severe with factor V defi ciency than with factor X or prothrombin defi ciency. Consider con- sanguinit y with rare autosomal recessive bleeding disorders. Multiple defects Rare familial coagulation factor defi ciencies described; often involves f actor VIII and another factor, e.g. combined FV and FVIII defi ciency. Other combinations s een. Further reading Bolton-Maggs, P.H. et al. (2004). The rare coagulation disorders \200\223re view with guidelines for management from the United Kingdom Hemophilia Center Doctors \200 \231 Organization. Hemophilia, 10, 593 \200\223628. 485 CONGENITAL THROMBOCYTOPENIAS Congenital thrombocytopenias Family history useful but \210\222ve family history does not exclude inherited abnormality, usually autosomal recessive. Non-inherited neonatal thrombocytopenia Infection in the neonate: relatively common cause o f neonatal thrombo- cytopenia. Also as a result of maternal toxoplasma, CMV, rubella when n eonatal thrombocytopenia resolves over several months. Maternal ITP: autoantibody crosses placenta and destroys fetal plate- lets, however severe thrombocytopenia rare and bleeding exceptional (unlike in NAIT see below). Recovery within 1 \200\2233 weeks. Drugs: drugs taken by mother can cause thrombocytopenia, neonatal thrombocytopenia usually resolves rapidly without any hemorrhage. Neonatal alloimmune thrombocytopenia (NAIT): similar mechanism to rhesus haemolytic disease of the new born (HDN) but IgG antibody is to platelet antigen, usually in HPA-1 +ve fetus of HPA-1 \210\222ve mother. Associated with severe bleeding including intracranial hemorrh age which may occur before delivery. Requires urgent diagnosis and transfu- sion of selecte d antigen \210\222ve platelets. Recovery may take several weeks. Marrow in \201 ltration: congenital leukemia very rare. Inherited neonatal thrombocytopenia Very rare. Platelet size and presence or absence of oth er clinical features help to classify. d platelet size: WAS, X-linked, eczema, susceptibili ty to infection, death at early age from bleeding, infection or lymphoma. n platelet size: amegakaryocytic thrombocytopenia including TAR syn- drome (thrombocytopenia with absent rad ius). Schulman \200\223Upshaw syn- drome \200\224neonatal TTP. i platelet size: commonest i nherited thrombocytopenias, Mediterranean thrombocytopenias (asymptomatic), May \200\223Heg glin anomaly (Dohle bodies in granulocytes, mild neutropenia, major hemorrhage rare, presen ce of other clinical features such as deafness, cataracts, nephritis identifi es variants, all due to mutations of MYH9 gene) BSS (associated with func- tional defect, E see Congenit al platelet function defi cits, p.486), gray platelet syndrome (reduced -granules), type 2B VWD (E see von Willebrand disease, p.472) and pseudo-VWD (platelet type VWD due to mutat ion in platelet membrane GPIb-IX). 486 CHAPTER 10 Haemostasis and thrombosis Congenital platelet function defects Rare. Acquired platelet dysfunction is much more likel y to be a cause of bleeding or easy bruising. 2 main hereditary qualitative defects are found: \200 Defective platelet membrane glycopr oteins (GPs) \200\224GT, abnormal GPIIb/IIIa in which there is severe bleeding, and absent aggregation response to all agonists except n agglutination with ristocetin, BSS, abnormal GPIb-IX-V complex, receptor for vWF, defective adhesion, variable bleeding can be severe, a bsent response to ristocetin. Abnormalities of platelet granules \200\224storage pool disease (SPD) \200\224 -granules (gray platelet syndrome), -granules (May \200\223 Hegglin anoma ly, Hermansky \200\223Pudlak syndrome, Chediak \200\223Higashi syndrome, TAR syndrome). Laboratory \200 Platelet count. \200 Platelet size. \200 Blood fi lm (examine granulo cytes as well as platelets). \200 PFA-100. \200 Platelet aggregation. \200 Flow cytom etry for detection of platelet membrane glycoproteins. Treatment \200 Avoid antiplatelet drugs. \200 Use pressure to control bleeding from min or cuts. \200 Desmopressin. \200 Tranexamic acid (15 \200\22325mg/kg body weight) 8-hou rly for 7 \200\22310d for minor surgery and dental work. Platelet transfusions are eff ective in major surgery and severe bleeding but alloimmunizat ion may occur causing platelet refractoriness. Recombinant VIIa considered for severe defects, e.g. GT. \200 Splenectomy has been used i n WAS. \200 Allogeneic BMT has been performed (GT and WAS). 487 CONGENITAL VASCULAR DISORDERS Congenital vascular disorders Hereditary haemorrhagic telangiectasia (Osler \200\223Weber \200\223 Rendu (OWR) syndrome) Autosomal dominant, multiple mucocutaneous and skin telangiec- tasia which bleed easily. Re current epistaxis, menorrhagia, and GI bleeds causing Fe defi ciency. Presentation may not be until later life. Development of pulmonary and cerebral AV malformations. Pulmonary AVMs may enlarge in pregnancy. Diagnosis by recognition of typical tel- angiectases and family history. Beware, another cause of bleeding may coexist in a OWR patient. Laboratory \200 FBC and fi lm may show Fe-defi cient picture, i.e. microcytic, hypochromic anemia, d MCV, raised platelets, d serum ferritin. \200 Angiography of mesent eric circulation when recurrent bleeding. \200 ENT examination. \200 CT scan to identif y pulmonary AV malformations or desaturation on exercise. Treatment \200 Fe supplementation if Fe defi cient. \200 Tranexamic acid if menorrhagia . \200 Antibiotics for surgical/dental procedures as risk of cerebral abscess due to bacteraemia and shunting in lungs. Consider interventional procedure, e.g. embolization (if angiography +ve). Estrogen may reduce frequency of bleeding episodes. Giant cavernous haemangioma Venous malformation, may cause DIC-like features due to activat ion of coagulation system within haemangioma, spontaneous regression may occur. 488 CHAPTER 10 Haemostasis and thrombosis Haemorrhagic disease of the newborn \200 Caused by defi ciency of the vitamin K-dependent factors. \200 Poor vitamin K transfer across placenta. \200 Signifi cant cause of blee ding in the neonatal period unless prevented by vitamin K. Three forms described \200\224early, classic, and late. Early Due to maternal ingestion of drugs that interfere with vitamin K metabolism \200\224w arfarin, phenytoin, barbiturates, rifampicin. Presents in 1st day of life. Umbilical cord a nd skin bleeding, post circumcision bleeding, ICH is rare. Prevented by maternal administra tion of vitamin K. Classic Presents at 2 \200\2235d of birth, almost exclusively a disease of breast-fed babie s, often full term and healthy, incidence 0.5/1000 deliveries. Human milk has less vitamin K than cows \200\231 and formula milk. \200 Bruising. \200 Bleeding from venepuncture s ites. \200 GI bleeding. \200 ICH. Late Presents at 2 \200\22312 weeks but can occur up to 6 months of age. Can present in bre ast-fed infants who did not receive vitamin K, may occur with chronic diarrhea but cholesta tic liver disease is often present \200\224 biliary atresia, cystic fi brosis, -1 antitry psin defi ciency. ICH common. Diagnosis \200\224laboratory \201 ndings \200 i PT and AP TT \200\224may be markedly ii. \200 n TT, Fgn, D-dimer/FDPs (cf. DIC). \200 Factor assa y (II, VII, IX, X) if in doubt. \200 Correction of coagulation abnormality in 72h with pa renteral vitamin K confi rms diagnosis. Diff erential diagnosis Exclude other causes of bleeding in the neonatal period, e.g. DIC, thrombocytopenia (platelets are n in haemorrhagic disease of the newborn), hemophilia. Radiology Scan for ICH/internal bleeding as required. Treatment Prevention is indicated, e.g. 1mg IM vitamin K1 at birth (or multiple oral doses but not as eff ective as IM. \200 Treatment should not be delayed when diagnosis suspecte d \200\2241mg SC or IV vitamin K1 (will correct PT and APTT to n for age within 72h). \200 If signifi cant bleeding give PCC (factor concentrate of II, VII, IX, X) or FFP 15mL/kg. Previous concerns of a causal link between parenteral vitamin K administration to the neonate and childhood cancer have been shown to be unfounded. 489 HAEMORRHAGIC DISEASE OF THE NEWBORN 490 CHAPTER 10 Haemostasis and thrombosis Thrombocytopenia (acquired) E See also Congenital thrombocytopenias, p.486 and beware pseud o- thrombocytopenia (E Platelets, p.462). Thrombocytopenia defi ned as platelet count <150 \227 109/L. May be due to: \200 d bone marrow production. \200 Short platelet survival \200\224i co nsumption, destruction, or sequestration (or combination). Dilution. Platelet counts >100 \227 109/L are not usually associated with bleeding. Purpur a, easy bruising, and prolonged post-traumatic bleeding are increasingly common as the plat elet count falls <50 \227 109/L. Although there is no platelet count at which a patient de fi nitely will or will not experience spontaneous bleeding, the risk is greater in patients with a platelet count <20 \227 109/L and increases further in those with a count <10 \227 109/L. d bone marrow production of platelets \200 Marrow failure: aplastic anemia (E see Aplasti c anemia, p.102). \200 Marrow infi ltration: leukaemias, myelodysplasia, myeloma, myelofi - brosis, lymphoma, metastatic carcinoma. Marrow suppression: predictable with cytotoxic drugs, radiotherapy. Idiosyncratic response \200\224e.g. chloramphenicol. Megaloblastic anemia (E see Vitamin B12 defi ciency, p.46). \200 Amegakaryocytic: ethanol , drugs (phenylbutazone, co-trimoxazole; penicillamine), chemicals, viral infection (e.g. HIV, parvovirus). \200 Hereditary non-co ngenital: Fanconi syndrome (E see Fanconi anemia, p.594). Short platelet survival Consumption \200 DIC (E see Disseminated intravascular disseminat ion, p.494). \200 TTP/HUS (E see Thrombotic thrombocytopenic purpura, p.538). \200 HITT (E see Heparin-induced thrombocytopenia, p.542). \200 Haemangioma (Kasabach \200\223Merr itt syndrome). \200 Congenital/acquired heart disease. \200 Cardiopulmonary bypass. Destruction \200 Immune: 1 : immune thrombocytopenia. \200 2 ITP: other autoimmune states (SLE, CLL, lymphoma) \200\224 drug-induced (heparin \200\224also HITT (E see Heparin-induced thrombocytopenia, p.542), go ld, quinidine, quinine, penicillins, cimetidine, digoxin, vancomycin). Infection (HIV, other viruses, malaria). \200 PTP (E see Specifi c thrombocytopenic syndr omes, p.492). Sequestration \200 Hypersplenism (E see Specifi c thrombocytopenic syndromes, p.492). 491 THROMBOCYTOPENIA (ACQUIRED) Dilution \200 Gestational thrombocytopenia. \200 Massive transfusion (E see Massive blo od loss, p.506). \200 Exchange transfusion. Clinical assessment \200 History: drugs, symptoms of viral illness. \200 Examination: s igns of infection, lymphadenopathy, hepatosplenomegaly. Investigations: FBC, is thrombocytopenia isolated or not? MPV \200\224 acquired BM disorders are a less likely cause of thrombocytopenia the higher the MPV (espec ially MPV >10fL). Blood fi lm: platelet clumps (pseudothrombocytopenia), RBC \200 fragmentation (DIC, TTP, HUS), white cells (atypical lymphocytes/ blasts). Others: ANA, dsDNA, monospot, HIV serology, creatinine, LFTs. \200 BM examination: if cle arly not due to short platelet survival. Further reading Provan, D. et al. (2010). International consensus report on the investigati on and management of primary immune thrombocytopenia. Blood, 115, 168 \200\22386. 492 CHAPTER 10 Haemostasis and thrombosis Speci \201 c thrombocytopenic syndromes ITP 2 thrombocytopenia (SLE and LPDs esp. low-grade NHL and CLL) may present with isolate d thrombocytopenia and underlying disorder may only be discovered on further investigation. Often refractory to therapy. Those with LPDs will require treatment of underlying conditio n. ITP in pregnancy Fetal thrombocytopenia may occur due to placental transfer of IgG anti- pl atelet antibodies in a pregnant woman with ITP but rare. Risk of ICH in fetus during delive ry is very low. No good predictor for fetal thrombocy- topenia. Treatment with prednisolone , or IVIg should be administered to the mother with thrombocytopenia severe enough to const itute a haemorrhagic risk to her. Avoid splenectomy \200\224high rate of fetal loss. Severe maternal hemorrhage at delivery is rare but may require platelet transfusion, IVIg and pos sibly splenectomy. Special antenatal treat- ment of the fetus is unnecessary but avoid prol onged and complicated labor. Ensure pediatric support at delivery and check neonatal platel et count \200\224monitor for several days (delayed thrombocytopenia). IVIg, prednisolone or exchange transfusion may be required.